Pigmentation Disorders

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.

Pigmented purpuric dermatoses (PPDs) are a group of common chronic disorders characterized by speckled, cayenne pepper–like petechiae and orange-brown discoloration of the skin resulting from capillaritis.¹ Pigmented purpuric dermatoses typically occur in the absence of underlying vascular insufficiency or other hematologic dysfunction. The 5 well-known clinicopathologic variants of PPD include Schamberg disease; purpura annularis telangiectodes of Majocchi; pigmented purpuric lichenoid dermatitis of Gougerot and Blum; eczematoidlike purpura of Doucas and Kapetanakis; and lichen aureus.² All PPDs share common characteristic clinical and histologic features. Clinically, patients generally present with symmetric petechiae and/or pigmented macules. All 5 PPD variants share similar histologic findings, including a vasculocentric lymphocytic infiltrate in the papillary dermis, swelling of the endothelial cells, erythrocyte extravasation, and often hemosiderin-laden macrophages.¹ Despite these clinical and histopathologic similarities, each variant contains additional distinctive features, such as telangiectasia (purpura annularis telangiectodes of Majocchi), a lichenoid infiltrate (pigmented purpuric lichenoid dermatitis of Gougerot and Blum), eczematous changes (eczematoidlike purpura of Doucas and Kapetanakis), and marked hemosiderin deposition (lichen aureus).

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare variant of PPD.^3-7 Clinically, these lesions appear similar to other PPDs; however, in addition to the characteristic changes associated with conventional PPD, histologic examination of GPPD reveals a granulomatous inflammatory reaction pattern. Although the pathogenesis of GPPD is not well understood, its association with hyperlipidemia may suggest a granulomatous response to capillaritis mediated by lipid deposition in the microvasculature.^6,7

We present 3 cases of GPPD and provide a review of the literature. In all of our patients, biopsy specimens were fixed in 10% buffered formalin and embedded in paraffin by standard methodologies, and all stains were performed on sections by standard methodologies. Based on a PubMed search of articles indexed for MEDLINE using the terms granulomatous pigmented purpuric dermatosis, sarcoidosis, pigmented purpuric dermatosis, granulomas, and pigmented purpuric dermatosis, we review 5 additional reports describing 10 total patients.^3-7

Case Reports

Patient 1

A 9-year-old white boy presented with a 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (Figure, A). The lesion appeared 3 to 4 years prior to presentation but had become progressively darker and centrally indurated over the last 2 years. The patient and his mother denied any history of trauma to the area. His medical history was unremarkable, and his current medications included fish oil and multivitamin tablets.

Histologic examination of a punch biopsy specimen taken from the center of the lesion revealed a lichenoid lymphohistiocytic infiltrate with marked red blood cell (RBC) extravasation and associated hemosiderin-laden macrophages. The lymphocytes comprising this infiltrate lacked cytologic atypia and exhibited minimal epidermotropism (Figure, B). Additionally, there was a superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised ofepithelioid histiocytes in the mid and deep dermis (Figure, C). Periodic acid–Schiff, acid-fast bacilli (AFB), and Fite stains were negative for organisms. Polarization was negative for refractile foreign material. Due to the patient’s age, no treatment was performed, and the lesion remains unchanged 1 year after biopsy.

Patient 2

A 49-year-old white woman presented with a 2-cm yellow-brown patch with a faint, nonblanchable, violaceous center on the right lateral thigh of 4 months’ duration. The patch initially appeared as a small asymptomatic purple papule. The patient denied any history of trauma to the area. A purified protein derivative (tuberculin) skin test was negative at the time of examination. The patient’s medical history was remarkable for renal calculi. Her current medications included progesterone; estradiol; lansoprazole; prenatal vitamins; vitamins C and E; zinc; and calcium. The patient had no family history of sarcoidosis. Complete blood cell count, urinalysis, liver function tests, and angiotensin-converting enzyme levels were unremarkable. Pulmonary function tests were normal, and there was no evidence of sarcoidosis on chest radiography. Initial biopsy of the lesion revealed a perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated RBCs in the papillary dermis (Figure, D). Similar to patient 1, the infiltrate lacked cytologic atypia and did not involve the overlying epidermis. There was perivascular granulomatous inflammation in the mid dermis (Figure, E). Periodic acid–Schiff, Warthin-Starry, and AFB stains were negative for organisms. Polarization was negative for refractile foreign material.

The lesion was treated with clobetasol propionate ointment 0.05% twice daily for 6 weeks with transient improvement, but the lesion recurred upon treatment cessation. Subsequent treatment with intralesional triamcinolone resulted in slight improvement of the lesion. A therapeutic trial of targeted pulsed dye laser treatment was ineffective. The lesion gradually increased in size over the next year with no therapy, and a repeat biopsy revealed a lichenoid lymphohistiocytic infiltrate with abundant extravasated RBCs consistent with persistent PPD. A granulomatous infiltrate was not evident in the superficial shave biopsy specimen.

Patient 3

A 75-year-old white woman presented with scattered, speckled, cayenne pepper–like, red-brown macules on the legs. Two years prior to presentation, a few scattered symmetrical macules appeared on the dorsal aspects of the feet, which gradually increased in number to form larger confluent patches that spread to the lower legs. The patient denied itching or burning but reported that the patches became painful when scratched and were aggravated by sun exposure. Her medical history was remarkable for asthma, chronic renal insufficiency, coronary artery disease, Barrett esophagus, obstructive sleep apnea, hypothyroidism, renal calculi, type 2 diabetes mellitus, and hyperlipidemia. Her current medications included carvedilol, valsartan, levothyroxine, aspirin, clopidogrel, furosemide, nitrofurantoin, temazepam, insulin, ezetimibe-simvastatin, and lansoprazole. Computed tomography of the chest revealed no signs of sarcoidosis. Pulmonary function tests revealed moderate obstructive lung disease. An ophthalmology examination showed no evidence of sarcoidosis. Laboratory results revealed an elevated glucose, blood urea nitrogen, creatinine, and triglyceride levels, as well as low hematocrit and vitamin D levels. Urinalysis, thyroid-stimulating hormone (thyrotropin) test, liver function tests, angiotensin-converting enzyme test, hepatitis B surface antigen, and IFN-g release assay were normal.

Histologic examination of a punch biopsy specimen revealed an inflammatory infiltrate confined to the papillary dermis. This infiltrate was comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated RBC extravasation and intimately associated granulomas (Figure, F). Additional inflammation in the deeper aspects of the dermis was not identified. Periodic acid–Schiff, AFB, and Fite stains were negative for organisms. Polarization was negative for refractile foreign material.

A 3-cm asymptomatic light brown patch with a nonblanching violaceous center on the right posterior thigh that was studded with pinpoint yellow papules (A). Lichenoid lymphohistiocytic infiltrate in the papillary dermis with marked red blood cell extravasation (B)(H&E, original magnification ×20). Superficial and deep perivascular mononuclear inflammatory infiltrate intermixed with numerous small granulomas comprised of epithelioid histiocytes in the mid and deep dermis (C)(H&E, original magnification ×20). Perivascular and interstitial lymphohistiocytic infiltrate with abundant extravasated red blood cells in the papillary dermis (D)(H&E, original magnification ×10). Perivascular lymphohistiocytic inflammation with epithelioid granulomas in the mid dermis (E)(H&E, original magnification ×20). Lymphohistiocytic inflammation in the papillary dermis comprised of an admixture of lymphocytes and histiocytes in a perivascular distribution with associated red blood cell extravasation and intimately associated granulomas (F)(H&E, original magnification ×20).

The patient was treated with topical steroids and minocycline 50 mg twice daily without improvement. The lesions improved after the patient underwent treatment with oral corticosteroids for pulmonary disease.

Comment

Pigmented purpuric dermatoses comprise a spectrum of clinical and pathologic conditions.^1,2 Granulomatous PPD is a much less common variant, characterized by a granulomatous infiltrate admixed with PPD. We report 3 additional cases and review the literature on this rare and interesting variant of PPD.

We noted several unifying clinicopathologic features among our patients and those previously reported in the literature (Table).^3-7 Including our cases, our review yielded 13 GPPD patients ranging in age from 9 to 75 years, with a mean age of 49.1 years. Two of our patients—patients 1 and 3—were the youngest and oldest patients, respectively, among the cases we reviewed. The majority of the cases we reviewed included patients of East Asian descent (6 Taiwanese; 2 Japanese; 1 Korean) as well as 4 white patients. No distinctive gender predilection was apparent, as our review included 8 females and 5 males.

Our review revealed that GPPD lesions typically involve the lower extremities and usually are asymptomatic, with the exception of occasional pruritus. Additional lesions have been reported on the dorsal aspect of the hands, and 1 case noted exclusive involvement of the wrist.⁶ Lesions of GPPD can range in their clinical appearance. Three of 13 patients presented with purpuric papules and 2 had brown pigmentation with hemorrhagic papules^3,4,6; the remaining 8 patients had erythematous or brown macules, papules, or plaques.^5-7 The most commonly associated disease condition was hyperlipidemia, which was reported in 7 of 13 cases.^5-7 Additional reported comorbidities included meningioma, renal calculi, obesity, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, hepatitis C virus, ulcerative colitis, thrombocytopenia, and hyperuricemia. Reported serologic abnormalities included a rare positive antinuclear antibody, rheumatoid factor, and cryoglobulins.^3,6 Therapeutic efficacy in the management of GPPD has not been well described; however, for the rare cases in which therapies were described, they were largely unsuccessful, with 1 patient exhibiting spontaneous improvement.^3,4

Granulomatous PPD also appears to exhibit a range of histologic findings. All cases of GPPD shared fundamental components, such as a brisk perivascular infiltrate accompanied by RBC extravasation with variable hemosiderin-laden macrophages and a granulomatous infiltrate. All of the reports we reviewed described an intimate association between these components, with the granulomas being essentially superimposed on typical PPD. As for other types of PPD, obvious vasculitis characterized by a vasculocentric inflammatory infiltrate and evidence of vascular injury, such as fibrinoid necrosis of the vessel wall, has not been described in GPPD.^3-7 Finally, histologic changes suggestive of a relationship with cutaneous T-cell lymphoma, cytologic atypia, and epidermotropism have been described for some forms of PPD but have not been described for GPPD.^3-8

Our case reports expand the histologic spectrum of GPPD. Although patient 3 exhibited a relatively intimate association of granulomas and PPD, 2 of our cases (patients 1 and 2) demonstrated a granulomatous infiltrate in the mid to deep dermis, which is separate from the more superficially situated lichenoid lymphohistiocytic infiltrate, RBC extravasation, and hemosiderin-laden macrophages noted in the papillary dermis. Considered along with the absence of an obvious clinicopathologic explanation for the granulomatous infiltrates (eg, polarizable material, infectious organisms, systemic disease), these 2 cases (patients 1 and 2) suggest a composite form of PPD that combines the lichenoid pattern of PPD of Gougerot and Blum with a deep granulomatous component of GPPD. The importance of this distinction lies in the potential for physicians to overlook this potentially informative histologic pattern if only a superficial biopsy is performed. The clinical relevance is unclear; however, in our experience, it has been challenging to treat this relatively small subset of patients who have exhibited a limited response to treatment with topical steroids, intralesional steroids, pulsed dye laser, and vitamin supplementation.

The cause of the granulomatous infiltrate in GPPD is poorly understood. Seven of 13 cases included in our review occurred in patients with a history of hyperlipidemia.^5-7 Some have postulated that the constellation of findings of GPPD in hyperlipidemic patients reflects an underlying vascular injury process induced by lipid deposition in the endothelial cells with subsequent RBC extravasation and a secondary granulomatous response to the lipid deposits.^6,7 However, given the occurrence of GPPD in patients without hyperlipidemia, other mechanisms also must be considered in the pathogenesis of GPPD, including a reaction to medications, systemic diseases, and infectious etiologies (eg, hepatitis B virus).^4,6 As additional cases are described in the literature, other unifying clinical etiologies for this histopathologic reaction pattern may emerge.

