During your career, you serve as staff member and leader to many different professional groups. Some are collaborative, collegial, and supportive. Others are competitive, antagonistic, or even combative. What are the benefits and downsides of each of these cultures and what can you do, as a hospitalist leader, to influence the character of your workplace?

• Unity of mission – In Boston, that was to “save lives,” and it motivated and activated the whole of the response.
• Generosity of spirit and action – Across the community, people were eager to assist in the response.
• Everyone stayed in their own lanes of responsibility and helped others succeed in theirs – There were law enforcement, medical, and resilience activities and the theme across the leaders was “how can I help make you a success?”
• No ego and no blame – There was a level of emotional intelligence and maturity among the leaders.
• A foundation of trusting relations – These leaders had known one another for years and, though the decisions were tough, they were confident in the motives and actions of the others.

While the discovery emerged from our crisis research, the findings equally apply to other, more routine work and interactions. Conduct your own assessment. Have you worked in groups in which these principles of swarm leadership characterized the experience? People were focused on a shared mission: They were available to assist one another; accomplished their work in ways that were respectful and supportive of their different responsibilities; did not claim undue credit or swipe at each another; and knew one another well enough to trust the others’ actions and motives.

The flip side of this continuum of collaboration and competition we term “suspicion leadership.” This is characterized by selfish ambitions; narcissistic actions; grabs for authority and resources; credit taking for the good and accusations for the bad; and an environment of mistrust and back stabbing.

Leaders influence the tone and tenor of their own group’s interactions as well as interactions among different working groups. As role models, if they articulate and demonstrate a mission that others can rally around, they forge that critical unity of mission. By contrast, suspicion leaders make it clear that “it is all about me and my priorities.” There is much work to be done, and swarm leaders ensure that people have the resources, autonomy, and support necessary to get the job done. On the other end, the work environment is burdened by the uncertainties about who does what and who is responsible. Swarm leaders are focused on “we” and suspicion leaders are caught up on “me.” There is no trust when people are suspicious of one another. Much can be accomplished when people believe in themselves, their colleagues, and the reasons that bring them together.

As a hospitalist leader, you influence where on this continuum your group will lie. It is your choice to be a role model for the principles of swarm, encouraging the same among others. When those principles become the beacons by which you work and relate, you will find an environment that inspires people to be and to do their best.

In the next column, how to build trust within your teams.

Dr. Marcus is director, Program on Health Care Negotiation and Conflict Resolution, at the Harvard T.H. Chan School of Public Health, in Boston.

During your career, you serve as staff member and leader to many different professional groups. Some are collaborative, collegial, and supportive. Others are competitive, antagonistic, or even combative. What are the benefits and downsides of each of these cultures and what can you do, as a hospitalist leader, to influence the character of your workplace?

• Unity of mission – In Boston, that was to “save lives,” and it motivated and activated the whole of the response.
• Generosity of spirit and action – Across the community, people were eager to assist in the response.
• Everyone stayed in their own lanes of responsibility and helped others succeed in theirs – There were law enforcement, medical, and resilience activities and the theme across the leaders was “how can I help make you a success?”
• No ego and no blame – There was a level of emotional intelligence and maturity among the leaders.
• A foundation of trusting relations – These leaders had known one another for years and, though the decisions were tough, they were confident in the motives and actions of the others.

While the discovery emerged from our crisis research, the findings equally apply to other, more routine work and interactions. Conduct your own assessment. Have you worked in groups in which these principles of swarm leadership characterized the experience? People were focused on a shared mission: They were available to assist one another; accomplished their work in ways that were respectful and supportive of their different responsibilities; did not claim undue credit or swipe at each another; and knew one another well enough to trust the others’ actions and motives.

The flip side of this continuum of collaboration and competition we term “suspicion leadership.” This is characterized by selfish ambitions; narcissistic actions; grabs for authority and resources; credit taking for the good and accusations for the bad; and an environment of mistrust and back stabbing.

Leaders influence the tone and tenor of their own group’s interactions as well as interactions among different working groups. As role models, if they articulate and demonstrate a mission that others can rally around, they forge that critical unity of mission. By contrast, suspicion leaders make it clear that “it is all about me and my priorities.” There is much work to be done, and swarm leaders ensure that people have the resources, autonomy, and support necessary to get the job done. On the other end, the work environment is burdened by the uncertainties about who does what and who is responsible. Swarm leaders are focused on “we” and suspicion leaders are caught up on “me.” There is no trust when people are suspicious of one another. Much can be accomplished when people believe in themselves, their colleagues, and the reasons that bring them together.

As a hospitalist leader, you influence where on this continuum your group will lie. It is your choice to be a role model for the principles of swarm, encouraging the same among others. When those principles become the beacons by which you work and relate, you will find an environment that inspires people to be and to do their best.

In the next column, how to build trust within your teams.

Dr. Marcus is director, Program on Health Care Negotiation and Conflict Resolution, at the Harvard T.H. Chan School of Public Health, in Boston.

During your career, you serve as staff member and leader to many different professional groups. Some are collaborative, collegial, and supportive. Others are competitive, antagonistic, or even combative. What are the benefits and downsides of each of these cultures and what can you do, as a hospitalist leader, to influence the character of your workplace?

• Unity of mission – In Boston, that was to “save lives,” and it motivated and activated the whole of the response.
• Generosity of spirit and action – Across the community, people were eager to assist in the response.
• Everyone stayed in their own lanes of responsibility and helped others succeed in theirs – There were law enforcement, medical, and resilience activities and the theme across the leaders was “how can I help make you a success?”
• No ego and no blame – There was a level of emotional intelligence and maturity among the leaders.
• A foundation of trusting relations – These leaders had known one another for years and, though the decisions were tough, they were confident in the motives and actions of the others.

While the discovery emerged from our crisis research, the findings equally apply to other, more routine work and interactions. Conduct your own assessment. Have you worked in groups in which these principles of swarm leadership characterized the experience? People were focused on a shared mission: They were available to assist one another; accomplished their work in ways that were respectful and supportive of their different responsibilities; did not claim undue credit or swipe at each another; and knew one another well enough to trust the others’ actions and motives.

The flip side of this continuum of collaboration and competition we term “suspicion leadership.” This is characterized by selfish ambitions; narcissistic actions; grabs for authority and resources; credit taking for the good and accusations for the bad; and an environment of mistrust and back stabbing.

Leaders influence the tone and tenor of their own group’s interactions as well as interactions among different working groups. As role models, if they articulate and demonstrate a mission that others can rally around, they forge that critical unity of mission. By contrast, suspicion leaders make it clear that “it is all about me and my priorities.” There is much work to be done, and swarm leaders ensure that people have the resources, autonomy, and support necessary to get the job done. On the other end, the work environment is burdened by the uncertainties about who does what and who is responsible. Swarm leaders are focused on “we” and suspicion leaders are caught up on “me.” There is no trust when people are suspicious of one another. Much can be accomplished when people believe in themselves, their colleagues, and the reasons that bring them together.

As a hospitalist leader, you influence where on this continuum your group will lie. It is your choice to be a role model for the principles of swarm, encouraging the same among others. When those principles become the beacons by which you work and relate, you will find an environment that inspires people to be and to do their best.

In the next column, how to build trust within your teams.

Dr. Marcus is director, Program on Health Care Negotiation and Conflict Resolution, at the Harvard T.H. Chan School of Public Health, in Boston.

SVS members, please remember to urge your physician assistants -- and other PAs you know who work in a vascular setting -- to apply to become charter members of the new SVS section created for them. The first step is becoming an affiliate member of the SVS. For our new charter PA members, SVS is waiving the application fee. For more information, email [email protected] or call the SVS Membership Department at 312-334-2313.

We welcome nurses and nurse practitioners as well. Please consider becoming a part of the Society for Vascular Nursing, which makes its management home at SVS.

SVS members, please remember to urge your physician assistants -- and other PAs you know who work in a vascular setting -- to apply to become charter members of the new SVS section created for them. The first step is becoming an affiliate member of the SVS. For our new charter PA members, SVS is waiving the application fee. For more information, email [email protected] or call the SVS Membership Department at 312-334-2313.

We welcome nurses and nurse practitioners as well. Please consider becoming a part of the Society for Vascular Nursing, which makes its management home at SVS.

SVS members, please remember to urge your physician assistants -- and other PAs you know who work in a vascular setting -- to apply to become charter members of the new SVS section created for them. The first step is becoming an affiliate member of the SVS. For our new charter PA members, SVS is waiving the application fee. For more information, email [email protected] or call the SVS Membership Department at 312-334-2313.

We welcome nurses and nurse practitioners as well. Please consider becoming a part of the Society for Vascular Nursing, which makes its management home at SVS.

Two months past its deadline, Congress has yet to fund the Children’s Health Insurance Program, leaving several states scrambling for cash.

Lawmakers grappling with the failed repeal of the Affordable Care Act allowed authorization of the program to lapse on Sept. 30. Although CHIP has always had broad bipartisan support, the House and Senate cannot agree on how to continue federal funding. And the Trump administration has been mostly silent on the issue.

CHIP benefits 9 million children nationwide and 370,000 pregnant women a year. It helps lower- and middle-income families who otherwise earn too much to be eligible for Medicaid. Like Medicaid, CHIP is paid for with state and federal funds, but the federal government covers close to 90% of the cost.

To keep the program going, states with unspent federal CHIP money have seen their excess sent to a handful of states running low on funds. But that is a bureaucratic Band-Aid; some large states are warning families they may not be able to rely on CHIP for much longer.

All told, the CMS has given out $1.2 billion in redistribution dollars since October. To keep the program going would cost the federal government $8.5 billion over 5 years, the Congressional Budget Office estimates.

Dec. 2 marked the 25th anniversary of Pennsylvania approving the original CHIP program, which served as a model for the national law, established in 1997. Since then, CHIP has been left in the fiscal lurch only once before. In 2007, CHIP went several weeks without funding authorization from Congress.

Here’s a quick look at what the shortfall may mean to daily life.
 

1. Are any kids hurting because Congress has failed to fund CHIP?

No. But states such as California will run out of money within weeks. That state alone accounts for nearly 15% of all children benefiting from CHIP. Without federal money, state programs could freeze enrollment or suspend operation.

2. What are states doing since Congress missed the deadline?

Most states are doing little except looking for other unspent federal funds or asking the federal government to send some unspent funds from other states. But some, such as Colorado, are sending warning letters to beneficiaries to tell them that the program could soon end and to look for alternatives. This could mean exploring the ACA marketplace for coverage or researching if a child qualifies for Medicaid.

Colorado said it has only enough CHIP funding to last through January and then the program, without federal dollars, will end.

Arizona officials announced Nov. 30 that it will use Medicaid funding to fill in the shortage of CHIP dollars to extend the life of its CHIP program.

Virginia officials plan to send out a similar notice to parents of CHIP members by early December.

Minnesota is keeping CHIP alive by paying the federal share with state funds.

In Oregon, Democratic Gov. Kate Brown recently said that she is ready to spend $35 million in state funds to keep CHIP running through December.

Nevada announced on Nov. 30 it had been approved for extra funding from the Centers for Medicare & Medicaid Services – nearly $5.7 million – which could keep CHIP alive through December and possibly January.

California, which leads the nation in CHIP enrollment, has received the lion’s share of CMS redistribution funds since October: nearly $692 million.

“Approximately 98% of the 1.3 million population now covered using CHIP funding would continue to receive coverage under the Medicaid program because of a legal obligation to cover them through September 2019,” said California Medicaid/CHIP spokesman Tony Cava. “If CHIP is not reauthorized, the governor and Legislature would need to deliberate on how best to address the population no longer eligible for federal CHIP funding.”
 

3. When is Congress likely to act?

Not sure. CHIP reauthorization could be included in an appropriations bill that Congress must pass to fund the government into 2018. (Congress now has funded the government through Dec. 8.) A “continuing resolution” bill would have to be approved by then to avert a government shutdown.

4. If CHIP is so popular among Republicans and Democrats, what’s the problem?

There is little debate about its worth and value, but the momentum on CHIP was lost amid disagreements over the Affordable Care Act. The House did extend authorization with a vote – mostly along party lines – on Nov. 3. The Senate itself has yet to vote. The Senate Finance Committee on Oct. 3 approved a bipartisan bill to extend the program for 5 years.

The sticking point is not whether to keep CHIP running but how to raise the cash needed. The House agreed to charge higher premiums to wealthier Medicare beneficiaries, cut money from the ACA’s preventive health fund and shorten the grace period for ACA enrollees who fail to make monthly premium payments.

Like the House bill, the Senate committee bill eliminated an ACA provision to increase CHIP matching funds – to states – by 23%. The increased funding would continue through fiscal year 2019 and fall to 11.5 percent in fiscal year 2020. It would be cut entirely in the following fiscal year.
 

5. How does CHIP differ based on where you live?

CHIP income eligibility levels vary by state. About 90% of children who qualify are from families earning 200% of poverty or less ($40,840 for a family of three). CHIP covers children up to age 19. But states have the option to cover pregnant women, and 18 states plus the District of Columbia do so.

