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Nephrogenic fibrosing dermopathy: two pediatric cases
NEPHROGENIC FIBROSING DERMOPATHY: TWO PEDIATRIC CASES FARHANA JAN, MD, JENNIFER M. SEGAL, MD, JONATHAN DYER, MD, PHILIP LEBOIT, MD, ELAINE SIEGFRIED, MD, AND ILONA J. FRIEDEN, MD
We report two pediatric cases of nephrogenic fibrosing dermopathy (NFD), first described in 2000. NFD is a condition in which individuals with renal dysfunction have development of extensive skin hardening and histopathologic evidence of a scleromyxedema-like condition. (J Pediatr 2003;143:678-81)
n September 2000, Cowper et al1 reported cases of a new fibrosing skin condition in adults with kidney disease. Since then, this condition has been noted in more than 50 patients throughout the United States and Europe. The first descriptions consisted of a case series of 15 patients with renal dialysis who had brawny hyperpigmentation with extensive thickening and hardening of the skin, with the variable presence of papules and subcutaneous nodules, located mainly over the extremities.1 Although these findings were clinically and histopathologically reminiscent of scleromyxedema, these patients lacked a serum monoclonal paraprotein, head and neck lesions, or systemic manifestations found in that condition. In 2001, the same group of authors reviewed the histopathologic findings in 14 cases of fibrosing cutaneous illness among patients with kidney disease and proposed a distinct term for this disorder: nephrogenic fibrosing dermopathy (NFD).2 To date, there have been no reports of NFD in the pediatric population. We report two pediatric cases of this unique fibrosing skin disorder.
I
CASE REPORTS Case 1 A 16-year-old premenarcheal white female patient with a lifelong history of kidney failure secondary to brachio-otorenal (BOR) syndrome was referred to the pediatric dermatology clinic in May 2001 with a 10-day history of worsening pruritic and painful, erosive vesicular lesions on her trunk and extremities. The patient had received peritoneal dialysis from 6 weeks of age until 2.5 years and thereafter received 2 kidney transplantations from her parents. The second transplantation, received from her mother in July 1995, underwent rejection several years later, and in April 2001, hemodialysis was initiated because of worsening renal function. Her skin lesions, which began approximately 1 week after dialysis was started, were initially noted on her inner thighs, then spread to the outer thighs, lower extremities, arms, and trunk. They quickly became thickened, indurated plaques associated with marked pain and pruritis. She had no prior history of skin disease. She had no family history of autoimmune disease or lymphedema. On physical examination, she was a chronically ill-appearing girl in severe pain. Marked nonpitting edema of the extremities was present, and the overlying skin had a peau d’orange texture. Thick, linear hyperkeratotic plaques with superficial erosions were present most prominently on the legs, with additional involvement of the arms (Figure) and, to a lesser degree, the torso and abdomen. Sharply demarcated areas of spared skin were present on the arms and legs. Her face was uninvolved.
NFD
678
Nephrogenic fibrosing dermopathy
From the Department of Dermatology, University of Cincinnati, Cincinnati, Ohio; the Department of Dermatology, Duke University, Durham, North Carolina; the Department of Dermatology, University of Missouri, and the Department of Pediatrics and Dermatology, St Louis University, St Louis, Missouri; and the Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, California. Submitted for publication Mar 25, 2003; revision received July 14, 2003; accepted Aug 22, 2003. Reprints not available from the authors. Please address correspondence to: Ilona J. Frieden, MD, Department of Dermatology, Box 0316, San Francisco, CA 94143-0316. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00538-9
Laboratory studies revealed normal serum concentration of IgG and IgM proteins without a monoclonal spike. A swab specimen was negative for herpes virus. An initial punch biopsy from the left outer thigh showed foci of mineralization in the dermis consistent with calcinosis cutis and an increase in interstitial spindled cells with interstitial mucinous material. A second punch biopsy specimen from the right upper arm, obtained nearly 2 months later, revealed a proliferation of spindled cells arrayed in the reticular dermis with associated deposition of interstitial mucin, extending into the subcutaneous septa. Calcinosis of the superficial dermis was present. No inflammatory cells were identified. The findings of this second biopsy confirmed the diagnosis of nephrogenic fibrosing dermopathy. Her therapeutic treatment consisted of symptomatic treatment of pain and pruritis with prednisone, doxepin, acetaminophen/hydrocodone, ondansetron, amitriptyline, and topical treatment with a hydrogel dressing (Vigilon, Bard Home Health) and emollients. Shortly after her first visit, management of kidney failure was changed from hemodialysis to peritoneal dialysis. Over the next 2 months, the lesions stopped spreading, although the patient had decreased range of motion secondary to her skin changes, particularly in the lower extremities. Her weekly dose of epoetin alfa (Epogen, Amgen, Thousand Oaks, Calif ) was reduced and eventually discontinued. Six weeks later, the patient’s cutaneous disease was still extensive but had improved slightly, with increased range of motion of the extremities. Approximately 6 weeks thereafter, due to low hematocrit, she restarted epoetin alfa at 3000 units per week, with no obvious worsening of her skin lesions. One year after onset of her skin disease, she received a cadaveric kidney transplant. Within days, the degree of edema and pruritus improved. Her skin, although not completely normal, has become much less indurated.
