Increased glycosaminoglycan accumulation as a genetic characteristic in cell cultures of one variety of dominant dystrophic epidermolysis bullosa.

Fibroblast cultures from patients with dominant dystrophic epidermolysis bullosa of the albopapuloid variety display deranged glycosaminoglycan metabolism. These cells accumulate increased amounts of sulfated glycosaminoglycans. The mechanism for the greater content of glycosaminoglycans appears to be related to increased synthesis. During the first 6-12 h, intracellular labeled glycosaminoglycans accumulated in the dominant dystrophic epidermolysis bullosa cells at about twice the rate as that of control fibroblasts. In addition, secretion of sulfated glycosaminoglycans was two- to threefold greater than in control cultures. In contrast, both pulse-chase and cross-correction experiments failed to show any evidence for defective degradation of the material. The biochemical trait is genetically specific for albopapuloid dominant dystrophic epidermolysis bullosa, since fibroblasts from patients with other varieties of epidermolysis bullosa did not accumulate increased glycosaminoglycans. The data suggest that in vitro abnormality in glycosaminoglycan metabolism could serve as an important marker for this variety of epidermolysis bullosa and be of genetic and prognostic value in the sporadic patient with epidermolysis bullosa. Although the precise relationship of the defect to the disease has not yet been defined, it is possible that excessive tissue accumulation of glycosaminoglycans may alter collagen fibril deposition, thus, impairing the structural integrity of the skin and leading to posttraumatic blisters and erosions that characterize the disease.

The effect of salicylate on the metabolism of normal and stimulated human lymphocytes in vitro.

The effect of salicylate on the metabolism of peripheral blood lymphocytes in tissue culture was investigated. Lymphocytes incubated with sodium salicylate at a concentration of 30 mg/100 ml showed increased glucose consumption, lactic acid production, and oxygen consumption, evidence for uncoupling of oxidative phosphorylation. No decrease in cell number or viability (trypan blue dye exclusion) was noted in salicylate-treated cultures. Normal DNA, RNA, and total protein synthesis measured by radioisotope incorporation was depressed in the salicylate-treated cultures. Increased DNA synthesis after the addition of a mitogen (PHA) or antigen (PPD) to the culture was strikingly suppressed by salicylate. The degree of suppression was proportional to the concentration of salicylate used. The effect on RNA and protein synthesis in stimulated lymphocytes was much less pronounced. Acetylsalicylic acid was found to be as active as sodium salicylate in suppressing DNA synthesis, but the p-OH congener (p-OH benzoic acid) did not alter cell respiration, glycolysis, viability, or DNA synthesis. The salicylate effect was reversible as evidenced by return of cellular reactivity upon removal of the drug from the media.

The ichthyosis mouse: histologic, histochemical, ultrastructural, and autoradiographic studies of interfollicular epidermis.

Interfollicular epidermis from back and tail of the recessive mutant mouse ichthyosis (ic/ic) was studied by histologic, histochemical, ultrastructural, and autoradiographic techniques and compared to heterozygous and Swiss S mouse epidermis. In the ic/ic mouse the stratum corneum was thickened, the granular layer prominent, and the stratum spinosum hyperplastic. Staining reactions for certain respiratory and lysosomal enzymes were more pronounced in epidermis of both back and tail. Ultrastructural studies of ic/ic epidermis demonstrated excessively clumped tonofilaments and increased numbers of mitochondria, ribonuclear protein particles, and membrane-coating granules in the stratum spinosum cells. Dilated intercellular junctions between the stratum spinosum and stratum granulosum cells were packed with membrane-coating and amorphous material. Profuse keratin-forming structures, abnormally large keratohyaline granules, and persistent mitochondria were seen in the stratum granulosum cells. In the stratum corneum, inclusions were prominent and persisted into the upper layers of cells, which were irregular in outline and greatly thickened. No differences in epidermal cell transit time or labeling index were demonstrated among the three types of mice.

Elastic fibers in fetal dermis.

Dermal elastic tissue in fetal skin was evaluated by light microscopy using three different staining techniques. Postmortem skin was obtained from the abdominal wall of 45 fetuses ranging in age from 8 to 42 weeks. Elastic fibers were first detected in skin from fetuses of 22 weeks and, with increasing gestational age, appeared to increase in quantity and complexity. Skin from fetuses older than 32 weeks had a well-developed network of elastic fibers throughout the dermis. There was no diminution of dermal elastic tissue during the latter part of the sixth lunar month as had been reported in a previous study.