Conclusion

Granulomatous PPD may comprise an underrecognized variant of PPD in cases when only a superficial biopsy is evaluated. Clinicians and pathologists should be aware of this variant, and in refractory cases of PPD, deeper sampling may be warranted to identify granulomas.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Case Report

A 14-year-old adolescent boy presented to the dermatology clinic at our institution for evaluation of a hyperpigmented hairy patch on the right side of the face that had been present since birth. The patient reported the lesion originally had involved the right cheek, neck, and back but had gradually expanded to include the right side of the upper lip and oral mucosa. His medical history was remarkable for acne, which was currently being managed with topical treatments. There was no family history of similar conditions. There were no mental or developmental deformities since birth.

Physical examination revealed a hyperpigmented patch with hypertrichosis on the right side of the body involving the back, neck, and cheek (Figure 1), as well as hyperpigmentation involving the right side of the upper lip and oral mucosa (Figure 2A). Slight facial asymmetry also was noted. Dental examination revealed irregular spacing and decreased growth of the teeth on the right side of the mouth (Figure 2B).

Figure 1. Hyperpigmented hairy patch on the right cheek (Becker nevus) in a patient with hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome).

Figure 2. Some hyperpigmentation involving the oral mucosa on the right side (A) and dental abnormalities (B).

A biopsy of the hyperpigmented patch on the back revealed mild regular acanthosis, basal hypermelanosis, slight papillomatosis, and hair structures within the dermis with features that were consistent with a Becker nevus. A dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars)(Figure 3). Computed axial tomography revealed enlargement of the maxillary bone on the right side.

Figure 3. Dental radiograph demonstrated hyperplasia of the right maxillary alveolus and basal bone area with 2 missing permanent teeth (fourth and fifth premolars).

The constellation of clinical, histopathologic, and radiologic findings was consistent with a diagnosis of hemimaxillary enlargement, asymmetry of the face, tooth abnormalities, and skin findings (HATS syndrome). The treatment plan involved surgical modification of the maxillary bone to correct the hyperplasia on the affected side and implanting 2 artificial premolars. Additionally, laser therapy using a Q-switched ruby laser, frequency-doubled Nd:YAG, 1550-nm erbium-doped fiber laser, or 755-nm alexandrite laser was considered to treat the hyperpigmentation associ-ated with the Becker nevus.

Comment

HATS syndrome is a rare, local developmental defect involving the first and second branchial arches. It generally is detected at birth or in early childhood and is associated with unilateral abnormalities of the bones, teeth, gums, and skin. It is more common in boys than girls (1.8:1.0 ratio), with an age range of 2 to 28 years; there is a peak in the first decade of life.¹ It was first described by Miles et al² in 1987 in a case of congenital mild facial asymmetry, unilateral enlargement of the maxillary gingiva and alveolar bone, hypoplastic teeth, and hypertrichosis in the affected area. The investigators at that time suggested the term hemimaxillofacial dysplasia (HD). In 1990, Danforth et al³ reported 8 additional cases with similar features but without known skin changes; they proposed the term segmental odontomaxillary dysplasia (SOD). In 1996, Desalvo et al⁴ reported a case of SOD involving a 7-year-old girl with an area of hypopigmentation of the lip on the affected side, and Packota et al⁵ described the radiographic features of 12 cases of SOD. In subsequent years, other cases of HD or SOD were reported in the literature.^1,6-16 In 2004, Welsch and Stein¹⁷ reported 1 patient with a Becker nevus of the skin and recommended the acronym HATS. Armstrong et al¹⁸ reported 2 cases of SOD with new histopathologic findings of the teeth (eg, fibrous enlargement of the pulps, an irregular pulp-dentin interface displaying many pseudoinclusions, pulp stones). In 2008, Porwal et al¹⁹ reported a case of HD in which maxillary hypoplasia rather than hyperplasia was noted, which emphasized the variability of the maxillary dysplasia. Koenig et al²⁰ reported a case of SOD with facial hypertrichosis, commissural lip clefting, and hyperlinear palms. Bhatia et al²¹ reported another case of SOD with a new finding of unilateral ectopic eyelashes.

The etiology remains unknown, but theories include an alteration that occurs in utero or in in-fancy; the possibility of a systemic or endocrine aberration; a postzygotic mutation resulting in genotypic and phenotypic mosaicism of bone and skin, similar to McCune-Albright syndrome; and viral or bacterial infection along the branches of the maxillary division of the trigeminal nerve.^1,15 Bone defects include unilateral enlargement of the maxillary alveolar process and thickening of the vertically oriented trabeculae, which is detected radiographically. A reduction in size of the maxillary sinus and nasal airway was reported in about one-half of cases¹ and can be detected easily by computed tomography scanning. Missing permanent premolar teeth, tooth shape abnormalities, delayed eruption of teeth, abnormal spacing of teeth, hypoplastic teeth, enlarged teeth, and gingival thickening also are common oral findings.¹ The skin manifestations of HATS syndrome are not static but progress well into adolescence¹⁵ and can include facial asymmetry, hypertrichosis, Becker nevus, hairy nevus, lip hypopigmentation, discontinuity of the vermilion border, depression of the cheek, and facial erythema.¹⁷

The differential diagnosis includes hemifacial hyperplasia, monostotic fibrous dysplasia, and regional odontodysplasia.¹ Little information is available concerning the treatment of patients with this condition.¹⁵ The reported treatment modalities include combined surgical and orthodontic treatment of unerupted teeth (premolar/canine), prosthodontic treatment, gingivoplasty, recontouring osteotomy for severe facial asymmetry, and reconstructive jaw surgery.^1,6,11,15 Successful treatment of Becker nevi with the Q-switched ruby laser, erbium:YAG laser, and 755-nm alexandrite laser have been reported.^22-24

Conclusion

There is a need for continued reporting of cases of HATS syndrome in addition to long-term follow-up to document the natural history of the condition and to establish the appropriate treatment.

Stretch marks (striae cutis distensae) are a common disfiguring skin condition characterized by linear bands of atrophic-appearing skin.¹ The prevalence of stretch marks associated with pregnancy ranges from 50% to 90%.² Although stretch marks do not pose a health risk, they often cause burning, itching, and emotional distress, and they can have a deep psychological impact on patients, particularly in young healthy women who are commonly affected by this condition.³

The cause of stretch marks currently is unknown, but they are known to develop in a variety of physiological and pathological states (eg, pregnancy, adolescent growth spurts, obesity, large weight gain, Cushing syndrome, Marfan syndrome, diabetes mellitus, long-term systemic or topical steroid use).^2-5 Clinically, newly formed stretch marks present as pink or purple linear lesions without substantial depression of the skin (striae rubra). Over time, the lesions lose their pigmentation, becoming depressed, atrophic, and white (striae alba).^2,3,6 The most commonly affected sites are the breasts, upper arms, abdomen, buttocks, and thighs.^3,4

Regardless of the etiology, the same histologic changes can be noted in the epidermis of all stretch marks, such as atrophy and loss of rete ridges, with features that are similar to scarring.³ Additionally, reorganization and diminution of the elastic fiber network of skin can be observed.⁷

A variety of treatment strategies are available for stretch marks, including topical preparations (eg, tretinoin, glycolic acid) and lasers.⁴ With current methods, no consistently effective therapies have been established yet. In this article, we present the results of a systematic review of the literature to address the effectiveness and safety of the available treatment options for stretch marks.

Methods

A literature search for randomized controlled trials (RCTs) related to the treatment of stretch marks was conducted on March 13, 2013, using the Cochrane Central Register of Controlled Trials, PubMed (from 1966), Embase (from 1974), Chinese Biomedical Literature Database (from 1978), China National Knowledge Infrastructure (from 1994), Chinese Science Journals Database (from 1989), and Wanfang Data (from 1995). Search terms included stretch marks, stretch mark, striae atrophicae, striae distensae, striae gravidarum, striae rubra, striae alba, lineae albicantes, striae, kikkisa, and random*.

We attempted to contact the original investigators of the 25 articles assessed for eligibility by e-mail to identify the randomization and answer other methodology questions to ensure that the studies included in the analysis were RCTs. Each of the 8 RCTs selected for inclusion was assessed independently by 2 investigators (L.L. and H.M.), and data extraction also was performed independently. Any differences in opinion were resolved by discussion. The risk of biases were assessed and 5 domains—random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data—were judged for each study included in the analysis using the Cochrane Collaboration’s domain-based evaluation tool as described in the Cochrane Handbook for Systematic Reviews of Interventions.⁸ Publication bias was not assessed due to insufficient data.

Studies ultimately were classified into 3 categories based on the risk of bias: (1) low risk of bias or low risk of bias for all key domains; (2) unclear risk of bias or unclear risk of bias for 1 or more key domains; and (3) high risk of bias or high risk of 1 or more key domains.

Results

Search Results

Figure 1 presents the literature search results. Of 300 total search results, 8 RCTs were selected for assessment,^9-16 which included a total of 240 patients (Table). The investigators of all 8 reports were contacted, but only 2 responses were received.^11,14 The full text of one article could not be obtained; therefore, we could not confirm that it was a true RCT and excluded it.¹⁷

Figure 1. Search results.

Risk of Bias

The risk of bias in methodology was evaluated for all 8 RCTs and the judgments were given for each domain (Figure 2). All the included studies claimed to be RCTs, but only 37.5% (3/8) of them used adequate randomizations, which were from a including computer-generated code,¹⁰ a table of randomized numbers,¹³ or the Microsoft Excel RND function (from the author by e-mail).¹⁴ The randomization methods in the other 5 studies were unclear. Allocation concealment was adequate in 1 trial¹³ but was unclear in the others. Three trials were double-blinded with the participants and outcome assessors blinded^10,13,16; in 2 of these studies investigators also were blinded.^10,13 There were 5 single-blinded trials; in 3 of these trials the outcome assessors were blinded^12,14,15 and 1 was investigator-blinded.⁹ The other study was stated to be single-blinded but with no further detail.¹¹ Due to the nature of the experimental design in 2 of the trials^12,15 (ie, effects of laser therapy compared to topical treatment or no therapy), participants could not be blinded to treatment types; however, participants were blinded in 1 trial that compared different types of lasers.¹⁶ Investigators from all studies reported participants who did not complete the trial or were lost to follow-up, ranging from 0% to 65.6%. Two trials reported no loss of follow-up.^11,12 Most trials had losses less than 20% except Pribanich et al¹³ who reported a loss of 65.6% of participants. One trial included a full analysis set,⁹ and none of the studies included an intention-to-treat analysis.

Figure 2. Risk of bias summary based on judgments about each risk of bias domain for each study. + indicates low risk of bias; ?, unclear risk of bias; -, high risk of bias.

The overall risk of bias was assessed for each study and none could be categorized as low risk. Six studies had 1 or more domains assessed as high risk of bias and were classified as high risk of bias.^9,11-15 The remaining 2 studies without high-risk domains had one or more domains assessed as unclear^10,16 and were therefore considered to be at unclear risk of bias overall.

Effects of Treatments

Among the 8 studies we assessed, there were different treatments, methods of comparison, product concentrations, and times of application. The methods for assessing outcomes (eg, the size and severity of stretch marks) also were varied. Therefore, it is difficult to perform a meta-analysis of the data, and all the evidence was from individual studies. A summary of the results is presented in the Table.