Some states call CHIP by different names. For example, it is known as Hoosier Healthwise in Indiana, PeachCare for Kids in Georgia and KidsCare in Arizona.
 

KHN’s coverage of children’s health care issues is supported in part by the Heising-Simons Foundation. Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Two months past its deadline, Congress has yet to fund the Children’s Health Insurance Program, leaving several states scrambling for cash.

Lawmakers grappling with the failed repeal of the Affordable Care Act allowed authorization of the program to lapse on Sept. 30. Although CHIP has always had broad bipartisan support, the House and Senate cannot agree on how to continue federal funding. And the Trump administration has been mostly silent on the issue.

CHIP benefits 9 million children nationwide and 370,000 pregnant women a year. It helps lower- and middle-income families who otherwise earn too much to be eligible for Medicaid. Like Medicaid, CHIP is paid for with state and federal funds, but the federal government covers close to 90% of the cost.

To keep the program going, states with unspent federal CHIP money have seen their excess sent to a handful of states running low on funds. But that is a bureaucratic Band-Aid; some large states are warning families they may not be able to rely on CHIP for much longer.

All told, the CMS has given out $1.2 billion in redistribution dollars since October. To keep the program going would cost the federal government $8.5 billion over 5 years, the Congressional Budget Office estimates.

Dec. 2 marked the 25th anniversary of Pennsylvania approving the original CHIP program, which served as a model for the national law, established in 1997. Since then, CHIP has been left in the fiscal lurch only once before. In 2007, CHIP went several weeks without funding authorization from Congress.

Here’s a quick look at what the shortfall may mean to daily life.
 

1. Are any kids hurting because Congress has failed to fund CHIP?

No. But states such as California will run out of money within weeks. That state alone accounts for nearly 15% of all children benefiting from CHIP. Without federal money, state programs could freeze enrollment or suspend operation.

2. What are states doing since Congress missed the deadline?

Most states are doing little except looking for other unspent federal funds or asking the federal government to send some unspent funds from other states. But some, such as Colorado, are sending warning letters to beneficiaries to tell them that the program could soon end and to look for alternatives. This could mean exploring the ACA marketplace for coverage or researching if a child qualifies for Medicaid.

Colorado said it has only enough CHIP funding to last through January and then the program, without federal dollars, will end.

Arizona officials announced Nov. 30 that it will use Medicaid funding to fill in the shortage of CHIP dollars to extend the life of its CHIP program.

Virginia officials plan to send out a similar notice to parents of CHIP members by early December.

Minnesota is keeping CHIP alive by paying the federal share with state funds.

In Oregon, Democratic Gov. Kate Brown recently said that she is ready to spend $35 million in state funds to keep CHIP running through December.

Nevada announced on Nov. 30 it had been approved for extra funding from the Centers for Medicare & Medicaid Services – nearly $5.7 million – which could keep CHIP alive through December and possibly January.

California, which leads the nation in CHIP enrollment, has received the lion’s share of CMS redistribution funds since October: nearly $692 million.

“Approximately 98% of the 1.3 million population now covered using CHIP funding would continue to receive coverage under the Medicaid program because of a legal obligation to cover them through September 2019,” said California Medicaid/CHIP spokesman Tony Cava. “If CHIP is not reauthorized, the governor and Legislature would need to deliberate on how best to address the population no longer eligible for federal CHIP funding.”
 

3. When is Congress likely to act?

Not sure. CHIP reauthorization could be included in an appropriations bill that Congress must pass to fund the government into 2018. (Congress now has funded the government through Dec. 8.) A “continuing resolution” bill would have to be approved by then to avert a government shutdown.

4. If CHIP is so popular among Republicans and Democrats, what’s the problem?

There is little debate about its worth and value, but the momentum on CHIP was lost amid disagreements over the Affordable Care Act. The House did extend authorization with a vote – mostly along party lines – on Nov. 3. The Senate itself has yet to vote. The Senate Finance Committee on Oct. 3 approved a bipartisan bill to extend the program for 5 years.

The sticking point is not whether to keep CHIP running but how to raise the cash needed. The House agreed to charge higher premiums to wealthier Medicare beneficiaries, cut money from the ACA’s preventive health fund and shorten the grace period for ACA enrollees who fail to make monthly premium payments.

Like the House bill, the Senate committee bill eliminated an ACA provision to increase CHIP matching funds – to states – by 23%. The increased funding would continue through fiscal year 2019 and fall to 11.5 percent in fiscal year 2020. It would be cut entirely in the following fiscal year.
 

5. How does CHIP differ based on where you live?

CHIP income eligibility levels vary by state. About 90% of children who qualify are from families earning 200% of poverty or less ($40,840 for a family of three). CHIP covers children up to age 19. But states have the option to cover pregnant women, and 18 states plus the District of Columbia do so.

Some states call CHIP by different names. For example, it is known as Hoosier Healthwise in Indiana, PeachCare for Kids in Georgia and KidsCare in Arizona.
 

KHN’s coverage of children’s health care issues is supported in part by the Heising-Simons Foundation. Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Two months past its deadline, Congress has yet to fund the Children’s Health Insurance Program, leaving several states scrambling for cash.

Lawmakers grappling with the failed repeal of the Affordable Care Act allowed authorization of the program to lapse on Sept. 30. Although CHIP has always had broad bipartisan support, the House and Senate cannot agree on how to continue federal funding. And the Trump administration has been mostly silent on the issue.

CHIP benefits 9 million children nationwide and 370,000 pregnant women a year. It helps lower- and middle-income families who otherwise earn too much to be eligible for Medicaid. Like Medicaid, CHIP is paid for with state and federal funds, but the federal government covers close to 90% of the cost.

To keep the program going, states with unspent federal CHIP money have seen their excess sent to a handful of states running low on funds. But that is a bureaucratic Band-Aid; some large states are warning families they may not be able to rely on CHIP for much longer.

All told, the CMS has given out $1.2 billion in redistribution dollars since October. To keep the program going would cost the federal government $8.5 billion over 5 years, the Congressional Budget Office estimates.

Dec. 2 marked the 25th anniversary of Pennsylvania approving the original CHIP program, which served as a model for the national law, established in 1997. Since then, CHIP has been left in the fiscal lurch only once before. In 2007, CHIP went several weeks without funding authorization from Congress.

Here’s a quick look at what the shortfall may mean to daily life.
 

1. Are any kids hurting because Congress has failed to fund CHIP?

No. But states such as California will run out of money within weeks. That state alone accounts for nearly 15% of all children benefiting from CHIP. Without federal money, state programs could freeze enrollment or suspend operation.

2. What are states doing since Congress missed the deadline?

Most states are doing little except looking for other unspent federal funds or asking the federal government to send some unspent funds from other states. But some, such as Colorado, are sending warning letters to beneficiaries to tell them that the program could soon end and to look for alternatives. This could mean exploring the ACA marketplace for coverage or researching if a child qualifies for Medicaid.

Colorado said it has only enough CHIP funding to last through January and then the program, without federal dollars, will end.

Arizona officials announced Nov. 30 that it will use Medicaid funding to fill in the shortage of CHIP dollars to extend the life of its CHIP program.

Virginia officials plan to send out a similar notice to parents of CHIP members by early December.

Minnesota is keeping CHIP alive by paying the federal share with state funds.

In Oregon, Democratic Gov. Kate Brown recently said that she is ready to spend $35 million in state funds to keep CHIP running through December.

Nevada announced on Nov. 30 it had been approved for extra funding from the Centers for Medicare & Medicaid Services – nearly $5.7 million – which could keep CHIP alive through December and possibly January.

California, which leads the nation in CHIP enrollment, has received the lion’s share of CMS redistribution funds since October: nearly $692 million.

“Approximately 98% of the 1.3 million population now covered using CHIP funding would continue to receive coverage under the Medicaid program because of a legal obligation to cover them through September 2019,” said California Medicaid/CHIP spokesman Tony Cava. “If CHIP is not reauthorized, the governor and Legislature would need to deliberate on how best to address the population no longer eligible for federal CHIP funding.”
 

3. When is Congress likely to act?

Not sure. CHIP reauthorization could be included in an appropriations bill that Congress must pass to fund the government into 2018. (Congress now has funded the government through Dec. 8.) A “continuing resolution” bill would have to be approved by then to avert a government shutdown.

4. If CHIP is so popular among Republicans and Democrats, what’s the problem?

There is little debate about its worth and value, but the momentum on CHIP was lost amid disagreements over the Affordable Care Act. The House did extend authorization with a vote – mostly along party lines – on Nov. 3. The Senate itself has yet to vote. The Senate Finance Committee on Oct. 3 approved a bipartisan bill to extend the program for 5 years.

The sticking point is not whether to keep CHIP running but how to raise the cash needed. The House agreed to charge higher premiums to wealthier Medicare beneficiaries, cut money from the ACA’s preventive health fund and shorten the grace period for ACA enrollees who fail to make monthly premium payments.

Like the House bill, the Senate committee bill eliminated an ACA provision to increase CHIP matching funds – to states – by 23%. The increased funding would continue through fiscal year 2019 and fall to 11.5 percent in fiscal year 2020. It would be cut entirely in the following fiscal year.
 

5. How does CHIP differ based on where you live?

CHIP income eligibility levels vary by state. About 90% of children who qualify are from families earning 200% of poverty or less ($40,840 for a family of three). CHIP covers children up to age 19. But states have the option to cover pregnant women, and 18 states plus the District of Columbia do so.

Some states call CHIP by different names. For example, it is known as Hoosier Healthwise in Indiana, PeachCare for Kids in Georgia and KidsCare in Arizona.
 

KHN’s coverage of children’s health care issues is supported in part by the Heising-Simons Foundation. Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.

“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.

Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.

Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.

While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.

The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.

There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).

“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.

There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.

The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”

Among the updated recommendations are the following:

• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).

• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).

• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).

• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).

• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).

The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.

The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.

“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.

Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.

Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.

While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.

The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.

There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).

“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.

There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.

The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”

Among the updated recommendations are the following:

• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).

• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).

• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).

• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).

• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).

The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.

The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.

“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.

Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.

Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.

While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.

The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.

There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).

“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.

There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.

The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”

Among the updated recommendations are the following:

• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).

• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).

• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).

• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).

• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).

The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.

Sjögren-Larsson syndrome (SLS) is a rare autosomal-recessive neurocutaneous disorder comprising a triad of ichthyosis, mental retardation, and spastic diplegia or quadriplegia.¹ The disorder was first described by Sjögren and Larsson² in 1957. Early reports of SLS were mainly in white patients, with a particularly high prevalence of 8.3 cases per 100,000 individuals in the county of Västerbotten in Sweden.³ Reports of SLS in Asian and Indian populations are rare.^4,5 We report a case of SLS in an Indian boy.

Case Report

A 12-year-old Indian boy born to nonconsanguineous parents after a full-term pregnancy with normal vaginal delivery presented with generalized dry scaly skin that had been present since 2 months of age. He had a history of delayed milestones (ie, facial recognition, sitting without support at 3 years of age), inability to walk, dysarthria, mental retardation). He had never attended school due to subnormal intellectual functioning. He had a single episode of a tonic-clonic seizure at 4 years of age but was not on any regular antiepileptic medication. There was a history of similar skin lesions in one male sibling of the patient and in 2 maternal uncles. None of them survived beyond early childhood, but detailed information regarding the cutaneous and neurologic manifestations in these family members was not available.

Cutaneous examination revealed lamellarlike ichthyosis on the dorsal aspects of the arms and legs (Figure 1A). Ichthyosis with lichenification was present on the neck, axillae, cubital and popliteal fossae, and abdomen (Figure 1B). The palms and soles showed keratoderma. Neurologic examination of the arms revealed mild rigidity and brisk reflexes. Examination of the legs showed marked rigidity, brisk knee jerks, ankle clonus, extensor plantar reflexes, flexion deformity with contractures, and scissor gait. A Goddard (Seguin) formboard test was performed and indicated a mental age of 4 years. The patient’s IQ was in the range of 25 to 30, indicating a severe degree of subnormality in intellectual functioning. The clinical presentation suggested a diagnosis of SLS.

A skin biopsy from the ichthyotic lesion showed hyperkeratosis, acanthosis, and papillomatosis with sparse superficial perivascular lymphocytic infiltrate, thus confirming the diagnosis of lamellar ichthyosis. Fundus examination was normal. Magnetic resonance imaging (MRI) of the brain revealed confluent symmetrical signal abnormalities along the body of the lateral ventricles, white matter in the perioccipital horn, and in deep white matter of centrum semiovale (Figure 2). Magnetic resonance spectroscopy revealed a narrow lipid peak at approximately 1.3 ppm in the region of signal abnormality (Figure 3). Thus, the diagnosis of SLS was confirmed. Measurement of fatty aldehyde dehydrogenase (FALDH) activity and genetic analysis were not performed due to unavailability.

