We here review the clinical and genetic features of the
Conradi-Hünermann-Happle syndrome. The disease is characterized by
chondrodysplasia punctata, linear
ichthyosis,
cataract, and short stature. The X-linked dominant mode of inheritance was first recognized by Rudolf Happle in the years 1977 to 1981, who also fully delineated the clinical spectrum of this clinico-genetic entity. In the past, linkage studies had firmly excluded the gene for this syndrome from the Xq28 region, but unfortunately had also failed to clearly map the gene elsewhere on the X-chromosome. Very recently, causative mutations were identified in a large number of patients in the gene for
emopamil binding protein. This gene is located on the short arm of Xp11.22-23 and also acts as a D8-D7
sterol isomerase. This enzymatic function plays a crucial role in
cholesterol biosynthesis. It is of note that very recent investigations by the Marburg group have disclosed that the
CHILD syndrome is likewise caused by a similar metabolic defect, namely a deficiency of a 3b-hydroxysteroid
dehydrogenase (NSDHL). In the pathway of
cholesterol biosynthesis this
enzyme functions "upstream" of D8-D7
sterol isomerase and was shown to underlie the mouse mutant bare patches. Molecular studies in these syndromes now allow us to determine which family members carry the mutation and have already provided evidence in the
Conradi-Hünermann-Happle syndrome for both gonadal and somatic mosaicism. As gonadal mosaicism seems to be frequent in this disease, a recurrence risk for further pregnancies has to be considered when dealing with a seemingly sporadic case.