Contact Dermatitis

Nephrogenic fibrosing dermopathy (NFD) is an acquired idiopathic disorder seen exclusively in patients with renal failure. It was first recognized in 1997 in a group of patients following renal transplant.1,2 Symmetric, thickened, fibrotic skin with brawny hyperpigmentation develops and primarily affects the limbs, sparing the head and neck. Associated symptoms include flexion contracture, pain, paresthesia, and/or severe pruritus. Yellow palmar papules and yellow scleral plaques also have been described. Although fibrosis initially was observed in the skin, more recent evidence suggests that NFD is a systemic disorder with variable and still unclear degrees of end organ damage, particularly pulmonary fibrosis.3-7 In light of the systemic involvement and newly described, rapidly progressive, fatal cases of NFD, the name has been changed to nephrogenic systemic fibrosis (NSF).3 Since 1997, more than 200 cases have been compiled through the Yale University NSF Registry. All patients have the unifying diagnosis of renal failure, but the disease has been observed in patients independent of age, gender, dialysis history, kidney transplant status, or the underlying cause of renal failure.8,9 The majority of cases have been reported in the United States and Europe, but new cases are now being reported in non-Western populations.10,11 Given the novelty of the disease and the limited number of cases, the etiology has been elusive; however, most new diseases have some iatrogenic component. Prior to onset, many patients with NSF experienced coagulation abnormalities, transplant rejection, or some type of vascular intervention. As a result, contrast agents became suspect. Grobner12 reported 5 patients with NSF who had magnetic resonance imaging with gadolinium (Gd)–diethylenetriamine-penta-acetic acid (DTPA) contrast 2 to 4 weeks prior to the onset of fibrosis. All of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status.12 Shortly after, Marckmann et al13 published a case series of 13 patients who developed NSF, all within 75 days of Gd contrast exposure; however, there was no correlation with metabolic acidosis in this study. Additional cases have been reported in association with exposure to Gd contrast.14,15 More recently, using electron microscopy with electron dispersion spectroscopy, Gd has been detected in the tissue of some patients with NSF.14,15 On June 8, 2006, the US Food and Drug Administration (FDA) released a public health advisory warning patients and physicians of the possible link between Gd-containing contrast agents and NSF.16 We report another case of NSF associated with Gd-DTPA exposure and propose a plausible explanation for the possible association and pathophysiology of NSF.

Case Report
A 54-year-old man with end-stage diabetic nephropathy status post–renal transplant was evaluated for induration and thickening of the skin. Two months prior, he presented with an infected nonhealing ulcer of the left foot and was admitted to the hospital for intravenous antibiotics. During his hospital stay, he developed an acute exacerbation of his renal failure with a peak creatinine level of 6.7 mg/dL (an increase from his baseline [2–3 mg/dL; reference range, 0.6–1.2 mg/dL]). Evaluation of the ulcer of the lower extremity included Gd-DTPA–enhanced magnetic resonance angiography (MRA) vascular imaging. The day of MRA evaluation, his bicarbonate level was low at 15 mmol/L (reference range, 21–28 mmol/L), his creatinine level was elevated at 4.4 mg/dL, his corrected calcium level was within reference range, and his phosphate level was elevated at 6.1 mg/dL (reference range, 2.5–4.5 mg/dL). The patient's renal status continued to decline over the next several days and hemodialysis was initiated. The patient recalled progressive firmness of the skin, which presented approximately 4 to 6 weeks after his Gd-DTPA exposure. He denied pain, pruritus, or loss of sensation in the affected areas. At and around the time of presentation, the patient was taking calcitriol, calcium, dapsone, darbepoetin alfa, diphenoxylate hydrochloride and atropine sulfate, guar gum, magnesium, metoprolol succinate, mycophenolate mofetil, pantoprazole sodium, prednisone, psyllium, simvastatin, tacrolimus, and warfarin sodium. He was not on an angiotensin-converting enzyme inhibitor. Physical examination revealed subtle erythema overlying woody induration of the skin extending from the bilateral mid upper arms to the hands and from the bilateral mid calves to the anterolateral thighs and flanks, with substantially reduced range of motion in the hands (Figures 1 and 2). Findings from a biopsy specimen showed an increase in cellularity of the dermis, thickened collagen bundles, and subcutaneous septae. Many cells had poorly defined cytoplasms and elongated, plump, enlarged nuclei. Evaluation with elastin stains showed thickened elastic fibers in the dermis. Alcian blue staining revealed an increase in mucin in the dermis and subcutaneous septae consistent with NSF.

Comment
Our patient, like previously described patients,12 had received Gd-DTPA for an MRA a few weeks prior to the onset of NSF. Grobner¹² also demonstrated that all of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status. At the time of Gd-contrast exposure, we can infer that our patient likely had metabolic acidosis based on his bicarbonate level of 15 mmol/L. So the question remains: Is Gd exposure in the presence of a metabolic, or other unclear alteration, the trigger for this new and potentially lethal disorder? Gadolinium is a rare toxic metal that, as a free ion, forms precipitates with anions, such as phosphate, carbonate, hydroxyl, or chloride, and can deposit in tissue.17 To reduce the toxicity, Gd contrast is chelated with other molecules (eg, DTPA) to form soluble ligand complexes, thus stabilizing it intravascularly. Stability is dependent on multiple parameters, including the thermodynamic stability constant, molecular kinetics, solubility constant, and selectivity constants.18 The half-life of chelated Gd is approximately 1.5 to 2 hours and demonstrates a 500-fold increase in renal excretion when compared with elemental Gd.17 In the healthy kidney, approximately 90% of injected Gd-DTPA is excreted in the first 24 hours. However, in cases of renal failure, the half-life of Gd can be more than 30 hours.19,20 Prompt hemodialysis can help clear Gd, with average excretory rates of 78.2% after the first session and up to 99.5% after a fourth session.20 There are 5 Gd-based contrast agents available for clinical use in the United States; however, none have been approved by the FDA for use in MRA.16 The stability of the agents has been studied in vitro and on animal models with healthy kidney function, but stability has not been evaluated in vivo in the setting of renal failure. All of the agents use chelators with very high affinity for Gd ion, but free ion can still be released in the presence of high concentrations of competing ions (metals or acids) or with prolonged exposure.17,19,21 Gadodiamide is the agent that has been used in the majority of patients with NSF reported in the literature, but it is too early at this time to implicate one agent over another and the FDA continues to investigate all Gd-based contrast agents as potential causes of NSF.12-14,16,18 Gadolinium contrast was first approved for clinical use in magnetic resonance imaging in 1988.12 In 1996, its use was favorably reported in patients with renal insufficiency.22 Since 1996, the use of Gd in patients with renal insufficiency has increased in frequency for vascular procedures such as aortography, dialysis fistulography, and renal angiography,17 which correlates well with the initial reports of NSF in 1997 in the United States and Europe.2 Delayed adaptation of this imaging technique could explain the later presentation of NSF in non-Western countries. Although the timing may correlate, how can one explain the possible pathophysiologic link between Gd and NSF? The histopathologic findings of NSF include thickened collagen bundles with surrounding clefts and a variable increase in mucin and elastic fibers. Immunohistochemistry reveals an increased proliferation of CD34+ fibrocytes, which are bone marrow–derived cells that circulate intravascularly and are thought to play a major role in wound healing.23-25 There is increased staining of CD34+/procollagen I+ circulating fibrocytes, transforming growth factor β1, CD68+/factor XIIIa+ monocytes, and multinucleated giant cells.12,23,24 In addition, 2 separate groups have detected Gd in the tissue of patients with NSF.14,15 The first group detected Gd particles in 4 of 13 tissue specimens from 7 patients using electron dispersion spectroscopy. In addition, they noted the Gd particles were likely to be associated with macrophages.14 These results were reproduced in a case report of a patient by Boyd et al.15 It is currently hypothesized that the deposition of CD34+/procollagen I+ circulating fibrocytes plays a major role in the pathophysiology of the disease, but the exact trigger, to this point, has been unclear.3,9 It now appears that Gd also plays a central role in the pathogenesis of NSF. Wound healing is similar in any tissue that has undergone injury and occurs through a stepwise process of inflammation, proliferation, and remodeling. Studies have looked at the role of macrophages in liver injury using a rat model and gadolinium chloride hexahydrate (GdCl3) to inhibit hepatic macrophages (Kupffer cells).26 The current hypothesis is that hepatic injury activates macrophages, resulting in release of proinflammatory cytokines and the subsequent recruitment of systemic macrophages and myofibrocytes.26 With inflammation, a profibrotic response occurs with deposition of types I and III collagen by fibrocytes. During the proliferation and remodeling phases, there is a systematic reversal of many of the cellular and molecular alterations of the inflammatory phase, which is essential to the restoration of healthy liver architecture and function.26 The Kupffer cells are thought to be integral to the repair process via cytokine-mediated paracrine or cell-to-cell stimulus that causes regression of myofibroblasts and degradation of excess collagen with matrix metalloproteinases. Prior experiments have revealed GdCl3-induced macrophage toxicity.27 It is speculated that elemental Gd is turbid above a pH of 6.0 and is engulfed by macrophages. The Gd aggregates may again dissolve in the acidic environment of the endosomes and attach to components of the vesicle membrane. Recycling of endosomes to the plasma membrane may gradually change the cellular membrane causing cell death.27 With the use of GdCl3, Roggin et al26 selectively inhibited Kupffer cells and observed delayed injury repair with increased extracellular matrix, bridging fibrosis and altered collagen metabolism, including increased type I collagen over time in livers of Gd-treated rats compared with the saline-treated controls. In addition, it is believed that fibrocytes undergo several phenotypic changes over the course of wound healing, resulting in modification of their interactions with the surrounding extracellular matrix.28 In 2004, Mori et al25 used a mouse model to show that more than 60% of the circulating bone marrow–derived CD13+/collagen I+/CD45+/CD34+ fibrocytes that migrate to sites of tissue injury become α-smooth muscle actin–positive myofibroblasts by day 7 post–wound healing. They noted down-regulation of expression of CD34 as cells underwent differentiation to myofibroblasts. They concluded that circulating fibrocytes undergo rapid phenotypic change under the influence of local factors once they have migrated to sites of injury.25 Based on these previously reported data, we hypothesize that in the presence of some unclear metabolic alteration, such as acidosis, and renal failure, exposure to high-dose Gd (as in MRA) for prolonged periods of time could result in Gd ion dissociation from its chelator. The Gd ion may precipitate with other anions, such as phosphate, or other metals, such as iron, and deposit in any tissue, resulting in local macrophage recruitment to engulf the elemental Gd. This theory could explain the initial tissue injury and the presence of multinucleated giant cells. The macrophages could recruit proinflammatory cells, such as CD34+ fibrocytes; however, the elemental Gd may cause early macrophage death, as previously demonstrated.27 The loss of macrophages could result in an aberrant tissue injury response with failure to progress to the remodeling stage. The persistent proinflammatory/recruitment stage with loss of functional macrophages could explain the high proportion of CD34+ fibrocytes, as they lack macrophage-derived stimulus to undergo appropriate phenotypic/functional change. Ultimately, we propose that NSF may stem from elemental Gd–induced macrophage death (Table).