The patient was treated with topical emollients for the ichthyosis. To reduce his dietary intake of long-chain fatty acids and increase the intake of omega-3 and omega-6 fatty acids, the patient’s parents were advised to use canola, mustard, and/or coconut oil for cooking for the patient, and skim milk was recommended instead of whole milk. Neurodevelopmental techniques in the form of stretching exercises were given to maintain his range of movements. Gutter splints were given to maintain the knees in extension for physiological standing and to prevent osteoporosis. Subsequently, the patient also underwent a multilevel soft-tissue release (hip and knee joints) to relieve the contractures. These measures resulted in considerable improvement and the patient was able to walk with support.

Comment

Presentation
The characteristic clinical features of SLS begin to develop during the intranatal period and infancy.^1,6 Pathologic skin involvement can be detected as early as week 23 of gestation. Preterm births associated with SLS have commonly been described.³ Ichthyosis often is evident at birth, but collodion membrane is uncommon. Severe pruritus is a marked feature unlike most other types of ichthyosis. The ichthyosis often is generalized with prominent involvement of the flexural areas and nape of the neck, varying from fine furfuraceous to larger lamellarlike scales. Velvety orange or brown lichenification often is a predominant feature in the flexures of the arms, legs, neck, and mid abdomen. Mental retardation, developmental delay, and spasticity usually become apparent at 1 to 2 years of age and subsequently are nonprogressive.^6,7 However, patients rarely have been described with normal intellectual functioning.⁷ Spasticity often is more severe in the lower limbs and may lead to contractures, kyphoscoliosis, hip dislocation, and short stature. Delayed speech and dysarthria are common. Parafoveal glistening white dots on the retina are a pathognomonic feature and typically appear in the first 2 years of life; however, they are seen in approximately 30% of patients and increase slightly in number with age.^6,8 There may be associated decreased visual acuity, photophobia, myopia, and astigmatism. Other clinical features include enamel hypoplasia, metaphyseal dysplasia, and epilepsy.^1,6

Gene Mutations
Sjögren-Larsson syndrome is caused by mutation in the aldehyde dehydrogenase 3 family member A2 gene, ALDH3A2 (17p11.2), which codes for FALDH.^1,6,7 The ALDH3A2 gene is 11 exons long and gives rise to 2 protein isoforms that differ in their carboxy-terminal domains; the major isoform, composed of 485 amino acids, localizes to the endoplasmic reticulum. The minor protein isoform (FALDHv) is composed of 508 amino acids, possesses a longer carboxy-terminal, and appears to be targeted to the peroxisome. Several mutations have been reported throughout the ALDH3A2 gene, including missense mutations (most common [38% of cases of SLS⁶]), deletions, insertions, splicing errors, and complex rearrangements. Although several of these mutations are private, several common mutations may be indicative of founder effects (ie, shared ancestry), consanguinity, or recurrent mutational events (mutation hotspots).^6,7 Despite the wide spectrum of mutations, there is very little phenotypic variation, with consistently severe cutaneous and neurological involvement occurring in a majority of patients.⁷ However, Lossos et al⁹ described remarkable phenotypic variation in 6 siblings of an Arab family and suggested that additional unknown genetic or environmental factors may compensate for the biochemical defect.

Lipid Metabolism
Fatty aldehyde dehydrogenase is expressed in almost all cells and tissues and catalyzes the oxidation of fatty aldehydes to fatty acids (eFigure 1). It also is a part of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex, which catalyzes fatty alcohol oxidation to fatty acid. Fatty aldehyde dehydrogenase deficiency leads to accumulation of long-chain alcohols (eg, hexadecanol, octadecanol, octadecenol) and diversion of fatty alcohol into alternate biosynthetic pathways such as wax esters and 1-O-alkyl-2,3-diacylglycerol.¹⁰ Other lipids that are increased are illustrated in eFigure 2. Accumulation of these lipids, toxic effects of abnormal lipids (especially fatty aldehydes and Schiff base protein-lipid adducts), and lack of essential lipids (eg, polyunsaturated fatty acids, ceramides 1 and 6, triglycerides) are responsible for the classical cutaneous, neurologic, and ophthalmologic features of SLS.

Neurologic Findings
Neurologic changes in SLS result from delayed and deficient myelination. Neuropathological studies have shown ballooning of myelin sheaths, extensive loss of myelin, axonal damage, and astrogliosis. The presence of lipoid material positive for periodic acid–Schiff that stains light rather than dark pink, dense distribution of round/ellipsoid bodies in the white matter of the cerebrum and brainstem positive for periodic acid–Schiff, and proliferation of perivascular macrophages containing lipofuscinlike pigments also have been described.¹³ Possibly, in the absence of FALDH, metabolism of plasmalogens (a major component of myelin) results in increased fatty aldehydes, which are either diverted to fatty alcohols or form adducts with phosphatidylethanolamine and myelin basic proteins (eFigure 1). Magnetic resonance imaging of the brain usually shows hypomyelination involving the periventricular white matter extending from the frontal to the occipital area.^7,14 Mild ventricular enlargement may be an additional feature.¹⁴

A useful application of MRI is the proton magnetic resonance spectroscopy, which quantifies the brain metabolites noninvasively, displaying them as a spectrum on a graph. The spectrum comprises a set of resonances/peaks distributed along an x-axis. The resonances of these metabolites are obtained after suppressing the large signals from water protons. Proton magnetic resonance spectroscopy of the normal brain shows 3 prominent peaks: (1) N-acetylaspartate (NAA) at 2.02 ppm, (2) creatine at 3.02 ppm, and (3) choline at 3.22 ppm. In SLS, cerebral proton MRI spectroscopy reveals a characteristic abnormal, prominent, and narrow lipid peak at 1.3 ppm (corresponding to hexadecanol and octadecanol) and may offer a quantitative parameter for monitoring the effects of therapeutic interventions.^7,14,15 The most intense lipid peaks are located in the periventricular regions in the anterior and posterior trigones. An abnormal but much smaller peak may be seen at 0.8 to 0.9 ppm, corresponding to phytol.¹⁴ Gradual emergence of these changes occurs in the first 2 years of life and then remains stable.¹⁵ Proton magnetic resonance spectroscopy also can be used for screening of SLS heterozygotes.¹⁶ Lipid peaks have been described in other disorders of lipid metabolism, but they are less intense, broader, and disappear on longer echo time sequences.¹⁴

Besides the characteristic parafoveal glistening white dots the retina, optical coherence tomography shows focal hyperreflectivitity in the perifoveal ganglion cell layer and inner plexiform layer of the retina as well as cystoid foveal degeneration.¹⁷ The intraretinal deposition of lipid metabolites probably leads to Müller cell degeneration with subsequent formation of cystoid spaces and atrophic changes in the fovea.

Measurement of FALDH or FAO activity in cultured skin fibroblasts and leukocytes using flurometric or gas chromatography mass spectrometry assays is a reliable biochemical test in cases of SLS as well as in heterozygotes.¹⁷ A decrease in FALDH/FAO activity also can be demonstrated by histochemical staining in skin biopsy.¹¹ Pathologic urinary excretion of LTB4 and 20-OH-LTB4 also is a biochemical marker of SLS. Mutation analysis for a specific gene defect is diagnostic in cases of SLS as well as in heterozygotes. Prenatal diagnosis of SLS is possible by assessing FALDH activity or gene defects in cultured chorionic villus fibroblasts and amniocytes.^18,19

Differential Diagnosis
The differential diagnosis of SLS includes congenital ichthyosiform erythroderma with neurological signs (Tay syndrome, Conradi-Hünermann-Happle syndrome) and neurocutaneous disorders such as neutral lipid storage disease and multiple sulfatase deficiency; however, the nature of the ichthyosis, presence of spastic diplegia/tetraplegia, characteristic parafoveal glistening white dots on the retina, and MRI and proton magnetic resonance spectroscopy findings help to easily differentiate SLS from these disorders.

Treatment
Treatment of SLS mainly is palliative. Ichthyosis can be treated with topical keratolytics, emollients, calcipotriol, and oral retinoids (acitretin).⁶ Zileuton, a 5-lipoxygenase inhibitor, inhibits synthesis of LTB4 and cysteinyl leukotrienes, thereby reducing the severity of pruritus and also has been shown to improve the speed of information processing.¹⁸ Similarly, montelukast, a leuko-triene antagonist, is helpful in relieving the agonizing pruritus.¹⁹ Experimental studies have shown that bezafibrate, a peroxisome proliferator-activated receptor α agonist, induces FALDH activity in fibroblasts of SLS patients that still have some residual FALDH activity, but further research is required to determine whether SLS patients could benefit from treatment.²⁰ Physiotherapy helps in relieving the spasticity to some extent, such as in our case. Dietary intervention with reduced fat intake (up to 30% of total daily calorific requirement) and supplementation with omega-3 and omega-6 fatty acids has shown variable results in anecdotal reports.^21-23 Gene therapy using recombinant adeno-associated virus 2 vectors to restore FALDH has been projected as a future treatment option.²⁴ Despite lack of effective treatment options, most patients of SLS survive well into adulthood.

Conclusion

Because ichthyosis is one of the earliest and prominent symptoms of SLS, a dermatologist can play an important role in early diagnosis. Any child with the classical pattern of ichthyosis should be thoroughly examined for early neurologic signs and investigated to rule out SLS. Proton magnetic resonance spectroscopy serves as a useful adjunct in the diagnosis of SLS by confirming the accumulation of abnormal lipids in the periventricular white matter, especially when specific enzyme analysis and genetic analysis are not available in resource-restricted settings.

Sjögren-Larsson syndrome (SLS) is a rare autosomal-recessive neurocutaneous disorder comprising a triad of ichthyosis, mental retardation, and spastic diplegia or quadriplegia.¹ The disorder was first described by Sjögren and Larsson² in 1957. Early reports of SLS were mainly in white patients, with a particularly high prevalence of 8.3 cases per 100,000 individuals in the county of Västerbotten in Sweden.³ Reports of SLS in Asian and Indian populations are rare.^4,5 We report a case of SLS in an Indian boy.

Case Report

A 12-year-old Indian boy born to nonconsanguineous parents after a full-term pregnancy with normal vaginal delivery presented with generalized dry scaly skin that had been present since 2 months of age. He had a history of delayed milestones (ie, facial recognition, sitting without support at 3 years of age), inability to walk, dysarthria, mental retardation). He had never attended school due to subnormal intellectual functioning. He had a single episode of a tonic-clonic seizure at 4 years of age but was not on any regular antiepileptic medication. There was a history of similar skin lesions in one male sibling of the patient and in 2 maternal uncles. None of them survived beyond early childhood, but detailed information regarding the cutaneous and neurologic manifestations in these family members was not available.

Cutaneous examination revealed lamellarlike ichthyosis on the dorsal aspects of the arms and legs (Figure 1A). Ichthyosis with lichenification was present on the neck, axillae, cubital and popliteal fossae, and abdomen (Figure 1B). The palms and soles showed keratoderma. Neurologic examination of the arms revealed mild rigidity and brisk reflexes. Examination of the legs showed marked rigidity, brisk knee jerks, ankle clonus, extensor plantar reflexes, flexion deformity with contractures, and scissor gait. A Goddard (Seguin) formboard test was performed and indicated a mental age of 4 years. The patient’s IQ was in the range of 25 to 30, indicating a severe degree of subnormality in intellectual functioning. The clinical presentation suggested a diagnosis of SLS.

A skin biopsy from the ichthyotic lesion showed hyperkeratosis, acanthosis, and papillomatosis with sparse superficial perivascular lymphocytic infiltrate, thus confirming the diagnosis of lamellar ichthyosis. Fundus examination was normal. Magnetic resonance imaging (MRI) of the brain revealed confluent symmetrical signal abnormalities along the body of the lateral ventricles, white matter in the perioccipital horn, and in deep white matter of centrum semiovale (Figure 2). Magnetic resonance spectroscopy revealed a narrow lipid peak at approximately 1.3 ppm in the region of signal abnormality (Figure 3). Thus, the diagnosis of SLS was confirmed. Measurement of fatty aldehyde dehydrogenase (FALDH) activity and genetic analysis were not performed due to unavailability.

The patient was treated with topical emollients for the ichthyosis. To reduce his dietary intake of long-chain fatty acids and increase the intake of omega-3 and omega-6 fatty acids, the patient’s parents were advised to use canola, mustard, and/or coconut oil for cooking for the patient, and skim milk was recommended instead of whole milk. Neurodevelopmental techniques in the form of stretching exercises were given to maintain his range of movements. Gutter splints were given to maintain the knees in extension for physiological standing and to prevent osteoporosis. Subsequently, the patient also underwent a multilevel soft-tissue release (hip and knee joints) to relieve the contractures. These measures resulted in considerable improvement and the patient was able to walk with support.