Carcinoembryonic antigen: increased plasma levels in recessive epidermolysis bullosa.

Circulating plasma levels of the oncofetal antigen, carcinoembryonic antigen, were examined in 18 patients with various forms of epidermolysis bullosa. Carcinoembryonic antigen was markedly elevated in the plasma of 4 of 6 patients with recessive dystrophic epidermolysis bullosa and in 1 of 2 patients with recessive epidermolysis bullosa letalis. In contrast, patients with dominantly inherited forms of the disease, dominant epidermolysis bullosa simplex and dominant dystrophic epidermolysis bullosa, had normal levels of antigen. In the recessive patients, the plasma levels of carcinoembryonic antigen appeared to correlate with the severity of cutaneous involvement. Alternatively, it is possible that expression of carcinoembryonic antigen is genetically linked to certain forms of recessive epidermolysis bullosa or is part of a pleiotropic effect of the gene coding for the disease.

The effect of antimicrobial agents on leukocyte chemotaxis.

The effects of several chemotherapeutic agents on the chemotaxis of human leukocytes were studied in an in vitro system using a Sykes-Moore chamber and a double-filter technique. Chemotactic factor was generated by the interaction of normal human serum and zymosan. At concentrations comparable to and below therapeutic blood levels, tetracycline HCl, erythromycin base and clindamycin HCl were all inhibitory, causing marked suppression of leukocyte chemotaxis and slight reduction of random migration. Penicillin G-Na, dapsone, and sulfapyridine did not alter white cell motility at the concentrations of drug tested. It is postulated that the capacity of some of these agents to inhibit leukocyte chemotaxis may account, in part, for their efficacy in inflammatory skin diseases such as acne vulgaris.

Colchicine-induced modulation of collagenase in human skin fibroblast cultures. II. A probe for defective regulation in epidermolysis bullosa.

The addition of colchicine to cultures of normal human skin fibroblasts produces a significant stimulation of collagenase. Because this finding implies a role for the microtubule system in the regulation of normal collagenase synthesis, we have used colchicine as a probe for aberrations in this enzyme in epidermolysis bullosa. In fibroblast cultures from the dominant simplex, dominant dystrophic, and recessive letalis forms of epidermolysis bullosa, 10(-6) M colchicine produced approximately a 2-fold increase in collagenase in the culture medium, a finding shown by biosynthetic studies to be attributable to enhanced synthesis of enzyme protein. In the case of typical recessive dystrophic epidermolysis bullosa, a disease characterized by excessive collagenase synthesis, the fibroblasts could also be stimulated to produce additional collagenase, despite having elevated baseline synthetic rates. In contrast, fibroblasts isolated from one recessive epidermolysis bullosa patient were resistant to the stimulatory effects of colchicine in concentrations up to 5 x 10(-6) M. In the absence of colchicine, collagenase synthesis in this patient's cells (termed REBc-) was 3-4 times that of normal controls, suggesting that the as yet undefined cellular function that is abrogated (or stimulated) by colchicine in normal cells may have been genetically impaired in these REBc- cells. Despite the resistance to colchicine, as manifested by the failure to stimulate collagenase, gross parameters of microtubular function, such as cell replication, were intact. Phenotypically, this patient had a form of epidermolysis bullosa intermediate between typical recessive dystrophic and recessive letalis forms of the disease. Although an experimentally induced blister was located in the lamina lucida, hypoplastic anchoring fibrils were also observed. These findings, in addition to the marked increase in collagenase synthesis, suggest the possibility that this patient may represent a compound heterozygote of two forms of epidermolysis bullosa and that colchicine may be useful in defining other such patients.

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.

The Gianotti-Crosti syndrome.

The Gianotti-Crosti syndrome is an infrequently recognized disorder with distinctive characteristics. The eruption, which lasts for two to eight weeks, consists of large, flat-topped, nonpruritic papules on the face, buttocks, and limbs. Its onset may be preceded by fever and upper respiratory tract symptoms. Associated findings include generalized lymphadenopathy, anicteric hepatitis, and HBs antigenemia. Two children with the syndrome are described to bring this entity to the attention of pediatricians.

The hair collar sign: marker for cranial dysraphism.