Case 2 An 8-year-old white boy with a 9-month history of membranoproliferative glomerulonephritis type II of unproven inciting event was admitted to the University of Missouri Children’s Hospital for rapid/acute progression of chronic kidney failure. He had previously been treated with prednisone for nephrotic syndrome. Peritoneal dialysis was initiated. Several episodes of uncontrolled hypertension required treatment in the pediatric intensive care unit and intravenous antihypertensive agents. Epoetin alfa (2000 units 3 times weekly) and iron replacement therapies were initiated on the seventh hospital day. A skin rash developed in the perianal area on the 10th hospital day, which was treated with topical nystatin for presumed Candida infection. Examination revealed flattopped, violaceous hyperkeratotic papules, confluent on the right buttock. Reticular hyperpigmentation was noted on the lower ankles and feet. No vesicles, pustules, or excoriations were noted. The lesions were believed to be consistent with an infiltrative or granulomatous process, such as eruptive xanthoma, perforating disorder of kidney disease, or granuNephrogenic Fibrosing Dermopathy: Two Pediatric Cases
Figure. White female patient (16 years old) with nephrogenic fibrosing dermopathy. Thickened infiltrative plaques are evident on the arm.
loma annulare. He was treated with Fluocinonide ointment (0.05%) under occlusion and remained on peritoneal dialysis. Two and one-half months later, he was evaluated for verrucous granulomatous-appearing plaques on the buttocks bilaterally, with violaceous papules between the buttocks. Dry, lichenified skin was noted bilaterally on the lower extremities, ankles, and dorsal foot. Brown dermal plaques clinically consistent with granuloma annulare were noted bilaterally on the feet. The lower back had a brown hyperpigmented plaque in the midline, and the elbows had lichenified skin-colored plaques bilaterally. Linear sclerodermoid plaques were noted bilaterally on the anterior shins. Biopsy specimens were taken from the lesional skin of the buttock and foot. Histopathologic findings from both samples were believed to be consistent with perforating disorder of kidney disease. The lesions were treated with Tazarotene (0.1%) topical gel (Tazorac, Allergen, Irvine, Calif), with resolution of the keratotic lesions. The sclerodermoid lesions were treated with high-potency topical steroids under occlusion, without effect. Four and one-half months after admission, the skin lesions had spread to involve the abdomen and arms. Diffuse hyperpigmentation was present, accentuated over the posterior neck and sacrum. Dry, wrinkled skin of the sacrum and lower 679
back was noted, with apparent loss of elasticity, especially over the sacrum. The patient was referred to a pediatric dermatologist, and repeat biopsy specimens revealed a scleromyxedema-like fibrosing dermatitis consistent with NFD. There was no family history of autoimmune disease or lymphedema. He underwent cadaveric kidney transplantation approximately 2 years after the onset of NFD, 15 months after having begun peritoneal dialysis. After transplantation, his skin lesions improved, with softening of the thickened lesions and no new affected areas. He subsequently rejected the kidney and was restarted on dialysis but has had no worsening of his skin condition.