All of the studies we evaluated assessed clinical improvement. Three studies reported the effects of topical tretinoin on stretch marks.^10,12,13 A small parallel study with unclear risk of bias indicated that white participants with erythematous stretch marks seemed to have a better response to treatment with tretinoin cream 0.1% for 24 weeks versus placebo.¹⁰ However, there was no significant difference between tretinoin cream 0.025% and placebo for patients with abdominal striae in another trial.¹³ The latter trial was performed with low risk of bias in methodology, but the dropout rate was high (65.6%), with only 11 of 32 participants completing the trial. It is likely that the small number of patients makes the power too low to detect significant differences between tretinoin cream 0.025% and placebo if such a difference indeed existed.¹³ Because the outcomes in these 2 trials were assessed in different ways, it is difficult to perform a meta-analysis on the data. More adverse effects, mainly erythema and scaling associated with itching or burning sensations, were reported with the higher concentration (0.05%) of tretinoin.¹⁰ Another study at a high risk of bias found that the combined use of tretinoin cream 0.05% and glycolic acid 10% was not as effective as fractional CO₂ laser therapy in improving the appearance of striae alba.¹² There also were 3 studies comparing the effects of laser therapy with another treatment or no treatment.^12,15,16 Two within-participant comparison studies with unclear or high risk of bias compared CO₂ fractional laser therapy with other active treatment methods in female participants with striae alba.^12,16 No difference between the fractional CO₂ laser and the 1550-nm nonablative fractional erbium:glass laser was reported,¹⁶ but the fractional CO₂ laser may be more effective than the topical therapy.¹² A small study (11 participants) at high risk of bias reported negative results for the 1450-nm mid-infrared diode laser compared to no treatment.¹⁵ Data on the adverse effects of laser therapy were available from these studies. Postinflammatory hyperpigmentation was found in all the 3 studies^12,15,16 and posttreatment erythema was mentioned in 2 studies.^15,16 Based on the individual studies, treatment with a cosmetic oil formulation was more effective than a moisturizer in improving clinical presentation of stretch marks in white patients.¹⁴ Women with striae rubra showed better response to treatment with onion extract cream versus no treatment.⁹ Limited data from 1 study showed that combined use of Active B (sodium ascorbyl phosphate, 3-aminopropyl-L-ascorbyl phosphate, carboxybetaglucan, hyaluronic acid) and Active A (hyaluronic acid, sodium salt 2 mg, sodium carboxymethyl betaglucan 0.1 mg, ascorbic acid 0.5 mg, arginine 1 mg, sodium chloride 9 mg, sterile water) might be more effective than the use of Active B or placebo.¹¹ These 3 studies are at high risk of bias and no obvious adverse effects were reported.^9,11,14

 
Comment

In the 8 trials included in our assessment, 5 used a within-participant design in which 2 different treatments were randomly administered to the left and right sides of the body, respectively.^9,12,14-16 Because the comparison of treatments was made based on results in the same patient versus 2 different treatment groups, the results may be more accurate. In the studies we reviewed, only 3 were placebo-controlled, which may only provide limited evidence on the comparative efficacy of the treatments used in these studies.^10,11,13 Most treatments were evaluated in single studies, and most studies had a small number of participants (range, 6–66 participants). A considerable number of the total participants withdrew from their respective studies or were lost during follow-up. In some cases, no reason was given,¹³ but in the others, it was because of an obvious side effect¹⁶ or noncompliance.¹⁴ Overall, the methodology quality was low, especially the methods of randomization and allocation concealment. Unsuccessful attempts to contact the original investigators made it difficult to make accurate assessments of the risk of bias in most of the studies included in our assessment. No study met all the risk of bias criteria, and none were classified as having a low risk of bias.

The impact of industry sponsorship on the direction and completeness of the results of the studies we reviewed is unclear. One study was funded by a grant from the manufacturer of the study product,¹⁴ and the medication used in another study was supplied by the manufacturer.¹³ Another study was supported in part by a company that had no part in the conduct, analysis, or reporting of the study.¹⁰ In one instance, the authors were employees of the manufacturer of the study product.⁹ The remaining studies made no declaration.^11,12,15,16

Thus the evidence from this review was insufficient to provide clear guidelines for practice. Because the results were based on a small number of patients and were of high or unclear risk of bias, caution must be taken when comparing the efficacy of the treatments administered in these studies; however, given the negligible reported side effects, tretinoin cream 0.1%, a cosmetic oil formulation, onion extract cream, or the combined use of Active A and Active B could reasonably be considered for the treatment of stretch marks. Laser therapies such as the fractional CO₂ laser or the 1550-nm fractional erbium:glass laser may be another effective choice.

 
Conclusion

In future investigations of stretch mark treatments, more high-quality, placebo-controlled trials are needed. One important issue is the varied outcome assessment among different studies, which makes the evaluation and pooling of different studies difficult. Therefore, future RCTs should measure clinical features with a uniform score system such as the visual analog scale or the patient and observer scar assessment scale and try to avoid individual made-up system to assess the outcome. Furthermore, quality-of-life assessment was not included in any of the reports we evaluated; rather all 8 studies focused on changes in the appearance of stretch marks only. Given the deep psychological impact that stretch marks can have on patients, measures for quality-of-life assessment, such as the dermatology life quality index, should be incorporated into future study designs to improve the relevance of the trial and allow comparisons among studies using different interventions.

Stretch marks (striae cutis distensae) are a common disfiguring skin condition characterized by linear bands of atrophic-appearing skin.¹ The prevalence of stretch marks associated with pregnancy ranges from 50% to 90%.² Although stretch marks do not pose a health risk, they often cause burning, itching, and emotional distress, and they can have a deep psychological impact on patients, particularly in young healthy women who are commonly affected by this condition.³

The cause of stretch marks currently is unknown, but they are known to develop in a variety of physiological and pathological states (eg, pregnancy, adolescent growth spurts, obesity, large weight gain, Cushing syndrome, Marfan syndrome, diabetes mellitus, long-term systemic or topical steroid use).^2-5 Clinically, newly formed stretch marks present as pink or purple linear lesions without substantial depression of the skin (striae rubra). Over time, the lesions lose their pigmentation, becoming depressed, atrophic, and white (striae alba).^2,3,6 The most commonly affected sites are the breasts, upper arms, abdomen, buttocks, and thighs.^3,4

Regardless of the etiology, the same histologic changes can be noted in the epidermis of all stretch marks, such as atrophy and loss of rete ridges, with features that are similar to scarring.³ Additionally, reorganization and diminution of the elastic fiber network of skin can be observed.⁷

A variety of treatment strategies are available for stretch marks, including topical preparations (eg, tretinoin, glycolic acid) and lasers.⁴ With current methods, no consistently effective therapies have been established yet. In this article, we present the results of a systematic review of the literature to address the effectiveness and safety of the available treatment options for stretch marks.

Methods

A literature search for randomized controlled trials (RCTs) related to the treatment of stretch marks was conducted on March 13, 2013, using the Cochrane Central Register of Controlled Trials, PubMed (from 1966), Embase (from 1974), Chinese Biomedical Literature Database (from 1978), China National Knowledge Infrastructure (from 1994), Chinese Science Journals Database (from 1989), and Wanfang Data (from 1995). Search terms included stretch marks, stretch mark, striae atrophicae, striae distensae, striae gravidarum, striae rubra, striae alba, lineae albicantes, striae, kikkisa, and random*.

We attempted to contact the original investigators of the 25 articles assessed for eligibility by e-mail to identify the randomization and answer other methodology questions to ensure that the studies included in the analysis were RCTs. Each of the 8 RCTs selected for inclusion was assessed independently by 2 investigators (L.L. and H.M.), and data extraction also was performed independently. Any differences in opinion were resolved by discussion. The risk of biases were assessed and 5 domains—random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data—were judged for each study included in the analysis using the Cochrane Collaboration’s domain-based evaluation tool as described in the Cochrane Handbook for Systematic Reviews of Interventions.⁸ Publication bias was not assessed due to insufficient data.

Studies ultimately were classified into 3 categories based on the risk of bias: (1) low risk of bias or low risk of bias for all key domains; (2) unclear risk of bias or unclear risk of bias for 1 or more key domains; and (3) high risk of bias or high risk of 1 or more key domains.

Results

Search Results

Figure 1 presents the literature search results. Of 300 total search results, 8 RCTs were selected for assessment,^9-16 which included a total of 240 patients (Table). The investigators of all 8 reports were contacted, but only 2 responses were received.^11,14 The full text of one article could not be obtained; therefore, we could not confirm that it was a true RCT and excluded it.¹⁷

Figure 1. Search results.

Risk of Bias

The risk of bias in methodology was evaluated for all 8 RCTs and the judgments were given for each domain (Figure 2). All the included studies claimed to be RCTs, but only 37.5% (3/8) of them used adequate randomizations, which were from a including computer-generated code,¹⁰ a table of randomized numbers,¹³ or the Microsoft Excel RND function (from the author by e-mail).¹⁴ The randomization methods in the other 5 studies were unclear. Allocation concealment was adequate in 1 trial¹³ but was unclear in the others. Three trials were double-blinded with the participants and outcome assessors blinded^10,13,16; in 2 of these studies investigators also were blinded.^10,13 There were 5 single-blinded trials; in 3 of these trials the outcome assessors were blinded^12,14,15 and 1 was investigator-blinded.⁹ The other study was stated to be single-blinded but with no further detail.¹¹ Due to the nature of the experimental design in 2 of the trials^12,15 (ie, effects of laser therapy compared to topical treatment or no therapy), participants could not be blinded to treatment types; however, participants were blinded in 1 trial that compared different types of lasers.¹⁶ Investigators from all studies reported participants who did not complete the trial or were lost to follow-up, ranging from 0% to 65.6%. Two trials reported no loss of follow-up.^11,12 Most trials had losses less than 20% except Pribanich et al¹³ who reported a loss of 65.6% of participants. One trial included a full analysis set,⁹ and none of the studies included an intention-to-treat analysis.

Figure 2. Risk of bias summary based on judgments about each risk of bias domain for each study. + indicates low risk of bias; ?, unclear risk of bias; -, high risk of bias.

The overall risk of bias was assessed for each study and none could be categorized as low risk. Six studies had 1 or more domains assessed as high risk of bias and were classified as high risk of bias.^9,11-15 The remaining 2 studies without high-risk domains had one or more domains assessed as unclear^10,16 and were therefore considered to be at unclear risk of bias overall.

Effects of Treatments

Among the 8 studies we assessed, there were different treatments, methods of comparison, product concentrations, and times of application. The methods for assessing outcomes (eg, the size and severity of stretch marks) also were varied. Therefore, it is difficult to perform a meta-analysis of the data, and all the evidence was from individual studies. A summary of the results is presented in the Table.

All of the studies we evaluated assessed clinical improvement. Three studies reported the effects of topical tretinoin on stretch marks.^10,12,13 A small parallel study with unclear risk of bias indicated that white participants with erythematous stretch marks seemed to have a better response to treatment with tretinoin cream 0.1% for 24 weeks versus placebo.¹⁰ However, there was no significant difference between tretinoin cream 0.025% and placebo for patients with abdominal striae in another trial.¹³ The latter trial was performed with low risk of bias in methodology, but the dropout rate was high (65.6%), with only 11 of 32 participants completing the trial. It is likely that the small number of patients makes the power too low to detect significant differences between tretinoin cream 0.025% and placebo if such a difference indeed existed.¹³ Because the outcomes in these 2 trials were assessed in different ways, it is difficult to perform a meta-analysis on the data. More adverse effects, mainly erythema and scaling associated with itching or burning sensations, were reported with the higher concentration (0.05%) of tretinoin.¹⁰ Another study at a high risk of bias found that the combined use of tretinoin cream 0.05% and glycolic acid 10% was not as effective as fractional CO₂ laser therapy in improving the appearance of striae alba.¹² There also were 3 studies comparing the effects of laser therapy with another treatment or no treatment.^12,15,16 Two within-participant comparison studies with unclear or high risk of bias compared CO₂ fractional laser therapy with other active treatment methods in female participants with striae alba.^12,16 No difference between the fractional CO₂ laser and the 1550-nm nonablative fractional erbium:glass laser was reported,¹⁶ but the fractional CO₂ laser may be more effective than the topical therapy.¹² A small study (11 participants) at high risk of bias reported negative results for the 1450-nm mid-infrared diode laser compared to no treatment.¹⁵ Data on the adverse effects of laser therapy were available from these studies. Postinflammatory hyperpigmentation was found in all the 3 studies^12,15,16 and posttreatment erythema was mentioned in 2 studies.^15,16 Based on the individual studies, treatment with a cosmetic oil formulation was more effective than a moisturizer in improving clinical presentation of stretch marks in white patients.¹⁴ Women with striae rubra showed better response to treatment with onion extract cream versus no treatment.⁹ Limited data from 1 study showed that combined use of Active B (sodium ascorbyl phosphate, 3-aminopropyl-L-ascorbyl phosphate, carboxybetaglucan, hyaluronic acid) and Active A (hyaluronic acid, sodium salt 2 mg, sodium carboxymethyl betaglucan 0.1 mg, ascorbic acid 0.5 mg, arginine 1 mg, sodium chloride 9 mg, sterile water) might be more effective than the use of Active B or placebo.¹¹ These 3 studies are at high risk of bias and no obvious adverse effects were reported.^9,11,14

 
Comment

In the 8 trials included in our assessment, 5 used a within-participant design in which 2 different treatments were randomly administered to the left and right sides of the body, respectively.^9,12,14-16 Because the comparison of treatments was made based on results in the same patient versus 2 different treatment groups, the results may be more accurate. In the studies we reviewed, only 3 were placebo-controlled, which may only provide limited evidence on the comparative efficacy of the treatments used in these studies.^10,11,13 Most treatments were evaluated in single studies, and most studies had a small number of participants (range, 6–66 participants). A considerable number of the total participants withdrew from their respective studies or were lost during follow-up. In some cases, no reason was given,¹³ but in the others, it was because of an obvious side effect¹⁶ or noncompliance.¹⁴ Overall, the methodology quality was low, especially the methods of randomization and allocation concealment. Unsuccessful attempts to contact the original investigators made it difficult to make accurate assessments of the risk of bias in most of the studies included in our assessment. No study met all the risk of bias criteria, and none were classified as having a low risk of bias.

