The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.

The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.

Pain management of junctional epidermolysis bullosa in an 11-year-Old boy.

Epidermolysis bullosa is a group of hereditary blistering disorders for which there is no definitive therapy. Wound care is an important component of management. Regular dressing changes are required to protect blistered and eroded skin, and to prevent secondary infection and sepsis. These dressing changes can be very painful for patients with extensive erosions. We report our experience of pain management in an 11-year-old boy with severe junctional epidermolysis bullosa. Amitryptiline and cognitive behavioral techniques were effective in relieving chronic pain and discomfort. Oral midazolam 0.33 mg/kg administered 20 minutes prior to baths and dressing changes substantially improved his tolerance of wound care.

Cutaneous manifestations of chronic granulomatous disease. A report of four cases and review of the literature.

BACKGROUND: Chronic granulomatous disease represents a group of genetic disorders in which impaired intracellular microbial killing by phagocytes leads to recurrent bacterial and fungal infections and granuloma formation. Cutaneous disease occurs in 60% to 70% of cases. The characteristic histologic finding of pigmented lipid macrophages in visceral granulomas has not been described previously in the skin. OBJECTIVE: Our purpose was to review our experience of skin disorders in chronic granulomatous disease. METHODS: We studied the clinical and histologic findings in four patients with chronic granulomatous disease and unusual skin lesions. We reviewed the skin disorders seen in five additional patients with chronic granulomatous disease referred to the pediatric dermatology clinic. The literature was reviewed for previously reported cutaneous manifestations of chronic granulomatous disease. RESULTS: A teenage boy with chronic granulomatous colitis had nonulcerating cutaneous granulomas from which no organisms were isolated. Histologic examination of both skin and bowel revealed the characteristic golden-yellow granular pigment in macrophages. A second boy had cutaneous aspergillosis involving the left foot; histologic examination revealed macrophages containing yellow-brown pigment at the periphery of the granulomatous inflammation. Two children had vesicular skin lesions. These lesions were recurrent in one boy for several years. In the second child they were associated with fatal intracranial and pulmonary infection. Histologic examination in both cases revealed a subcorneal polymorphonuclear infiltrate and perivascular macrophages containing yellow-brown pigment. Cultures were either negative or revealed organisms that are normally nonpathogenic skin commensals, such as coagulase-negative staphylococci. CONCLUSION: The cutaneous manifestations of chronic granulomatous disease encompass a variety of infections and inflammatory lesions. Diagnostic and therapeutic problems may arise because of difficulty in isolating a causative organism. The characteristic pigmented macrophages of visceral granulomas can also be found in skin lesions.

Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children.

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.

Transient erythroporphyria of infancy.

We describe a neonate with hemolytic disease of the newborn in whom a photosensitivity eruption developed during phototherapy for treatment of hyperbilirubinemia. Free erythrocyte protoporphyrin and zinc protoporphyrin levels were markedly elevated during the neonatal period. Porphyrin levels were normal at 19 weeks of age. The infant had residual skin atrophy and showed clinical and radiologic evidence of kernicterus. The pathogenesis of transient porphyrinemia associated with hemolytic disease of the newborn is unclear.

Treatment of molluscum contagiosum with oral cimetidine: clinical experience in 13 patients.

Our purpose was to determine if oral cimetidine, a histamine-receptor antagonist, might be of benefit in the treatment of extensive molluscum contagiosum in children. We present 13 pediatric patients in whom conventional treatment modalities for molluscum contagiosum were unsuccessful or difficult to apply. They were treated with a two-month course of oral cimetidine 40 mg/kg/day. All but three children who completed treatment experienced clearance of all lesions. These children had no new lesions but had persistence of several lesions. One child did not take the drug and did not clear. No adverse effects were observed. We conclude that oral cimetidine may be of benefit in the management of widespread or facial molluscum contagiosum in immunocompetent children.

Wells' syndrome in childhood: case report and review of the literature.

We report a severe case of Wells' syndrome, or eosinophilic cellulitis, after a bee sting in a 4-year-old girl. The patient had a widespread, painful, blistering eruption that was subsequently complicated by Pseudomonas aeruginosa superinfection and septicemia, hypoalbuminemia, anemia, and neutropenia. The skin lesions responded to systemic steroid therapy. There was residual scarring alopecia of the scalp. There have been 17 previous reports of childhood Wells' syndrome. We believe that this disorder is a distinct entity that should be considered in the differential diagnosis of blistering diseases in children.

Oral pemphigus vulgaris associated with inflammatory bowel disease and herpetic gingivostomatitis in an 11-year-old girl.

An 11-year-old girl with recently diagnosed oral pemphigus vulgaris developed a severe exacerbation of mouth ulceration due to superinfection with herpes simplex virus type I. A concurrent diagnosis of chronic inflammatory bowel disease was established to explain symptoms of weight loss and intermittent bloody diarrhea that predated the oral ulceration by several years. Herpes simplex infection is a recognized complication of pemphigus vulgaris that may be mistaken for a recrudescence of the disease. The association of pemphigus with chronic inflammatory bowel disease has been documented in a small number of adults. Its relationship to pyostomatitis vegetans, an acknowledged marker for ulcerative colitis and Crohn disease, remains unclear.