Although there appears to be a strong association between Gd exposure and NSF, potential triggers are still being evaluated. In the past decade, there has been a dramatic shift to the use of MRA with Gd contrast in patients with renal failure due to known contrast-induced nephropathy observed with iodinated contrast. Considering the number of patients with renal failure receiving Gd contrast, Gd exposure alone is unlikely to be the sole cause of NSF and is more likely a component in a multifactorial process; however, the other risk factors remain elusive. MRA technology has been lifesaving for many patients with renal failure and remains a medical necessity in many situations, but the possible link to NSF may result in a need to modify current medical practices. The FDA's public health advisory strongly recommends prompt initiation of dialysis in any patient with advanced kidney disease who undergoes MRA with Gd.16 With the potential association of the dissociation of Gd chelates in an acidic environment, it also may be prudent to consider normalizing the pH of patients with bicarbonate infusion prior to MRA. At this time, further studies evaluating the safety of Gd contrast, its possible link to NSF, and the possible role of macrophage inhibition in the pathophysiology of NSF are needed.

Nephrogenic fibrosing dermopathy (NFD) is an acquired idiopathic disorder seen exclusively in patients with renal failure. It was first recognized in 1997 in a group of patients following renal transplant.1,2 Symmetric, thickened, fibrotic skin with brawny hyperpigmentation develops and primarily affects the limbs, sparing the head and neck. Associated symptoms include flexion contracture, pain, paresthesia, and/or severe pruritus. Yellow palmar papules and yellow scleral plaques also have been described. Although fibrosis initially was observed in the skin, more recent evidence suggests that NFD is a systemic disorder with variable and still unclear degrees of end organ damage, particularly pulmonary fibrosis.3-7 In light of the systemic involvement and newly described, rapidly progressive, fatal cases of NFD, the name has been changed to nephrogenic systemic fibrosis (NSF).3 Since 1997, more than 200 cases have been compiled through the Yale University NSF Registry. All patients have the unifying diagnosis of renal failure, but the disease has been observed in patients independent of age, gender, dialysis history, kidney transplant status, or the underlying cause of renal failure.8,9 The majority of cases have been reported in the United States and Europe, but new cases are now being reported in non-Western populations.10,11 Given the novelty of the disease and the limited number of cases, the etiology has been elusive; however, most new diseases have some iatrogenic component. Prior to onset, many patients with NSF experienced coagulation abnormalities, transplant rejection, or some type of vascular intervention. As a result, contrast agents became suspect. Grobner12 reported 5 patients with NSF who had magnetic resonance imaging with gadolinium (Gd)–diethylenetriamine-penta-acetic acid (DTPA) contrast 2 to 4 weeks prior to the onset of fibrosis. All of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status.12 Shortly after, Marckmann et al13 published a case series of 13 patients who developed NSF, all within 75 days of Gd contrast exposure; however, there was no correlation with metabolic acidosis in this study. Additional cases have been reported in association with exposure to Gd contrast.14,15 More recently, using electron microscopy with electron dispersion spectroscopy, Gd has been detected in the tissue of some patients with NSF.14,15 On June 8, 2006, the US Food and Drug Administration (FDA) released a public health advisory warning patients and physicians of the possible link between Gd-containing contrast agents and NSF.16 We report another case of NSF associated with Gd-DTPA exposure and propose a plausible explanation for the possible association and pathophysiology of NSF.

Case Report
A 54-year-old man with end-stage diabetic nephropathy status post–renal transplant was evaluated for induration and thickening of the skin. Two months prior, he presented with an infected nonhealing ulcer of the left foot and was admitted to the hospital for intravenous antibiotics. During his hospital stay, he developed an acute exacerbation of his renal failure with a peak creatinine level of 6.7 mg/dL (an increase from his baseline [2–3 mg/dL; reference range, 0.6–1.2 mg/dL]). Evaluation of the ulcer of the lower extremity included Gd-DTPA–enhanced magnetic resonance angiography (MRA) vascular imaging. The day of MRA evaluation, his bicarbonate level was low at 15 mmol/L (reference range, 21–28 mmol/L), his creatinine level was elevated at 4.4 mg/dL, his corrected calcium level was within reference range, and his phosphate level was elevated at 6.1 mg/dL (reference range, 2.5–4.5 mg/dL). The patient's renal status continued to decline over the next several days and hemodialysis was initiated. The patient recalled progressive firmness of the skin, which presented approximately 4 to 6 weeks after his Gd-DTPA exposure. He denied pain, pruritus, or loss of sensation in the affected areas. At and around the time of presentation, the patient was taking calcitriol, calcium, dapsone, darbepoetin alfa, diphenoxylate hydrochloride and atropine sulfate, guar gum, magnesium, metoprolol succinate, mycophenolate mofetil, pantoprazole sodium, prednisone, psyllium, simvastatin, tacrolimus, and warfarin sodium. He was not on an angiotensin-converting enzyme inhibitor. Physical examination revealed subtle erythema overlying woody induration of the skin extending from the bilateral mid upper arms to the hands and from the bilateral mid calves to the anterolateral thighs and flanks, with substantially reduced range of motion in the hands (Figures 1 and 2). Findings from a biopsy specimen showed an increase in cellularity of the dermis, thickened collagen bundles, and subcutaneous septae. Many cells had poorly defined cytoplasms and elongated, plump, enlarged nuclei. Evaluation with elastin stains showed thickened elastic fibers in the dermis. Alcian blue staining revealed an increase in mucin in the dermis and subcutaneous septae consistent with NSF.

Comment
Our patient, like previously described patients,12 had received Gd-DTPA for an MRA a few weeks prior to the onset of NSF. Grobner¹² also demonstrated that all of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status. At the time of Gd-contrast exposure, we can infer that our patient likely had metabolic acidosis based on his bicarbonate level of 15 mmol/L. So the question remains: Is Gd exposure in the presence of a metabolic, or other unclear alteration, the trigger for this new and potentially lethal disorder? Gadolinium is a rare toxic metal that, as a free ion, forms precipitates with anions, such as phosphate, carbonate, hydroxyl, or chloride, and can deposit in tissue.17 To reduce the toxicity, Gd contrast is chelated with other molecules (eg, DTPA) to form soluble ligand complexes, thus stabilizing it intravascularly. Stability is dependent on multiple parameters, including the thermodynamic stability constant, molecular kinetics, solubility constant, and selectivity constants.18 The half-life of chelated Gd is approximately 1.5 to 2 hours and demonstrates a 500-fold increase in renal excretion when compared with elemental Gd.17 In the healthy kidney, approximately 90% of injected Gd-DTPA is excreted in the first 24 hours. However, in cases of renal failure, the half-life of Gd can be more than 30 hours.19,20 Prompt hemodialysis can help clear Gd, with average excretory rates of 78.2% after the first session and up to 99.5% after a fourth session.20 There are 5 Gd-based contrast agents available for clinical use in the United States; however, none have been approved by the FDA for use in MRA.16 The stability of the agents has been studied in vitro and on animal models with healthy kidney function, but stability has not been evaluated in vivo in the setting of renal failure. All of the agents use chelators with very high affinity for Gd ion, but free ion can still be released in the presence of high concentrations of competing ions (metals or acids) or with prolonged exposure.17,19,21 Gadodiamide is the agent that has been used in the majority of patients with NSF reported in the literature, but it is too early at this time to implicate one agent over another and the FDA continues to investigate all Gd-based contrast agents as potential causes of NSF.12-14,16,18 Gadolinium contrast was first approved for clinical use in magnetic resonance imaging in 1988.12 In 1996, its use was favorably reported in patients with renal insufficiency.22 Since 1996, the use of Gd in patients with renal insufficiency has increased in frequency for vascular procedures such as aortography, dialysis fistulography, and renal angiography,17 which correlates well with the initial reports of NSF in 1997 in the United States and Europe.2 Delayed adaptation of this imaging technique could explain the later presentation of NSF in non-Western countries. Although the timing may correlate, how can one explain the possible pathophysiologic link between Gd and NSF? The histopathologic findings of NSF include thickened collagen bundles with surrounding clefts and a variable increase in mucin and elastic fibers. Immunohistochemistry reveals an increased proliferation of CD34+ fibrocytes, which are bone marrow–derived cells that circulate intravascularly and are thought to play a major role in wound healing.23-25 There is increased staining of CD34+/procollagen I+ circulating fibrocytes, transforming growth factor β1, CD68+/factor XIIIa+ monocytes, and multinucleated giant cells.12,23,24 In addition, 2 separate groups have detected Gd in the tissue of patients with NSF.14,15 The first group detected Gd particles in 4 of 13 tissue specimens from 7 patients using electron dispersion spectroscopy. In addition, they noted the Gd particles were likely to be associated with macrophages.14 These results were reproduced in a case report of a patient by Boyd et al.15 It is currently hypothesized that the deposition of CD34+/procollagen I+ circulating fibrocytes plays a major role in the pathophysiology of the disease, but the exact trigger, to this point, has been unclear.3,9 It now appears that Gd also plays a central role in the pathogenesis of NSF. Wound healing is similar in any tissue that has undergone injury and occurs through a stepwise process of inflammation, proliferation, and remodeling. Studies have looked at the role of macrophages in liver injury using a rat model and gadolinium chloride hexahydrate (GdCl3) to inhibit hepatic macrophages (Kupffer cells).26 The current hypothesis is that hepatic injury activates macrophages, resulting in release of proinflammatory cytokines and the subsequent recruitment of systemic macrophages and myofibrocytes.26 With inflammation, a profibrotic response occurs with deposition of types I and III collagen by fibrocytes. During the proliferation and remodeling phases, there is a systematic reversal of many of the cellular and molecular alterations of the inflammatory phase, which is essential to the restoration of healthy liver architecture and function.26 The Kupffer cells are thought to be integral to the repair process via cytokine-mediated paracrine or cell-to-cell stimulus that causes regression of myofibroblasts and degradation of excess collagen with matrix metalloproteinases. Prior experiments have revealed GdCl3-induced macrophage toxicity.27 It is speculated that elemental Gd is turbid above a pH of 6.0 and is engulfed by macrophages. The Gd aggregates may again dissolve in the acidic environment of the endosomes and attach to components of the vesicle membrane. Recycling of endosomes to the plasma membrane may gradually change the cellular membrane causing cell death.27 With the use of GdCl3, Roggin et al26 selectively inhibited Kupffer cells and observed delayed injury repair with increased extracellular matrix, bridging fibrosis and altered collagen metabolism, including increased type I collagen over time in livers of Gd-treated rats compared with the saline-treated controls. In addition, it is believed that fibrocytes undergo several phenotypic changes over the course of wound healing, resulting in modification of their interactions with the surrounding extracellular matrix.28 In 2004, Mori et al25 used a mouse model to show that more than 60% of the circulating bone marrow–derived CD13+/collagen I+/CD45+/CD34+ fibrocytes that migrate to sites of tissue injury become α-smooth muscle actin–positive myofibroblasts by day 7 post–wound healing. They noted down-regulation of expression of CD34 as cells underwent differentiation to myofibroblasts. They concluded that circulating fibrocytes undergo rapid phenotypic change under the influence of local factors once they have migrated to sites of injury.25 Based on these previously reported data, we hypothesize that in the presence of some unclear metabolic alteration, such as acidosis, and renal failure, exposure to high-dose Gd (as in MRA) for prolonged periods of time could result in Gd ion dissociation from its chelator. The Gd ion may precipitate with other anions, such as phosphate, or other metals, such as iron, and deposit in any tissue, resulting in local macrophage recruitment to engulf the elemental Gd. This theory could explain the initial tissue injury and the presence of multinucleated giant cells. The macrophages could recruit proinflammatory cells, such as CD34+ fibrocytes; however, the elemental Gd may cause early macrophage death, as previously demonstrated.27 The loss of macrophages could result in an aberrant tissue injury response with failure to progress to the remodeling stage. The persistent proinflammatory/recruitment stage with loss of functional macrophages could explain the high proportion of CD34+ fibrocytes, as they lack macrophage-derived stimulus to undergo appropriate phenotypic/functional change. Ultimately, we propose that NSF may stem from elemental Gd–induced macrophage death (Table).