DISCUSSION Several case reports and two reviews of the emergence of scleromyxedema-like cutaneous change among patients with kidney disease have recently been published.1-6 Investigators from the Centers for Disease Control (CDC) created a case definition5 and identified 8 additional cases. Cowper et al2 detailed the histopathologic findings in 14 cases of NFD and helped clarify the features distinguishing this condition from other cutaneous fibrosing conditions, namely scleromyxedema, morphea/scleroderma, and b-2 microglobulin amyloidosis, which can complicate kidney failure. The skin lesions of NFD are characterized by indurated papules and plaques, brawny thickening of the skin with a peau d’orange appearance, and occasionally joint contractures.2 They are typically present on the extremities, buttocks, and trunk, rarely involving the face. Pruritus, burning, and pain are common symptoms.2 The histologic features of NFD can range from a subtle increase in dermal fibroblasts in early lesions to a florid proliferation of dermal fibroblasts, thickened collagen bundles with surrounding clefts, and increased dermal mucin and elastic fibers extending through the subcutis along thickened septa of fatty lobules. Additionally, there are increased numbers of CD-34-positive dermal dendrocytes and Factor XIIIa and CD-68-positive mononucleated and multinucleated cells, with a scant perivascular lymphocytic infiltrate seen only in a few cases.2 Scleromyxedema, a condition with many similarities to NFD, differs in its predilection for facial involvement and the presence of a monoclonal serum paraprotein, lacking in patients with NFD. NFD also lacks pools of dermal mucin or plasma cell infiltrates often found in scleromyxedema. Although systemic scleroderma and its localized cutaneous form, morphea, can cause tightening and induration of the skin, the histolopathologic findings are easily distinguishable. Systemic sclerosis and morphea have interstitial lymphohistiocytic infiltrates and a decrease (rather than increase) in dermal spindle cells.2 All reported cases of NFD share a common diagnosis of renal insufficiency. Of those reported by Cowper et al, 12 of 14 were undergoing hemodialysis at the time of onset of skin lesions. The initiation of dialysis before development of cutaneous disease ranged from days to 10 years. The causes of kidney disease and associated medical regimens varied, neither 680
Jan et al
sex nor ethnicity predilections were observed, and patient ages ranged from 31 to 74 years.2 Although the clustering of patients in hemodialysis centers suggests a possible toxin or infectious agent, the underlying cause of NFD remains unclear; a systematic epidemiologic study has therefore been initiated to identify the potential responsible factors.2 Four additional adult cases of NFD have recently been reported by Mackay-Wiggan et al.3 Patient ages ranged from 42 to 61 years, with kidney disease secondary to vaso-occlusive disease, diabetes, or hypertension. Three of the 4 patients had significant anasarca and began immunosuppressive medications just before the onset of skin lesions. Interestingly, one patient had onset of cutaneous fibrosis before hemodialysis or kidney transplantation. All four patients had positive anticardiolipin antibodies. The authors hypothesized that an accumulated substance intrinsic to kidney failure reacting with the antiphospholipid antibody, o, alternatively, edema coupled with immunosuppression, may stimulate fibroblast proliferation and the dermal mucin deposition seen in NFD.3 Anticardiolipin antibodies were not tested in our patients. In a small case-control study with control subjects who had received kidney transplantation but did not have NFD, those with NFD were more likely to have poor renal function after transplantation, including need for hemodialysis and/or medications associated with severe disease.5 In addition to scleroderma and scleromyxedema, the differential diagnosis for sclerotic skin disease and mucin deposition in the pediatric population includes scleredema, an extremely rare condition in which mucin deposition leads to diffuse induration of the subcutaneous tissue.7,8 Most pediatric cases are thought to be caused by an antecedent viral or bacterial infection. The neck, face, and upper extremities and trunk are usually involved, with the abrupt development of symmetric erythema and induration, without pain or pruritis. Even more rarely, scleredema can be caused by an associated monoclonal gammopathy.7 Cases have also been described in individuals with long-standing diabetes mellitus. Both of our pediatric cases had other histologic features that are often seen in patients with kidney disease, namely, calcinosis cutis and perforating collagenosis,9 but repeat biopsies definitively confirmed the diagnosis of NFD. Although no specific treatment has been found to treat NFD, improvement of renal function seems to ameliorate the condition. Thus until the causative factors involved in NFD are uncovered, treatment presently consists of supportive management of associated pain and pruritis, but ultimately with adequate correction of renal dysfunction through successful kidney transplantation. Plasmapheresis and thalidomide also have been used as treatments and are reportedly effective in some cases.10
REFERENCES 1. Cowper SE, Robin HS, Steinberg SM, Su LD, Supta S, LeBoit PE. Scleromyxeoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356:1000-1. 2. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopath 2001;23:383-93.