Comment

Presentation
The characteristic clinical features of SLS begin to develop during the intranatal period and infancy.^1,6 Pathologic skin involvement can be detected as early as week 23 of gestation. Preterm births associated with SLS have commonly been described.³ Ichthyosis often is evident at birth, but collodion membrane is uncommon. Severe pruritus is a marked feature unlike most other types of ichthyosis. The ichthyosis often is generalized with prominent involvement of the flexural areas and nape of the neck, varying from fine furfuraceous to larger lamellarlike scales. Velvety orange or brown lichenification often is a predominant feature in the flexures of the arms, legs, neck, and mid abdomen. Mental retardation, developmental delay, and spasticity usually become apparent at 1 to 2 years of age and subsequently are nonprogressive.^6,7 However, patients rarely have been described with normal intellectual functioning.⁷ Spasticity often is more severe in the lower limbs and may lead to contractures, kyphoscoliosis, hip dislocation, and short stature. Delayed speech and dysarthria are common. Parafoveal glistening white dots on the retina are a pathognomonic feature and typically appear in the first 2 years of life; however, they are seen in approximately 30% of patients and increase slightly in number with age.^6,8 There may be associated decreased visual acuity, photophobia, myopia, and astigmatism. Other clinical features include enamel hypoplasia, metaphyseal dysplasia, and epilepsy.^1,6

Gene Mutations
Sjögren-Larsson syndrome is caused by mutation in the aldehyde dehydrogenase 3 family member A2 gene, ALDH3A2 (17p11.2), which codes for FALDH.^1,6,7 The ALDH3A2 gene is 11 exons long and gives rise to 2 protein isoforms that differ in their carboxy-terminal domains; the major isoform, composed of 485 amino acids, localizes to the endoplasmic reticulum. The minor protein isoform (FALDHv) is composed of 508 amino acids, possesses a longer carboxy-terminal, and appears to be targeted to the peroxisome. Several mutations have been reported throughout the ALDH3A2 gene, including missense mutations (most common [38% of cases of SLS⁶]), deletions, insertions, splicing errors, and complex rearrangements. Although several of these mutations are private, several common mutations may be indicative of founder effects (ie, shared ancestry), consanguinity, or recurrent mutational events (mutation hotspots).^6,7 Despite the wide spectrum of mutations, there is very little phenotypic variation, with consistently severe cutaneous and neurological involvement occurring in a majority of patients.⁷ However, Lossos et al⁹ described remarkable phenotypic variation in 6 siblings of an Arab family and suggested that additional unknown genetic or environmental factors may compensate for the biochemical defect.

Lipid Metabolism
Fatty aldehyde dehydrogenase is expressed in almost all cells and tissues and catalyzes the oxidation of fatty aldehydes to fatty acids (eFigure 1). It also is a part of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex, which catalyzes fatty alcohol oxidation to fatty acid. Fatty aldehyde dehydrogenase deficiency leads to accumulation of long-chain alcohols (eg, hexadecanol, octadecanol, octadecenol) and diversion of fatty alcohol into alternate biosynthetic pathways such as wax esters and 1-O-alkyl-2,3-diacylglycerol.¹⁰ Other lipids that are increased are illustrated in eFigure 2. Accumulation of these lipids, toxic effects of abnormal lipids (especially fatty aldehydes and Schiff base protein-lipid adducts), and lack of essential lipids (eg, polyunsaturated fatty acids, ceramides 1 and 6, triglycerides) are responsible for the classical cutaneous, neurologic, and ophthalmologic features of SLS.

Neurologic Findings
Neurologic changes in SLS result from delayed and deficient myelination. Neuropathological studies have shown ballooning of myelin sheaths, extensive loss of myelin, axonal damage, and astrogliosis. The presence of lipoid material positive for periodic acid–Schiff that stains light rather than dark pink, dense distribution of round/ellipsoid bodies in the white matter of the cerebrum and brainstem positive for periodic acid–Schiff, and proliferation of perivascular macrophages containing lipofuscinlike pigments also have been described.¹³ Possibly, in the absence of FALDH, metabolism of plasmalogens (a major component of myelin) results in increased fatty aldehydes, which are either diverted to fatty alcohols or form adducts with phosphatidylethanolamine and myelin basic proteins (eFigure 1). Magnetic resonance imaging of the brain usually shows hypomyelination involving the periventricular white matter extending from the frontal to the occipital area.^7,14 Mild ventricular enlargement may be an additional feature.¹⁴

A useful application of MRI is the proton magnetic resonance spectroscopy, which quantifies the brain metabolites noninvasively, displaying them as a spectrum on a graph. The spectrum comprises a set of resonances/peaks distributed along an x-axis. The resonances of these metabolites are obtained after suppressing the large signals from water protons. Proton magnetic resonance spectroscopy of the normal brain shows 3 prominent peaks: (1) N-acetylaspartate (NAA) at 2.02 ppm, (2) creatine at 3.02 ppm, and (3) choline at 3.22 ppm. In SLS, cerebral proton MRI spectroscopy reveals a characteristic abnormal, prominent, and narrow lipid peak at 1.3 ppm (corresponding to hexadecanol and octadecanol) and may offer a quantitative parameter for monitoring the effects of therapeutic interventions.^7,14,15 The most intense lipid peaks are located in the periventricular regions in the anterior and posterior trigones. An abnormal but much smaller peak may be seen at 0.8 to 0.9 ppm, corresponding to phytol.¹⁴ Gradual emergence of these changes occurs in the first 2 years of life and then remains stable.¹⁵ Proton magnetic resonance spectroscopy also can be used for screening of SLS heterozygotes.¹⁶ Lipid peaks have been described in other disorders of lipid metabolism, but they are less intense, broader, and disappear on longer echo time sequences.¹⁴

Besides the characteristic parafoveal glistening white dots the retina, optical coherence tomography shows focal hyperreflectivitity in the perifoveal ganglion cell layer and inner plexiform layer of the retina as well as cystoid foveal degeneration.¹⁷ The intraretinal deposition of lipid metabolites probably leads to Müller cell degeneration with subsequent formation of cystoid spaces and atrophic changes in the fovea.

Measurement of FALDH or FAO activity in cultured skin fibroblasts and leukocytes using flurometric or gas chromatography mass spectrometry assays is a reliable biochemical test in cases of SLS as well as in heterozygotes.¹⁷ A decrease in FALDH/FAO activity also can be demonstrated by histochemical staining in skin biopsy.¹¹ Pathologic urinary excretion of LTB4 and 20-OH-LTB4 also is a biochemical marker of SLS. Mutation analysis for a specific gene defect is diagnostic in cases of SLS as well as in heterozygotes. Prenatal diagnosis of SLS is possible by assessing FALDH activity or gene defects in cultured chorionic villus fibroblasts and amniocytes.^18,19

Differential Diagnosis
The differential diagnosis of SLS includes congenital ichthyosiform erythroderma with neurological signs (Tay syndrome, Conradi-Hünermann-Happle syndrome) and neurocutaneous disorders such as neutral lipid storage disease and multiple sulfatase deficiency; however, the nature of the ichthyosis, presence of spastic diplegia/tetraplegia, characteristic parafoveal glistening white dots on the retina, and MRI and proton magnetic resonance spectroscopy findings help to easily differentiate SLS from these disorders.

Treatment
Treatment of SLS mainly is palliative. Ichthyosis can be treated with topical keratolytics, emollients, calcipotriol, and oral retinoids (acitretin).⁶ Zileuton, a 5-lipoxygenase inhibitor, inhibits synthesis of LTB4 and cysteinyl leukotrienes, thereby reducing the severity of pruritus and also has been shown to improve the speed of information processing.¹⁸ Similarly, montelukast, a leuko-triene antagonist, is helpful in relieving the agonizing pruritus.¹⁹ Experimental studies have shown that bezafibrate, a peroxisome proliferator-activated receptor α agonist, induces FALDH activity in fibroblasts of SLS patients that still have some residual FALDH activity, but further research is required to determine whether SLS patients could benefit from treatment.²⁰ Physiotherapy helps in relieving the spasticity to some extent, such as in our case. Dietary intervention with reduced fat intake (up to 30% of total daily calorific requirement) and supplementation with omega-3 and omega-6 fatty acids has shown variable results in anecdotal reports.^21-23 Gene therapy using recombinant adeno-associated virus 2 vectors to restore FALDH has been projected as a future treatment option.²⁴ Despite lack of effective treatment options, most patients of SLS survive well into adulthood.

Conclusion

Because ichthyosis is one of the earliest and prominent symptoms of SLS, a dermatologist can play an important role in early diagnosis. Any child with the classical pattern of ichthyosis should be thoroughly examined for early neurologic signs and investigated to rule out SLS. Proton magnetic resonance spectroscopy serves as a useful adjunct in the diagnosis of SLS by confirming the accumulation of abnormal lipids in the periventricular white matter, especially when specific enzyme analysis and genetic analysis are not available in resource-restricted settings.

Sjögren-Larsson syndrome (SLS) is a rare autosomal-recessive neurocutaneous disorder comprising a triad of ichthyosis, mental retardation, and spastic diplegia or quadriplegia.¹ The disorder was first described by Sjögren and Larsson² in 1957. Early reports of SLS were mainly in white patients, with a particularly high prevalence of 8.3 cases per 100,000 individuals in the county of Västerbotten in Sweden.³ Reports of SLS in Asian and Indian populations are rare.^4,5 We report a case of SLS in an Indian boy.

Case Report

A 12-year-old Indian boy born to nonconsanguineous parents after a full-term pregnancy with normal vaginal delivery presented with generalized dry scaly skin that had been present since 2 months of age. He had a history of delayed milestones (ie, facial recognition, sitting without support at 3 years of age), inability to walk, dysarthria, mental retardation). He had never attended school due to subnormal intellectual functioning. He had a single episode of a tonic-clonic seizure at 4 years of age but was not on any regular antiepileptic medication. There was a history of similar skin lesions in one male sibling of the patient and in 2 maternal uncles. None of them survived beyond early childhood, but detailed information regarding the cutaneous and neurologic manifestations in these family members was not available.

Cutaneous examination revealed lamellarlike ichthyosis on the dorsal aspects of the arms and legs (Figure 1A). Ichthyosis with lichenification was present on the neck, axillae, cubital and popliteal fossae, and abdomen (Figure 1B). The palms and soles showed keratoderma. Neurologic examination of the arms revealed mild rigidity and brisk reflexes. Examination of the legs showed marked rigidity, brisk knee jerks, ankle clonus, extensor plantar reflexes, flexion deformity with contractures, and scissor gait. A Goddard (Seguin) formboard test was performed and indicated a mental age of 4 years. The patient’s IQ was in the range of 25 to 30, indicating a severe degree of subnormality in intellectual functioning. The clinical presentation suggested a diagnosis of SLS.

A skin biopsy from the ichthyotic lesion showed hyperkeratosis, acanthosis, and papillomatosis with sparse superficial perivascular lymphocytic infiltrate, thus confirming the diagnosis of lamellar ichthyosis. Fundus examination was normal. Magnetic resonance imaging (MRI) of the brain revealed confluent symmetrical signal abnormalities along the body of the lateral ventricles, white matter in the perioccipital horn, and in deep white matter of centrum semiovale (Figure 2). Magnetic resonance spectroscopy revealed a narrow lipid peak at approximately 1.3 ppm in the region of signal abnormality (Figure 3). Thus, the diagnosis of SLS was confirmed. Measurement of fatty aldehyde dehydrogenase (FALDH) activity and genetic analysis were not performed due to unavailability.

The patient was treated with topical emollients for the ichthyosis. To reduce his dietary intake of long-chain fatty acids and increase the intake of omega-3 and omega-6 fatty acids, the patient’s parents were advised to use canola, mustard, and/or coconut oil for cooking for the patient, and skim milk was recommended instead of whole milk. Neurodevelopmental techniques in the form of stretching exercises were given to maintain his range of movements. Gutter splints were given to maintain the knees in extension for physiological standing and to prevent osteoporosis. Subsequently, the patient also underwent a multilevel soft-tissue release (hip and knee joints) to relieve the contractures. These measures resulted in considerable improvement and the patient was able to walk with support.

Comment

Presentation
The characteristic clinical features of SLS begin to develop during the intranatal period and infancy.^1,6 Pathologic skin involvement can be detected as early as week 23 of gestation. Preterm births associated with SLS have commonly been described.³ Ichthyosis often is evident at birth, but collodion membrane is uncommon. Severe pruritus is a marked feature unlike most other types of ichthyosis. The ichthyosis often is generalized with prominent involvement of the flexural areas and nape of the neck, varying from fine furfuraceous to larger lamellarlike scales. Velvety orange or brown lichenification often is a predominant feature in the flexures of the arms, legs, neck, and mid abdomen. Mental retardation, developmental delay, and spasticity usually become apparent at 1 to 2 years of age and subsequently are nonprogressive.^6,7 However, patients rarely have been described with normal intellectual functioning.⁷ Spasticity often is more severe in the lower limbs and may lead to contractures, kyphoscoliosis, hip dislocation, and short stature. Delayed speech and dysarthria are common. Parafoveal glistening white dots on the retina are a pathognomonic feature and typically appear in the first 2 years of life; however, they are seen in approximately 30% of patients and increase slightly in number with age.^6,8 There may be associated decreased visual acuity, photophobia, myopia, and astigmatism. Other clinical features include enamel hypoplasia, metaphyseal dysplasia, and epilepsy.^1,6

Gene Mutations
Sjögren-Larsson syndrome is caused by mutation in the aldehyde dehydrogenase 3 family member A2 gene, ALDH3A2 (17p11.2), which codes for FALDH.^1,6,7 The ALDH3A2 gene is 11 exons long and gives rise to 2 protein isoforms that differ in their carboxy-terminal domains; the major isoform, composed of 485 amino acids, localizes to the endoplasmic reticulum. The minor protein isoform (FALDHv) is composed of 508 amino acids, possesses a longer carboxy-terminal, and appears to be targeted to the peroxisome. Several mutations have been reported throughout the ALDH3A2 gene, including missense mutations (most common [38% of cases of SLS⁶]), deletions, insertions, splicing errors, and complex rearrangements. Although several of these mutations are private, several common mutations may be indicative of founder effects (ie, shared ancestry), consanguinity, or recurrent mutational events (mutation hotspots).^6,7 Despite the wide spectrum of mutations, there is very little phenotypic variation, with consistently severe cutaneous and neurological involvement occurring in a majority of patients.⁷ However, Lossos et al⁹ described remarkable phenotypic variation in 6 siblings of an Arab family and suggested that additional unknown genetic or environmental factors may compensate for the biochemical defect.