Although there appears to be a strong association between Gd exposure and NSF, potential triggers are still being evaluated. In the past decade, there has been a dramatic shift to the use of MRA with Gd contrast in patients with renal failure due to known contrast-induced nephropathy observed with iodinated contrast. Considering the number of patients with renal failure receiving Gd contrast, Gd exposure alone is unlikely to be the sole cause of NSF and is more likely a component in a multifactorial process; however, the other risk factors remain elusive. MRA technology has been lifesaving for many patients with renal failure and remains a medical necessity in many situations, but the possible link to NSF may result in a need to modify current medical practices. The FDA's public health advisory strongly recommends prompt initiation of dialysis in any patient with advanced kidney disease who undergoes MRA with Gd.16 With the potential association of the dissociation of Gd chelates in an acidic environment, it also may be prudent to consider normalizing the pH of patients with bicarbonate infusion prior to MRA. At this time, further studies evaluating the safety of Gd contrast, its possible link to NSF, and the possible role of macrophage inhibition in the pathophysiology of NSF are needed.

Nephrogenic fibrosing dermopathy (NFD) is an acquired idiopathic disorder seen exclusively in patients with renal failure. It was first recognized in 1997 in a group of patients following renal transplant.1,2 Symmetric, thickened, fibrotic skin with brawny hyperpigmentation develops and primarily affects the limbs, sparing the head and neck. Associated symptoms include flexion contracture, pain, paresthesia, and/or severe pruritus. Yellow palmar papules and yellow scleral plaques also have been described. Although fibrosis initially was observed in the skin, more recent evidence suggests that NFD is a systemic disorder with variable and still unclear degrees of end organ damage, particularly pulmonary fibrosis.3-7 In light of the systemic involvement and newly described, rapidly progressive, fatal cases of NFD, the name has been changed to nephrogenic systemic fibrosis (NSF).3 Since 1997, more than 200 cases have been compiled through the Yale University NSF Registry. All patients have the unifying diagnosis of renal failure, but the disease has been observed in patients independent of age, gender, dialysis history, kidney transplant status, or the underlying cause of renal failure.8,9 The majority of cases have been reported in the United States and Europe, but new cases are now being reported in non-Western populations.10,11 Given the novelty of the disease and the limited number of cases, the etiology has been elusive; however, most new diseases have some iatrogenic component. Prior to onset, many patients with NSF experienced coagulation abnormalities, transplant rejection, or some type of vascular intervention. As a result, contrast agents became suspect. Grobner12 reported 5 patients with NSF who had magnetic resonance imaging with gadolinium (Gd)–diethylenetriamine-penta-acetic acid (DTPA) contrast 2 to 4 weeks prior to the onset of fibrosis. All of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status.12 Shortly after, Marckmann et al13 published a case series of 13 patients who developed NSF, all within 75 days of Gd contrast exposure; however, there was no correlation with metabolic acidosis in this study. Additional cases have been reported in association with exposure to Gd contrast.14,15 More recently, using electron microscopy with electron dispersion spectroscopy, Gd has been detected in the tissue of some patients with NSF.14,15 On June 8, 2006, the US Food and Drug Administration (FDA) released a public health advisory warning patients and physicians of the possible link between Gd-containing contrast agents and NSF.16 We report another case of NSF associated with Gd-DTPA exposure and propose a plausible explanation for the possible association and pathophysiology of NSF.

Case Report
A 54-year-old man with end-stage diabetic nephropathy status post–renal transplant was evaluated for induration and thickening of the skin. Two months prior, he presented with an infected nonhealing ulcer of the left foot and was admitted to the hospital for intravenous antibiotics. During his hospital stay, he developed an acute exacerbation of his renal failure with a peak creatinine level of 6.7 mg/dL (an increase from his baseline [2–3 mg/dL; reference range, 0.6–1.2 mg/dL]). Evaluation of the ulcer of the lower extremity included Gd-DTPA–enhanced magnetic resonance angiography (MRA) vascular imaging. The day of MRA evaluation, his bicarbonate level was low at 15 mmol/L (reference range, 21–28 mmol/L), his creatinine level was elevated at 4.4 mg/dL, his corrected calcium level was within reference range, and his phosphate level was elevated at 6.1 mg/dL (reference range, 2.5–4.5 mg/dL). The patient's renal status continued to decline over the next several days and hemodialysis was initiated. The patient recalled progressive firmness of the skin, which presented approximately 4 to 6 weeks after his Gd-DTPA exposure. He denied pain, pruritus, or loss of sensation in the affected areas. At and around the time of presentation, the patient was taking calcitriol, calcium, dapsone, darbepoetin alfa, diphenoxylate hydrochloride and atropine sulfate, guar gum, magnesium, metoprolol succinate, mycophenolate mofetil, pantoprazole sodium, prednisone, psyllium, simvastatin, tacrolimus, and warfarin sodium. He was not on an angiotensin-converting enzyme inhibitor. Physical examination revealed subtle erythema overlying woody induration of the skin extending from the bilateral mid upper arms to the hands and from the bilateral mid calves to the anterolateral thighs and flanks, with substantially reduced range of motion in the hands (Figures 1 and 2). Findings from a biopsy specimen showed an increase in cellularity of the dermis, thickened collagen bundles, and subcutaneous septae. Many cells had poorly defined cytoplasms and elongated, plump, enlarged nuclei. Evaluation with elastin stains showed thickened elastic fibers in the dermis. Alcian blue staining revealed an increase in mucin in the dermis and subcutaneous septae consistent with NSF.