The Journal of Pediatrics November 2003
3. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003;48:55-60. 4. McNeill AM, Barr RJ. Scleromyxedema-like fibromucinosis in a patient undergoing hemodialysis. Int J Dermatol 2002;41:364-7. 5. Fibrosing skin condition among patients with renal disease: United States and Europe 1997-2002. MMWR/Morb Mortal Wkly Rep 2002;51:25-6. 6. Streams BN, Liu V, Liegeois N, Moschella SM. Clinical and pathologic features of nephrogenic fibrosing dermopathy: a report of two cases. J Am Acad Dermatol 2003;48:42-7.
7. Jackson EM, English JC. Diffuse cutaneous mucinoses. Dermatol Clin 2002;20:493-501. 8. Heilbron B, Saxe N. Scleredema in an infant. Arch Dermatol 1986;122:1417-9. 9. Robinson-Bostom L, DiGiovanna JJ. Cutaneous manifestations of endstage renal disease. J Am Acad Dermatol 2000;43:975-86. 10. Baron PW, Cantos K, Hillebrand DJ, Hu K-Q, Ojogho ON, NehlsenCannarella S, et al. Nephrogenic fibrosing dermopathy following liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 2003;25:204-9.
50 Years Ago in The Journal of Pediatrics THE TREATMENT OF TUBERCULOUS MENINGITIS IN CHILDREN Kendig EL Jr, Ownby R Jr, Trevathan GE, Sutton LE Jr. J Pediatr 1953;39:532-5. In the early 1950s, data were just beginning to be published on the successful treatment of tuberculous meningitis in children by using antimicrobials. In the paper cited above, the authors summarize their experience in treating a large group of children with this disease. The standard antituberculous regimen used by these investigators consisted of intramuscular and intrathecal streptomycin combined with oral thiazosulfone (a dapsone derivative). Intrathecal purified protein derivative was used in two patients with advanced disease. In later cases in the series, para-aminosalicylic acid was substituted for thiazosulfone, and a new drug, isoniazid, was added to the regimen, both of these changes in line with newly published therapeutic recommendations from the Committee on Therapy. Despite treatment, the overall mortality rate in this group of children remained very high at 55%. Much progress has been made in the past half century in the evaluation and treatment of children with tuberculous meningitis. Potent and generally nontoxic anti-tuberculous regimens have replaced the regimens of the past.1 Isoniazid, the medication just appearing on the scene 50 years ago, has become a mainstay of antituberculous therapy, usually supplemented in current treatment regimens with the newer antimicrobials, rifampin and pyrazinamide. Streptomycin, although still in use as a part of combination treatment regimens, has a much more limited role than in the past. If tuberculous meningitis is diagnosed early and treated appropriately, the prognosis for the child is quite good.2 Unfortunately, despite progress in the development of medications for the treatment of disease, recent studies suggest that work still needs to be done to improve overall outcome. In a series recently published in The Journal of children with tuberculous meningitis, overall mortality was 16% and one fifth of the survivors were left with neurologic sequelae.2 Prognosis was closely tied to the stage of disease at time of presentation. For a substantial number of these patients, health care providers had evaluated the children earlier in their disease courses and failed to make a diagnosis of tuberculous disease. For more than one third of the children, an adult contact had been diagnosed with tuberculosis before disease onset in the child, yet appropriate intervention had not occurred. These data suggest that further improvements in the outcome of tuberculous meningitis in children could be achieved by educating physicians on the sometimes subtle presentation of disease and by strengthening the public health infrastructure in appropriate areas. Stephen J. Barenkamp, MD, Division of Pediatric Infectious Disease Department of Pediatrics, St Louis University School of Medicine St Louis, MO 63104-1095
YMPD505 10.1067/S0022-3476(03)00546-8
REFERENCES 1. 2.
Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001;345:189-200. Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995;127:27-33.