The impact of industry sponsorship on the direction and completeness of the results of the studies we reviewed is unclear. One study was funded by a grant from the manufacturer of the study product,¹⁴ and the medication used in another study was supplied by the manufacturer.¹³ Another study was supported in part by a company that had no part in the conduct, analysis, or reporting of the study.¹⁰ In one instance, the authors were employees of the manufacturer of the study product.⁹ The remaining studies made no declaration.^11,12,15,16

Thus the evidence from this review was insufficient to provide clear guidelines for practice. Because the results were based on a small number of patients and were of high or unclear risk of bias, caution must be taken when comparing the efficacy of the treatments administered in these studies; however, given the negligible reported side effects, tretinoin cream 0.1%, a cosmetic oil formulation, onion extract cream, or the combined use of Active A and Active B could reasonably be considered for the treatment of stretch marks. Laser therapies such as the fractional CO₂ laser or the 1550-nm fractional erbium:glass laser may be another effective choice.

 
Conclusion

In future investigations of stretch mark treatments, more high-quality, placebo-controlled trials are needed. One important issue is the varied outcome assessment among different studies, which makes the evaluation and pooling of different studies difficult. Therefore, future RCTs should measure clinical features with a uniform score system such as the visual analog scale or the patient and observer scar assessment scale and try to avoid individual made-up system to assess the outcome. Furthermore, quality-of-life assessment was not included in any of the reports we evaluated; rather all 8 studies focused on changes in the appearance of stretch marks only. Given the deep psychological impact that stretch marks can have on patients, measures for quality-of-life assessment, such as the dermatology life quality index, should be incorporated into future study designs to improve the relevance of the trial and allow comparisons among studies using different interventions.

Stretch marks (striae cutis distensae) are a common disfiguring skin condition characterized by linear bands of atrophic-appearing skin.¹ The prevalence of stretch marks associated with pregnancy ranges from 50% to 90%.² Although stretch marks do not pose a health risk, they often cause burning, itching, and emotional distress, and they can have a deep psychological impact on patients, particularly in young healthy women who are commonly affected by this condition.³

The cause of stretch marks currently is unknown, but they are known to develop in a variety of physiological and pathological states (eg, pregnancy, adolescent growth spurts, obesity, large weight gain, Cushing syndrome, Marfan syndrome, diabetes mellitus, long-term systemic or topical steroid use).^2-5 Clinically, newly formed stretch marks present as pink or purple linear lesions without substantial depression of the skin (striae rubra). Over time, the lesions lose their pigmentation, becoming depressed, atrophic, and white (striae alba).^2,3,6 The most commonly affected sites are the breasts, upper arms, abdomen, buttocks, and thighs.^3,4

Regardless of the etiology, the same histologic changes can be noted in the epidermis of all stretch marks, such as atrophy and loss of rete ridges, with features that are similar to scarring.³ Additionally, reorganization and diminution of the elastic fiber network of skin can be observed.⁷

A variety of treatment strategies are available for stretch marks, including topical preparations (eg, tretinoin, glycolic acid) and lasers.⁴ With current methods, no consistently effective therapies have been established yet. In this article, we present the results of a systematic review of the literature to address the effectiveness and safety of the available treatment options for stretch marks.

Methods

A literature search for randomized controlled trials (RCTs) related to the treatment of stretch marks was conducted on March 13, 2013, using the Cochrane Central Register of Controlled Trials, PubMed (from 1966), Embase (from 1974), Chinese Biomedical Literature Database (from 1978), China National Knowledge Infrastructure (from 1994), Chinese Science Journals Database (from 1989), and Wanfang Data (from 1995). Search terms included stretch marks, stretch mark, striae atrophicae, striae distensae, striae gravidarum, striae rubra, striae alba, lineae albicantes, striae, kikkisa, and random*.

We attempted to contact the original investigators of the 25 articles assessed for eligibility by e-mail to identify the randomization and answer other methodology questions to ensure that the studies included in the analysis were RCTs. Each of the 8 RCTs selected for inclusion was assessed independently by 2 investigators (L.L. and H.M.), and data extraction also was performed independently. Any differences in opinion were resolved by discussion. The risk of biases were assessed and 5 domains—random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data—were judged for each study included in the analysis using the Cochrane Collaboration’s domain-based evaluation tool as described in the Cochrane Handbook for Systematic Reviews of Interventions.⁸ Publication bias was not assessed due to insufficient data.

Studies ultimately were classified into 3 categories based on the risk of bias: (1) low risk of bias or low risk of bias for all key domains; (2) unclear risk of bias or unclear risk of bias for 1 or more key domains; and (3) high risk of bias or high risk of 1 or more key domains.

Results

Search Results

Figure 1 presents the literature search results. Of 300 total search results, 8 RCTs were selected for assessment,^9-16 which included a total of 240 patients (Table). The investigators of all 8 reports were contacted, but only 2 responses were received.^11,14 The full text of one article could not be obtained; therefore, we could not confirm that it was a true RCT and excluded it.¹⁷

Figure 1. Search results.

Risk of Bias

The risk of bias in methodology was evaluated for all 8 RCTs and the judgments were given for each domain (Figure 2). All the included studies claimed to be RCTs, but only 37.5% (3/8) of them used adequate randomizations, which were from a including computer-generated code,¹⁰ a table of randomized numbers,¹³ or the Microsoft Excel RND function (from the author by e-mail).¹⁴ The randomization methods in the other 5 studies were unclear. Allocation concealment was adequate in 1 trial¹³ but was unclear in the others. Three trials were double-blinded with the participants and outcome assessors blinded^10,13,16; in 2 of these studies investigators also were blinded.^10,13 There were 5 single-blinded trials; in 3 of these trials the outcome assessors were blinded^12,14,15 and 1 was investigator-blinded.⁹ The other study was stated to be single-blinded but with no further detail.¹¹ Due to the nature of the experimental design in 2 of the trials^12,15 (ie, effects of laser therapy compared to topical treatment or no therapy), participants could not be blinded to treatment types; however, participants were blinded in 1 trial that compared different types of lasers.¹⁶ Investigators from all studies reported participants who did not complete the trial or were lost to follow-up, ranging from 0% to 65.6%. Two trials reported no loss of follow-up.^11,12 Most trials had losses less than 20% except Pribanich et al¹³ who reported a loss of 65.6% of participants. One trial included a full analysis set,⁹ and none of the studies included an intention-to-treat analysis.

Figure 2. Risk of bias summary based on judgments about each risk of bias domain for each study. + indicates low risk of bias; ?, unclear risk of bias; -, high risk of bias.

The overall risk of bias was assessed for each study and none could be categorized as low risk. Six studies had 1 or more domains assessed as high risk of bias and were classified as high risk of bias.^9,11-15 The remaining 2 studies without high-risk domains had one or more domains assessed as unclear^10,16 and were therefore considered to be at unclear risk of bias overall.

Effects of Treatments

Among the 8 studies we assessed, there were different treatments, methods of comparison, product concentrations, and times of application. The methods for assessing outcomes (eg, the size and severity of stretch marks) also were varied. Therefore, it is difficult to perform a meta-analysis of the data, and all the evidence was from individual studies. A summary of the results is presented in the Table.

All of the studies we evaluated assessed clinical improvement. Three studies reported the effects of topical tretinoin on stretch marks.^10,12,13 A small parallel study with unclear risk of bias indicated that white participants with erythematous stretch marks seemed to have a better response to treatment with tretinoin cream 0.1% for 24 weeks versus placebo.¹⁰ However, there was no significant difference between tretinoin cream 0.025% and placebo for patients with abdominal striae in another trial.¹³ The latter trial was performed with low risk of bias in methodology, but the dropout rate was high (65.6%), with only 11 of 32 participants completing the trial. It is likely that the small number of patients makes the power too low to detect significant differences between tretinoin cream 0.025% and placebo if such a difference indeed existed.¹³ Because the outcomes in these 2 trials were assessed in different ways, it is difficult to perform a meta-analysis on the data. More adverse effects, mainly erythema and scaling associated with itching or burning sensations, were reported with the higher concentration (0.05%) of tretinoin.¹⁰ Another study at a high risk of bias found that the combined use of tretinoin cream 0.05% and glycolic acid 10% was not as effective as fractional CO₂ laser therapy in improving the appearance of striae alba.¹² There also were 3 studies comparing the effects of laser therapy with another treatment or no treatment.^12,15,16 Two within-participant comparison studies with unclear or high risk of bias compared CO₂ fractional laser therapy with other active treatment methods in female participants with striae alba.^12,16 No difference between the fractional CO₂ laser and the 1550-nm nonablative fractional erbium:glass laser was reported,¹⁶ but the fractional CO₂ laser may be more effective than the topical therapy.¹² A small study (11 participants) at high risk of bias reported negative results for the 1450-nm mid-infrared diode laser compared to no treatment.¹⁵ Data on the adverse effects of laser therapy were available from these studies. Postinflammatory hyperpigmentation was found in all the 3 studies^12,15,16 and posttreatment erythema was mentioned in 2 studies.^15,16 Based on the individual studies, treatment with a cosmetic oil formulation was more effective than a moisturizer in improving clinical presentation of stretch marks in white patients.¹⁴ Women with striae rubra showed better response to treatment with onion extract cream versus no treatment.⁹ Limited data from 1 study showed that combined use of Active B (sodium ascorbyl phosphate, 3-aminopropyl-L-ascorbyl phosphate, carboxybetaglucan, hyaluronic acid) and Active A (hyaluronic acid, sodium salt 2 mg, sodium carboxymethyl betaglucan 0.1 mg, ascorbic acid 0.5 mg, arginine 1 mg, sodium chloride 9 mg, sterile water) might be more effective than the use of Active B or placebo.¹¹ These 3 studies are at high risk of bias and no obvious adverse effects were reported.^9,11,14

 
Comment

In the 8 trials included in our assessment, 5 used a within-participant design in which 2 different treatments were randomly administered to the left and right sides of the body, respectively.^9,12,14-16 Because the comparison of treatments was made based on results in the same patient versus 2 different treatment groups, the results may be more accurate. In the studies we reviewed, only 3 were placebo-controlled, which may only provide limited evidence on the comparative efficacy of the treatments used in these studies.^10,11,13 Most treatments were evaluated in single studies, and most studies had a small number of participants (range, 6–66 participants). A considerable number of the total participants withdrew from their respective studies or were lost during follow-up. In some cases, no reason was given,¹³ but in the others, it was because of an obvious side effect¹⁶ or noncompliance.¹⁴ Overall, the methodology quality was low, especially the methods of randomization and allocation concealment. Unsuccessful attempts to contact the original investigators made it difficult to make accurate assessments of the risk of bias in most of the studies included in our assessment. No study met all the risk of bias criteria, and none were classified as having a low risk of bias.