Comment
Our patient, like previously described patients,12 had received Gd-DTPA for an MRA a few weeks prior to the onset of NSF. Grobner¹² also demonstrated that all of the patients with NSF were acidotic, in contrast to a similar unaffected group of patients with normal acid-base status. At the time of Gd-contrast exposure, we can infer that our patient likely had metabolic acidosis based on his bicarbonate level of 15 mmol/L. So the question remains: Is Gd exposure in the presence of a metabolic, or other unclear alteration, the trigger for this new and potentially lethal disorder? Gadolinium is a rare toxic metal that, as a free ion, forms precipitates with anions, such as phosphate, carbonate, hydroxyl, or chloride, and can deposit in tissue.17 To reduce the toxicity, Gd contrast is chelated with other molecules (eg, DTPA) to form soluble ligand complexes, thus stabilizing it intravascularly. Stability is dependent on multiple parameters, including the thermodynamic stability constant, molecular kinetics, solubility constant, and selectivity constants.18 The half-life of chelated Gd is approximately 1.5 to 2 hours and demonstrates a 500-fold increase in renal excretion when compared with elemental Gd.17 In the healthy kidney, approximately 90% of injected Gd-DTPA is excreted in the first 24 hours. However, in cases of renal failure, the half-life of Gd can be more than 30 hours.19,20 Prompt hemodialysis can help clear Gd, with average excretory rates of 78.2% after the first session and up to 99.5% after a fourth session.20 There are 5 Gd-based contrast agents available for clinical use in the United States; however, none have been approved by the FDA for use in MRA.16 The stability of the agents has been studied in vitro and on animal models with healthy kidney function, but stability has not been evaluated in vivo in the setting of renal failure. All of the agents use chelators with very high affinity for Gd ion, but free ion can still be released in the presence of high concentrations of competing ions (metals or acids) or with prolonged exposure.17,19,21 Gadodiamide is the agent that has been used in the majority of patients with NSF reported in the literature, but it is too early at this time to implicate one agent over another and the FDA continues to investigate all Gd-based contrast agents as potential causes of NSF.12-14,16,18 Gadolinium contrast was first approved for clinical use in magnetic resonance imaging in 1988.12 In 1996, its use was favorably reported in patients with renal insufficiency.22 Since 1996, the use of Gd in patients with renal insufficiency has increased in frequency for vascular procedures such as aortography, dialysis fistulography, and renal angiography,17 which correlates well with the initial reports of NSF in 1997 in the United States and Europe.2 Delayed adaptation of this imaging technique could explain the later presentation of NSF in non-Western countries. Although the timing may correlate, how can one explain the possible pathophysiologic link between Gd and NSF? The histopathologic findings of NSF include thickened collagen bundles with surrounding clefts and a variable increase in mucin and elastic fibers. Immunohistochemistry reveals an increased proliferation of CD34+ fibrocytes, which are bone marrow–derived cells that circulate intravascularly and are thought to play a major role in wound healing.23-25 There is increased staining of CD34+/procollagen I+ circulating fibrocytes, transforming growth factor β1, CD68+/factor XIIIa+ monocytes, and multinucleated giant cells.12,23,24 In addition, 2 separate groups have detected Gd in the tissue of patients with NSF.14,15 The first group detected Gd particles in 4 of 13 tissue specimens from 7 patients using electron dispersion spectroscopy. In addition, they noted the Gd particles were likely to be associated with macrophages.14 These results were reproduced in a case report of a patient by Boyd et al.15 It is currently hypothesized that the deposition of CD34+/procollagen I+ circulating fibrocytes plays a major role in the pathophysiology of the disease, but the exact trigger, to this point, has been unclear.3,9 It now appears that Gd also plays a central role in the pathogenesis of NSF. Wound healing is similar in any tissue that has undergone injury and occurs through a stepwise process of inflammation, proliferation, and remodeling. Studies have looked at the role of macrophages in liver injury using a rat model and gadolinium chloride hexahydrate (GdCl3) to inhibit hepatic macrophages (Kupffer cells).26 The current hypothesis is that hepatic injury activates macrophages, resulting in release of proinflammatory cytokines and the subsequent recruitment of systemic macrophages and myofibrocytes.26 With inflammation, a profibrotic response occurs with deposition of types I and III collagen by fibrocytes. During the proliferation and remodeling phases, there is a systematic reversal of many of the cellular and molecular alterations of the inflammatory phase, which is essential to the restoration of healthy liver architecture and function.26 The Kupffer cells are thought to be integral to the repair process via cytokine-mediated paracrine or cell-to-cell stimulus that causes regression of myofibroblasts and degradation of excess collagen with matrix metalloproteinases. Prior experiments have revealed GdCl3-induced macrophage toxicity.27 It is speculated that elemental Gd is turbid above a pH of 6.0 and is engulfed by macrophages. The Gd aggregates may again dissolve in the acidic environment of the endosomes and attach to components of the vesicle membrane. Recycling of endosomes to the plasma membrane may gradually change the cellular membrane causing cell death.27 With the use of GdCl3, Roggin et al26 selectively inhibited Kupffer cells and observed delayed injury repair with increased extracellular matrix, bridging fibrosis and altered collagen metabolism, including increased type I collagen over time in livers of Gd-treated rats compared with the saline-treated controls. In addition, it is believed that fibrocytes undergo several phenotypic changes over the course of wound healing, resulting in modification of their interactions with the surrounding extracellular matrix.28 In 2004, Mori et al25 used a mouse model to show that more than 60% of the circulating bone marrow–derived CD13+/collagen I+/CD45+/CD34+ fibrocytes that migrate to sites of tissue injury become α-smooth muscle actin–positive myofibroblasts by day 7 post–wound healing. They noted down-regulation of expression of CD34 as cells underwent differentiation to myofibroblasts. They concluded that circulating fibrocytes undergo rapid phenotypic change under the influence of local factors once they have migrated to sites of injury.25 Based on these previously reported data, we hypothesize that in the presence of some unclear metabolic alteration, such as acidosis, and renal failure, exposure to high-dose Gd (as in MRA) for prolonged periods of time could result in Gd ion dissociation from its chelator. The Gd ion may precipitate with other anions, such as phosphate, or other metals, such as iron, and deposit in any tissue, resulting in local macrophage recruitment to engulf the elemental Gd. This theory could explain the initial tissue injury and the presence of multinucleated giant cells. The macrophages could recruit proinflammatory cells, such as CD34+ fibrocytes; however, the elemental Gd may cause early macrophage death, as previously demonstrated.27 The loss of macrophages could result in an aberrant tissue injury response with failure to progress to the remodeling stage. The persistent proinflammatory/recruitment stage with loss of functional macrophages could explain the high proportion of CD34+ fibrocytes, as they lack macrophage-derived stimulus to undergo appropriate phenotypic/functional change. Ultimately, we propose that NSF may stem from elemental Gd–induced macrophage death (Table).

Although there appears to be a strong association between Gd exposure and NSF, potential triggers are still being evaluated. In the past decade, there has been a dramatic shift to the use of MRA with Gd contrast in patients with renal failure due to known contrast-induced nephropathy observed with iodinated contrast. Considering the number of patients with renal failure receiving Gd contrast, Gd exposure alone is unlikely to be the sole cause of NSF and is more likely a component in a multifactorial process; however, the other risk factors remain elusive. MRA technology has been lifesaving for many patients with renal failure and remains a medical necessity in many situations, but the possible link to NSF may result in a need to modify current medical practices. The FDA's public health advisory strongly recommends prompt initiation of dialysis in any patient with advanced kidney disease who undergoes MRA with Gd.16 With the potential association of the dissociation of Gd chelates in an acidic environment, it also may be prudent to consider normalizing the pH of patients with bicarbonate infusion prior to MRA. At this time, further studies evaluating the safety of Gd contrast, its possible link to NSF, and the possible role of macrophage inhibition in the pathophysiology of NSF are needed.

Brachioradial pruritus is an enigmatic entity characterized by pruritus localized to the skin overlying the proximal heads of the brachioradialis muscle, with few other clinical symptoms.1-5 It was first described by Waisman⁶ in 1968. Brachioradial pruritus characteristically affects middle-aged women residing in tropical to temperate climates, though it may occur in males and individuals residing in other climates.1-8 It often presents as tingling, burning pruritus on the dorsal aspect of the forearm. Pruritus may be unilateral or bilateral and may extend up the arm and across the upper back. It often is described as burning, stinging, or painful, and is seasonal in nature, often presenting in late summer and lasting into December.1-5 Brachioradial pruritus was originally associated with solar exposure and UV radiation. Later, Heyl9 proposed that cervical nerve root impingement or injury secondary to cervical trauma was causative. Although a true cause remains elusive, both actinic damage and cervical spine disease are likely involved. We discuss an otherwise healthy woman who presented with nonspecific pruritus consistent with brachioradial pruritus.

Case Report
A 46-year-old woman presented with persistent pruritus of the left proximal lateral forearm. The pruritus had been present for several years and was recalcitrant to a multitude of therapeutic modalities, including topical corticosteroids and oral antihistamines. Application of heat did not affect her symptoms; however, application of cold compresses did alleviate some of the pruritus. Her medical history was noncontributory. Her surgical history was pertinent for prior anterior cervical discectomy and fusion from C4 to C6. Physical examination revealed no obvious cutaneous lesions in the site other than mild erythema secondary to scratching. Magnetic resonance imaging of her cervical spine revealed a left-sided osteophyte causing minimal left neural foraminal stenosis at the level of C3 to C4 (Figure). Electromyography and nerve conduction velocity studies of the left upper extremity revealed a mildly prolonged left median sensory latency. The patient was treated with topical capsaicin cream with moderate success. She also was advised to avoid sun exposure to the affected area.

Comment
Brachioradial pruritus affects a focal circumscribed area of the proximal lateral forearm. The area typically involves a sun-exposed region and may include the forearm, arm, shoulder, neck, and/or upper thorax.2 Middle-aged women are most commonly affected, with tingling, burning, and pruritus of the affected area.1 Symptoms may last from August to December and may subside during the winter.1-5 Pruritus may be unilateral or bilateral. The nature of the pruritus is often described as burning, stinging, or painful, and manifests a seasonal relation, with high incidence in late summer corresponding with the highest UV exposure.1 Patients may report intensification of pruritus with scratching, which may be related to damage of peripheral nerve fibers.2,10 This intensification may, in part, be secondary to chronic UVA irradiation.11 Involvement of C fibers containing neuropeptides responsible for pruritus explains the rationale for treatment with topical capsaicin.2,5 Application of ice often is the only means of alleviating pruritus.10,12 The consistency of relief with ice is useful in the diagnostic screening of this entity.10 The neurophysiology of pruritus is not fully understood. However, it is known that Aδ and C fibers are responsible for the transmission of pruritus.9 Pruritus can be categorized as pruritoceptive (originating in the skin) or neurogenic (originating in the central nervous system), or a combination of both. The Aδ and C fibers are co-responsive to temperature change as well as pruritus. Increases in skin temperature lower the threshold of cutaneous pruritus receptor units.13 The neural pathway for pruritus has been established. Nociceptor C fibers transmit impulses to the dorsal horn of the spinal cord and then to the thalamus via the spinothalamic tract.14 Scratching typically relieves the sensation of pruritus.15 The gate-control theory postulates that afferent sensory input from cutaneous C fibers is modulated by a gate-control system at the level of the spinal cord.5,16,17 A subsequent Aδ impulse may act in a negative feedback method to shut off C-fiber stimulation. However, stimulation of Aδ fibers in brachioradial pruritus paradoxically seems to potentiate the sensation of pruritus.5 Wallengren5 suggested that local damage to peripheral nerve fibers could be responsible for this potentiation of pruritic sensation. Kumakiri et al18 demonstrated ultrastructural damage to dermal nerve fibers following UVA irradiation. UV radiation has been shown to cause a sensitizing effect on sensory nerve fibers and lower the threshold for sensory nerve stimulation, which may occur via direct effects of UV exposure or by release of neural mediators.19 The pathophysiology of brachioradial pruritus is controversial. The 2 proposed associations are UV exposure and cervical spine disease.20 Wallengren and Sundler2 proposed that solar-induced nerve injury is responsible for brachioradial pruritus. UV radiation may be an eliciting factor, while cervical spine disease may be a predisposing factor.2 On the contrary, Fisher21 reported on the association of cervical nerve root impingement and involvement of 1 or more of the C5 to C8 cervical nerve root segments. Brachioradial pruritus has been reported in association with an ependymoma and secondary to cervical nerve compression.9,22 In a report by Heyl,9 4 of 14 patients demonstrated evidence of degenerative changes and osteoarthritis between C4 and C7. In addition, Heyl9 noted that brachioradial pruritus may be caused by compression of structures not identified by cervical radiographs. In a series of 11 patients with brachioradial pruritus who underwent radiography of the spine, Goodkin et al12 found that all patients demonstrated radiographic abnormalities of the cervical spine. Magnetic resonance imaging is the most reliable diagnostic method for cervical nerve root compression.20,22 Recently, Crevits20 suggested that neural damage from peripheral nerves by solar radiation or local injury or from central sensory pathways, such as cervical spine disease, is a nonspecific cause. In view of the literature, a definitive pathophysiology for brachioradial pruritus does not exist. It is clear that it is a unique clinical entity, but the pathophysiologic basis is not known. While the association between cervical spine disease and brachioradial pruritus is not fully understood, the prevalence of cervical spine disease is higher in patients with brachioradial pruritus.12 It has not been determined if this association is causal or causative.20 A similar localized itch syndrome, notalgia paresthetica (NP), also has been examined with respect to cervical spine pathology.12,23-25 NP is similar to brachioradial pruritus but involves the dorsal spinal nerves. Savk et al23 found the presence of vertebral column pathology in 7 of 10 patients with NP. A subsequent larger study involving 43 patients with NP reported that in 34 patients (79%), spinal pathology had been detected by radiographs. Additionally, in 65% of patients (28/43), changes were most prominent in the vertebrae and corresponded to clinically involved dermatomes.24 However, not all pathologies are detectable via radiographic imaging.25 Thus, Savk and Savk25 reinforced the necessity of clinical and radiographic examination. Histologic examination is not necessary for the clinical diagnosis of brachioradial pruritus. Cutaneous biopsies most often demonstrate nonspecific findings and/or chronic solar damage. Wallengren and Sundler2 compared cutaneous biopsies in afflicted and control patients utilizing antibodies against a pan-neuronal marker, protein gene product 9.5, calcitonin gene-related peptide, and vanilloid receptor subtype 1 (VR1) for capsaicin-sensitive nerve structures. The number of protein gene product 9.5 immunoreative nerve fibers was reduced in pruritic skin by 23% to 43%.2 These findings suggest that brachioradial pruritus may be elicited by exposure to UV radiation and/or heat. Wallengren and Sundler2 noted one patient who relapsed with pruritus during the winter following use of a heating pad to relieve neck pain, which supports the notion that UV radiation and/or heat may be causative. Immunohistochemical studies demonstrated protein gene product 9.5 immunoreactive nerve fibers in a dense population in the epidermis and the dermis and calcitonin gene-related peptide immunoreactive nerve fibers located primarily in the dermis. Capsaicin-sensitive VR1 immunoreactive nerve fibers were located as free nerve fibers.2 Wallengren and Sundler2 proposed that the VR1 structures are associated with thermoreception. The reduction in nerve fibers via all markers in patients with brachioradial pruritus implicates their role. Furthermore, these histologic changes resemble those found in patients after serial phototherapy.2,26 Underlying cervical spine disease may amplify this pruritus. Treatment of brachioradial pruritus includes a multitude of possible topical and oral modalities, such as topical capsaicin, gabapentin, carbamazepine, oxcarbamazepine, cervical spine manipulation, anti-inflammatory medications, surgical rib resection, avoidance of sun exposure, and lamotrigine.1,3,5,12,20,21,27-32 Pruritus is a common symptom with a multitude of potential causes, some of which are never diagnosed. The absence of cutaneous signs makes diagnosis more difficult; however, the consistency of anatomic location and historical characteristics make the diagnosis of brachioradial pruritus possible. In addition, relief of pruritus with application of ice helps to confirm the diagnosis.10 A familial form of brachioradial pruritus was reported with a dominant and possible X-linked inheritance pattern.33 While an association between brachioradial pruritus and cervical spine disease is present, cervical spine disease alone cannot explain the pathophysiology of brachioradial pruritus. Furthermore, cervical spine disease undetectable by radiography may hinder a definitive understanding of this association. It is likely that both UV exposure and cervical spine disease contribute to this entity.

