We identified loss-of-function mutations in ATP6V0A2, encoding the a2 subunit of the V-type H+ ATPase, in several families with autosomal recessive cutis laxa type II or wrinkly skin syndrome. The mutations result in abnormal glycosylation of serum proteins (CDG-II) and cause an impairment of Golgi trafficking in fibroblasts from affected individuals. These results indicate that the a2 subunit of the proton pump has an important role in Golgi function.
Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.
Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.
Skin diseases are common in children. However, only a very few prospective epidemiologic surveys are available in the literature. The present survey was directed at determining the spectrum and pattern of skin diseases of children in Kuwait. A total of 10,000 consecutive new patients were studied; 96% were children of Arab descent. A female preponderance (52%) was observed, and infants constituted the largest group within the patient population (28.7%). A total of 162 dermatoses were recorded. Atopic dermatitis was the most prevalent dermatosis (31.3%), followed by viral warts (13.1%), alopecia areata (6.7%), pityriasis alba (5.25%), psoriasis (4%), and diaper dermatitis (4%). Atopic dermatitis was the most frequently seen dermatosis in children of all age groups, whereas, viral warts were more prevalent in school-age children. The prevalence of alopecia areata and psoriasis was higher than reported earlier in other ethnic groups. A female preponderance was seen in children with alopecia areata, psoriasis, vitiligo, acne vulgaris, contact dermatitis, and pityriasis rosea. Dermatitis, superficial cutaneous infections, and nevi/nevoid disorders were the important groups studied.
One hundred and twelve cases of childhood psoriasis, constituting 5% of all psoriasis patients registered in our clinic, were studied over a period of nine years (January 1980 to December 1988). There were 57 male and 55 female patients. Age of onset ranged from 1 month to 13 years, with a mean and median age of 7 years. A positive family history of psoriasis was elicited from 9.8% of patients. The commonest form of psoriasis found was plaque (69.6%), followed by guttate (25.9%). Infection was the most common triggering factor, occurring in 15.2% of cases. Many of these findings are at variance with observations reported elsewhere for this age group.
Lichen planus (LP) in children is a rare entity. We report 23 cases of childhood LP seen over a period of 7 years. Ninety-six percent of the children were of Arab ancestry. There were 52% boys and 48% girls. Classic LP was the most common clinical variant (70%), followed by eruptive generalized LP (13%). A majority of the patients had mild, localized disease. Oral involvement was seen in 39% of patients. Topical steroids were the mainstay of treatment in most of the cases. Children with chronic and recurrent disease responded to dapsone therapy, whereas in those with eruptive and widespread disease, UVB phototherapy was found to be safe and effective. The present report highlights the salient clinical features, treatment, and course of LP in children in Kuwait compared to those reported in children of other countries as well as those of adults.
Alopecia areata (AA) is prevalent among children in Kuwait. In this prospective survey we studied 215 children with AA to determine their clinical and epidemiologic features. Ninety-seven percent of the children were of Arab ancestry. Girls outnumbered boys by a 2.5:1 ratio. The peak age of onset was seen between 2 and 6 years of age with a mean age of onset at 5.7 +/- 2.8 years. A majority of the patients (80.5%) had mild disease and extensive disease (more than 50% hair loss) was seen in 13% of the children. A positive family history of AA was obtained in 51.6% of cases and nail changes were seen in 26.5% of the children. The age of onset, a positive family history of AA, and associated atopic disorders were observed to have no influence on the extent and severity of the disease. The results were compared with those reported elsewhere for this age group.
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