Lipid Metabolism
Fatty aldehyde dehydrogenase is expressed in almost all cells and tissues and catalyzes the oxidation of fatty aldehydes to fatty acids (eFigure 1). It also is a part of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex, which catalyzes fatty alcohol oxidation to fatty acid. Fatty aldehyde dehydrogenase deficiency leads to accumulation of long-chain alcohols (eg, hexadecanol, octadecanol, octadecenol) and diversion of fatty alcohol into alternate biosynthetic pathways such as wax esters and 1-O-alkyl-2,3-diacylglycerol.¹⁰ Other lipids that are increased are illustrated in eFigure 2. Accumulation of these lipids, toxic effects of abnormal lipids (especially fatty aldehydes and Schiff base protein-lipid adducts), and lack of essential lipids (eg, polyunsaturated fatty acids, ceramides 1 and 6, triglycerides) are responsible for the classical cutaneous, neurologic, and ophthalmologic features of SLS.

Neurologic Findings
Neurologic changes in SLS result from delayed and deficient myelination. Neuropathological studies have shown ballooning of myelin sheaths, extensive loss of myelin, axonal damage, and astrogliosis. The presence of lipoid material positive for periodic acid–Schiff that stains light rather than dark pink, dense distribution of round/ellipsoid bodies in the white matter of the cerebrum and brainstem positive for periodic acid–Schiff, and proliferation of perivascular macrophages containing lipofuscinlike pigments also have been described.¹³ Possibly, in the absence of FALDH, metabolism of plasmalogens (a major component of myelin) results in increased fatty aldehydes, which are either diverted to fatty alcohols or form adducts with phosphatidylethanolamine and myelin basic proteins (eFigure 1). Magnetic resonance imaging of the brain usually shows hypomyelination involving the periventricular white matter extending from the frontal to the occipital area.^7,14 Mild ventricular enlargement may be an additional feature.¹⁴

A useful application of MRI is the proton magnetic resonance spectroscopy, which quantifies the brain metabolites noninvasively, displaying them as a spectrum on a graph. The spectrum comprises a set of resonances/peaks distributed along an x-axis. The resonances of these metabolites are obtained after suppressing the large signals from water protons. Proton magnetic resonance spectroscopy of the normal brain shows 3 prominent peaks: (1) N-acetylaspartate (NAA) at 2.02 ppm, (2) creatine at 3.02 ppm, and (3) choline at 3.22 ppm. In SLS, cerebral proton MRI spectroscopy reveals a characteristic abnormal, prominent, and narrow lipid peak at 1.3 ppm (corresponding to hexadecanol and octadecanol) and may offer a quantitative parameter for monitoring the effects of therapeutic interventions.^7,14,15 The most intense lipid peaks are located in the periventricular regions in the anterior and posterior trigones. An abnormal but much smaller peak may be seen at 0.8 to 0.9 ppm, corresponding to phytol.¹⁴ Gradual emergence of these changes occurs in the first 2 years of life and then remains stable.¹⁵ Proton magnetic resonance spectroscopy also can be used for screening of SLS heterozygotes.¹⁶ Lipid peaks have been described in other disorders of lipid metabolism, but they are less intense, broader, and disappear on longer echo time sequences.¹⁴

Besides the characteristic parafoveal glistening white dots the retina, optical coherence tomography shows focal hyperreflectivitity in the perifoveal ganglion cell layer and inner plexiform layer of the retina as well as cystoid foveal degeneration.¹⁷ The intraretinal deposition of lipid metabolites probably leads to Müller cell degeneration with subsequent formation of cystoid spaces and atrophic changes in the fovea.

Measurement of FALDH or FAO activity in cultured skin fibroblasts and leukocytes using flurometric or gas chromatography mass spectrometry assays is a reliable biochemical test in cases of SLS as well as in heterozygotes.¹⁷ A decrease in FALDH/FAO activity also can be demonstrated by histochemical staining in skin biopsy.¹¹ Pathologic urinary excretion of LTB4 and 20-OH-LTB4 also is a biochemical marker of SLS. Mutation analysis for a specific gene defect is diagnostic in cases of SLS as well as in heterozygotes. Prenatal diagnosis of SLS is possible by assessing FALDH activity or gene defects in cultured chorionic villus fibroblasts and amniocytes.^18,19

Differential Diagnosis
The differential diagnosis of SLS includes congenital ichthyosiform erythroderma with neurological signs (Tay syndrome, Conradi-Hünermann-Happle syndrome) and neurocutaneous disorders such as neutral lipid storage disease and multiple sulfatase deficiency; however, the nature of the ichthyosis, presence of spastic diplegia/tetraplegia, characteristic parafoveal glistening white dots on the retina, and MRI and proton magnetic resonance spectroscopy findings help to easily differentiate SLS from these disorders.

Treatment
Treatment of SLS mainly is palliative. Ichthyosis can be treated with topical keratolytics, emollients, calcipotriol, and oral retinoids (acitretin).⁶ Zileuton, a 5-lipoxygenase inhibitor, inhibits synthesis of LTB4 and cysteinyl leukotrienes, thereby reducing the severity of pruritus and also has been shown to improve the speed of information processing.¹⁸ Similarly, montelukast, a leuko-triene antagonist, is helpful in relieving the agonizing pruritus.¹⁹ Experimental studies have shown that bezafibrate, a peroxisome proliferator-activated receptor α agonist, induces FALDH activity in fibroblasts of SLS patients that still have some residual FALDH activity, but further research is required to determine whether SLS patients could benefit from treatment.²⁰ Physiotherapy helps in relieving the spasticity to some extent, such as in our case. Dietary intervention with reduced fat intake (up to 30% of total daily calorific requirement) and supplementation with omega-3 and omega-6 fatty acids has shown variable results in anecdotal reports.^21-23 Gene therapy using recombinant adeno-associated virus 2 vectors to restore FALDH has been projected as a future treatment option.²⁴ Despite lack of effective treatment options, most patients of SLS survive well into adulthood.

Conclusion

Because ichthyosis is one of the earliest and prominent symptoms of SLS, a dermatologist can play an important role in early diagnosis. Any child with the classical pattern of ichthyosis should be thoroughly examined for early neurologic signs and investigated to rule out SLS. Proton magnetic resonance spectroscopy serves as a useful adjunct in the diagnosis of SLS by confirming the accumulation of abnormal lipids in the periventricular white matter, especially when specific enzyme analysis and genetic analysis are not available in resource-restricted settings.

It is customary at the end of the year for editors of journals and magazines to publish “the best and the worst of the year” or top 10 lists of events or articles of the year, or even the “most important” discoveries or people of the year. Some publications survey their readers; others invite experts to opine on the selection. What is nearly always missing from these newsworthy roundups are the criteria for determining what meets the mark. But this is a crucial piece of missing information, and without it, many of these rankings have little worth.

Words like important, best, and worst are not factual claims but value judgments. For a value judgment to have validity, there must be a substantive basis for making the determination. Put less ponderously, readers need to understand what makes a person, action, or decision valuable or important.

Being a medical ethicist, I tend to think in terms of good and bad, right and wrong—hence, the title of this editorial. But even these essential terms of evaluation in our language must have a frame of reference or at least a description to have meaning when applied, especially if the terms are to be compared. For moral philosophy, the parent of medical ethics, these frames or bases for making judgments about the rightness or wrongness of conduct are often found in ethical theories.

Three of the most recognized and significant ethical theories are consequentialist, deontology, and virtue ethics. It is important to understand these theories to grasp how I decided on my list of the right and wrong of 2017. However due to space limitations, I will only provide a nutshell summary of these theories. Readers interested in cracking the nut wider may want to consult the references on ethical theory at the end of the essay.¹

Consequentialist theories—utilitarianism being the most well known in health care—argue that what makes an action right or good is what brings about the most happiness for the most people. What is determinative of rightness is the outcome.

In direct opposition to consequentialism is deontology. The consequences do not matter at all to the deontologist, right and good have to do with intent, and the only truly right intent is acting for the sake of duty alone.

Virtue ethics finds the core of right and good in the character of the virtuous person. Right actions and good intent each spring from the root of an individual of moral excellence.²

Establishing these ethical theories as the criteria for judgment, I now turn to my choice for the right and the good, the “best” of federal practice in 2017. (Next month my editorial will focus on the bad or the “worst” of 2017 federal health care.) Upfront, I acknowledge these choices are subjective, but I justify them by using the theories set forth. We welcome readers to send us their selections.

The Best

While journalists and politicians have widely criticized the White House response (or lack thereof) to the destructive storms that occurred during this hurricane season, little attention has been paid to the response of the 3 federal health care agencies, which was quick, dedicated, and caring. And it is this response that makes it my best of 2017. The vulnerability of areas from Houston to Puerto Rico, some of which still lack the basic services of civilization, are struggling with loss of life and hope, powerless to protect what is left in the wake of the storms, only amplifies the desperate need for the human and material resources that the DoD, VA, and PHS have committed.

Testifying before the Senate Homeland Security and Governmental Affairs Committee, Robert G. Salesses, deputy assistant secretary of defense, chronicled the outpouring of DoD aid. “Military units cleared critical roadways, transported life-sustaining commodities, provided fuel distribution, conducted assessments of civilian hospitals, and provided medical support to include evacuating patients back to the continental United States.”³

The VA Disaster Emergency Medical Personnel system also went into high gear. In my facility and in many others, there were so many volunteers that facility leaders had to balance their clinical needs with the selfless desire to help the veterans and fellow federal practitioners who were in harm’s way.

According to Susan Wentzell, VISN 8 deputy communication manager and content manager:

“Despite the destruction caused by these monster storms, Veterans continued to receive vital health care and other support, thanks to the selfless efforts of thousands of dedicated VA employees who rallied together to provide around-the-clock care for patients sheltered-in-place in the eight large, hurricane-constructed VA hospitals and to get services back up and running in dozens of outpatient clinics impacted in the Southeast corridor of the U.S. and the Caribbean.”⁴

When Hurricane Maria ravaged Puerto Rico, medical personnel from the VA and the PHS Commissioned Corps staffed Federal Medical Stations in Manati and Bayamon, Puerto Rico, which provided cared for up to 250 people at a time. The officers of the Commissioned Corps also helped support the civilian health care infrastructure.

From a utilitarian perspective, the benefit of these relief efforts is obvious. They were literally life-saving and health preserving for the thousands who were injured in the wreckage of wind and rain, ill from the collapse of public services, as well as those psychologically traumatized. And had these men and women of the VA, PHS, and DoD not come to the aid of the victims of these unprecedented national disasters, the toll of human suffering and bereavement would have been far worse.

Deontologically, each of these government employees did their duty; many volunteered, and even those who were ordered to assist did so with a compassion and dedication that went far beyond doing a job. None of the historic drives of humankind to place themselves in harm’s way—power, money, or fame—motivated those who answered the call; only a duty to serve and an intention to help.

Each person who left the security of home and the comfort of friends and family displayed the highest qualities of virtue ethics: altruism, professionalism, empathy, and integrity among other virtues.

In preparing for this column, I read stories of health care practitioners and nonclinical staff who not only reached out, but also reached beyond any expectation, clearly demonstrating outstanding professionalism and humanism.

I end with just one of these inspirational accounts. As Hurricane Irma approached the Florida coast, veteran employee Tim Myers braved the coming storm to get to work. That is far harder and braver than it seems, because Myers, who is a pharmacy technician and delivers medications to inpatients at the James A. Haley VA, is a quadriplegic in a wheelchair. The humility of his laconic description of his supererogatory conduct is equally impressive. “I appreciate that, but it really wasn’t that big of a deal to me,” Myers said.  “I mean, I had to get here.”⁵

It is customary at the end of the year for editors of journals and magazines to publish “the best and the worst of the year” or top 10 lists of events or articles of the year, or even the “most important” discoveries or people of the year. Some publications survey their readers; others invite experts to opine on the selection. What is nearly always missing from these newsworthy roundups are the criteria for determining what meets the mark. But this is a crucial piece of missing information, and without it, many of these rankings have little worth.

