Keratitis-ichthyosis-deafness syndrome: disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients.

BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital disorder characterized by the association of skin lesions, hearing loss and vascularizing keratitis. KID syndrome is caused by autosomal dominant mutations in the connexin 26 gene (GJB2). OBJECTIVES: To establish whether there is a correlation between genotype and phenotype in KID syndrome. METHODS: Clinical examination and molecular analysis of GJB2 were performed in a cohort of 14 patients with KID syndrome originating from 11 families. We also reviewed the 23 cases with molecular analysis previously reported in the literature. RESULTS: The patients displayed the classical signs of KID syndrome with the additional finding of inflammatory nodules in six patients (43%); this clinical finding has not been described previously in the literature. One patient presented at the age of 18 years with a fatal carcinoma of the tongue, an extremely rare reported complication. For seven of the 11 families (64%) the disease was sporadic, whereas it was familial in the remaining four families (36%). Twelve patients (86%) were heterozygous for the p.Asp50Asn mutation and two patients (14%) were heterozygous for the p.Ser17Phe mutation. Surprisingly, a family in which we personally examined the healthy parents had two affected children heterozygous for the p.Asp50Asn mutation, suggesting germinal mosaicism. Compared with patients with the p.Asp50Asn mutation, the two patients with the p.Ser17Phe mutation had more severe skin involvement. One of these two patients experienced a carcinoma of the tongue. CONCLUSIONS: Familial cases appear to be more frequent than reported in the literature. The possibility of germinal mosaicism must be taken into account for genetic counselling. This study also suggests that patients with the p.Ser17Phe mutation may have a more severe phenotype and could be at higher risk for tongue carcinoma.

Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis.

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis with no specific treatment or prenatal diagnosis available at present. The recent identification of SPINK5, which encodes a serine protease inhibitor, as the defective gene enables DNA based prenatal diagnosis to be carried out. Here we report the first direct molecular prenatal diagnosis of a lethal form due to a recurrent SPINK5 mutation in three consanguineous Turkish families. XmnI restriction enzyme digestion and DNA sequencing demonstrated that each deceased affected child was homozygous for mutation 153delT inherited from each parent. Analysis of fetal DNA from amniotic fluid cells in Family 1 and from a chorionic villus sampling in Family 3 showed that the fetus was heterozygous for 153delT in both cases. The pregnancies were carried to term and the newborns were unaffected. In Family 2, fetal DNA analysis from chorionic villus biopsy showed in a first pregnancy that the fetus was homozygous for 153delT. The pregnancy was terminated at 13 weeks and DNA analysis of fetal keratinocytes confirmed the prenatal prediction. In a second pregnancy in Family 2, fetal DNA analysis showed heterozygosity for 153delT, and the pregnancy was continued. Direct SPINK5 mutation analysis in families at risk for NS represents the first early, rapid and reliable method for prenatal diagnosis of this life threatening form of ichthyosis.