Nephrogenic Fibrosing Dermopathy: Two Pediatric Cases
681
We report two pediatric cases of nephrogenic fibrosing dermopathy (NFD), first described in 2000. NFD is a condition in which individuals with renal dysfunction have development of extensive skin hardening and histopathologic evidence of a scleromyxedema-like condition. (J Pediatr 2003;143:678-81)
n September 2000, Cowper et al1 reported cases of a new fibrosing skin condition in adults with kidney disease. Since then, this condition has been noted in more than 50 patients throughout the United States and Europe. The first descriptions consisted of a case series of 15 patients with renal dialysis who had brawny hyperpigmentation with extensive thickening and hardening of the skin, with the variable presence of papules and subcutaneous nodules, located mainly over the extremities.1 Although these findings were clinically and histopathologically reminiscent of scleromyxedema, these patients lacked a serum monoclonal paraprotein, head and neck lesions, or systemic manifestations found in that condition. In 2001, the same group of authors reviewed the histopathologic findings in 14 cases of fibrosing cutaneous illness among patients with kidney disease and proposed a distinct term for this disorder: nephrogenic fibrosing dermopathy (NFD).2 To date, there have been no reports of NFD in the pediatric population. We report two pediatric cases of this unique fibrosing skin disorder.
I
CASE REPORTS Case 1 A 16-year-old premenarcheal white female patient with a lifelong history of kidney failure secondary to brachio-otorenal (BOR) syndrome was referred to the pediatric dermatology clinic in May 2001 with a 10-day history of worsening pruritic and painful, erosive vesicular lesions on her trunk and extremities. The patient had received peritoneal dialysis from 6 weeks of age until 2.5 years and thereafter received 2 kidney transplantations from her parents. The second transplantation, received from her mother in July 1995, underwent rejection several years later, and in April 2001, hemodialysis was initiated because of worsening renal function. Her skin lesions, which began approximately 1 week after dialysis was started, were initially noted on her inner thighs, then spread to the outer thighs, lower extremities, arms, and trunk. They quickly became thickened, indurated plaques associated with marked pain and pruritis. She had no prior history of skin disease. She had no family history of autoimmune disease or lymphedema. On physical examination, she was a chronically ill-appearing girl in severe pain. Marked nonpitting edema of the extremities was present, and the overlying skin had a peau d’orange texture. Thick, linear hyperkeratotic plaques with superficial erosions were present most prominently on the legs, with additional involvement of the arms (Figure) and, to a lesser degree, the torso and abdomen. Sharply demarcated areas of spared skin were present on the arms and legs. Her face was uninvolved.
NFD
678
Nephrogenic fibrosing dermopathy
From the Department of Dermatology, University of Cincinnati, Cincinnati, Ohio; the Department of Dermatology, Duke University, Durham, North Carolina; the Department of Dermatology, University of Missouri, and the Department of Pediatrics and Dermatology, St Louis University, St Louis, Missouri; and the Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, California. Submitted for publication Mar 25, 2003; revision received July 14, 2003; accepted Aug 22, 2003. Reprints not available from the authors. Please address correspondence to: Ilona J. Frieden, MD, Department of Dermatology, Box 0316, San Francisco, CA 94143-0316. E-mail: [email protected]. Copyright ª 2003 Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0 10.1067/S0022-3476(03)00538-9
Laboratory studies revealed normal serum concentration of IgG and IgM proteins without a monoclonal spike. A swab specimen was negative for herpes virus. An initial punch biopsy from the left outer thigh showed foci of mineralization in the dermis consistent with calcinosis cutis and an increase in interstitial spindled cells with interstitial mucinous material. A second punch biopsy specimen from the right upper arm, obtained nearly 2 months later, revealed a proliferation of spindled cells arrayed in the reticular dermis with associated deposition of interstitial mucin, extending into the subcutaneous septa. Calcinosis of the superficial dermis was present. No inflammatory cells were identified. The findings of this second biopsy confirmed the diagnosis of nephrogenic fibrosing dermopathy. Her therapeutic treatment consisted of symptomatic treatment of pain and pruritis with prednisone, doxepin, acetaminophen/hydrocodone, ondansetron, amitriptyline, and topical treatment with a hydrogel dressing (Vigilon, Bard Home Health) and emollients. Shortly after her first visit, management of kidney failure was changed from hemodialysis to peritoneal dialysis. Over the next 2 months, the lesions stopped spreading, although the patient had decreased range of motion secondary to her skin changes, particularly in the lower extremities. Her weekly dose of epoetin alfa (Epogen, Amgen, Thousand Oaks, Calif ) was reduced and eventually discontinued. Six weeks later, the patient’s cutaneous disease was still extensive but had improved slightly, with increased range of motion of the extremities. Approximately 6 weeks thereafter, due to low hematocrit, she restarted epoetin alfa at 3000 units per week, with no obvious worsening of her skin lesions. One year after onset of her skin disease, she received a cadaveric kidney transplant. Within days, the degree of edema and pruritus improved. Her skin, although not completely normal, has become much less indurated.