Words like important, best, and worst are not factual claims but value judgments. For a value judgment to have validity, there must be a substantive basis for making the determination. Put less ponderously, readers need to understand what makes a person, action, or decision valuable or important.

Being a medical ethicist, I tend to think in terms of good and bad, right and wrong—hence, the title of this editorial. But even these essential terms of evaluation in our language must have a frame of reference or at least a description to have meaning when applied, especially if the terms are to be compared. For moral philosophy, the parent of medical ethics, these frames or bases for making judgments about the rightness or wrongness of conduct are often found in ethical theories.

Three of the most recognized and significant ethical theories are consequentialist, deontology, and virtue ethics. It is important to understand these theories to grasp how I decided on my list of the right and wrong of 2017. However due to space limitations, I will only provide a nutshell summary of these theories. Readers interested in cracking the nut wider may want to consult the references on ethical theory at the end of the essay.¹

Consequentialist theories—utilitarianism being the most well known in health care—argue that what makes an action right or good is what brings about the most happiness for the most people. What is determinative of rightness is the outcome.

In direct opposition to consequentialism is deontology. The consequences do not matter at all to the deontologist, right and good have to do with intent, and the only truly right intent is acting for the sake of duty alone.

Virtue ethics finds the core of right and good in the character of the virtuous person. Right actions and good intent each spring from the root of an individual of moral excellence.²

Establishing these ethical theories as the criteria for judgment, I now turn to my choice for the right and the good, the “best” of federal practice in 2017. (Next month my editorial will focus on the bad or the “worst” of 2017 federal health care.) Upfront, I acknowledge these choices are subjective, but I justify them by using the theories set forth. We welcome readers to send us their selections.

The Best

While journalists and politicians have widely criticized the White House response (or lack thereof) to the destructive storms that occurred during this hurricane season, little attention has been paid to the response of the 3 federal health care agencies, which was quick, dedicated, and caring. And it is this response that makes it my best of 2017. The vulnerability of areas from Houston to Puerto Rico, some of which still lack the basic services of civilization, are struggling with loss of life and hope, powerless to protect what is left in the wake of the storms, only amplifies the desperate need for the human and material resources that the DoD, VA, and PHS have committed.

Testifying before the Senate Homeland Security and Governmental Affairs Committee, Robert G. Salesses, deputy assistant secretary of defense, chronicled the outpouring of DoD aid. “Military units cleared critical roadways, transported life-sustaining commodities, provided fuel distribution, conducted assessments of civilian hospitals, and provided medical support to include evacuating patients back to the continental United States.”³

The VA Disaster Emergency Medical Personnel system also went into high gear. In my facility and in many others, there were so many volunteers that facility leaders had to balance their clinical needs with the selfless desire to help the veterans and fellow federal practitioners who were in harm’s way.

According to Susan Wentzell, VISN 8 deputy communication manager and content manager:

“Despite the destruction caused by these monster storms, Veterans continued to receive vital health care and other support, thanks to the selfless efforts of thousands of dedicated VA employees who rallied together to provide around-the-clock care for patients sheltered-in-place in the eight large, hurricane-constructed VA hospitals and to get services back up and running in dozens of outpatient clinics impacted in the Southeast corridor of the U.S. and the Caribbean.”⁴

When Hurricane Maria ravaged Puerto Rico, medical personnel from the VA and the PHS Commissioned Corps staffed Federal Medical Stations in Manati and Bayamon, Puerto Rico, which provided cared for up to 250 people at a time. The officers of the Commissioned Corps also helped support the civilian health care infrastructure.

From a utilitarian perspective, the benefit of these relief efforts is obvious. They were literally life-saving and health preserving for the thousands who were injured in the wreckage of wind and rain, ill from the collapse of public services, as well as those psychologically traumatized. And had these men and women of the VA, PHS, and DoD not come to the aid of the victims of these unprecedented national disasters, the toll of human suffering and bereavement would have been far worse.

Deontologically, each of these government employees did their duty; many volunteered, and even those who were ordered to assist did so with a compassion and dedication that went far beyond doing a job. None of the historic drives of humankind to place themselves in harm’s way—power, money, or fame—motivated those who answered the call; only a duty to serve and an intention to help.

Each person who left the security of home and the comfort of friends and family displayed the highest qualities of virtue ethics: altruism, professionalism, empathy, and integrity among other virtues.

In preparing for this column, I read stories of health care practitioners and nonclinical staff who not only reached out, but also reached beyond any expectation, clearly demonstrating outstanding professionalism and humanism.

I end with just one of these inspirational accounts. As Hurricane Irma approached the Florida coast, veteran employee Tim Myers braved the coming storm to get to work. That is far harder and braver than it seems, because Myers, who is a pharmacy technician and delivers medications to inpatients at the James A. Haley VA, is a quadriplegic in a wheelchair. The humility of his laconic description of his supererogatory conduct is equally impressive. “I appreciate that, but it really wasn’t that big of a deal to me,” Myers said.  “I mean, I had to get here.”⁵

It is customary at the end of the year for editors of journals and magazines to publish “the best and the worst of the year” or top 10 lists of events or articles of the year, or even the “most important” discoveries or people of the year. Some publications survey their readers; others invite experts to opine on the selection. What is nearly always missing from these newsworthy roundups are the criteria for determining what meets the mark. But this is a crucial piece of missing information, and without it, many of these rankings have little worth.

Words like important, best, and worst are not factual claims but value judgments. For a value judgment to have validity, there must be a substantive basis for making the determination. Put less ponderously, readers need to understand what makes a person, action, or decision valuable or important.

Being a medical ethicist, I tend to think in terms of good and bad, right and wrong—hence, the title of this editorial. But even these essential terms of evaluation in our language must have a frame of reference or at least a description to have meaning when applied, especially if the terms are to be compared. For moral philosophy, the parent of medical ethics, these frames or bases for making judgments about the rightness or wrongness of conduct are often found in ethical theories.

Three of the most recognized and significant ethical theories are consequentialist, deontology, and virtue ethics. It is important to understand these theories to grasp how I decided on my list of the right and wrong of 2017. However due to space limitations, I will only provide a nutshell summary of these theories. Readers interested in cracking the nut wider may want to consult the references on ethical theory at the end of the essay.¹

Consequentialist theories—utilitarianism being the most well known in health care—argue that what makes an action right or good is what brings about the most happiness for the most people. What is determinative of rightness is the outcome.

In direct opposition to consequentialism is deontology. The consequences do not matter at all to the deontologist, right and good have to do with intent, and the only truly right intent is acting for the sake of duty alone.

Virtue ethics finds the core of right and good in the character of the virtuous person. Right actions and good intent each spring from the root of an individual of moral excellence.²

Establishing these ethical theories as the criteria for judgment, I now turn to my choice for the right and the good, the “best” of federal practice in 2017. (Next month my editorial will focus on the bad or the “worst” of 2017 federal health care.) Upfront, I acknowledge these choices are subjective, but I justify them by using the theories set forth. We welcome readers to send us their selections.

The Best

While journalists and politicians have widely criticized the White House response (or lack thereof) to the destructive storms that occurred during this hurricane season, little attention has been paid to the response of the 3 federal health care agencies, which was quick, dedicated, and caring. And it is this response that makes it my best of 2017. The vulnerability of areas from Houston to Puerto Rico, some of which still lack the basic services of civilization, are struggling with loss of life and hope, powerless to protect what is left in the wake of the storms, only amplifies the desperate need for the human and material resources that the DoD, VA, and PHS have committed.

Testifying before the Senate Homeland Security and Governmental Affairs Committee, Robert G. Salesses, deputy assistant secretary of defense, chronicled the outpouring of DoD aid. “Military units cleared critical roadways, transported life-sustaining commodities, provided fuel distribution, conducted assessments of civilian hospitals, and provided medical support to include evacuating patients back to the continental United States.”³

The VA Disaster Emergency Medical Personnel system also went into high gear. In my facility and in many others, there were so many volunteers that facility leaders had to balance their clinical needs with the selfless desire to help the veterans and fellow federal practitioners who were in harm’s way.

According to Susan Wentzell, VISN 8 deputy communication manager and content manager:

“Despite the destruction caused by these monster storms, Veterans continued to receive vital health care and other support, thanks to the selfless efforts of thousands of dedicated VA employees who rallied together to provide around-the-clock care for patients sheltered-in-place in the eight large, hurricane-constructed VA hospitals and to get services back up and running in dozens of outpatient clinics impacted in the Southeast corridor of the U.S. and the Caribbean.”⁴

When Hurricane Maria ravaged Puerto Rico, medical personnel from the VA and the PHS Commissioned Corps staffed Federal Medical Stations in Manati and Bayamon, Puerto Rico, which provided cared for up to 250 people at a time. The officers of the Commissioned Corps also helped support the civilian health care infrastructure.

From a utilitarian perspective, the benefit of these relief efforts is obvious. They were literally life-saving and health preserving for the thousands who were injured in the wreckage of wind and rain, ill from the collapse of public services, as well as those psychologically traumatized. And had these men and women of the VA, PHS, and DoD not come to the aid of the victims of these unprecedented national disasters, the toll of human suffering and bereavement would have been far worse.

Deontologically, each of these government employees did their duty; many volunteered, and even those who were ordered to assist did so with a compassion and dedication that went far beyond doing a job. None of the historic drives of humankind to place themselves in harm’s way—power, money, or fame—motivated those who answered the call; only a duty to serve and an intention to help.

Each person who left the security of home and the comfort of friends and family displayed the highest qualities of virtue ethics: altruism, professionalism, empathy, and integrity among other virtues.

In preparing for this column, I read stories of health care practitioners and nonclinical staff who not only reached out, but also reached beyond any expectation, clearly demonstrating outstanding professionalism and humanism.

I end with just one of these inspirational accounts. As Hurricane Irma approached the Florida coast, veteran employee Tim Myers braved the coming storm to get to work. That is far harder and braver than it seems, because Myers, who is a pharmacy technician and delivers medications to inpatients at the James A. Haley VA, is a quadriplegic in a wheelchair. The humility of his laconic description of his supererogatory conduct is equally impressive. “I appreciate that, but it really wasn’t that big of a deal to me,” Myers said.  “I mean, I had to get here.”⁵

Case Report

A 58-year-old man presented for evaluation of a pruritic rash involving the pubic area of 30 years’ duration. Multiple primary care physicians and dermatologists had evaluated the patient during this period, but he noted a specific diagnosis had not been rendered and multiple treatments had been unsuccessful. The patient described a rash, which was absent at the time of evaluation, as a self-remitting and exacerbating irritation typically induced by sweating and physical activity. The patient also stated that the irritation was associated with a strong, distinct, musty odor that severely interrupted his sex life and decreased his quality of life. Prior treatments included various topical corticosteroids, topical and oral antibiotics, and various homeopathic treatments that were minimally efficacious or nonefficacious. He was unsure if antifungals had previously been prescribed.

The patient’s medical history was notable for pulmonary interstitial fibrosis, anxiety, posttraumatic stress disorder, and mild glucose intolerance. The patient had no pertinent surgical history and no known drug allergies. Current medications included a bronchodilating inhaler, escitalopram, trazodone, buspirone, clonazepam, prazosin, gabapentin, and azithromycin for current upper respiratory tract infection. The patient was a former smoker and a social drinker.

On physical evaluation the pubic area displayed slight patchy erythema without a papular component and was otherwise unremarkable to the unaided eye. Upon palpation of the skin, there were no remarkable findings. Under dermoscopic evaluation, small white-yellow concretions along the hair shaft were noticed. Evaluation with a Wood lamp is shown in Figure 1.

The patient was treated empirically with ketoconazole cream 2% applied to the affected area once daily until follow-up 3 weeks later. The patient also was advised to shave the pubic area to remove potentially infected hairs, as white piedra (WP) was suspected. A diagnosis of WP was confirmed on histologic evaluation of pubic hair samples approximately 1 to 2 weeks later (Figure 2).

At 3-week follow-up, Wood lamp evaluation did not identify concretions along the pubic hair shafts. The patient was symptom free and extremely pleased. Of note, the patient did not shave the pubic area and was counseled on recurrence.

Comment

Piedra (meaning stone in Spanish) describes a group of fungal infections that present with gritty concretions on the hair shaft.^1,2 In 1911, Horta³ classified piedra into 2 subtypes: black piedra, caused by Piedraia hortae, and WP, caused by Trichosporon species. Black piedra occurs more frequently in tropical countries and commonly affects hair shafts on the scalp.⁴ White piedra most commonly affects the pubic area, with rare cases in scalp and facial hair.^1,5-7

Epidemiology
White piedra is seen worldwide, including Europe, South America, India, Southeast Asia, Africa, South America, and southern parts of the United States. The majority of cases occur in tropical and temperate regions.¹ White piedra likely is underdiagnosed; for example, in a study of 166 young men with genital concerns in Houston, Texas, Trichosporon was isolated in 40% of cultured scrotal hairs.⁸

Species Identification
There are several species of WP; special techniques must be used to differentiate them, which is beyond the scope of this case. The known species include Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides, and Trichosporon ovoides.¹Trichosporon asahii and T mucoides have been known to cause systemic infections in immunocompromised hosts known as trichosporonosis.^1,9 As an example of a special technique used for species recognition, Sugita et al¹⁰ used sequence analysis of the ribosomal DNA intergenic spacer 1 regions to distinguish T asahii isolates. Identification of species may be warranted in the proper clinical scenario; however, histologic evaluation by an experienced dermatopathologist frequently is sufficient to identify the Trichosporon genus.