The impact of industry sponsorship on the direction and completeness of the results of the studies we reviewed is unclear. One study was funded by a grant from the manufacturer of the study product,¹⁴ and the medication used in another study was supplied by the manufacturer.¹³ Another study was supported in part by a company that had no part in the conduct, analysis, or reporting of the study.¹⁰ In one instance, the authors were employees of the manufacturer of the study product.⁹ The remaining studies made no declaration.^11,12,15,16

Thus the evidence from this review was insufficient to provide clear guidelines for practice. Because the results were based on a small number of patients and were of high or unclear risk of bias, caution must be taken when comparing the efficacy of the treatments administered in these studies; however, given the negligible reported side effects, tretinoin cream 0.1%, a cosmetic oil formulation, onion extract cream, or the combined use of Active A and Active B could reasonably be considered for the treatment of stretch marks. Laser therapies such as the fractional CO₂ laser or the 1550-nm fractional erbium:glass laser may be another effective choice.

 
Conclusion

In future investigations of stretch mark treatments, more high-quality, placebo-controlled trials are needed. One important issue is the varied outcome assessment among different studies, which makes the evaluation and pooling of different studies difficult. Therefore, future RCTs should measure clinical features with a uniform score system such as the visual analog scale or the patient and observer scar assessment scale and try to avoid individual made-up system to assess the outcome. Furthermore, quality-of-life assessment was not included in any of the reports we evaluated; rather all 8 studies focused on changes in the appearance of stretch marks only. Given the deep psychological impact that stretch marks can have on patients, measures for quality-of-life assessment, such as the dermatology life quality index, should be incorporated into future study designs to improve the relevance of the trial and allow comparisons among studies using different interventions.

Religious practices can lead to cutaneous changes, and awareness of these changes is of paramount importance in establishing the cause. We review the cutaneous changes related to religious practices, including the Semitic religions, Hinduism, and Sikhism (Table). The most widely followed Semitic religions are Christianity, Islam, and Judaism. Christianity and Islam collectively account for more than half of the world’s population.¹

Christianity
Christian individuals are prone to blisters that develop below the knees due to repeated kneeling in prayer.² A case of allergic contact dermatitis to a wooden cross made from Dalbergia nigra has been reported.³ Localized swelling with hypertrichosis due to muscular hypertrophy in the lower neck above the interscapular region has been described in well-built men who lift weights to bear pasos (floats with wooden sculptures) during Holy Week in Seville, Spain.⁴

Islam
Cutaneous signs of piety have been well documented in Muslim individuals. The most common presentation is hyperpigmentation of the forehead, usually noted as a secondary finding in patients seeking treatment of unrelated symptoms.⁵ Cutaneous changes in this region correspond with the area of the forehead that rests on the carpet during prayer. Macules typically present on the upper central aspect of the forehead close to the hairline and/or in pairs above the medial ends of the eyebrows; sometimes 3 or 4 lesions may be present in this area with involvement of the nasion (Figure 1).⁶

In Saudi Arabia where Sunni Islam predominates, Muslim individuals observe prayer 5 times per day. Calluses have been observed in areas of the body that are frequently subject to friction during this practice.⁷ For instance, calluses are more prominent on the right knee (Figure 2) and the left ankle, which bear the individual’s weight during prayer, and typically become nodular over time (Figure 3). In Arabic, these calluses are referred to as zabiba.⁸

A notable finding in followers of Shia Islam, which predominates in Iran, is the development of small nodules on the forehead, possibly caused by rubbing the forehead on a flat disclike prayer stone called a mohr during daily prayer,⁹ which is said to enhance public esteem.¹⁰ The nodules generally are asymptomatic, but some individuals experience minimal pain on pressure.⁸ Ulceration of the nodules has rarely been observed.⁷

Limited access to thick and soft carpets and rarely bony exostoses or obesity are factors associated with prayer that can lead to skin changes (known as prayer signs), as they render the skin sensitive to pressure. Localized alopecia may occur on the forehead in individuals with low or pointed hairlines. An unexplained finding noted by one of the authors (K.A.) in some elderly Muslim individuals is that hair located on the forehead at the point of pressure during prayer remains pigmented, while the rest of the hair on the scalp turns white. Hyperpigmentation of the knuckles may be seen in individuals who use closed fists to rise from the ground following prayer. Except for mild hyperpigmentation of the knees,⁷ Muslim women rarely develop these changes, as they either do not pray,¹⁰ particularly during menstruation or puerperium, or they have more subcutaneous fat for protection.⁷ Some Muslim individuals who pray regularly at home may be conscious of these skin changes and therefore use a soft pillow to rest the forehead during prayer.

The histopathologic findings of prayer signs depend on the extent of lichenification and typically show compact hyperkeratosis or orthokeratosis, hypergranulosis, acanthosis, and mild dermal inflammation.⁸ Increased dermal vascularization and papillary fibrosis unlike that seen in lichen simplex chronicus have been described from skin changes in the lower limbs due to prayer practices.⁷ Additional findings in forehead biopsies include multiple comedones and epidermoid cysts in elderly patients showing a foreign body granulomatous reaction to hair fragments.¹⁰ Deposition of mucinous material in the dermal collagen in a prayer nodule on the forehead has been described in a Shiite individual, possibly due to repetitive microtrauma from the use of a prayer stone.⁹ Infections developed from sharing communal facilities or performing ritual sacrifices (eg, tinea,¹¹ orf¹²) are prevalent during the yearly Hajj pilgrimage at Makkah, Saudi Arabia, in addition to other infectious and noninfectious dermatoses.¹³ Muslim women wearing headscarves secured at the neck with a safety pin have developed vitiligo at that site due to friction.¹⁴ Occasionally, Muslim individuals may apply perfumes before prayers, which may cause allergic contact dermatitis.

Judaism
Hyperpigmentation has been described in Jewish men at Talmudic seminaries due to the practice of reciting scriptures, which involves a rocking motion known as daven that leads to friction on the back.¹⁵ Lesions associated with this practice typically appear as isolated macules or a continuous linear patch over the skin of the bony protuberances of the inferior thoracic and lumbar vertebrae. Allergic contact dermatitis has been reported in Jewish individuals due to exposure to a variety of agents during religious practices, such as potassium dichromate, which is present in the leather used to make phylacteries or tefillin (boxes containing scripture that are secured to the forehead with straps that are then tied to the left arm during prayer). This finding has been noted in some or all areas of contact including the forehead, scalp, neck, left wrist, and waist.¹⁶

It is customary for both Orthodox Jewish and Muslim women to be concealed by clothing, which predisposes them to vitamin D deficiency^17,18 but also protects them from developing malignant melanoma.¹⁹ Neonates have developed genital herpetic infections following circumcision due to the ancient practice of having the mohel (the person who performs the Jewish circumcision) suck on the wound until the bleeding stops.²⁰

Hinduism
Hinduism espouses an eclectic philosophy of life subsuming numerous beliefs involving guardian deities, invoked by sacred marks, symbols, and rituals. Marks generally are placed on the forehead or other specified sites on the body. Sandalwood paste as well as vibhuti and kumkum powders most commonly are used, which can cause allergic contact dermatitis. Vibhuti is holy ash prepared by burning balls of dried cow dung in a fire pit with rice husk and clarified butter. Kumkum is prepared by alkalinizing turmeric powder, which turns red in color. A case of contact allergic dermatitis was reported in a Hindu priest who regularly used sandalwood paste on the forehead and as a balm for an ailment of the hands and feet.²¹ In our experience, vibhuti also has caused dermatitis on the forehead as well as on the neck and arms. The main difference between the 2 eruptions is that sandalwood dermatitis generally is localized to the center of the forehead as a circular or vertical mark or often in the center of the left palm, which is used to mix sandalwood powder with water to make a paste (Figure 4), while vibhuti contact dermatitis typically presents as a broad horizontal patch on the forehead because the powder is smeared with the middle 3 fingers (Figure 5). Perfumes used by some Muslim individuals before prayer that are applied on the clothes can mimic this type of contact dermatitis, but eruptions typically are confined to the fingers and palms.²² Contact dermatitis caused by necklaces made with beads of the stem of the Ocimum sanctum (holy basil) plant and seeds of the evergreen tree Elaeocarpus ganitrus have been reported.²³ Calluses are sometimes seen in individuals who meditate for long hours while sitting in a cross-legged position and usually occur on or uncommonly below the lateral malleolus of the right foot, similar to practitioners of yoga.²⁴

Hemorrhaging and crusting below the lateral malleolus of the right foot have been reported in Buddhist monks due to sitting in a cross-legged position for prolonged periods of meditation.²⁵ Hyperpigmentation of the knees, ankles, and interphalangeal joints of the feet has been seen after sitting in the traditional Japanese meditative position.²⁶ Tattoos of Hindu gods are common, while tattoos are forbidden in Islam and Judaism. Attributes of prominent deities branded on the body may be seen. Discrete sarcoidlike nodules along the axillae and chest wall have been attributed to a Hindu ritual (kavadi) that is performed annually as a form of self-inflicted punishment for their sins in which devotees pierce the chest wall with spokes to form a base over a heavy cage in which offerings are carried, and skewers passed through the cheeks have resulted in similar nodules in the oral cavity.^27,28 Consumption of cow’s urine during rituals may induce acute urticaria.²⁹ Lichen planus of the trunk³⁰ and leukoderma of the waist³¹ may be induced by köbnerization or contact allergy from wearing sacred threads, respectively.

Sikhism
Sikhism, a religion founded in the 15th century, epitomizes the high-water mark of the syncretism between Hinduism and Islam. Men must abstain from cutting their hair; pulling and knotting the hair to maintain a coiffure can cause traction alopecia in the submandibular region and the frontal and parietal areas of the scalp as well as ridging and furrowing of the scalp resembling cutis verticis gyrata. Fixer, a product used to keep the beard intact, can cause contact dermatitis. The tight broad band of cloth (known as a ribbon) that is worn around the head to keep hair intact beneath a turban may cause forehead lesions. Discoid lupus erythematosus–like lesions or painful chondrodermatitis of the pinnae due to pressure from wearing a starched turban have been observed, also called “turban ear” from prominence of both anthelices.^32,33 A case of a Sikh man who developed oral sarcoidal lesions from body piercing has been reported.²⁸

Conclusion
Knowledge of the religious practices of patients would help in recognizing puzzling and peculiar dermatoses. It may not be possible to eliminate the causes of these conditions, but methods to reduce their effects on the skin can be discussed with patients.

Acknowledgments—We are grateful to the valuable help rendered by Joginder Kumar, MD, New Delhi, India, and C. Indira, MD, Hyderabad, India.

