The Conradi-Hünermann-Happle syndrome is caused by mutations in the gene that encodes a ³8-³7 sterol isomerase and is biochemically related to the CHILD syndrome

ARTICLE

In this review we wish to call attention to an important milestone in the history of dermatological genetics: the unravelling of the molecular and biochemical basis of the Conradi-Hünermann-Happle (CHH) syndrome. In the years 1977 to 1981 this disease was fully described by Happle [1-4] as an X-linked dominant gene defect that is characterized by linear ichthyosis following the lines of Blaschko (Fig. 1), chondrodysplasia punctata (Fig. 2), cataracts and short stature. Although chondrodysplasia punctata as a hallmark of this syndrome was already described by Conradi [5] and a further case was later reported by Hünermann [6], it was the ingenious achievement of Happle to recognize the X-linked dominant inheritance by interpreting the linear skin lesions observed in this syndrome as the visible consequences of X-inactivation [7].

Apart from the peculiar cutaneous involvement the CHH syndrome features chondrodysplasia punctata, i.e. punctate calcifications of the epiphyseal regions that usually result in an asymmetric shortening of long bones, often severe kyphoscoliosis, facial dysplasia, and congenital hip dislocation. Unilateral and sectorial cataracts belong to the typical clinical spectrum of this syndrome and again represent functional consequences of X-inactivation.

Because the mouse mutant bare patches (Bpa) has striking similarities to the human disease as far as the cutaneous, skeletal and ocular abnormalities are concerned, Happle et al. [8] suggested that the gene for the Bpa mouse mutant is homologous to the gene for the human disease. This plausible hypothesis was considerably weakened by gene mapping studies excluding Xq28 as a candidate region [9] and was disproven by the very recent molecular findings showing mutations in the emopamil binding protein (EBP) in a large number of patients suffering from the CHH syndrome [10-11, 13].

The dual function of emopamil binding protein

The EBP gene resides on the short arm of the X-chromosome at Xp11.22-23 and is expressed in many tissues [10]. It acts as a delta8-delta7 sterol isomerase and converts cholest8(9)-en-3beta-ol (8,9 cholestenol) in cholest-7-en-3beta-ol (lathosterol) (Fig. 3) [14]. Emopamil binding protein is located in the membrane of the endoplasmatic reticulum and has 4 transmembrane domains. The C and N terminal domains are found in the cytoplasm. It has an important role in cholesterol biosynthesis. Apart from acting as a delta8-delta7 sterol isomerase it also functions as a receptor for the antiischemic drug emopamil. As this function was first discovered the protein was named accordingly [14].

How did emopamil binding protein come into the picture?

The EBP story is basically a triumph of the candidate gene approach. Attempts to map the gene for the CHH syndrome in a small number of families had excluded the Xq28 region, but unfortunately had also failed to clearly put the gene on the map of the X-chromosome elsewhere [15]. Seen in retrospective the main reason for failure of the linkage approach was, however, the very limited number of extended families that were available at that time. Even today most cases of CHH syndrome seem to be sporadic.

A fresh approach in an attempt to elucidate the biochemical and molecular basis of the CHH syndrome came when Kelley et al. [16] applied a clinically based comparative phenotype-genotype logic. They argued that chondrodysplasia punctata, a cardinal feature of the CHH syndrome, is also found in the autosomal recessive Smith-Lemli-Opitz (SLO) syndrome. The SLO syndrome had previously been shown to be due to a defect in another enzyme of the cholesterol biosynthesis pathway, namely the delta7-sterol reductase [17]. Kelley and coworkers [16] assumed that a similar metabolic defect could also be involved in the CHH syndrome and therefore performed lipid chemical analyses and thus obtained the first pathobiochemical clue for the involvement of a defect of a sterol metabolism in patients with CHH syndrome.

From this point it was rather straightforward to look for X-linked genes having a known function in cholesterol biosynthesis and there were two such genes on the X-chromosome. One of them was NSDHL, a gene that has very recently been shown to be responsible in the mouse for the Bpa phenotype [18]. The other one was emopamil binding protein and it turned out that this gene is deficient in the human disease and also in a mouse mutant called "tattered" (Td) that closely resembles the phenotype of the Bpa mutant. Because both EBP and NSDHL have pivotal functions in the same biochemical pathway and because they both undergo X-inactivation, the striking similarity between the mouse mutants Td and Bpa can now be under-stood and it is obvious why the Bpa mouse had been erroneously taken to be the homologue of the gene for the CHH syndrome.

Anticipation and genotype/phenotype relationship

A puzzling feature of the CHH syndrome has been the observation of tremendous intrafamilial variation. Two different types of intrafamilial variation can be distinguished: a) intrafamilial variation within the same generation and b) intrafamilial variation with stepwise increases in disease expression from one generation to the other (anticipation). While variation within the same generation can be easily explained by different degrees of X-inactivation, a stepwise increase in disease expression from one generation to the other is more difficult to account for. It was this observation that initially prompted one of us (HT) to assume the involvement of an unstable premutation (trinucleotide repeat mechanism) [15].

To gain more insight into this and other puzzling phenomena we recently analyzed the EBP gene in 7 families using PCR, heteroduplex analysis and direct sequencing of the PCR products to screen for mutations. While we identified mutations in all families and in all females with the full blown disease, we failed to detect the mutations in lymphocyte DNA of a grandmother who clearly showed clinical signs of having a mild disease phenotype characterized by short stature and a highly pathognomonic sectorial cataract [13]. The most likely genetic interpretation for this constellation of findings is to assume both gonadal and somatic mosaicism in this grandmother. We have observed one other family in which two girls are affected by the CHH syndrome while both parents are unaffected. Therefore gonadal mosaicism may be common in patients with this disease and will have consequences on the counselling of female sporadic cases. Clinicians should point out to their families that in this syndrome a sporadic occurrence does not necessarily imply a de novo mutation. Rather, gonadal mosaicism seems to be frequent and therefore a recurrence risk for further pregnancies has to be considered even when dealing with a sporadic case.

Gonadal mosaicism may also in part be responsible for the phenomenon of anticipation. Other factors which contribute to this phenomenon include random differences in X-inactivation and a reduced reproductive fitness of those women who are very severely affected and who usually are the index cases and therefore often represent the youngest generation.

The CHILD syndrome is caused by a 3beta-hydroxysteroid dehydrogenase (NSDHL) deficiency

When revising this review it became known that the CHILD syndrome is caused by a 3beta-hydroxysteroid dehydrogenase deficiency (NSDHL) [19]. In the pathway of cholesterol biosynthesis this enzyme functions "upstream" of delta8-delta7 sterol isomerase and was shown to underlie the mouse mutant bare patches [18]. Thus currently three different human diseases are due to closely related metabolic defects in cholesterol synthesis and the list may still expand in the near future. Clearly, the discovery of the metabolic defect in the Smith-Lemli-Opitz syndrome paved the way for elucidating the Conradi-Hünermann-Happle syndrome. The demonstration of a delta8-delta7 sterol isomerase defect in this latter disease then prompted the Marburg group to investigate the NSDHL gene in the CHILD syndrome and we are sure other X-linked skin diseases such as focal dermal hypoplasia or incontinentia pigmenti may also turn out to involve cholesterol metabolism. These are exciting times for medical, molecular and biochemical geneticists and for us as clinicians, too. As the biochemical basis of the CHH syndrome and the CHILD syndrome has now been established to concern defined metabolic defects new therapeutic approaches such as intervention with a cholesterol enriched diet become feasible and may help to influence the ichthyosis or cataract formation in these diseases.

Article accepted on 17/4/00

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