Brachioradial pruritus is an enigmatic entity characterized by pruritus localized to the skin overlying the proximal heads of the brachioradialis muscle, with few other clinical symptoms.1-5 It was first described by Waisman⁶ in 1968. Brachioradial pruritus characteristically affects middle-aged women residing in tropical to temperate climates, though it may occur in males and individuals residing in other climates.1-8 It often presents as tingling, burning pruritus on the dorsal aspect of the forearm. Pruritus may be unilateral or bilateral and may extend up the arm and across the upper back. It often is described as burning, stinging, or painful, and is seasonal in nature, often presenting in late summer and lasting into December.1-5 Brachioradial pruritus was originally associated with solar exposure and UV radiation. Later, Heyl9 proposed that cervical nerve root impingement or injury secondary to cervical trauma was causative. Although a true cause remains elusive, both actinic damage and cervical spine disease are likely involved. We discuss an otherwise healthy woman who presented with nonspecific pruritus consistent with brachioradial pruritus.

Case Report
A 46-year-old woman presented with persistent pruritus of the left proximal lateral forearm. The pruritus had been present for several years and was recalcitrant to a multitude of therapeutic modalities, including topical corticosteroids and oral antihistamines. Application of heat did not affect her symptoms; however, application of cold compresses did alleviate some of the pruritus. Her medical history was noncontributory. Her surgical history was pertinent for prior anterior cervical discectomy and fusion from C4 to C6. Physical examination revealed no obvious cutaneous lesions in the site other than mild erythema secondary to scratching. Magnetic resonance imaging of her cervical spine revealed a left-sided osteophyte causing minimal left neural foraminal stenosis at the level of C3 to C4 (Figure). Electromyography and nerve conduction velocity studies of the left upper extremity revealed a mildly prolonged left median sensory latency. The patient was treated with topical capsaicin cream with moderate success. She also was advised to avoid sun exposure to the affected area.

Comment
Brachioradial pruritus affects a focal circumscribed area of the proximal lateral forearm. The area typically involves a sun-exposed region and may include the forearm, arm, shoulder, neck, and/or upper thorax.2 Middle-aged women are most commonly affected, with tingling, burning, and pruritus of the affected area.1 Symptoms may last from August to December and may subside during the winter.1-5 Pruritus may be unilateral or bilateral. The nature of the pruritus is often described as burning, stinging, or painful, and manifests a seasonal relation, with high incidence in late summer corresponding with the highest UV exposure.1 Patients may report intensification of pruritus with scratching, which may be related to damage of peripheral nerve fibers.2,10 This intensification may, in part, be secondary to chronic UVA irradiation.11 Involvement of C fibers containing neuropeptides responsible for pruritus explains the rationale for treatment with topical capsaicin.2,5 Application of ice often is the only means of alleviating pruritus.10,12 The consistency of relief with ice is useful in the diagnostic screening of this entity.10 The neurophysiology of pruritus is not fully understood. However, it is known that Aδ and C fibers are responsible for the transmission of pruritus.9 Pruritus can be categorized as pruritoceptive (originating in the skin) or neurogenic (originating in the central nervous system), or a combination of both. The Aδ and C fibers are co-responsive to temperature change as well as pruritus. Increases in skin temperature lower the threshold of cutaneous pruritus receptor units.13 The neural pathway for pruritus has been established. Nociceptor C fibers transmit impulses to the dorsal horn of the spinal cord and then to the thalamus via the spinothalamic tract.14 Scratching typically relieves the sensation of pruritus.15 The gate-control theory postulates that afferent sensory input from cutaneous C fibers is modulated by a gate-control system at the level of the spinal cord.5,16,17 A subsequent Aδ impulse may act in a negative feedback method to shut off C-fiber stimulation. However, stimulation of Aδ fibers in brachioradial pruritus paradoxically seems to potentiate the sensation of pruritus.5 Wallengren5 suggested that local damage to peripheral nerve fibers could be responsible for this potentiation of pruritic sensation. Kumakiri et al18 demonstrated ultrastructural damage to dermal nerve fibers following UVA irradiation. UV radiation has been shown to cause a sensitizing effect on sensory nerve fibers and lower the threshold for sensory nerve stimulation, which may occur via direct effects of UV exposure or by release of neural mediators.19 The pathophysiology of brachioradial pruritus is controversial. The 2 proposed associations are UV exposure and cervical spine disease.20 Wallengren and Sundler2 proposed that solar-induced nerve injury is responsible for brachioradial pruritus. UV radiation may be an eliciting factor, while cervical spine disease may be a predisposing factor.2 On the contrary, Fisher21 reported on the association of cervical nerve root impingement and involvement of 1 or more of the C5 to C8 cervical nerve root segments. Brachioradial pruritus has been reported in association with an ependymoma and secondary to cervical nerve compression.9,22 In a report by Heyl,9 4 of 14 patients demonstrated evidence of degenerative changes and osteoarthritis between C4 and C7. In addition, Heyl9 noted that brachioradial pruritus may be caused by compression of structures not identified by cervical radiographs. In a series of 11 patients with brachioradial pruritus who underwent radiography of the spine, Goodkin et al12 found that all patients demonstrated radiographic abnormalities of the cervical spine. Magnetic resonance imaging is the most reliable diagnostic method for cervical nerve root compression.20,22 Recently, Crevits20 suggested that neural damage from peripheral nerves by solar radiation or local injury or from central sensory pathways, such as cervical spine disease, is a nonspecific cause. In view of the literature, a definitive pathophysiology for brachioradial pruritus does not exist. It is clear that it is a unique clinical entity, but the pathophysiologic basis is not known. While the association between cervical spine disease and brachioradial pruritus is not fully understood, the prevalence of cervical spine disease is higher in patients with brachioradial pruritus.12 It has not been determined if this association is causal or causative.20 A similar localized itch syndrome, notalgia paresthetica (NP), also has been examined with respect to cervical spine pathology.12,23-25 NP is similar to brachioradial pruritus but involves the dorsal spinal nerves. Savk et al23 found the presence of vertebral column pathology in 7 of 10 patients with NP. A subsequent larger study involving 43 patients with NP reported that in 34 patients (79%), spinal pathology had been detected by radiographs. Additionally, in 65% of patients (28/43), changes were most prominent in the vertebrae and corresponded to clinically involved dermatomes.24 However, not all pathologies are detectable via radiographic imaging.25 Thus, Savk and Savk25 reinforced the necessity of clinical and radiographic examination. Histologic examination is not necessary for the clinical diagnosis of brachioradial pruritus. Cutaneous biopsies most often demonstrate nonspecific findings and/or chronic solar damage. Wallengren and Sundler2 compared cutaneous biopsies in afflicted and control patients utilizing antibodies against a pan-neuronal marker, protein gene product 9.5, calcitonin gene-related peptide, and vanilloid receptor subtype 1 (VR1) for capsaicin-sensitive nerve structures. The number of protein gene product 9.5 immunoreative nerve fibers was reduced in pruritic skin by 23% to 43%.2 These findings suggest that brachioradial pruritus may be elicited by exposure to UV radiation and/or heat. Wallengren and Sundler2 noted one patient who relapsed with pruritus during the winter following use of a heating pad to relieve neck pain, which supports the notion that UV radiation and/or heat may be causative. Immunohistochemical studies demonstrated protein gene product 9.5 immunoreactive nerve fibers in a dense population in the epidermis and the dermis and calcitonin gene-related peptide immunoreactive nerve fibers located primarily in the dermis. Capsaicin-sensitive VR1 immunoreactive nerve fibers were located as free nerve fibers.2 Wallengren and Sundler2 proposed that the VR1 structures are associated with thermoreception. The reduction in nerve fibers via all markers in patients with brachioradial pruritus implicates their role. Furthermore, these histologic changes resemble those found in patients after serial phototherapy.2,26 Underlying cervical spine disease may amplify this pruritus. Treatment of brachioradial pruritus includes a multitude of possible topical and oral modalities, such as topical capsaicin, gabapentin, carbamazepine, oxcarbamazepine, cervical spine manipulation, anti-inflammatory medications, surgical rib resection, avoidance of sun exposure, and lamotrigine.1,3,5,12,20,21,27-32 Pruritus is a common symptom with a multitude of potential causes, some of which are never diagnosed. The absence of cutaneous signs makes diagnosis more difficult; however, the consistency of anatomic location and historical characteristics make the diagnosis of brachioradial pruritus possible. In addition, relief of pruritus with application of ice helps to confirm the diagnosis.10 A familial form of brachioradial pruritus was reported with a dominant and possible X-linked inheritance pattern.33 While an association between brachioradial pruritus and cervical spine disease is present, cervical spine disease alone cannot explain the pathophysiology of brachioradial pruritus. Furthermore, cervical spine disease undetectable by radiography may hinder a definitive understanding of this association. It is likely that both UV exposure and cervical spine disease contribute to this entity.