Religious practices can lead to cutaneous changes, and awareness of these changes is of paramount importance in establishing the cause. We review the cutaneous changes related to religious practices, including the Semitic religions, Hinduism, and Sikhism (Table). The most widely followed Semitic religions are Christianity, Islam, and Judaism. Christianity and Islam collectively account for more than half of the world’s population.¹

Christianity
Christian individuals are prone to blisters that develop below the knees due to repeated kneeling in prayer.² A case of allergic contact dermatitis to a wooden cross made from Dalbergia nigra has been reported.³ Localized swelling with hypertrichosis due to muscular hypertrophy in the lower neck above the interscapular region has been described in well-built men who lift weights to bear pasos (floats with wooden sculptures) during Holy Week in Seville, Spain.⁴

Islam
Cutaneous signs of piety have been well documented in Muslim individuals. The most common presentation is hyperpigmentation of the forehead, usually noted as a secondary finding in patients seeking treatment of unrelated symptoms.⁵ Cutaneous changes in this region correspond with the area of the forehead that rests on the carpet during prayer. Macules typically present on the upper central aspect of the forehead close to the hairline and/or in pairs above the medial ends of the eyebrows; sometimes 3 or 4 lesions may be present in this area with involvement of the nasion (Figure 1).⁶

In Saudi Arabia where Sunni Islam predominates, Muslim individuals observe prayer 5 times per day. Calluses have been observed in areas of the body that are frequently subject to friction during this practice.⁷ For instance, calluses are more prominent on the right knee (Figure 2) and the left ankle, which bear the individual’s weight during prayer, and typically become nodular over time (Figure 3). In Arabic, these calluses are referred to as zabiba.⁸

A notable finding in followers of Shia Islam, which predominates in Iran, is the development of small nodules on the forehead, possibly caused by rubbing the forehead on a flat disclike prayer stone called a mohr during daily prayer,⁹ which is said to enhance public esteem.¹⁰ The nodules generally are asymptomatic, but some individuals experience minimal pain on pressure.⁸ Ulceration of the nodules has rarely been observed.⁷

Limited access to thick and soft carpets and rarely bony exostoses or obesity are factors associated with prayer that can lead to skin changes (known as prayer signs), as they render the skin sensitive to pressure. Localized alopecia may occur on the forehead in individuals with low or pointed hairlines. An unexplained finding noted by one of the authors (K.A.) in some elderly Muslim individuals is that hair located on the forehead at the point of pressure during prayer remains pigmented, while the rest of the hair on the scalp turns white. Hyperpigmentation of the knuckles may be seen in individuals who use closed fists to rise from the ground following prayer. Except for mild hyperpigmentation of the knees,⁷ Muslim women rarely develop these changes, as they either do not pray,¹⁰ particularly during menstruation or puerperium, or they have more subcutaneous fat for protection.⁷ Some Muslim individuals who pray regularly at home may be conscious of these skin changes and therefore use a soft pillow to rest the forehead during prayer.

The histopathologic findings of prayer signs depend on the extent of lichenification and typically show compact hyperkeratosis or orthokeratosis, hypergranulosis, acanthosis, and mild dermal inflammation.⁸ Increased dermal vascularization and papillary fibrosis unlike that seen in lichen simplex chronicus have been described from skin changes in the lower limbs due to prayer practices.⁷ Additional findings in forehead biopsies include multiple comedones and epidermoid cysts in elderly patients showing a foreign body granulomatous reaction to hair fragments.¹⁰ Deposition of mucinous material in the dermal collagen in a prayer nodule on the forehead has been described in a Shiite individual, possibly due to repetitive microtrauma from the use of a prayer stone.⁹ Infections developed from sharing communal facilities or performing ritual sacrifices (eg, tinea,¹¹ orf¹²) are prevalent during the yearly Hajj pilgrimage at Makkah, Saudi Arabia, in addition to other infectious and noninfectious dermatoses.¹³ Muslim women wearing headscarves secured at the neck with a safety pin have developed vitiligo at that site due to friction.¹⁴ Occasionally, Muslim individuals may apply perfumes before prayers, which may cause allergic contact dermatitis.

Judaism
Hyperpigmentation has been described in Jewish men at Talmudic seminaries due to the practice of reciting scriptures, which involves a rocking motion known as daven that leads to friction on the back.¹⁵ Lesions associated with this practice typically appear as isolated macules or a continuous linear patch over the skin of the bony protuberances of the inferior thoracic and lumbar vertebrae. Allergic contact dermatitis has been reported in Jewish individuals due to exposure to a variety of agents during religious practices, such as potassium dichromate, which is present in the leather used to make phylacteries or tefillin (boxes containing scripture that are secured to the forehead with straps that are then tied to the left arm during prayer). This finding has been noted in some or all areas of contact including the forehead, scalp, neck, left wrist, and waist.¹⁶

It is customary for both Orthodox Jewish and Muslim women to be concealed by clothing, which predisposes them to vitamin D deficiency^17,18 but also protects them from developing malignant melanoma.¹⁹ Neonates have developed genital herpetic infections following circumcision due to the ancient practice of having the mohel (the person who performs the Jewish circumcision) suck on the wound until the bleeding stops.²⁰

Hinduism
Hinduism espouses an eclectic philosophy of life subsuming numerous beliefs involving guardian deities, invoked by sacred marks, symbols, and rituals. Marks generally are placed on the forehead or other specified sites on the body. Sandalwood paste as well as vibhuti and kumkum powders most commonly are used, which can cause allergic contact dermatitis. Vibhuti is holy ash prepared by burning balls of dried cow dung in a fire pit with rice husk and clarified butter. Kumkum is prepared by alkalinizing turmeric powder, which turns red in color. A case of contact allergic dermatitis was reported in a Hindu priest who regularly used sandalwood paste on the forehead and as a balm for an ailment of the hands and feet.²¹ In our experience, vibhuti also has caused dermatitis on the forehead as well as on the neck and arms. The main difference between the 2 eruptions is that sandalwood dermatitis generally is localized to the center of the forehead as a circular or vertical mark or often in the center of the left palm, which is used to mix sandalwood powder with water to make a paste (Figure 4), while vibhuti contact dermatitis typically presents as a broad horizontal patch on the forehead because the powder is smeared with the middle 3 fingers (Figure 5). Perfumes used by some Muslim individuals before prayer that are applied on the clothes can mimic this type of contact dermatitis, but eruptions typically are confined to the fingers and palms.²² Contact dermatitis caused by necklaces made with beads of the stem of the Ocimum sanctum (holy basil) plant and seeds of the evergreen tree Elaeocarpus ganitrus have been reported.²³ Calluses are sometimes seen in individuals who meditate for long hours while sitting in a cross-legged position and usually occur on or uncommonly below the lateral malleolus of the right foot, similar to practitioners of yoga.²⁴

Hemorrhaging and crusting below the lateral malleolus of the right foot have been reported in Buddhist monks due to sitting in a cross-legged position for prolonged periods of meditation.²⁵ Hyperpigmentation of the knees, ankles, and interphalangeal joints of the feet has been seen after sitting in the traditional Japanese meditative position.²⁶ Tattoos of Hindu gods are common, while tattoos are forbidden in Islam and Judaism. Attributes of prominent deities branded on the body may be seen. Discrete sarcoidlike nodules along the axillae and chest wall have been attributed to a Hindu ritual (kavadi) that is performed annually as a form of self-inflicted punishment for their sins in which devotees pierce the chest wall with spokes to form a base over a heavy cage in which offerings are carried, and skewers passed through the cheeks have resulted in similar nodules in the oral cavity.^27,28 Consumption of cow’s urine during rituals may induce acute urticaria.²⁹ Lichen planus of the trunk³⁰ and leukoderma of the waist³¹ may be induced by köbnerization or contact allergy from wearing sacred threads, respectively.

Sikhism
Sikhism, a religion founded in the 15th century, epitomizes the high-water mark of the syncretism between Hinduism and Islam. Men must abstain from cutting their hair; pulling and knotting the hair to maintain a coiffure can cause traction alopecia in the submandibular region and the frontal and parietal areas of the scalp as well as ridging and furrowing of the scalp resembling cutis verticis gyrata. Fixer, a product used to keep the beard intact, can cause contact dermatitis. The tight broad band of cloth (known as a ribbon) that is worn around the head to keep hair intact beneath a turban may cause forehead lesions. Discoid lupus erythematosus–like lesions or painful chondrodermatitis of the pinnae due to pressure from wearing a starched turban have been observed, also called “turban ear” from prominence of both anthelices.^32,33 A case of a Sikh man who developed oral sarcoidal lesions from body piercing has been reported.²⁸

Conclusion
Knowledge of the religious practices of patients would help in recognizing puzzling and peculiar dermatoses. It may not be possible to eliminate the causes of these conditions, but methods to reduce their effects on the skin can be discussed with patients.

Acknowledgments—We are grateful to the valuable help rendered by Joginder Kumar, MD, New Delhi, India, and C. Indira, MD, Hyderabad, India.

Religious practices can lead to cutaneous changes, and awareness of these changes is of paramount importance in establishing the cause. We review the cutaneous changes related to religious practices, including the Semitic religions, Hinduism, and Sikhism (Table). The most widely followed Semitic religions are Christianity, Islam, and Judaism. Christianity and Islam collectively account for more than half of the world’s population.¹

Christianity
Christian individuals are prone to blisters that develop below the knees due to repeated kneeling in prayer.² A case of allergic contact dermatitis to a wooden cross made from Dalbergia nigra has been reported.³ Localized swelling with hypertrichosis due to muscular hypertrophy in the lower neck above the interscapular region has been described in well-built men who lift weights to bear pasos (floats with wooden sculptures) during Holy Week in Seville, Spain.⁴

Islam
Cutaneous signs of piety have been well documented in Muslim individuals. The most common presentation is hyperpigmentation of the forehead, usually noted as a secondary finding in patients seeking treatment of unrelated symptoms.⁵ Cutaneous changes in this region correspond with the area of the forehead that rests on the carpet during prayer. Macules typically present on the upper central aspect of the forehead close to the hairline and/or in pairs above the medial ends of the eyebrows; sometimes 3 or 4 lesions may be present in this area with involvement of the nasion (Figure 1).⁶

In Saudi Arabia where Sunni Islam predominates, Muslim individuals observe prayer 5 times per day. Calluses have been observed in areas of the body that are frequently subject to friction during this practice.⁷ For instance, calluses are more prominent on the right knee (Figure 2) and the left ankle, which bear the individual’s weight during prayer, and typically become nodular over time (Figure 3). In Arabic, these calluses are referred to as zabiba.⁸

A notable finding in followers of Shia Islam, which predominates in Iran, is the development of small nodules on the forehead, possibly caused by rubbing the forehead on a flat disclike prayer stone called a mohr during daily prayer,⁹ which is said to enhance public esteem.¹⁰ The nodules generally are asymptomatic, but some individuals experience minimal pain on pressure.⁸ Ulceration of the nodules has rarely been observed.⁷

Limited access to thick and soft carpets and rarely bony exostoses or obesity are factors associated with prayer that can lead to skin changes (known as prayer signs), as they render the skin sensitive to pressure. Localized alopecia may occur on the forehead in individuals with low or pointed hairlines. An unexplained finding noted by one of the authors (K.A.) in some elderly Muslim individuals is that hair located on the forehead at the point of pressure during prayer remains pigmented, while the rest of the hair on the scalp turns white. Hyperpigmentation of the knuckles may be seen in individuals who use closed fists to rise from the ground following prayer. Except for mild hyperpigmentation of the knees,⁷ Muslim women rarely develop these changes, as they either do not pray,¹⁰ particularly during menstruation or puerperium, or they have more subcutaneous fat for protection.⁷ Some Muslim individuals who pray regularly at home may be conscious of these skin changes and therefore use a soft pillow to rest the forehead during prayer.

The histopathologic findings of prayer signs depend on the extent of lichenification and typically show compact hyperkeratosis or orthokeratosis, hypergranulosis, acanthosis, and mild dermal inflammation.⁸ Increased dermal vascularization and papillary fibrosis unlike that seen in lichen simplex chronicus have been described from skin changes in the lower limbs due to prayer practices.⁷ Additional findings in forehead biopsies include multiple comedones and epidermoid cysts in elderly patients showing a foreign body granulomatous reaction to hair fragments.¹⁰ Deposition of mucinous material in the dermal collagen in a prayer nodule on the forehead has been described in a Shiite individual, possibly due to repetitive microtrauma from the use of a prayer stone.⁹ Infections developed from sharing communal facilities or performing ritual sacrifices (eg, tinea,¹¹ orf¹²) are prevalent during the yearly Hajj pilgrimage at Makkah, Saudi Arabia, in addition to other infectious and noninfectious dermatoses.¹³ Muslim women wearing headscarves secured at the neck with a safety pin have developed vitiligo at that site due to friction.¹⁴ Occasionally, Muslim individuals may apply perfumes before prayers, which may cause allergic contact dermatitis.

