The Conradi-Hunermann-Happle syndrome (CDPX2) and emopamil binding protein:: novel mutations, and somatic and gonadal mosaicism

The Conradi-Hunermann-Happle (CHH) syndrome (X-chromosomal dominant chondrodysplasia punctata type II; MIM 302960) is an X-linked dominant disorder that is characterized by ichthyosis, chondrodysplasia punctata, cataracts and short stature. The disease occurs almost exclusively in females and shows increased disease expression in successive generations (anticipation), Recently, causative mutations in the emopamil binding protein (EBP) have been identified. To better appreciate the genetics of this syndrome we analyzed the ESP gene in seven independent families using PCR, conformation-sensitive gel electrophoresis, direct sequencing and restriction enzyme analysis. We found five novel mutations: three nonsense mutations in exon 2 and exon 3 and two frameshift mutations, one deletion in exon 4 and an insertion in exon 5, In two families, known mutations affecting exon 2 were identified, Surprisingly, we failed to detect the mutation in a grandmother exhibiting minor disease symptoms such as sectorial cataract and attribute this to gonadal and somatic mosaicism, Gonadal mosaicism appeared also to be involved in the case of healthy parents having two affected girls, one of whom died due to the disease, We conclude that gonadal mosaicism has to be considered when dealing with seemingly sporadic cases.