Brachioradial pruritus is an enigmatic entity characterized by pruritus localized to the skin overlying the proximal heads of the brachioradialis muscle, with few other clinical symptoms.1-5 It was first described by Waisman⁶ in 1968. Brachioradial pruritus characteristically affects middle-aged women residing in tropical to temperate climates, though it may occur in males and individuals residing in other climates.1-8 It often presents as tingling, burning pruritus on the dorsal aspect of the forearm. Pruritus may be unilateral or bilateral and may extend up the arm and across the upper back. It often is described as burning, stinging, or painful, and is seasonal in nature, often presenting in late summer and lasting into December.1-5 Brachioradial pruritus was originally associated with solar exposure and UV radiation. Later, Heyl9 proposed that cervical nerve root impingement or injury secondary to cervical trauma was causative. Although a true cause remains elusive, both actinic damage and cervical spine disease are likely involved. We discuss an otherwise healthy woman who presented with nonspecific pruritus consistent with brachioradial pruritus.

Case Report
A 46-year-old woman presented with persistent pruritus of the left proximal lateral forearm. The pruritus had been present for several years and was recalcitrant to a multitude of therapeutic modalities, including topical corticosteroids and oral antihistamines. Application of heat did not affect her symptoms; however, application of cold compresses did alleviate some of the pruritus. Her medical history was noncontributory. Her surgical history was pertinent for prior anterior cervical discectomy and fusion from C4 to C6. Physical examination revealed no obvious cutaneous lesions in the site other than mild erythema secondary to scratching. Magnetic resonance imaging of her cervical spine revealed a left-sided osteophyte causing minimal left neural foraminal stenosis at the level of C3 to C4 (Figure). Electromyography and nerve conduction velocity studies of the left upper extremity revealed a mildly prolonged left median sensory latency. The patient was treated with topical capsaicin cream with moderate success. She also was advised to avoid sun exposure to the affected area.

Comment
Brachioradial pruritus affects a focal circumscribed area of the proximal lateral forearm. The area typically involves a sun-exposed region and may include the forearm, arm, shoulder, neck, and/or upper thorax.2 Middle-aged women are most commonly affected, with tingling, burning, and pruritus of the affected area.1 Symptoms may last from August to December and may subside during the winter.1-5 Pruritus may be unilateral or bilateral. The nature of the pruritus is often described as burning, stinging, or painful, and manifests a seasonal relation, with high incidence in late summer corresponding with the highest UV exposure.1 Patients may report intensification of pruritus with scratching, which may be related to damage of peripheral nerve fibers.2,10 This intensification may, in part, be secondary to chronic UVA irradiation.11 Involvement of C fibers containing neuropeptides responsible for pruritus explains the rationale for treatment with topical capsaicin.2,5 Application of ice often is the only means of alleviating pruritus.10,12 The consistency of relief with ice is useful in the diagnostic screening of this entity.10 The neurophysiology of pruritus is not fully understood. However, it is known that Aδ and C fibers are responsible for the transmission of pruritus.9 Pruritus can be categorized as pruritoceptive (originating in the skin) or neurogenic (originating in the central nervous system), or a combination of both. The Aδ and C fibers are co-responsive to temperature change as well as pruritus. Increases in skin temperature lower the threshold of cutaneous pruritus receptor units.13 The neural pathway for pruritus has been established. Nociceptor C fibers transmit impulses to the dorsal horn of the spinal cord and then to the thalamus via the spinothalamic tract.14 Scratching typically relieves the sensation of pruritus.15 The gate-control theory postulates that afferent sensory input from cutaneous C fibers is modulated by a gate-control system at the level of the spinal cord.5,16,17 A subsequent Aδ impulse may act in a negative feedback method to shut off C-fiber stimulation. However, stimulation of Aδ fibers in brachioradial pruritus paradoxically seems to potentiate the sensation of pruritus.5 Wallengren5 suggested that local damage to peripheral nerve fibers could be responsible for this potentiation of pruritic sensation. Kumakiri et al18 demonstrated ultrastructural damage to dermal nerve fibers following UVA irradiation. UV radiation has been shown to cause a sensitizing effect on sensory nerve fibers and lower the threshold for sensory nerve stimulation, which may occur via direct effects of UV exposure or by release of neural mediators.19 The pathophysiology of brachioradial pruritus is controversial. The 2 proposed associations are UV exposure and cervical spine disease.20 Wallengren and Sundler2 proposed that solar-induced nerve injury is responsible for brachioradial pruritus. UV radiation may be an eliciting factor, while cervical spine disease may be a predisposing factor.2 On the contrary, Fisher21 reported on the association of cervical nerve root impingement and involvement of 1 or more of the C5 to C8 cervical nerve root segments. Brachioradial pruritus has been reported in association with an ependymoma and secondary to cervical nerve compression.9,22 In a report by Heyl,9 4 of 14 patients demonstrated evidence of degenerative changes and osteoarthritis between C4 and C7. In addition, Heyl9 noted that brachioradial pruritus may be caused by compression of structures not identified by cervical radiographs. In a series of 11 patients with brachioradial pruritus who underwent radiography of the spine, Goodkin et al12 found that all patients demonstrated radiographic abnormalities of the cervical spine. Magnetic resonance imaging is the most reliable diagnostic method for cervical nerve root compression.20,22 Recently, Crevits20 suggested that neural damage from peripheral nerves by solar radiation or local injury or from central sensory pathways, such as cervical spine disease, is a nonspecific cause. In view of the literature, a definitive pathophysiology for brachioradial pruritus does not exist. It is clear that it is a unique clinical entity, but the pathophysiologic basis is not known. While the association between cervical spine disease and brachioradial pruritus is not fully understood, the prevalence of cervical spine disease is higher in patients with brachioradial pruritus.12 It has not been determined if this association is causal or causative.20 A similar localized itch syndrome, notalgia paresthetica (NP), also has been examined with respect to cervical spine pathology.12,23-25 NP is similar to brachioradial pruritus but involves the dorsal spinal nerves. Savk et al23 found the presence of vertebral column pathology in 7 of 10 patients with NP. A subsequent larger study involving 43 patients with NP reported that in 34 patients (79%), spinal pathology had been detected by radiographs. Additionally, in 65% of patients (28/43), changes were most prominent in the vertebrae and corresponded to clinically involved dermatomes.24 However, not all pathologies are detectable via radiographic imaging.25 Thus, Savk and Savk25 reinforced the necessity of clinical and radiographic examination. Histologic examination is not necessary for the clinical diagnosis of brachioradial pruritus. Cutaneous biopsies most often demonstrate nonspecific findings and/or chronic solar damage. Wallengren and Sundler2 compared cutaneous biopsies in afflicted and control patients utilizing antibodies against a pan-neuronal marker, protein gene product 9.5, calcitonin gene-related peptide, and vanilloid receptor subtype 1 (VR1) for capsaicin-sensitive nerve structures. The number of protein gene product 9.5 immunoreative nerve fibers was reduced in pruritic skin by 23% to 43%.2 These findings suggest that brachioradial pruritus may be elicited by exposure to UV radiation and/or heat. Wallengren and Sundler2 noted one patient who relapsed with pruritus during the winter following use of a heating pad to relieve neck pain, which supports the notion that UV radiation and/or heat may be causative. Immunohistochemical studies demonstrated protein gene product 9.5 immunoreactive nerve fibers in a dense population in the epidermis and the dermis and calcitonin gene-related peptide immunoreactive nerve fibers located primarily in the dermis. Capsaicin-sensitive VR1 immunoreactive nerve fibers were located as free nerve fibers.2 Wallengren and Sundler2 proposed that the VR1 structures are associated with thermoreception. The reduction in nerve fibers via all markers in patients with brachioradial pruritus implicates their role. Furthermore, these histologic changes resemble those found in patients after serial phototherapy.2,26 Underlying cervical spine disease may amplify this pruritus. Treatment of brachioradial pruritus includes a multitude of possible topical and oral modalities, such as topical capsaicin, gabapentin, carbamazepine, oxcarbamazepine, cervical spine manipulation, anti-inflammatory medications, surgical rib resection, avoidance of sun exposure, and lamotrigine.1,3,5,12,20,21,27-32 Pruritus is a common symptom with a multitude of potential causes, some of which are never diagnosed. The absence of cutaneous signs makes diagnosis more difficult; however, the consistency of anatomic location and historical characteristics make the diagnosis of brachioradial pruritus possible. In addition, relief of pruritus with application of ice helps to confirm the diagnosis.10 A familial form of brachioradial pruritus was reported with a dominant and possible X-linked inheritance pattern.33 While an association between brachioradial pruritus and cervical spine disease is present, cervical spine disease alone cannot explain the pathophysiology of brachioradial pruritus. Furthermore, cervical spine disease undetectable by radiography may hinder a definitive understanding of this association. It is likely that both UV exposure and cervical spine disease contribute to this entity.

Dermatitis herpetiformis (DH) is a chronic pruritic cutaneous eruption associated with gluten-sensitive enteropathy (celiac disease [CD]) and immunoglobulin A (IgA) deposition in the skin. While the disease is not uncommon among adolescents, DH is rarely seen in prepubertal patients. Children with DH present similarly to adults; however, uncommon skin findings have been reported. Because of an increased risk for autoimmune diseases and lymphoma, accurate diagnosis and treatment are imperative. We present a case of DH in a 6-year-old Latino boy previously diagnosed with atopic dermatitis and recurrent urticaria. Our aim is to highlight the various cutaneous presentations of DH and encourage clinicians to consider this diagnosis in young patients with recalcitrant atypical skin disease.
Case Report
A 6-year-old Latino boy presented with a history of pruritic skin lesions (beginning at the age of 9 months) previously diagnosed as atopic dermatitis and recurrent urticaria. His pediatrician prescribed topical steroids and oral diphenhydramine hydrochloride, without improvement. On examination, the patient had few excoriated edematous papules on his buttocks (Figure 1) and urticarial plaques on his upper extremity. His skin was xerotic but lacked any lichenified plaques or papules in the antecubital and popliteal fossae. The patient denied any associated nausea or diarrhea. Family history was negative for atopy and autoimmune disease. The mother reported that the patient was, at one time, "small for his age" but is now closer in size to his peers.