Transmission
The 2 most common causative organisms of WP are T inkin and T ovoides. Furthermore, T inkin causes the vast majority of WP in the pubic region.⁸Trichosporon species may be found in air, soil, water, and sewage,⁷ and have been isolated in hair samples from horses, dogs, and monkeys.¹¹ The mode of transmission in humans remains elusive but has been reported from poor personal hygiene and bathing in stagnant water as well as sexual transmission in the case of pubic infestation.^5,8,11-13

Diagnosis and Differential
White piedra is characterized by the presence of adherent tan to white nodules along the hair shafts. The concretions tend to be softer than black piedra and, unlike trichomycosis, normally do not fluoresce.¹ They do not encircle the hair shaft as hair casts do and can be readily distinguished from Trichomycosis axillaris, black piedra, pediculosis, and trichorrhexis nodosa on microscopic examination.¹⁴ The hair shaft concretions of WP are difficult to visualize with the unaided eye. As a result, it is easily misdiagnosed.¹⁵ Upon palpation of the infected hair shafts, a grainy sensation is evident. Dermoscopy improves visualization, and fluorescence was useful in our case. Microscopic evaluation will identify the adherent organism and is readily cultured on Sabouraud agar.¹⁶ Although Trichosporon species typically do not fluoresce,¹ Wood lamp examination occasionally may reveal the organism, such as in our case. A possible explanation for this finding is the synergistic relationship with Corynebacterium,¹⁷ some producing fluorescent chemicals. Growth of Trichosporon species may be enhanced by or even dependent on Corynebacterium; therefore, WP is likely a coinfection of fungus and bacteria.^17,18 Studies also name a novel species of Brevibacterium in relationship with genital WP.¹⁹ This species was described as producing a foul odor, as in our patient.

Treatment
The American Academy of Dermatology’s Guidelines Committee recommends complete removal of the infected hairs.¹ The recommendation traditionally is hair removal in conjunction with topical or oral medications,¹ such as topical imidazoles, ciclopirox olamine, selenium sulfide 2%, chlorhexidine solution, zinc pyrithione, amphotericin B lotion, and oral itraconazole. Recurrence rates are high and spontaneous remission sometimes occurs.^9,20 Triazole antifungals currently are preferred for treatment of Trichosporon infections.⁵ Patients should be counseled to dispose of undergarments, as the organism has been recovered from cotton fibers and are a source of reinfection.^1,21

Conclusion

White piedra, though relatively uncommon, is likely underdiagnosed in the United States and should be suspected in any patient presenting with irritation and a foul odor in the genital area or multiple failed therapies for a nonspecific genital dermatitis. This clinical scenario warrants dermoscopic and Wood lamp examination of the affected skin and hair shafts in addition to microscopic examination of pubic hair shafts by a dermatopathologist. Fluorescence under Wood lamp may aid in diagnosis, and conflicting findings may be attributed to its synergistic relationship with Corynebacterium and Brevibacterium coinfection. Proper treatment includes shaving of the affected hair, oral or topical antifungal treatment, and disposal of affected clothing.

Case Report

A 58-year-old man presented for evaluation of a pruritic rash involving the pubic area of 30 years’ duration. Multiple primary care physicians and dermatologists had evaluated the patient during this period, but he noted a specific diagnosis had not been rendered and multiple treatments had been unsuccessful. The patient described a rash, which was absent at the time of evaluation, as a self-remitting and exacerbating irritation typically induced by sweating and physical activity. The patient also stated that the irritation was associated with a strong, distinct, musty odor that severely interrupted his sex life and decreased his quality of life. Prior treatments included various topical corticosteroids, topical and oral antibiotics, and various homeopathic treatments that were minimally efficacious or nonefficacious. He was unsure if antifungals had previously been prescribed.

The patient’s medical history was notable for pulmonary interstitial fibrosis, anxiety, posttraumatic stress disorder, and mild glucose intolerance. The patient had no pertinent surgical history and no known drug allergies. Current medications included a bronchodilating inhaler, escitalopram, trazodone, buspirone, clonazepam, prazosin, gabapentin, and azithromycin for current upper respiratory tract infection. The patient was a former smoker and a social drinker.

On physical evaluation the pubic area displayed slight patchy erythema without a papular component and was otherwise unremarkable to the unaided eye. Upon palpation of the skin, there were no remarkable findings. Under dermoscopic evaluation, small white-yellow concretions along the hair shaft were noticed. Evaluation with a Wood lamp is shown in Figure 1.

The patient was treated empirically with ketoconazole cream 2% applied to the affected area once daily until follow-up 3 weeks later. The patient also was advised to shave the pubic area to remove potentially infected hairs, as white piedra (WP) was suspected. A diagnosis of WP was confirmed on histologic evaluation of pubic hair samples approximately 1 to 2 weeks later (Figure 2).

At 3-week follow-up, Wood lamp evaluation did not identify concretions along the pubic hair shafts. The patient was symptom free and extremely pleased. Of note, the patient did not shave the pubic area and was counseled on recurrence.

Comment

Piedra (meaning stone in Spanish) describes a group of fungal infections that present with gritty concretions on the hair shaft.^1,2 In 1911, Horta³ classified piedra into 2 subtypes: black piedra, caused by Piedraia hortae, and WP, caused by Trichosporon species. Black piedra occurs more frequently in tropical countries and commonly affects hair shafts on the scalp.⁴ White piedra most commonly affects the pubic area, with rare cases in scalp and facial hair.^1,5-7

Epidemiology
White piedra is seen worldwide, including Europe, South America, India, Southeast Asia, Africa, South America, and southern parts of the United States. The majority of cases occur in tropical and temperate regions.¹ White piedra likely is underdiagnosed; for example, in a study of 166 young men with genital concerns in Houston, Texas, Trichosporon was isolated in 40% of cultured scrotal hairs.⁸

Species Identification
There are several species of WP; special techniques must be used to differentiate them, which is beyond the scope of this case. The known species include Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides, and Trichosporon ovoides.¹Trichosporon asahii and T mucoides have been known to cause systemic infections in immunocompromised hosts known as trichosporonosis.^1,9 As an example of a special technique used for species recognition, Sugita et al¹⁰ used sequence analysis of the ribosomal DNA intergenic spacer 1 regions to distinguish T asahii isolates. Identification of species may be warranted in the proper clinical scenario; however, histologic evaluation by an experienced dermatopathologist frequently is sufficient to identify the Trichosporon genus.

Transmission
The 2 most common causative organisms of WP are T inkin and T ovoides. Furthermore, T inkin causes the vast majority of WP in the pubic region.⁸Trichosporon species may be found in air, soil, water, and sewage,⁷ and have been isolated in hair samples from horses, dogs, and monkeys.¹¹ The mode of transmission in humans remains elusive but has been reported from poor personal hygiene and bathing in stagnant water as well as sexual transmission in the case of pubic infestation.^5,8,11-13

Diagnosis and Differential
White piedra is characterized by the presence of adherent tan to white nodules along the hair shafts. The concretions tend to be softer than black piedra and, unlike trichomycosis, normally do not fluoresce.¹ They do not encircle the hair shaft as hair casts do and can be readily distinguished from Trichomycosis axillaris, black piedra, pediculosis, and trichorrhexis nodosa on microscopic examination.¹⁴ The hair shaft concretions of WP are difficult to visualize with the unaided eye. As a result, it is easily misdiagnosed.¹⁵ Upon palpation of the infected hair shafts, a grainy sensation is evident. Dermoscopy improves visualization, and fluorescence was useful in our case. Microscopic evaluation will identify the adherent organism and is readily cultured on Sabouraud agar.¹⁶ Although Trichosporon species typically do not fluoresce,¹ Wood lamp examination occasionally may reveal the organism, such as in our case. A possible explanation for this finding is the synergistic relationship with Corynebacterium,¹⁷ some producing fluorescent chemicals. Growth of Trichosporon species may be enhanced by or even dependent on Corynebacterium; therefore, WP is likely a coinfection of fungus and bacteria.^17,18 Studies also name a novel species of Brevibacterium in relationship with genital WP.¹⁹ This species was described as producing a foul odor, as in our patient.

Treatment
The American Academy of Dermatology’s Guidelines Committee recommends complete removal of the infected hairs.¹ The recommendation traditionally is hair removal in conjunction with topical or oral medications,¹ such as topical imidazoles, ciclopirox olamine, selenium sulfide 2%, chlorhexidine solution, zinc pyrithione, amphotericin B lotion, and oral itraconazole. Recurrence rates are high and spontaneous remission sometimes occurs.^9,20 Triazole antifungals currently are preferred for treatment of Trichosporon infections.⁵ Patients should be counseled to dispose of undergarments, as the organism has been recovered from cotton fibers and are a source of reinfection.^1,21

Conclusion

White piedra, though relatively uncommon, is likely underdiagnosed in the United States and should be suspected in any patient presenting with irritation and a foul odor in the genital area or multiple failed therapies for a nonspecific genital dermatitis. This clinical scenario warrants dermoscopic and Wood lamp examination of the affected skin and hair shafts in addition to microscopic examination of pubic hair shafts by a dermatopathologist. Fluorescence under Wood lamp may aid in diagnosis, and conflicting findings may be attributed to its synergistic relationship with Corynebacterium and Brevibacterium coinfection. Proper treatment includes shaving of the affected hair, oral or topical antifungal treatment, and disposal of affected clothing.

Case Report

A 58-year-old man presented for evaluation of a pruritic rash involving the pubic area of 30 years’ duration. Multiple primary care physicians and dermatologists had evaluated the patient during this period, but he noted a specific diagnosis had not been rendered and multiple treatments had been unsuccessful. The patient described a rash, which was absent at the time of evaluation, as a self-remitting and exacerbating irritation typically induced by sweating and physical activity. The patient also stated that the irritation was associated with a strong, distinct, musty odor that severely interrupted his sex life and decreased his quality of life. Prior treatments included various topical corticosteroids, topical and oral antibiotics, and various homeopathic treatments that were minimally efficacious or nonefficacious. He was unsure if antifungals had previously been prescribed.

The patient’s medical history was notable for pulmonary interstitial fibrosis, anxiety, posttraumatic stress disorder, and mild glucose intolerance. The patient had no pertinent surgical history and no known drug allergies. Current medications included a bronchodilating inhaler, escitalopram, trazodone, buspirone, clonazepam, prazosin, gabapentin, and azithromycin for current upper respiratory tract infection. The patient was a former smoker and a social drinker.

On physical evaluation the pubic area displayed slight patchy erythema without a papular component and was otherwise unremarkable to the unaided eye. Upon palpation of the skin, there were no remarkable findings. Under dermoscopic evaluation, small white-yellow concretions along the hair shaft were noticed. Evaluation with a Wood lamp is shown in Figure 1.

The patient was treated empirically with ketoconazole cream 2% applied to the affected area once daily until follow-up 3 weeks later. The patient also was advised to shave the pubic area to remove potentially infected hairs, as white piedra (WP) was suspected. A diagnosis of WP was confirmed on histologic evaluation of pubic hair samples approximately 1 to 2 weeks later (Figure 2).

At 3-week follow-up, Wood lamp evaluation did not identify concretions along the pubic hair shafts. The patient was symptom free and extremely pleased. Of note, the patient did not shave the pubic area and was counseled on recurrence.

Comment

Piedra (meaning stone in Spanish) describes a group of fungal infections that present with gritty concretions on the hair shaft.^1,2 In 1911, Horta³ classified piedra into 2 subtypes: black piedra, caused by Piedraia hortae, and WP, caused by Trichosporon species. Black piedra occurs more frequently in tropical countries and commonly affects hair shafts on the scalp.⁴ White piedra most commonly affects the pubic area, with rare cases in scalp and facial hair.^1,5-7

Epidemiology
White piedra is seen worldwide, including Europe, South America, India, Southeast Asia, Africa, South America, and southern parts of the United States. The majority of cases occur in tropical and temperate regions.¹ White piedra likely is underdiagnosed; for example, in a study of 166 young men with genital concerns in Houston, Texas, Trichosporon was isolated in 40% of cultured scrotal hairs.⁸

Species Identification
There are several species of WP; special techniques must be used to differentiate them, which is beyond the scope of this case. The known species include Trichosporon asahii, Trichosporon asteroides, Trichosporon cutaneum, Trichosporon inkin, Trichosporon mucoides, and Trichosporon ovoides.¹Trichosporon asahii and T mucoides have been known to cause systemic infections in immunocompromised hosts known as trichosporonosis.^1,9 As an example of a special technique used for species recognition, Sugita et al¹⁰ used sequence analysis of the ribosomal DNA intergenic spacer 1 regions to distinguish T asahii isolates. Identification of species may be warranted in the proper clinical scenario; however, histologic evaluation by an experienced dermatopathologist frequently is sufficient to identify the Trichosporon genus.