Judaism
Hyperpigmentation has been described in Jewish men at Talmudic seminaries due to the practice of reciting scriptures, which involves a rocking motion known as daven that leads to friction on the back.¹⁵ Lesions associated with this practice typically appear as isolated macules or a continuous linear patch over the skin of the bony protuberances of the inferior thoracic and lumbar vertebrae. Allergic contact dermatitis has been reported in Jewish individuals due to exposure to a variety of agents during religious practices, such as potassium dichromate, which is present in the leather used to make phylacteries or tefillin (boxes containing scripture that are secured to the forehead with straps that are then tied to the left arm during prayer). This finding has been noted in some or all areas of contact including the forehead, scalp, neck, left wrist, and waist.¹⁶

It is customary for both Orthodox Jewish and Muslim women to be concealed by clothing, which predisposes them to vitamin D deficiency^17,18 but also protects them from developing malignant melanoma.¹⁹ Neonates have developed genital herpetic infections following circumcision due to the ancient practice of having the mohel (the person who performs the Jewish circumcision) suck on the wound until the bleeding stops.²⁰

Hinduism
Hinduism espouses an eclectic philosophy of life subsuming numerous beliefs involving guardian deities, invoked by sacred marks, symbols, and rituals. Marks generally are placed on the forehead or other specified sites on the body. Sandalwood paste as well as vibhuti and kumkum powders most commonly are used, which can cause allergic contact dermatitis. Vibhuti is holy ash prepared by burning balls of dried cow dung in a fire pit with rice husk and clarified butter. Kumkum is prepared by alkalinizing turmeric powder, which turns red in color. A case of contact allergic dermatitis was reported in a Hindu priest who regularly used sandalwood paste on the forehead and as a balm for an ailment of the hands and feet.²¹ In our experience, vibhuti also has caused dermatitis on the forehead as well as on the neck and arms. The main difference between the 2 eruptions is that sandalwood dermatitis generally is localized to the center of the forehead as a circular or vertical mark or often in the center of the left palm, which is used to mix sandalwood powder with water to make a paste (Figure 4), while vibhuti contact dermatitis typically presents as a broad horizontal patch on the forehead because the powder is smeared with the middle 3 fingers (Figure 5). Perfumes used by some Muslim individuals before prayer that are applied on the clothes can mimic this type of contact dermatitis, but eruptions typically are confined to the fingers and palms.²² Contact dermatitis caused by necklaces made with beads of the stem of the Ocimum sanctum (holy basil) plant and seeds of the evergreen tree Elaeocarpus ganitrus have been reported.²³ Calluses are sometimes seen in individuals who meditate for long hours while sitting in a cross-legged position and usually occur on or uncommonly below the lateral malleolus of the right foot, similar to practitioners of yoga.²⁴

Hemorrhaging and crusting below the lateral malleolus of the right foot have been reported in Buddhist monks due to sitting in a cross-legged position for prolonged periods of meditation.²⁵ Hyperpigmentation of the knees, ankles, and interphalangeal joints of the feet has been seen after sitting in the traditional Japanese meditative position.²⁶ Tattoos of Hindu gods are common, while tattoos are forbidden in Islam and Judaism. Attributes of prominent deities branded on the body may be seen. Discrete sarcoidlike nodules along the axillae and chest wall have been attributed to a Hindu ritual (kavadi) that is performed annually as a form of self-inflicted punishment for their sins in which devotees pierce the chest wall with spokes to form a base over a heavy cage in which offerings are carried, and skewers passed through the cheeks have resulted in similar nodules in the oral cavity.^27,28 Consumption of cow’s urine during rituals may induce acute urticaria.²⁹ Lichen planus of the trunk³⁰ and leukoderma of the waist³¹ may be induced by köbnerization or contact allergy from wearing sacred threads, respectively.

Sikhism
Sikhism, a religion founded in the 15th century, epitomizes the high-water mark of the syncretism between Hinduism and Islam. Men must abstain from cutting their hair; pulling and knotting the hair to maintain a coiffure can cause traction alopecia in the submandibular region and the frontal and parietal areas of the scalp as well as ridging and furrowing of the scalp resembling cutis verticis gyrata. Fixer, a product used to keep the beard intact, can cause contact dermatitis. The tight broad band of cloth (known as a ribbon) that is worn around the head to keep hair intact beneath a turban may cause forehead lesions. Discoid lupus erythematosus–like lesions or painful chondrodermatitis of the pinnae due to pressure from wearing a starched turban have been observed, also called “turban ear” from prominence of both anthelices.^32,33 A case of a Sikh man who developed oral sarcoidal lesions from body piercing has been reported.²⁸

Conclusion
Knowledge of the religious practices of patients would help in recognizing puzzling and peculiar dermatoses. It may not be possible to eliminate the causes of these conditions, but methods to reduce their effects on the skin can be discussed with patients.

Acknowledgments—We are grateful to the valuable help rendered by Joginder Kumar, MD, New Delhi, India, and C. Indira, MD, Hyderabad, India.

A recent online study by Gerami et al in the Journal of the American Academy of Dermatology highlighted a new genomic method using messenger RNA to classify pigmented lesions as benign or malignant using a noninvasive adhesive patch developed by DermTech International. Patches were applied to the surface of pigmented lesions (42 melanomas; 22 nevi), vigorously rubbed, removed, frozen, and sent to the proprietary laboratory for RNA extraction and gene expression analysis. Then each lesion was excised for pathologic review. A 2-gene signature was discovered, including CMIP and LINC00518, differentiating melanoma from nevi with sensitivity of 97.6% and specificity of 72.7%.

What’s the issue?

Along with our evolving understanding and case-specific use of noninvasive modalities to diagnose difficult pigmented lesions, we add this test to the number of other tests and imaging approaches that seem perhaps too good to be true. A test that strips epithelial cells and involves no wound care but explores true gene differences likely sits better with us than surface microscopy, dermoscopy, and other imaging because, in this case, it provides a signature. A result. Similar to a pregnancy test, right? We wish. The diversity of pigmented lesions, especially the ones that stump us even on pathologic review, will likely prove too cryptic for 1 test to decode, but as these modalities evolve, their signatures will hopefully merge between researchers and industry to create a pigmented lesion map that we can all read. What noninvasive modalities do you use in your practices for pigmented lesions? How do you think this test will fit in?

We want to know your views! Tell us what you think.

A recent online study by Gerami et al in the Journal of the American Academy of Dermatology highlighted a new genomic method using messenger RNA to classify pigmented lesions as benign or malignant using a noninvasive adhesive patch developed by DermTech International. Patches were applied to the surface of pigmented lesions (42 melanomas; 22 nevi), vigorously rubbed, removed, frozen, and sent to the proprietary laboratory for RNA extraction and gene expression analysis. Then each lesion was excised for pathologic review. A 2-gene signature was discovered, including CMIP and LINC00518, differentiating melanoma from nevi with sensitivity of 97.6% and specificity of 72.7%.

What’s the issue?

Along with our evolving understanding and case-specific use of noninvasive modalities to diagnose difficult pigmented lesions, we add this test to the number of other tests and imaging approaches that seem perhaps too good to be true. A test that strips epithelial cells and involves no wound care but explores true gene differences likely sits better with us than surface microscopy, dermoscopy, and other imaging because, in this case, it provides a signature. A result. Similar to a pregnancy test, right? We wish. The diversity of pigmented lesions, especially the ones that stump us even on pathologic review, will likely prove too cryptic for 1 test to decode, but as these modalities evolve, their signatures will hopefully merge between researchers and industry to create a pigmented lesion map that we can all read. What noninvasive modalities do you use in your practices for pigmented lesions? How do you think this test will fit in?

We want to know your views! Tell us what you think.

A recent online study by Gerami et al in the Journal of the American Academy of Dermatology highlighted a new genomic method using messenger RNA to classify pigmented lesions as benign or malignant using a noninvasive adhesive patch developed by DermTech International. Patches were applied to the surface of pigmented lesions (42 melanomas; 22 nevi), vigorously rubbed, removed, frozen, and sent to the proprietary laboratory for RNA extraction and gene expression analysis. Then each lesion was excised for pathologic review. A 2-gene signature was discovered, including CMIP and LINC00518, differentiating melanoma from nevi with sensitivity of 97.6% and specificity of 72.7%.

What’s the issue?

Along with our evolving understanding and case-specific use of noninvasive modalities to diagnose difficult pigmented lesions, we add this test to the number of other tests and imaging approaches that seem perhaps too good to be true. A test that strips epithelial cells and involves no wound care but explores true gene differences likely sits better with us than surface microscopy, dermoscopy, and other imaging because, in this case, it provides a signature. A result. Similar to a pregnancy test, right? We wish. The diversity of pigmented lesions, especially the ones that stump us even on pathologic review, will likely prove too cryptic for 1 test to decode, but as these modalities evolve, their signatures will hopefully merge between researchers and industry to create a pigmented lesion map that we can all read. What noninvasive modalities do you use in your practices for pigmented lesions? How do you think this test will fit in?

We want to know your views! Tell us what you think.

The Diagnosis: Blaschkoid Punctate Vitiligo

Based on the patient’s clinical appearance as well as the histologic findings, the diagnosis of vitiligo was made. Although vitiligo is certainly not uncommon and punctate vitiligo is a known clinical presentation,¹ punctate vitiliginous depigmentation conforming to lines of Blaschko is unique. Follicular repigmentation in a patch of vitiligo potentially could lead to this “spotty” appearance, but our patient maintained that the band was never confluently depigmented and that small macules arose within normally pigmented skin. The patient’s adult age at onset makes this case even more unusual.

Follicular repigmentation in vitiligo is fairly well understood, as the perifollicular pigment is formed by upward migration of activated melanoblasts in the outer root sheath.² Follicular depigmentation as well as selective or initial loss of melanocytes around hair follicles in early vitiligo has not been described. It is unclear if the seemingly folliculocentric nature of the patient’s vitiliginous macules was a false observation, coincidental, or actually related to selective melanocyte loss around follicles.

Blaschkoid distribution has been described in numerous skin disorders and is known to be based on genetic mosaicism.³ Most of these disorders are X-linked and/or congenital. However, many acquired skin conditions have been described exhibiting blaschkoid distribution, such as vitiligo, psoriasis, lichen planus, atopic dermatitis, and mycosis fungoides.^4,5

Confettilike depigmentation has been described as an unusual clinical variant of vitiligo.¹ It also has been reported after psoralen plus UVA therapy in patients with more classic vitiligo,⁶ numerous domestic chemicals,⁷ and in association with mycosis fungoides.⁸ In these cases, punctate lesions were disseminated, symmetric on extremities, or limited to areas exposed to chemicals.

The Diagnosis: Blaschkoid Punctate Vitiligo

Based on the patient’s clinical appearance as well as the histologic findings, the diagnosis of vitiligo was made. Although vitiligo is certainly not uncommon and punctate vitiligo is a known clinical presentation,¹ punctate vitiliginous depigmentation conforming to lines of Blaschko is unique. Follicular repigmentation in a patch of vitiligo potentially could lead to this “spotty” appearance, but our patient maintained that the band was never confluently depigmented and that small macules arose within normally pigmented skin. The patient’s adult age at onset makes this case even more unusual.

Follicular repigmentation in vitiligo is fairly well understood, as the perifollicular pigment is formed by upward migration of activated melanoblasts in the outer root sheath.² Follicular depigmentation as well as selective or initial loss of melanocytes around hair follicles in early vitiligo has not been described. It is unclear if the seemingly folliculocentric nature of the patient’s vitiliginous macules was a false observation, coincidental, or actually related to selective melanocyte loss around follicles.

Blaschkoid distribution has been described in numerous skin disorders and is known to be based on genetic mosaicism.³ Most of these disorders are X-linked and/or congenital. However, many acquired skin conditions have been described exhibiting blaschkoid distribution, such as vitiligo, psoriasis, lichen planus, atopic dermatitis, and mycosis fungoides.^4,5

Confettilike depigmentation has been described as an unusual clinical variant of vitiligo.¹ It also has been reported after psoralen plus UVA therapy in patients with more classic vitiligo,⁶ numerous domestic chemicals,⁷ and in association with mycosis fungoides.⁸ In these cases, punctate lesions were disseminated, symmetric on extremities, or limited to areas exposed to chemicals.