A punch biopsy was obtained from an urticarial plaque on his arm and treatment was initiated with desonide cream 0.05% twice daily to the affected areas. The biopsy revealed collections of neutrophils in the papillary dermis as well as clefting at the dermoepidermal junction (Figure 2). A second biopsy for direct immunofluorescence (DIF) was performed from perilesional gluteal skin. This specimen exhibited granular immunoglobulin A (IgA) deposits in the papillary dermis, thus confirming the diagnosis of dermatitis herpetiformis (DH).

Evaluation by a gastroenterologist who performed serologic testing and endoscopic biopsy of the small intestine further substantiated the diagnosis. In the serum, the presence of immunoglobulin G antigliadin (42.3 U/mL; reference, 100 U/mL; reference, <10), IgA anti–tissue transglutaminase (anti-tTGase)(>100 U/mL; reference, <4), and IgA antiendomysial (positive; reference, negative) antibodies were detected. The intestinal biopsy revealed villous atrophy accompanied by duodenitis consistent with celiac disease (CD). HLA typing was not performed. A complete blood count with differential blood count, comprehensive metabolic panel, thyroxine, thyroid stimulating hormone, and thyroglobulin antibodies were all within reference range. The patient was initiated on a gluten-free diet and subsequently developed fewer lesions and reduced pruritus.

Comment

DH is a cutaneous manifestation of CD, which is an immune-mediated enteropathy caused by gluten sensitivity. The symptoms of childhood CD include persistent diarrhea, failure to thrive, abdominal pain, and vomiting. Iron deficiency anemia also may be present as well as other sequelae of malabsorption. Although patients with DH usually do not have gastrointestinal symptoms, virtually all patients with DH show evidence of the same gluten-sensitive enteropathy of the small bowel.
Gluten is a grain protein found in wheat, barley, and rye, but not in oats. Gliadin, the alcohol-soluble fraction of gluten, is believed to be the inciting stimulus.1 In addition to antigliadin antibodies, patients with DH have circulating antiendomysial and antitransglutaminase antibodies with uncertain roles in pathogenesis. The prevailing theory suggests that gluten sensitivity leads to the formation of IgA antibodies to gluten-transglutaminase complexes. These antibodies cross-react with other transglutaminases, specifically epidermal transglutaminase, which is highly homologous. Deposition of IgA–transglutaminase 3 complexes within the papillary dermis cause skin lesions of DH.2,3
Childhood DH is rare, with an uncertain incidence and prevalence. Cases have been reported in children as young as 8 months,4 but most children receive the diagnosis between the ages of 2 and 7 years.5 DH is most prevalent in individuals of Northern European descent. In adults, men with DH outnumber women by a ratio of nearly 2:16; however, among childhood cases, there is a female predominance.5,7 A genetic predisposition for gluten sensitivity is supported by the high prevalence of DH and CD among first-degree relatives of known patients with DH and CD as well as a documented HLA association. The DQ2 and DQ8 alleles are most closely linked with DH and CD.8
The clinical presentation of DH is characterized by symmetrically distributed papulovesicular lesions and urticarial plaques, often favoring the back, buttocks, and extensor surfaces of the extremities. Because the lesions are intensely pruritic, intact vesicles are rarely observed by the clinician. Children, by most accounts, present similarly to adults; however, uncommon skin findings may be present and include isolated involvement of the palms,9 hemorrhagic lesions of the palms and soles,10 deep dermal papules and nodules,11 and facial lesions.5,11 Powell et al12 described a case with a predominance of urticarial lesions. Thus, childhood DH often is misdiagnosed as atopic dermatitis, papular urticaria, scabies, linear IgA dermatosis, or chronic urticaria. Recalcitrant cases of these diseases or patients who present with atypical findings of common diseases like atopic dermatitis should prompt the clinician to consider DH in the differential diagnosis.
The gold standard for diagnosing DH is DIF of a biopsy from perilesional skin, which shows granular IgA deposits most often localized to the papillary dermis. For routine histology, a biopsy of an intact vesicle is preferred where neutrophils in the papillary dermis and clefting at the dermoepidermal junction are seen. Although granular IgA deposits seen on DIF are highly specific for DH, up to 10% of cases may have a negative DIF.13,14 To confirm the diagnosis, serologic testing for anti-tTGase antibodies is useful. Using an enzyme-linked immunosorbent assay, tTGase antibodies can be detected in serum with specificity and sensitivity above 90% for patients on normal diets.15,16 Desai et al17 documented the cost-effectiveness of enzyme-linked immunosorbent assay tTGase testing and proposed that serologic testing be used primarily in the diagnosis of DH. Once patients remove gluten from their diet, the skin lesions and enteropathy resolve. Furthermore, tTGase antibodies decrease to levels within reference range in the absence of gluten; thus, serologic testing can be used to monitor dietary compliance.
Patients with DH are at higher risk for autoimmune diseases, particularly Hashimoto thyroiditis, pernicious anemia, and type 1 diabetes mellitus, among others.18-20 The association between DH and lymphoma, mostly T-cell lymphoma, is well-documented, with 78% of lymphomas arising from the small bowel, thus warranting vigilant surveillance and regular follow-up with a gastroenterologist.21 Lewis et al,22 in a retrospective study of 487 patients with DH, found that lymphoma only occurred in patients not on gluten-free diets or in patients who had followed the gluten-free diet for less than 5 years. Moreover, patients in this study who did adhere to the gluten-free diet had no increased risk for developing lymphoma over the general population.22
The primary treatment of DH is a gluten-free diet that is protective against the development of lymphoma. Dietary compliance is challenging, especially for children; therefore, referral to a dietician familiar with this area is helpful. Because months of dietary restriction are needed before a response is noted, many patients require pharmacologic treatment with dapsone. The recommended starting dose for children is 2 mg/kg daily with titration based on clinical response.23 Most patients will have a rapid response to dapsone within 48 to 72 hours. However, the enteropathy is unaffected by dapsone therapy and patients should be encouraged to maintain dietary compliance.

Conclusion

Childhood DH is rare and can present with atypical lesions involving the palms and soles, urticarial lesions, deep dermal papules and nodules, and facial lesions. If aware of these unusual presentations, clinicians may consider the diagnosis of DH and act to further evaluate cases of suspected common diseases not responding to treatment.

Dermatitis herpetiformis (DH) is a chronic pruritic cutaneous eruption associated with gluten-sensitive enteropathy (celiac disease [CD]) and immunoglobulin A (IgA) deposition in the skin. While the disease is not uncommon among adolescents, DH is rarely seen in prepubertal patients. Children with DH present similarly to adults; however, uncommon skin findings have been reported. Because of an increased risk for autoimmune diseases and lymphoma, accurate diagnosis and treatment are imperative. We present a case of DH in a 6-year-old Latino boy previously diagnosed with atopic dermatitis and recurrent urticaria. Our aim is to highlight the various cutaneous presentations of DH and encourage clinicians to consider this diagnosis in young patients with recalcitrant atypical skin disease.
Case Report
A 6-year-old Latino boy presented with a history of pruritic skin lesions (beginning at the age of 9 months) previously diagnosed as atopic dermatitis and recurrent urticaria. His pediatrician prescribed topical steroids and oral diphenhydramine hydrochloride, without improvement. On examination, the patient had few excoriated edematous papules on his buttocks (Figure 1) and urticarial plaques on his upper extremity. His skin was xerotic but lacked any lichenified plaques or papules in the antecubital and popliteal fossae. The patient denied any associated nausea or diarrhea. Family history was negative for atopy and autoimmune disease. The mother reported that the patient was, at one time, "small for his age" but is now closer in size to his peers.

A punch biopsy was obtained from an urticarial plaque on his arm and treatment was initiated with desonide cream 0.05% twice daily to the affected areas. The biopsy revealed collections of neutrophils in the papillary dermis as well as clefting at the dermoepidermal junction (Figure 2). A second biopsy for direct immunofluorescence (DIF) was performed from perilesional gluteal skin. This specimen exhibited granular immunoglobulin A (IgA) deposits in the papillary dermis, thus confirming the diagnosis of dermatitis herpetiformis (DH).

Evaluation by a gastroenterologist who performed serologic testing and endoscopic biopsy of the small intestine further substantiated the diagnosis. In the serum, the presence of immunoglobulin G antigliadin (42.3 U/mL; reference, 100 U/mL; reference, <10), IgA anti–tissue transglutaminase (anti-tTGase)(>100 U/mL; reference, <4), and IgA antiendomysial (positive; reference, negative) antibodies were detected. The intestinal biopsy revealed villous atrophy accompanied by duodenitis consistent with celiac disease (CD). HLA typing was not performed. A complete blood count with differential blood count, comprehensive metabolic panel, thyroxine, thyroid stimulating hormone, and thyroglobulin antibodies were all within reference range. The patient was initiated on a gluten-free diet and subsequently developed fewer lesions and reduced pruritus.