Transmission
The 2 most common causative organisms of WP are T inkin and T ovoides. Furthermore, T inkin causes the vast majority of WP in the pubic region.⁸Trichosporon species may be found in air, soil, water, and sewage,⁷ and have been isolated in hair samples from horses, dogs, and monkeys.¹¹ The mode of transmission in humans remains elusive but has been reported from poor personal hygiene and bathing in stagnant water as well as sexual transmission in the case of pubic infestation.^5,8,11-13

Diagnosis and Differential
White piedra is characterized by the presence of adherent tan to white nodules along the hair shafts. The concretions tend to be softer than black piedra and, unlike trichomycosis, normally do not fluoresce.¹ They do not encircle the hair shaft as hair casts do and can be readily distinguished from Trichomycosis axillaris, black piedra, pediculosis, and trichorrhexis nodosa on microscopic examination.¹⁴ The hair shaft concretions of WP are difficult to visualize with the unaided eye. As a result, it is easily misdiagnosed.¹⁵ Upon palpation of the infected hair shafts, a grainy sensation is evident. Dermoscopy improves visualization, and fluorescence was useful in our case. Microscopic evaluation will identify the adherent organism and is readily cultured on Sabouraud agar.¹⁶ Although Trichosporon species typically do not fluoresce,¹ Wood lamp examination occasionally may reveal the organism, such as in our case. A possible explanation for this finding is the synergistic relationship with Corynebacterium,¹⁷ some producing fluorescent chemicals. Growth of Trichosporon species may be enhanced by or even dependent on Corynebacterium; therefore, WP is likely a coinfection of fungus and bacteria.^17,18 Studies also name a novel species of Brevibacterium in relationship with genital WP.¹⁹ This species was described as producing a foul odor, as in our patient.

Treatment
The American Academy of Dermatology’s Guidelines Committee recommends complete removal of the infected hairs.¹ The recommendation traditionally is hair removal in conjunction with topical or oral medications,¹ such as topical imidazoles, ciclopirox olamine, selenium sulfide 2%, chlorhexidine solution, zinc pyrithione, amphotericin B lotion, and oral itraconazole. Recurrence rates are high and spontaneous remission sometimes occurs.^9,20 Triazole antifungals currently are preferred for treatment of Trichosporon infections.⁵ Patients should be counseled to dispose of undergarments, as the organism has been recovered from cotton fibers and are a source of reinfection.^1,21

Conclusion

White piedra, though relatively uncommon, is likely underdiagnosed in the United States and should be suspected in any patient presenting with irritation and a foul odor in the genital area or multiple failed therapies for a nonspecific genital dermatitis. This clinical scenario warrants dermoscopic and Wood lamp examination of the affected skin and hair shafts in addition to microscopic examination of pubic hair shafts by a dermatopathologist. Fluorescence under Wood lamp may aid in diagnosis, and conflicting findings may be attributed to its synergistic relationship with Corynebacterium and Brevibacterium coinfection. Proper treatment includes shaving of the affected hair, oral or topical antifungal treatment, and disposal of affected clothing.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

In 1960, Gorlin and Goltz¹ first described nevoid basal cell carcinoma syndrome (NBCCS) as a distinct clinical entity with multiple basal cell carcinomas (BCCs), jaw cysts, and bifid ribs. This rare autosomal-dominant genodermatosis has a minimal prevalence of 1 case per 57,000 individuals² and no sexual predilection.³ Nevoid basal cell carcinoma syndrome is caused by a mutation in the human homolog of a Drosophila gene, patched 1 (PTCH1), which is located on chromosome 9q22.^3.4,5 The major clinical diagnostic criteria includes multiple BCCs, odontogenic keratocysts, palmar or plantar pits, ectopic calcification of the falx cerebri, and a family history of NBCCS.⁶ Basal cell carcinoma formation is affected by both skin pigmentation and sun exposure; 80% of white patients with NBCCS will develop at least 1 BCC compared to only 40% of black patients with NBCCS.⁷ Goldstein et al⁸ postulated that this disparity is associated with increased skin pigmentation providing UV radiation protection, thus decreasing the tumor burden. We report a case of an 11-year-old black boy with NBCCS to highlight the treatment considerations in pediatric cases of NBCCS.

Case Report

An 11-year-old boy with Fitzpatrick skin type V presented with a history of multiple facial lesions after undergoing excision of large keratocysts from the right maxilla, left maxilla, and right mandible. Physical examination revealed multiple light to dark brown facial papules (Figure 1), palmar and plantar pitting (Figure 2), and frontal bossing.

He was previously diagnosed with autism and his surgical history was notable only for excision of the keratocysts. The patient was not taking any medications and did not have any drug allergies. There was no maternal family history of skin cancer or related syndromes; his paternal family history was unknown. A shave biopsy was performed on a facial papule from the right nasolabial fold. Histopathologic evaluation revealed findings consistent with a pigmented nodular BCC (Figure 3). The patient was subsequently sent for magnetic resonance imaging of the brain, which demonstrated calcifications along the tentorium. Genetic consultation confirmed a heterozygous mutation of the PTCH1 gene.

Over the next 12 months, the patient had multiple biopsy-proven pigmented BCCs. Initial management of these carcinomas located on cosmetically sensitive areas, including the upper eyelid and penis, were excised by a pediatric plastic surgeon. A truncal carcinoma was treated with electrodesiccation and curettage, which resulted in keloid formation. Early suspicious lesions were treated with imiquimod cream 5% 5 times weekly in combination with the prophylactic use of tretinoin cream 0.1%. Despite this treatment regimen, the patient continued to demonstrate multiple small clinical pigmented BCCs along the malar surfaces of the cheeks and dorsum of the nose. The patient’s mother deferred chemoprevention with an oral retinoid due to the extensive side-effect profile and long-term necessity of administration.

Management also encompassed BCC surveillance every 4 months; annual digital panorex of the jaw; routine dental screening; routine developmental screening; annual follow-up with a geneticist to ensure multidisciplinary care; and annual vision, hearing, and speech-screening examinations. Strict sun-protective measures were encouraged, including wearing a hat during physical education class.

Comment

Classification and Clinical Presentation
Nevoid basal cell carcinoma syndrome is a multisystem disorder that requires close monitoring under multidisciplinary care. Evans et al⁶ defined the diagnostic criteria of NBCCS to require the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria include multiple BCCs, an odontogenic keratocyst or polyostotic bone cyst, palmar or plantar pits, ectopic calcification of the falx cerebri, and family history of NBCCS. The minor criteria are defined as congenital skeletal anomalies; macrocephaly with frontal bossing; cardiac or ovarian fibromas; medulloblastoma; lymphomesenteric cysts; and congenital malformations such as cleft lip or palate, polydactyly, or eye anomalies.⁶ The mean age of initial BCC diagnosis is 21 years, with proliferation of cancers between puberty and 35 years of age.^7,9 Our case is unique due to the patient’s young age at the time of diagnosis as well as his presentation with multiple BCCs with a darker skin type. Kimonis et al⁷ reported that approximately 20% of black patients develop their first BCC by the age of 21 years and 40% by 35 years. The presence of multiple BCCs is complicated by the limited treatment options in a pediatric patient. The patient’s inability to withstand multiple procedures contributed to our clinical decision to have multiple lesions removed under general anesthesia by a pediatric plastic surgeon.

Due to the patient’s young age of onset, we placed a great emphasis on close surveillance and management. A management protocol for pediatric patients with NBCCS was described by Bree and Shah; BCNS Colloquium Group¹⁰ (eTable). We closely followed this protocol for surveillance; however, we scheduled dermatologic examinations every 4 months due to his extensive history of BCCs.

Management
Our case presents a challenging therapeutic and management dilemma. The management of NBCCS utilizes a multitude of treatment modalities, but many of them posed cosmetic challenges in our patient such as postinflammatory hypopigmentation and the propensity for keloid formation. Although surgical excision or Mohs micrographic surgery is the standard of treatment of nodular BCCs, we were limited due to the patient’s inability to tolerate multiple surgical procedures without the use of general anesthesia.

Case reports have discussed the use of CO₂ laser resurfacing for management of multiple facial BCCs in patients with NBCCS. Doctoroff et al¹¹ treated a patient with 45 facial BCCs with full-face CO₂ laser resurfacing, and in a 10-month follow-up period the patient developed 6 new BCCs on the face. Nouri et al¹² described 3 cases of multiple BCCs on the face, trunk, and extremities treated with ultrapulse CO₂ laser with postoperative Mohs sections verifying complete histologic clearance of tumors. All 3 patients had Fitzpatrick skin type IV; their ages were 2, 16, and 35 years. Local anesthesia was used in the 2-year-old patient and intravenous sedation in the 16-year-old patient.¹² Although CO₂ laser therapy may be a practical treatment option, it posed too many cosmetic concerns in our patient.

Photodynamic therapy (PDT) is an emerging treatment option for NBCCS patients. Itkin and Gilchrest¹³ treated 2 NBCCS patients with δ-aminolevulinic acid for 1 to 5 hours prior to treatment with blue light therapy. Complete clearance was documented in 89% (8/9) of superficial BCCs and 31% (5/16) of nodular BCCs on the face, indicating that blue light treatment may reduce the cutaneous tumor burden.¹³ Oseroff et al¹⁴ reported similar success in treating 3 children with NBCCS with 20% δ-aminolevulinic acid for 24 hours under occlusion followed by red light treatment. After 1 to 3 treatments, the children had 85% to 98% total clearance, demonstrating it as a viable treatment option in young patients that yields excellent cosmetic results and is well tolerated.¹⁴ Photodynamic therapy is reported to have a low risk of carcinogenicity¹⁵; however, there has been 1 reported case of melanoma developing at the site of multiple PDT treatments.¹⁶ Thus, the risk of carcinogenicity is increasingly bothersome in NBCCS patients due to their sensitivity to exposure. The limited number of studies using topical PDT on pediatric patients, the lack of treatment protocols for pediatric patients, and the need to use general anesthesia for pediatric patients all posed limitations to the use of PDT in our case.

Imiquimod cream 5% was shown in randomized, vehicle-controlled studies to be a safe and effective treatment of superficial BCCs when used 5 days weekly for 6 weeks.¹⁷ These studies excluded patients with NBCCS; however, other studies have been completed in patients with NBCCS. Kagy and Amonette¹⁸ successfully treated 3 nonfacial BCCs in a patient with NBCCS with imiquimod cream 5% daily for 18 weeks, with complete histologic resolution of the tumors. Micali et al¹⁹ also treated 4 patients with NBCCS using imiquimod cream 5% 3 to 5 times weekly for 8 to 14 weeks. Thirteen of 17 BCCs resolved, as confirmed with histologic evaluation.¹⁹ One case report revealed a child with NBCCS who was successfully managed with topical fluorouracil and topical tretinoin for more than 10 years.²⁰ Our patient used imiquimod cream 5% 5 times weekly, which inhibited the growth of existing lesions but did not clear them entirely, as they were nodular in nature.

Chemoprevention with oral retinoids breaches a controversial treatment topic. In 1989, a case study of an NBCCS patient treated with surgical excision and oral etretinate for 12 months documented reduction of large tumors.²¹ A multicenter clinical trial reported that low-dose isotretinoin (10 mg daily) is ineffective in preventing the occurrence of new BCC formation in patients with a history of 2 or more sporadic BCCs.²² Chemoprevention with oral retinoids is well known for being effective for squamous cell carcinomas and actinic keratosis; however, the treatment is less effective for BCCs.²² Most importantly, the extensive side-effect profile and toxicity associated with long-term administration of oral retinoids prohibits many practitioners from routinely using them in pediatric NBCCS patients.

Nevoid basal cell carcinoma syndrome patients are exquisitely sensitive to ionizing radiation and the effects of UV exposure. Therefore, it is essential to emphasize the importance of sun-protective measures such as sun avoidance, broad-spectrum sunscreen use, and sun-protective clothing.

Conclusion

Nevoid basal cell carcinoma syndrome is a multisystem disorder with a notable predisposition for skin cancer. Our case demonstrates the treatment considerations in a pediatric patient with Fitzpatrick skin type V. Pediatric NBCCS patients develop BCCs at a young age and will continue to develop additional lesions throughout life; therefore, skin preservation is an important consideration when choosing the appropriate treatment regimen. Particularly in our patient, utilizing multiple strategic treatment modalities in combination with chemoprevention moving forward will be a continued management challenge. Strict adherence to a surveillance protocol is encouraged to closely monitor the systemic manifestations of the disorder.

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

MONTREAL – African American breast cancer survivors who participated in fitness tracking and an online support program saw small but significant reductions in weight and improvement in quality of life, according to a new study.

Further, patients who reported a low baseline quality of life (QOL) achieved as much or more weight loss as did those whose QOL was initially high, said Jeanne Ferrante, MD, MPH, professor of family medicine and community health at Robert Wood Johnson Medical School, New Brunswick, N.J.

shironosov/Thinkstock

Dr. Ferrante reported no conflicts of interest.

[email protected]

On Twitter @karioakes

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.