The Diagnosis: Blaschkoid Punctate Vitiligo

Based on the patient’s clinical appearance as well as the histologic findings, the diagnosis of vitiligo was made. Although vitiligo is certainly not uncommon and punctate vitiligo is a known clinical presentation,¹ punctate vitiliginous depigmentation conforming to lines of Blaschko is unique. Follicular repigmentation in a patch of vitiligo potentially could lead to this “spotty” appearance, but our patient maintained that the band was never confluently depigmented and that small macules arose within normally pigmented skin. The patient’s adult age at onset makes this case even more unusual.

Follicular repigmentation in vitiligo is fairly well understood, as the perifollicular pigment is formed by upward migration of activated melanoblasts in the outer root sheath.² Follicular depigmentation as well as selective or initial loss of melanocytes around hair follicles in early vitiligo has not been described. It is unclear if the seemingly folliculocentric nature of the patient’s vitiliginous macules was a false observation, coincidental, or actually related to selective melanocyte loss around follicles.

Blaschkoid distribution has been described in numerous skin disorders and is known to be based on genetic mosaicism.³ Most of these disorders are X-linked and/or congenital. However, many acquired skin conditions have been described exhibiting blaschkoid distribution, such as vitiligo, psoriasis, lichen planus, atopic dermatitis, and mycosis fungoides.^4,5

Confettilike depigmentation has been described as an unusual clinical variant of vitiligo.¹ It also has been reported after psoralen plus UVA therapy in patients with more classic vitiligo,⁶ numerous domestic chemicals,⁷ and in association with mycosis fungoides.⁸ In these cases, punctate lesions were disseminated, symmetric on extremities, or limited to areas exposed to chemicals.

The spectrum of idiopathic ultraviolet-induced dermatoses includes the most severe variant, polymorphous light eruption (PMLE), in which erythematous papules, papulovesicles, and plaques form from a delayed type IV hypersensitivity reaction to the sun. Its milder cousins, benign summer light eruption and juvenile springtime eruption, are milder, more transient variants.

Patients may experience sudden-onset, pruritic, sometimes painful papules and papulovesicles or cheilitis within 30 minutes to several hours of exposure to UV light in areas normally covered in the winter months. The rash subsides over 1-7 days (or sooner with effective topical steroid administration and strict sun avoidance) and without scarring. Occasionally, patients experience systemic flulike symptoms after sun exposure. Triggers can be UVA, UVB, or UVC. However, because most cases appear in the spring, describing these variants as benign summer light eruption is something of a misnomer.

These seasonal rashes are often underrecognized in skin of color patients, particularly those with Fitzpatrick skin types III-VI, because many practitioners assume a protective role of melanin (Photochem. Photobiol. Sci. 2013;12:65-77). A study by Kerr and Lim identified 280 patients with photodermatoses; 135 (48%) were African American, 110 (40%) were white, and 35 (12%) were other ethnicities. They noted a significantly higher proportion of African Americans with PMLE, compared with whites (J. Am. Acad. Dermatol. 2007;57:638-43). Also, Native Americans have a hereditary form of PMLE with autosomal dominant inheritance that can involve the face and is most common in patients with Fitzpatrick skin types III-VI.

For sun-sensitive patients, and especially skin of color patients, diagnosis and treatment include ruling out other photosensitive diseases such as systemic lupus, and then counseling about the importance of sun avoidance and the use of sunscreens, which include both UVA and UVB protection. Prophylactic phototherapy or photochemotherapy at the beginning of spring for several weeks may prevent flare-ups throughout the summer. PUVA (psoralen and UVA) therapy, as well as UVB phototherapy, have been successful at preventing flares in several studies. Topical steroids, antihistamines, and oral prednisone are mainstays of treatment for severe flares, alone or in combination with phototherapy. For severe cases, or those recalcitrant to first-line treatment, antimalarials, azathioprine, and thalidomide have been used with variable efficacy.

Particularly at this time of year, I always ask patients with photo-distributed rashes about their ethnicities. One can never assume ethnicity, culture, skin type, background, or even photosensitivity based on skin color alone. I have been surprised by the many patients with dark skin who may have Native American origins who present with photosensitive rashes, or the many patients with hereditary photosensitive rashes with fair skin. Our beautiful, multicultural society makes it harder to define or categorize dermatoses by skin type alone, based on the definitions we have set for skin type in our literature today.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Skin & Allergy News. Dr. Talakoub is in private practice at McLean (Va.) Dermatology Center. Dr. Wesley practices dermatology in Beverly Hills, Calif.

The spectrum of idiopathic ultraviolet-induced dermatoses includes the most severe variant, polymorphous light eruption (PMLE), in which erythematous papules, papulovesicles, and plaques form from a delayed type IV hypersensitivity reaction to the sun. Its milder cousins, benign summer light eruption and juvenile springtime eruption, are milder, more transient variants.

Patients may experience sudden-onset, pruritic, sometimes painful papules and papulovesicles or cheilitis within 30 minutes to several hours of exposure to UV light in areas normally covered in the winter months. The rash subsides over 1-7 days (or sooner with effective topical steroid administration and strict sun avoidance) and without scarring. Occasionally, patients experience systemic flulike symptoms after sun exposure. Triggers can be UVA, UVB, or UVC. However, because most cases appear in the spring, describing these variants as benign summer light eruption is something of a misnomer.

These seasonal rashes are often underrecognized in skin of color patients, particularly those with Fitzpatrick skin types III-VI, because many practitioners assume a protective role of melanin (Photochem. Photobiol. Sci. 2013;12:65-77). A study by Kerr and Lim identified 280 patients with photodermatoses; 135 (48%) were African American, 110 (40%) were white, and 35 (12%) were other ethnicities. They noted a significantly higher proportion of African Americans with PMLE, compared with whites (J. Am. Acad. Dermatol. 2007;57:638-43). Also, Native Americans have a hereditary form of PMLE with autosomal dominant inheritance that can involve the face and is most common in patients with Fitzpatrick skin types III-VI.

For sun-sensitive patients, and especially skin of color patients, diagnosis and treatment include ruling out other photosensitive diseases such as systemic lupus, and then counseling about the importance of sun avoidance and the use of sunscreens, which include both UVA and UVB protection. Prophylactic phototherapy or photochemotherapy at the beginning of spring for several weeks may prevent flare-ups throughout the summer. PUVA (psoralen and UVA) therapy, as well as UVB phototherapy, have been successful at preventing flares in several studies. Topical steroids, antihistamines, and oral prednisone are mainstays of treatment for severe flares, alone or in combination with phototherapy. For severe cases, or those recalcitrant to first-line treatment, antimalarials, azathioprine, and thalidomide have been used with variable efficacy.

Particularly at this time of year, I always ask patients with photo-distributed rashes about their ethnicities. One can never assume ethnicity, culture, skin type, background, or even photosensitivity based on skin color alone. I have been surprised by the many patients with dark skin who may have Native American origins who present with photosensitive rashes, or the many patients with hereditary photosensitive rashes with fair skin. Our beautiful, multicultural society makes it harder to define or categorize dermatoses by skin type alone, based on the definitions we have set for skin type in our literature today.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Skin & Allergy News. Dr. Talakoub is in private practice at McLean (Va.) Dermatology Center. Dr. Wesley practices dermatology in Beverly Hills, Calif.

The spectrum of idiopathic ultraviolet-induced dermatoses includes the most severe variant, polymorphous light eruption (PMLE), in which erythematous papules, papulovesicles, and plaques form from a delayed type IV hypersensitivity reaction to the sun. Its milder cousins, benign summer light eruption and juvenile springtime eruption, are milder, more transient variants.

Patients may experience sudden-onset, pruritic, sometimes painful papules and papulovesicles or cheilitis within 30 minutes to several hours of exposure to UV light in areas normally covered in the winter months. The rash subsides over 1-7 days (or sooner with effective topical steroid administration and strict sun avoidance) and without scarring. Occasionally, patients experience systemic flulike symptoms after sun exposure. Triggers can be UVA, UVB, or UVC. However, because most cases appear in the spring, describing these variants as benign summer light eruption is something of a misnomer.

These seasonal rashes are often underrecognized in skin of color patients, particularly those with Fitzpatrick skin types III-VI, because many practitioners assume a protective role of melanin (Photochem. Photobiol. Sci. 2013;12:65-77). A study by Kerr and Lim identified 280 patients with photodermatoses; 135 (48%) were African American, 110 (40%) were white, and 35 (12%) were other ethnicities. They noted a significantly higher proportion of African Americans with PMLE, compared with whites (J. Am. Acad. Dermatol. 2007;57:638-43). Also, Native Americans have a hereditary form of PMLE with autosomal dominant inheritance that can involve the face and is most common in patients with Fitzpatrick skin types III-VI.

For sun-sensitive patients, and especially skin of color patients, diagnosis and treatment include ruling out other photosensitive diseases such as systemic lupus, and then counseling about the importance of sun avoidance and the use of sunscreens, which include both UVA and UVB protection. Prophylactic phototherapy or photochemotherapy at the beginning of spring for several weeks may prevent flare-ups throughout the summer. PUVA (psoralen and UVA) therapy, as well as UVB phototherapy, have been successful at preventing flares in several studies. Topical steroids, antihistamines, and oral prednisone are mainstays of treatment for severe flares, alone or in combination with phototherapy. For severe cases, or those recalcitrant to first-line treatment, antimalarials, azathioprine, and thalidomide have been used with variable efficacy.

Particularly at this time of year, I always ask patients with photo-distributed rashes about their ethnicities. One can never assume ethnicity, culture, skin type, background, or even photosensitivity based on skin color alone. I have been surprised by the many patients with dark skin who may have Native American origins who present with photosensitive rashes, or the many patients with hereditary photosensitive rashes with fair skin. Our beautiful, multicultural society makes it harder to define or categorize dermatoses by skin type alone, based on the definitions we have set for skin type in our literature today.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Skin & Allergy News. Dr. Talakoub is in private practice at McLean (Va.) Dermatology Center. Dr. Wesley practices dermatology in Beverly Hills, Calif.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.

The Diagnosis: Carotenemia

Laboratory parameters including thyroid function testing as well as total protein and bilirubin levels were within reference range. Testing revealed multiple food allergies to almonds, oranges, cashews, garlic, peanuts, and cantaloupe. The patient was treated with a dietary expansion based on his allergy testing.

ß-Carotene converts to vitamin A in the intestine and acts as a lipochrome. Lack of conversion can be noted as an inborn error of metabolism.¹ Many green, yellow, and orange fruits and vegetables contain ß-carotene, including carrots, sweet potatoes, squash, green beans, papayas, and pumpkins.^1-3 ß-Carotene also is used as a vitamin supplement⁴ or therapeutic agent in photosensitive disorders such as genetic porphyrias.⁵

ß-Carotene can accumulate in the stratum corneum and impart a yellow color to the skin when the circulating levels are high; this coloration is termed carotenemia.^1,4 Carotenemia is common in infants and young children who have diets rich in green and orange vegetable purees.⁶ Carotenemia limited to thick areas of the skin, such as the palms and soles, can be seen in adults who eat large amounts of carrots; generalized carotenemia is rare.^1,4

Carotenemia is a benign condition of excess cutaneous buildup of ß-carotene through excessive intake of carotene-rich foods^1-4 or nutritional supplements⁷ or through association with anorexia, liver disease, renal disease, hypothyroidism, or diabetes mellitus.^1,4,8,9 Carotene deposits usually are most notable in areas with thick stratum corneum, such as the nasolabial folds, palms, and soles, as opposed to areas such as the conjunctivae and mucosa.^1,4

Carotenemia may mimic jaundice and should be differentiated through scleral examination for icterus and bilirubin levels. Carotene levels can be tested but generally are unnecessary. Carotenemia can be seen in liver or renal disease and can exacerbate the yellow coloration seen in jaundiced individuals.^1,4,9

Because it is a benign condition, the pathology usually is limited to skin discoloration, as seen in our patient. Although this condition can be reversed with a modified diet, our patient had multiple food allergies that further restricted his vegetarian diet, thereby limiting the modifications that he was willing to make to his diet.

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.