Comment

DH is a cutaneous manifestation of CD, which is an immune-mediated enteropathy caused by gluten sensitivity. The symptoms of childhood CD include persistent diarrhea, failure to thrive, abdominal pain, and vomiting. Iron deficiency anemia also may be present as well as other sequelae of malabsorption. Although patients with DH usually do not have gastrointestinal symptoms, virtually all patients with DH show evidence of the same gluten-sensitive enteropathy of the small bowel.
Gluten is a grain protein found in wheat, barley, and rye, but not in oats. Gliadin, the alcohol-soluble fraction of gluten, is believed to be the inciting stimulus.1 In addition to antigliadin antibodies, patients with DH have circulating antiendomysial and antitransglutaminase antibodies with uncertain roles in pathogenesis. The prevailing theory suggests that gluten sensitivity leads to the formation of IgA antibodies to gluten-transglutaminase complexes. These antibodies cross-react with other transglutaminases, specifically epidermal transglutaminase, which is highly homologous. Deposition of IgA–transglutaminase 3 complexes within the papillary dermis cause skin lesions of DH.2,3
Childhood DH is rare, with an uncertain incidence and prevalence. Cases have been reported in children as young as 8 months,4 but most children receive the diagnosis between the ages of 2 and 7 years.5 DH is most prevalent in individuals of Northern European descent. In adults, men with DH outnumber women by a ratio of nearly 2:16; however, among childhood cases, there is a female predominance.5,7 A genetic predisposition for gluten sensitivity is supported by the high prevalence of DH and CD among first-degree relatives of known patients with DH and CD as well as a documented HLA association. The DQ2 and DQ8 alleles are most closely linked with DH and CD.8
The clinical presentation of DH is characterized by symmetrically distributed papulovesicular lesions and urticarial plaques, often favoring the back, buttocks, and extensor surfaces of the extremities. Because the lesions are intensely pruritic, intact vesicles are rarely observed by the clinician. Children, by most accounts, present similarly to adults; however, uncommon skin findings may be present and include isolated involvement of the palms,9 hemorrhagic lesions of the palms and soles,10 deep dermal papules and nodules,11 and facial lesions.5,11 Powell et al12 described a case with a predominance of urticarial lesions. Thus, childhood DH often is misdiagnosed as atopic dermatitis, papular urticaria, scabies, linear IgA dermatosis, or chronic urticaria. Recalcitrant cases of these diseases or patients who present with atypical findings of common diseases like atopic dermatitis should prompt the clinician to consider DH in the differential diagnosis.
The gold standard for diagnosing DH is DIF of a biopsy from perilesional skin, which shows granular IgA deposits most often localized to the papillary dermis. For routine histology, a biopsy of an intact vesicle is preferred where neutrophils in the papillary dermis and clefting at the dermoepidermal junction are seen. Although granular IgA deposits seen on DIF are highly specific for DH, up to 10% of cases may have a negative DIF.13,14 To confirm the diagnosis, serologic testing for anti-tTGase antibodies is useful. Using an enzyme-linked immunosorbent assay, tTGase antibodies can be detected in serum with specificity and sensitivity above 90% for patients on normal diets.15,16 Desai et al17 documented the cost-effectiveness of enzyme-linked immunosorbent assay tTGase testing and proposed that serologic testing be used primarily in the diagnosis of DH. Once patients remove gluten from their diet, the skin lesions and enteropathy resolve. Furthermore, tTGase antibodies decrease to levels within reference range in the absence of gluten; thus, serologic testing can be used to monitor dietary compliance.
Patients with DH are at higher risk for autoimmune diseases, particularly Hashimoto thyroiditis, pernicious anemia, and type 1 diabetes mellitus, among others.18-20 The association between DH and lymphoma, mostly T-cell lymphoma, is well-documented, with 78% of lymphomas arising from the small bowel, thus warranting vigilant surveillance and regular follow-up with a gastroenterologist.21 Lewis et al,22 in a retrospective study of 487 patients with DH, found that lymphoma only occurred in patients not on gluten-free diets or in patients who had followed the gluten-free diet for less than 5 years. Moreover, patients in this study who did adhere to the gluten-free diet had no increased risk for developing lymphoma over the general population.22
The primary treatment of DH is a gluten-free diet that is protective against the development of lymphoma. Dietary compliance is challenging, especially for children; therefore, referral to a dietician familiar with this area is helpful. Because months of dietary restriction are needed before a response is noted, many patients require pharmacologic treatment with dapsone. The recommended starting dose for children is 2 mg/kg daily with titration based on clinical response.23 Most patients will have a rapid response to dapsone within 48 to 72 hours. However, the enteropathy is unaffected by dapsone therapy and patients should be encouraged to maintain dietary compliance.

Conclusion

Childhood DH is rare and can present with atypical lesions involving the palms and soles, urticarial lesions, deep dermal papules and nodules, and facial lesions. If aware of these unusual presentations, clinicians may consider the diagnosis of DH and act to further evaluate cases of suspected common diseases not responding to treatment.

Dermatitis herpetiformis (DH) is a chronic pruritic cutaneous eruption associated with gluten-sensitive enteropathy (celiac disease [CD]) and immunoglobulin A (IgA) deposition in the skin. While the disease is not uncommon among adolescents, DH is rarely seen in prepubertal patients. Children with DH present similarly to adults; however, uncommon skin findings have been reported. Because of an increased risk for autoimmune diseases and lymphoma, accurate diagnosis and treatment are imperative. We present a case of DH in a 6-year-old Latino boy previously diagnosed with atopic dermatitis and recurrent urticaria. Our aim is to highlight the various cutaneous presentations of DH and encourage clinicians to consider this diagnosis in young patients with recalcitrant atypical skin disease.
Case Report
A 6-year-old Latino boy presented with a history of pruritic skin lesions (beginning at the age of 9 months) previously diagnosed as atopic dermatitis and recurrent urticaria. His pediatrician prescribed topical steroids and oral diphenhydramine hydrochloride, without improvement. On examination, the patient had few excoriated edematous papules on his buttocks (Figure 1) and urticarial plaques on his upper extremity. His skin was xerotic but lacked any lichenified plaques or papules in the antecubital and popliteal fossae. The patient denied any associated nausea or diarrhea. Family history was negative for atopy and autoimmune disease. The mother reported that the patient was, at one time, "small for his age" but is now closer in size to his peers.

A punch biopsy was obtained from an urticarial plaque on his arm and treatment was initiated with desonide cream 0.05% twice daily to the affected areas. The biopsy revealed collections of neutrophils in the papillary dermis as well as clefting at the dermoepidermal junction (Figure 2). A second biopsy for direct immunofluorescence (DIF) was performed from perilesional gluteal skin. This specimen exhibited granular immunoglobulin A (IgA) deposits in the papillary dermis, thus confirming the diagnosis of dermatitis herpetiformis (DH).

Evaluation by a gastroenterologist who performed serologic testing and endoscopic biopsy of the small intestine further substantiated the diagnosis. In the serum, the presence of immunoglobulin G antigliadin (42.3 U/mL; reference, 100 U/mL; reference, <10), IgA anti–tissue transglutaminase (anti-tTGase)(>100 U/mL; reference, <4), and IgA antiendomysial (positive; reference, negative) antibodies were detected. The intestinal biopsy revealed villous atrophy accompanied by duodenitis consistent with celiac disease (CD). HLA typing was not performed. A complete blood count with differential blood count, comprehensive metabolic panel, thyroxine, thyroid stimulating hormone, and thyroglobulin antibodies were all within reference range. The patient was initiated on a gluten-free diet and subsequently developed fewer lesions and reduced pruritus.

Comment

DH is a cutaneous manifestation of CD, which is an immune-mediated enteropathy caused by gluten sensitivity. The symptoms of childhood CD include persistent diarrhea, failure to thrive, abdominal pain, and vomiting. Iron deficiency anemia also may be present as well as other sequelae of malabsorption. Although patients with DH usually do not have gastrointestinal symptoms, virtually all patients with DH show evidence of the same gluten-sensitive enteropathy of the small bowel.
Gluten is a grain protein found in wheat, barley, and rye, but not in oats. Gliadin, the alcohol-soluble fraction of gluten, is believed to be the inciting stimulus.1 In addition to antigliadin antibodies, patients with DH have circulating antiendomysial and antitransglutaminase antibodies with uncertain roles in pathogenesis. The prevailing theory suggests that gluten sensitivity leads to the formation of IgA antibodies to gluten-transglutaminase complexes. These antibodies cross-react with other transglutaminases, specifically epidermal transglutaminase, which is highly homologous. Deposition of IgA–transglutaminase 3 complexes within the papillary dermis cause skin lesions of DH.2,3
Childhood DH is rare, with an uncertain incidence and prevalence. Cases have been reported in children as young as 8 months,4 but most children receive the diagnosis between the ages of 2 and 7 years.5 DH is most prevalent in individuals of Northern European descent. In adults, men with DH outnumber women by a ratio of nearly 2:16; however, among childhood cases, there is a female predominance.5,7 A genetic predisposition for gluten sensitivity is supported by the high prevalence of DH and CD among first-degree relatives of known patients with DH and CD as well as a documented HLA association. The DQ2 and DQ8 alleles are most closely linked with DH and CD.8
The clinical presentation of DH is characterized by symmetrically distributed papulovesicular lesions and urticarial plaques, often favoring the back, buttocks, and extensor surfaces of the extremities. Because the lesions are intensely pruritic, intact vesicles are rarely observed by the clinician. Children, by most accounts, present similarly to adults; however, uncommon skin findings may be present and include isolated involvement of the palms,9 hemorrhagic lesions of the palms and soles,10 deep dermal papules and nodules,11 and facial lesions.5,11 Powell et al12 described a case with a predominance of urticarial lesions. Thus, childhood DH often is misdiagnosed as atopic dermatitis, papular urticaria, scabies, linear IgA dermatosis, or chronic urticaria. Recalcitrant cases of these diseases or patients who present with atypical findings of common diseases like atopic dermatitis should prompt the clinician to consider DH in the differential diagnosis.
The gold standard for diagnosing DH is DIF of a biopsy from perilesional skin, which shows granular IgA deposits most often localized to the papillary dermis. For routine histology, a biopsy of an intact vesicle is preferred where neutrophils in the papillary dermis and clefting at the dermoepidermal junction are seen. Although granular IgA deposits seen on DIF are highly specific for DH, up to 10% of cases may have a negative DIF.13,14 To confirm the diagnosis, serologic testing for anti-tTGase antibodies is useful. Using an enzyme-linked immunosorbent assay, tTGase antibodies can be detected in serum with specificity and sensitivity above 90% for patients on normal diets.15,16 Desai et al17 documented the cost-effectiveness of enzyme-linked immunosorbent assay tTGase testing and proposed that serologic testing be used primarily in the diagnosis of DH. Once patients remove gluten from their diet, the skin lesions and enteropathy resolve. Furthermore, tTGase antibodies decrease to levels within reference range in the absence of gluten; thus, serologic testing can be used to monitor dietary compliance.
Patients with DH are at higher risk for autoimmune diseases, particularly Hashimoto thyroiditis, pernicious anemia, and type 1 diabetes mellitus, among others.18-20 The association between DH and lymphoma, mostly T-cell lymphoma, is well-documented, with 78% of lymphomas arising from the small bowel, thus warranting vigilant surveillance and regular follow-up with a gastroenterologist.21 Lewis et al,22 in a retrospective study of 487 patients with DH, found that lymphoma only occurred in patients not on gluten-free diets or in patients who had followed the gluten-free diet for less than 5 years. Moreover, patients in this study who did adhere to the gluten-free diet had no increased risk for developing lymphoma over the general population.22
The primary treatment of DH is a gluten-free diet that is protective against the development of lymphoma. Dietary compliance is challenging, especially for children; therefore, referral to a dietician familiar with this area is helpful. Because months of dietary restriction are needed before a response is noted, many patients require pharmacologic treatment with dapsone. The recommended starting dose for children is 2 mg/kg daily with titration based on clinical response.23 Most patients will have a rapid response to dapsone within 48 to 72 hours. However, the enteropathy is unaffected by dapsone therapy and patients should be encouraged to maintain dietary compliance.

Conclusion

Childhood DH is rare and can present with atypical lesions involving the palms and soles, urticarial lesions, deep dermal papules and nodules, and facial lesions. If aware of these unusual presentations, clinicians may consider the diagnosis of DH and act to further evaluate cases of suspected common diseases not responding to treatment.