Abnormal facial appearance, body asymmetry, limb deformities, and internal malformations.

We describe a newborn girl with multiple congenital anomalies and abnormal phenotype comprising underdeveloped corpus callosum with ventriculomegaly, chorioretinal atrophy, pulmonary arterial hypertension, annular pancreas, horseshoe kidney, asymmetric limb and chest anomalies, spinal segmentation defects, hypertrichosis, and unusual face with large anterior fontanel, high anterior hairline, broad forehead, mildly underdeveloped midface, hypertelorism, depressed nasal bridge, short and upturned nose, large mouth, retrognathia, and large and malformed ears. Work-up included cytogenetic studies of lymphocytes and skin fibroblasts, subtelomere Multiplex Ligation-dependent Probe Amplification (MLPA), whole-genome oligo-array, and molecular analysis of SETBP1 and NSDHL: no abnormalities were found. Mucopolysaccharide urinary excretion was elevated. Results of metabolic studies for sterol and peroxisomal abnormalities in fibroblasts were normal. Additional electronic microscopy studies in skin fibroblasts did not show evidence for storage in fibroblasts or lysosomal changes. Nosologic considerations allowed exclusion of Schinzel-Giedion and Urioste syndrome. This condition seems not to have been described before; a segregating Mendelian mutation is assumed.

Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (HED) can be caused by mutations in the X-linked ectodysplasin A (ED1) gene or the autosomal ectodysplasin A-receptor (EDAR) and EDAR-associated death domain (EDARADD) genes. X-linked and autosomal forms are sometimes clinically indistinguishable. For genetic counseling in families, it is therefore important to know the gene involved. In 24 of 42 unrelated patients with features of HED, we found a mutation in ED1. ED1-negative patients were screened for mutations in EDAR and EDARADD. We found mutations in EDAR in 5 of these 18 patients. One mutation, p.Glu354X, is novel. In EDARADD, a novel variant p.Ser93Phe, probably a neutral polymorphism, was also found. Clinically, there was a difference between autosomal dominant and autosomal recessive HED patients. The phenotype in patients with mutations in both EDAR alleles was comparable to males with X-linked HED. Patients with autosomal dominant HED had features comparable to those of female carriers of X-linked HED. The teeth of these patients were quite severely affected. Hypohidrosis and sparse hair were also evident, but less severe. This study confirms Chassaing et al's earlier finding that mutations in EDAR account for approximately 25% of non-ED1-related HED. Mutations leading to a premature stop codon have a recessive effect except when the stop codon is in the last exon. Heterozygous missense mutations in the functional domains of the gene may have a dominant-negative effect with much variation in expression. Patients with homozygous or compound heterozygous mutations in the EDAR gene have a more severe phenotype than those with a heterozygous missense, nonsense or frame-shift mutation.