Case 2 An 8-year-old white boy with a 9-month history of membranoproliferative glomerulonephritis type II of unproven inciting event was admitted to the University of Missouri Children’s Hospital for rapid/acute progression of chronic kidney failure. He had previously been treated with prednisone for nephrotic syndrome. Peritoneal dialysis was initiated. Several episodes of uncontrolled hypertension required treatment in the pediatric intensive care unit and intravenous antihypertensive agents. Epoetin alfa (2000 units 3 times weekly) and iron replacement therapies were initiated on the seventh hospital day. A skin rash developed in the perianal area on the 10th hospital day, which was treated with topical nystatin for presumed Candida infection. Examination revealed flattopped, violaceous hyperkeratotic papules, confluent on the right buttock. Reticular hyperpigmentation was noted on the lower ankles and feet. No vesicles, pustules, or excoriations were noted. The lesions were believed to be consistent with an infiltrative or granulomatous process, such as eruptive xanthoma, perforating disorder of kidney disease, or granuNephrogenic Fibrosing Dermopathy: Two Pediatric Cases
Figure. White female patient (16 years old) with nephrogenic fibrosing dermopathy. Thickened infiltrative plaques are evident on the arm.
loma annulare. He was treated with Fluocinonide ointment (0.05%) under occlusion and remained on peritoneal dialysis. Two and one-half months later, he was evaluated for verrucous granulomatous-appearing plaques on the buttocks bilaterally, with violaceous papules between the buttocks. Dry, lichenified skin was noted bilaterally on the lower extremities, ankles, and dorsal foot. Brown dermal plaques clinically consistent with granuloma annulare were noted bilaterally on the feet. The lower back had a brown hyperpigmented plaque in the midline, and the elbows had lichenified skin-colored plaques bilaterally. Linear sclerodermoid plaques were noted bilaterally on the anterior shins. Biopsy specimens were taken from the lesional skin of the buttock and foot. Histopathologic findings from both samples were believed to be consistent with perforating disorder of kidney disease. The lesions were treated with Tazarotene (0.1%) topical gel (Tazorac, Allergen, Irvine, Calif), with resolution of the keratotic lesions. The sclerodermoid lesions were treated with high-potency topical steroids under occlusion, without effect. Four and one-half months after admission, the skin lesions had spread to involve the abdomen and arms. Diffuse hyperpigmentation was present, accentuated over the posterior neck and sacrum. Dry, wrinkled skin of the sacrum and lower 679
back was noted, with apparent loss of elasticity, especially over the sacrum. The patient was referred to a pediatric dermatologist, and repeat biopsy specimens revealed a scleromyxedema-like fibrosing dermatitis consistent with NFD. There was no family history of autoimmune disease or lymphedema. He underwent cadaveric kidney transplantation approximately 2 years after the onset of NFD, 15 months after having begun peritoneal dialysis. After transplantation, his skin lesions improved, with softening of the thickened lesions and no new affected areas. He subsequently rejected the kidney and was restarted on dialysis but has had no worsening of his skin condition.