OBJECTIVE: To call attention to a cutaneous marker for neural tube closure defects of the scalp, the "hair collar" sign. This finding consists of a ring of long, dark, coarse hair surrounding a midline scalp nodule. METHODS AND RESULTS: Four children with small congenital scalp nodules and the hair collar sign were studied from the standpoint of clinical findings, radiologic scans, and histology of the excised nodules. All four had an overlying vascular stain in addition to the hair collar. Patients 1 and 2 were found to have encephaloceles, and one had heterotopic brain tissue. The fourth family refused surgery, but the clinical and radiologic findings were consistent with a diagnosis of atretic encephaloceles. One infant had agenesis of the corpus callosum and a Dandy-Walker malformation as associated findings. CONCLUSIONS: The "hair collar" sign should alert the pediatrician to the possibility of ectopic neural tissue in the scalp and/or underlying central nervous system malformations.

Uncombable hair (pili trianguli et canaliculi): evidence for dominant inheritance with complete penetrance based on scanning electron microscopy.

Uncombable or spun-glass hair (pili trianguli et canaliculi) is an uncommon condition in which the hair is "unmanageable" and has a distinct appearance on scanning electron microscopy. The hair is usually grossly abnormal in infancy and childhood, but may become normal later in life. Although dominant inheritance has been observed, most cases have been sporadic. Both recessive and dominant transmission with incomplete penetrance have been suggested as modes of inheritance. We report the occurrence of this condition in a young girl, her brother, and her father. Although the proposita and her brother had characteristically uncombable hair, their father appeared normal and denied any history of hair abnormality. However, the characteristic hair morphology was observed on scanning electron microscopy in all 3 relatives, documenting dominant transmission and complete penetrance of the gene in this family.

Dyskeratosis congenita with linear areas of severe cutaneous involvement.

Dyskeratosis congenita (DC) is a rare hereditary disorder of skin which may be associated with aplastic anemia. The pattern of inheritance is X-linked recessive in most instances, but autosomal dominant and autosomal recessive types have been documented. Reticulated hyperpigmentation usually is the first manifestation. The pigmentary changes may be limited to neck, upper chest, and proximal parts of the limbs initially but within affected areas the involvement is always diffuse. We report on a patient with typical diffuse cutaneous signs of dyskeratosis congenita superimposed with hyperpigmentation that was more pronounced along Blaschko's lines. To explain this phenomenon, we assume that the patient has the autosomal dominant type and that loss of heterozygosity occurred in a somatic cell giving rise to a population of cells that migrated along these lines during embryogenesis.

Asymptomatic dermatophyte carriers in the households of children with tinea capitis.

OBJECTIVES: To determine the prevalence of the carrier state in household contacts in children with tinea capitis, the duration of the carrier state, factors associated with carriage, and the proportion of carriers who develop clinical disease. DESIGN: Cross-sectional, cohort, prevalence study. SETTING: General pediatric clinic serving an indigent, inner-city, African American population. PATIENTS: Household contacts in children with tinea capitis. Index cases and carriers (no clinical evidence of infection) were identified by culture. Carriers were monitored until the results of their culture became negative, they developed clinical disease, or a 6-month period had elapsed. RESULTS: Fifty-six index cases and 114 contacts (50 adults and 64 children) were evaluated. Ninety-eight percent of the dermatophytes identified in index cases and 100% in carriers were Trichophyton tonsurans. At the initial visit, 18 (16%) of 114 (95% confidence interval [95% CI], 10-24) of contacts were carriers and 14 (32%) of 44 of the families studied had at least 1 carrier. At the 2-, 4-, and 6-month visits, the carrier state persisted in 7 (41%) of 17 (95% CI, 19-67), 3 (20%) of 15 (95% CI, 4-48), and 2 (13%) of 15 (95% CI, 2-40), respectively. Three of the carriers were lost to follow-up. Of the carriers, 1 (7%) of 15 (95% CI, 0.2-32) developed tinea capitis. Univariate and multivariate analysis showed no association of carrier state to age, sex, comb sharing, or cosleeping. However, cosleeping and comb sharing were common among the contacts, occurring 75% and 78% of the time, respectively, making statistical correlation difficult with our sample size. CONCLUSIONS: Initial prevalence of asymptomatic carriage of dermatophytes among household contacts of a child with tinea capitis was 16%, with 41% of carriers persisting up to 2 months. Thirty-two percent of families had at least 1 member who was a carrier. Seven percent of the carriers developed an active infection. Treatment of carriers with sporicidal shampoo should be considered since they may act as a reservoir for infection or develop active disease. The high prevalence of cosleeping and comb sharing may be important factors in the spread of the disease.