Ocular findings of incontinentia pigmenti in a male infant with Klinefelter syndrome.

A male infant with Klinefelter karyotype (47, XXY) manifested both the typical dermatologic findings of the X-linked dominant disorder incontinentia pigmenti (Bloch-Sulzberger syndrome) and ocular findings including retinal pigmentary changes, peripheral retinal avascularity, and preretinal fibrovascular proliferation. To our knowledge, this is the first reported case of incontinentia pigmenti with this specific abnormal genotype manifesting ocular findings.

Skin signs of nutritional disorders.

Children, especially infants, require adequate calories and nutrients to meet the high demands of normal growth and development; protein, essential fatty acids, vitamins and minerals are all important in achieving this goal. Malnutrition results from deficiency in one or more of these basic nutrients. It may be caused by (1) insufficient dietary intake, (2) malabsorption, (3) poor utilization of nutrients, and (4) increased catabolism. A range of clinical and metabolic changes occurs as a result of profound and generalized abnormalities at a cellular level. Mucocutaneous changes constitute one of the variable and multisystemic clinical manifestations of malnutrition. Although some signs are characteristic of a specific nutrient deficiency, an overlap of skin manifestations is observed in multiple deficiency states. The periorificial glazed erythema and hair loss of zinc deficiency also may be seen in patients with essential fatty acid deficiency, biotinidase deficiency, and even kwashiorkor. Mucous membrane changes associated with deficiency of many water-soluble vitamins may likewise be difficult to distinguish.

Osteoma cutis as a presenting sign of pseudohypoparathyroidism.

Four unrelated children with osteoma cutis and Albright hereditary osteodystrophy (pseudohypoparathyroidism and pseudopseudohypoparathyroidism) are described. All four patients were normocalcemic when they were first seen with cutaneous ossification. A diagnosis of Albright hereditary osteodystrophy was established on the basis of associated somatic features, radiographic abnormalities, and family history. Progression to pseudohypoparathyroidism was documented in two children who developed hypocalcemia at 2 and 3 years of age, respectively. Early recognition of the skin manifestations of this syndrome and careful follow-up are important to prevent the deleterious effects of hypocalcemia. Osteoma cutis is a common sign of Albright hereditary osteodystrophy in infancy and childhood, and its significance should not be overlooked, even in the normocalcemic patient.

The sign of Leser-Trélat in a young woman with osteogenic sarcoma.

The sign of Leser-Trélat refers to a sudden increase in size and number of seborrheic keratoses associated with internal malignancy. The validity of this cutaneous sign continues to be debated, particularly because of the prevalence of both seborrheic keratoses and malignancy in the elderly population. Preceding inflammatory skin conditions are known to precipitate eruptions of seborrheic keratoses in otherwise healthy persons. These cutaneous lesions may also be associated with other markers of underlying malignancy such as acanthosis nigricans. We present a young female patient with osteogenic sarcoma in whom eruptive seborrheic keratoses developed. We believe this case is representative of the sign of Leser-Trélat.

Solitary morphea profunda in a 5-year-old girl: case report and review of the literature.

A 5-year-old girl had a solitary sclerotic plaque on the back of recent onset. The histopathologic features were consistent with morphea profunda. Thickening and homogenization of collagen bundles were demonstrated in the dermis and subcutaneous tissues, admixed with a prominent lymphocytic and plasma cell inflammatory infiltrate. Solitary morphea profunda is a variant of localized scleroderma that has not been reported previously in childhood. Cases described in the literature as nodular or keloid morphea may represent a similar entity.

Normal peroxisomal function and absent skeletal manifestations in Conradi-Hünermann syndrome.

We describe a child with the classic cutaneous and ocular manifestations of Conradi-Hünermann syndrome in whom repeated roentgenographic studies during the first 2 years of life revealed no evidence of epiphyseal stippling. The findings in this case and others from the literature suggest that skeletal changes may be absent or show limited expression in patients with this condition and that chondrodysplasia punctata should not be considered an invariable feature of Conradi-Hünermann syndrome. Studies of peroxisomal function in our patient failed to confirm two previous reports of a significant reduction in activity of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase in this disorder.

Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child.

We describe an 11-year-old girl in whom multiple cutaneous granular cell tumors were associated with a giant speckled lentiginous nevus and an extensive nevus flammeus. An association between granular cell tumors and pigmented skin lesions has been reported twice previously and supports a neural origin for these tumors. An abnormality of neural crest development is proposed to explain the coexistence of three uncommon and unusually extensive cutaneous disorders in this patient. This case may represent a further variant of phakomatosis pigmentovascularis.