DISCUSSION Several case reports and two reviews of the emergence of scleromyxedema-like cutaneous change among patients with kidney disease have recently been published.1-6 Investigators from the Centers for Disease Control (CDC) created a case definition5 and identified 8 additional cases. Cowper et al2 detailed the histopathologic findings in 14 cases of NFD and helped clarify the features distinguishing this condition from other cutaneous fibrosing conditions, namely scleromyxedema, morphea/scleroderma, and b-2 microglobulin amyloidosis, which can complicate kidney failure. The skin lesions of NFD are characterized by indurated papules and plaques, brawny thickening of the skin with a peau d’orange appearance, and occasionally joint contractures.2 They are typically present on the extremities, buttocks, and trunk, rarely involving the face. Pruritus, burning, and pain are common symptoms.2 The histologic features of NFD can range from a subtle increase in dermal fibroblasts in early lesions to a florid proliferation of dermal fibroblasts, thickened collagen bundles with surrounding clefts, and increased dermal mucin and elastic fibers extending through the subcutis along thickened septa of fatty lobules. Additionally, there are increased numbers of CD-34-positive dermal dendrocytes and Factor XIIIa and CD-68-positive mononucleated and multinucleated cells, with a scant perivascular lymphocytic infiltrate seen only in a few cases.2 Scleromyxedema, a condition with many similarities to NFD, differs in its predilection for facial involvement and the presence of a monoclonal serum paraprotein, lacking in patients with NFD. NFD also lacks pools of dermal mucin or plasma cell infiltrates often found in scleromyxedema. Although systemic scleroderma and its localized cutaneous form, morphea, can cause tightening and induration of the skin, the histolopathologic findings are easily distinguishable. Systemic sclerosis and morphea have interstitial lymphohistiocytic infiltrates and a decrease (rather than increase) in dermal spindle cells.2 All reported cases of NFD share a common diagnosis of renal insufficiency. Of those reported by Cowper et al, 12 of 14 were undergoing hemodialysis at the time of onset of skin lesions. The initiation of dialysis before development of cutaneous disease ranged from days to 10 years. The causes of kidney disease and associated medical regimens varied, neither 680
Jan et al
sex nor ethnicity predilections were observed, and patient ages ranged from 31 to 74 years.2 Although the clustering of patients in hemodialysis centers suggests a possible toxin or infectious agent, the underlying cause of NFD remains unclear; a systematic epidemiologic study has therefore been initiated to identify the potential responsible factors.2 Four additional adult cases of NFD have recently been reported by Mackay-Wiggan et al.3 Patient ages ranged from 42 to 61 years, with kidney disease secondary to vaso-occlusive disease, diabetes, or hypertension. Three of the 4 patients had significant anasarca and began immunosuppressive medications just before the onset of skin lesions. Interestingly, one patient had onset of cutaneous fibrosis before hemodialysis or kidney transplantation. All four patients had positive anticardiolipin antibodies. The authors hypothesized that an accumulated substance intrinsic to kidney failure reacting with the antiphospholipid antibody, o, alternatively, edema coupled with immunosuppression, may stimulate fibroblast proliferation and the dermal mucin deposition seen in NFD.3 Anticardiolipin antibodies were not tested in our patients. In a small case-control study with control subjects who had received kidney transplantation but did not have NFD, those with NFD were more likely to have poor renal function after transplantation, including need for hemodialysis and/or medications associated with severe disease.5 In addition to scleroderma and scleromyxedema, the differential diagnosis for sclerotic skin disease and mucin deposition in the pediatric population includes scleredema, an extremely rare condition in which mucin deposition leads to diffuse induration of the subcutaneous tissue.7,8 Most pediatric cases are thought to be caused by an antecedent viral or bacterial infection. The neck, face, and upper extremities and trunk are usually involved, with the abrupt development of symmetric erythema and induration, without pain or pruritis. Even more rarely, scleredema can be caused by an associated monoclonal gammopathy.7 Cases have also been described in individuals with long-standing diabetes mellitus. Both of our pediatric cases had other histologic features that are often seen in patients with kidney disease, namely, calcinosis cutis and perforating collagenosis,9 but repeat biopsies definitively confirmed the diagnosis of NFD. Although no specific treatment has been found to treat NFD, improvement of renal function seems to ameliorate the condition. Thus until the causative factors involved in NFD are uncovered, treatment presently consists of supportive management of associated pain and pruritis, but ultimately with adequate correction of renal dysfunction through successful kidney transplantation. Plasmapheresis and thalidomide also have been used as treatments and are reportedly effective in some cases.10
REFERENCES 1. Cowper SE, Robin HS, Steinberg SM, Su LD, Supta S, LeBoit PE. Scleromyxeoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000;356:1000-1. 2. Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopath 2001;23:383-93.