Cutaneous eruptions in congenital tuberculosis.

Systemic tuberculosis with morphologic skin lesions that were essentially identical developed in two infants who were born of tuberculous mothers. In each patient, the infection induced erythematous papules with central crusted dells, noted four and eight weeks after birth, respectively. In each case, the diagnosis of tuberculosis was made by examination of tissue that was obtained at laparotomy. In neither patient was Mycobacterium tuberculosis found in the skin lesions. The conditions of both patients responded well to antituberculous therapy. This article reviews the possible categorization of the skin lesions in these infants.

Childhood epidermolysis bullosa acquisita. Detection in a 5-year-old girl.

A 5 1/2-year-old girl with a blistering disease involving the skin and the oral, ocular, and anogenital mucosa is described. The initial clinical, histologic, and immunofluorescence findings suggested a diagnosis of cicatricial pemphigoid. However, immunoelectron microscopy demonstrated linear deposits of several immunoreactants within the sub-lamina densa region of the dermoepidermal junction, consistent with the diagnosis of epidermolysis bullosa acquisita. Although epidermolysis bullosa acquisita is considered a disease of adult onset, it should be included in the differential diagnosis of blistering diseases in children.

Eruptive vellus hair cysts.

Two children had a hyperpigmented monomorphous papular eruption of several years' duration. Biopsy specimens demonstrated cysts in the middle dermis that contained multiple fragmented vellus hair shafts. The eruption in one child involuted spontaneously. The cause of these lesions is obscure. The term eruptive vellus hair cysts is proposed for this entity.

Etretinate therapy for generalized pustular psoriasis in children.

Two children, 19 months of age, were independently treated with a compassionate protocol of etretinate therapy for recalcitrant, debilitating pustular psoriasis. Laboratory test results, roentgenograms of the spine, and bone age were periodically monitored. Over a 31/2-year period of intermittent treatment with a maximum dosage of 1.5 mg/kg/d, both children showed remarkable improvement with no apparent drug effect on growth and development. Side effects included xerosis, skin fragility and transient, minimal elevations of aspartate aminotransferase, lactic dehydrogenase, and triglyceride levels. Etretinate therapy may prove to be a viable treatment option for the child with intractable pustular psoriasis that seriously impairs quality of life.

Eruptive syringoma.

Eruptive syringoma is a rare variant of syringoma that appears on anterior surfaces of the body, including the neck, chest, and arms. Textbooks state that this eccrine-derived tumor arises at puberty. We describe four cases of eruptive syringoma that began in childhood. We review the literature on this entity and suggest that the disorder typically presents between the ages of 4 and 10 years. Eruptive syringoma is a benign tumor that should be considered among the papular dermatoses of childhood.

Congenital migratory ichthyosiform dermatosis with neurologic and ophthalmologic abnormalities.

We encountered two patients with a congenital migratory ichthyosiform dermatosis, retinal colobomas, conductive hearing loss, seizures, mental retardation, and similar facial features. The results of electron microscopic studies performed on skin biopsy specimens from the patients differed significantly from those of previously reported cases of ichthyosiform dermatoses with associated neurologic and ophthalmologic abnormalities; they appear to represent a new neuroectodermal syndrome.

Cutaneous T-cell lymphoma (parapsoriasis en plaque). An association with pityriasis lichenoides et varioliformis acuta in young children.

Pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC) are related benign disorders without recognized association with cutaneous T-cell lymphoma (CTCL). We report the cases of two children with documented PLEVA evolving into CTCL over several years. One child had the clinical lesions of PLC but the dermatopathologic findings of PLEVA at age 2 years. At age 12 years, he had skin changes of poikiloderma atrophicans vasculare and dermatopathologic findings consistent with parapsoriasis en plaque. The second child presented at age 7 years with scaling dermatitis and dermatopathologic findings of PLEVA. At age 12 years, the histologic diagnosis was parapsoriasis. Monoclonal antibody studies performed on biopsy specimens from both patients revealed 70% to 100% cells staining with CD5, 80% to 90% staining with CD4, 30% to 50% staining with CD8, and an increase in CD1-staining cells in the papillary dermis, indicating a predominantly helper T-cell infiltrate. We believe that PLC and PLEVA may be part of the spectrum of CTCL. Furthermore, CTCL may be more common in young children than once thought.