The Journal of Pediatrics November 2003
3. Mackay-Wiggan JM, Cohen DJ, Hardy MA, Knobler EH, Grossman ME. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003;48:55-60. 4. McNeill AM, Barr RJ. Scleromyxedema-like fibromucinosis in a patient undergoing hemodialysis. Int J Dermatol 2002;41:364-7. 5. Fibrosing skin condition among patients with renal disease: United States and Europe 1997-2002. MMWR/Morb Mortal Wkly Rep 2002;51:25-6. 6. Streams BN, Liu V, Liegeois N, Moschella SM. Clinical and pathologic features of nephrogenic fibrosing dermopathy: a report of two cases. J Am Acad Dermatol 2003;48:42-7.
7. Jackson EM, English JC. Diffuse cutaneous mucinoses. Dermatol Clin 2002;20:493-501. 8. Heilbron B, Saxe N. Scleredema in an infant. Arch Dermatol 1986;122:1417-9. 9. Robinson-Bostom L, DiGiovanna JJ. Cutaneous manifestations of endstage renal disease. J Am Acad Dermatol 2000;43:975-86. 10. Baron PW, Cantos K, Hillebrand DJ, Hu K-Q, Ojogho ON, NehlsenCannarella S, et al. Nephrogenic fibrosing dermopathy following liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 2003;25:204-9.
50 Years Ago in The Journal of Pediatrics THE TREATMENT OF TUBERCULOUS MENINGITIS IN CHILDREN Kendig EL Jr, Ownby R Jr, Trevathan GE, Sutton LE Jr. J Pediatr 1953;39:532-5. In the early 1950s, data were just beginning to be published on the successful treatment of tuberculous meningitis in children by using antimicrobials. In the paper cited above, the authors summarize their experience in treating a large group of children with this disease. The standard antituberculous regimen used by these investigators consisted of intramuscular and intrathecal streptomycin combined with oral thiazosulfone (a dapsone derivative). Intrathecal purified protein derivative was used in two patients with advanced disease. In later cases in the series, para-aminosalicylic acid was substituted for thiazosulfone, and a new drug, isoniazid, was added to the regimen, both of these changes in line with newly published therapeutic recommendations from the Committee on Therapy. Despite treatment, the overall mortality rate in this group of children remained very high at 55%. Much progress has been made in the past half century in the evaluation and treatment of children with tuberculous meningitis. Potent and generally nontoxic anti-tuberculous regimens have replaced the regimens of the past.1 Isoniazid, the medication just appearing on the scene 50 years ago, has become a mainstay of antituberculous therapy, usually supplemented in current treatment regimens with the newer antimicrobials, rifampin and pyrazinamide. Streptomycin, although still in use as a part of combination treatment regimens, has a much more limited role than in the past. If tuberculous meningitis is diagnosed early and treated appropriately, the prognosis for the child is quite good.2 Unfortunately, despite progress in the development of medications for the treatment of disease, recent studies suggest that work still needs to be done to improve overall outcome. In a series recently published in The Journal of children with tuberculous meningitis, overall mortality was 16% and one fifth of the survivors were left with neurologic sequelae.2 Prognosis was closely tied to the stage of disease at time of presentation. For a substantial number of these patients, health care providers had evaluated the children earlier in their disease courses and failed to make a diagnosis of tuberculous disease. For more than one third of the children, an adult contact had been diagnosed with tuberculosis before disease onset in the child, yet appropriate intervention had not occurred. These data suggest that further improvements in the outcome of tuberculous meningitis in children could be achieved by educating physicians on the sometimes subtle presentation of disease and by strengthening the public health infrastructure in appropriate areas. Stephen J. Barenkamp, MD, Division of Pediatric Infectious Disease Department of Pediatrics, St Louis University School of Medicine St Louis, MO 63104-1095
YMPD505 10.1067/S0022-3476(03)00546-8
REFERENCES 1. 2.
Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001;345:189-200. Doerr CA, Starke JR, Ong LT. Clinical and public health aspects of tuberculous meningitis in children. J Pediatr 1995;127:27-33.
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