Gestión de Eventos (EM)

The identification of the genetic components o f caudal dysgenesis is m ade difficult by the phenotypic heterogeneity of the disorder. Segregation in fam ilies m ost often fits a M endelian, autosom al dom inant mode o f inheritance (W elch and Aterman, 1984; Chatkupt et a l , 1994). However, it is possible that different genes are involved in the aetiology o f sim ilar or the same phenotypes in different families.

The genetic com ponent of sporadic cases is m ore difficult to assess. It was originally proposed that caudal regression resulted from an em bryonic insult rather than a genetic cause and it is now know n that m aternal diabetes is responsible for many sporadic cases (Passarge and Lenz, 1966; Stanley et al.,

1979; Kalter, 1993). The im portance o f other, unknow n environm ental factors that give rise to sporadic cases is highlighted in a report o f m onozygotic twins, one o f which is normal, whereas the other has sacral agenesis with absence of sacral vertebrae and associated urogenital abnorm alities (Craw furd et a l ,

1992). However, the occurrence o f chrom osom al abnorm alities in some sporadic cases, with no maternal diabetes, indicates that genetic com ponents are also im portant in these cases (Savage et a l , 1997).

Caudal dysgenesis and 7q36. Some progress towards identifying genes involved in the aetiology o f caudal dysgenesis has been m ade by

studying fam ilies of selected patients who share the same clinical features. Lynch et a l (1995) analysed two families with com plete or partial Currarino triad of symptoms (two and three generations respectively) and com patible with autosom al dom inant inheritance, in which there were at least three m em bers with sacral agenesis and anorectal m alform ations. Using linkage and haplotype analysis, they concluded that a sacral agenesis gene m aps to 7q36, betw een the D7S396 marker and the telomere. Lerone et a l (1997) confirm ed this result by haplotype analysis of a four-generation fam ily with recurrence of partial or complete Currarino triad of symptoms and M asuno et al. (1996) reported a 5-year-old fem ale with Currarino triad and a de novo

7q35 deletion.

The 7q36 region has been im plicated in other forms o f caudal dysgenesis. Savage et al. (1997) identified a fem ale fetus m onosom ie for 7q36.1, w ith intrauterine growth retardation, severe sacral hypoplasia, but no other internal congenital abnormalities. In addition and of considerable

interest are cases with 7q deletions where caudal m alform ations are associated with cranial abnormalities, in particular holoprosencephaly (HPE). M orichon- D elvallez et al. (1993) refer to four cases involving HPE and sacral problem s with a cytologically visible deletion at 7q36. And there are at least four reports of 7q36 deletions in other cases showing either m ild HPE or

m icrocephaly and various caudal problems (M asuno et a l , 1996; R oessler et a l , 1997b; Vance et al., 1998). Nevertheless, not all cases o f caudal

dysgenesis with HPE have 7q36 deletions. Chen et a l (1997) describe a fetus w ith HPE, lum bar SBO, imperforate anus, absent external genitalia and

sirenom elia and an apparently normal 46,XX karyotype.

One im portant developm ental gene that maps to 7q36 is the Sonic Hedgehog gene {SHE). S H E shows various mutations in patients w ith HPE, but no associated caudal problems (Roessler et a l, 1996; Roessler et a l ,

1997a). S E E was investigated as a causal gene in sacral agenesis, how ever, in a study of DNA from 16 individuals with sacral agenesis and 5 fam ilies with sacral agenesis linked to 7q36, Vargas et al. (1998) found no m utations in the

prom oter and coding region of SH H (this study included the two fam ilies described by Lynch et al., 1995). Thus, if SH H is not the sacral agenesis gene there must be another locus at 7q36, close to the SH H gene. Indeed such a gene has very recently been identified as a m em ber of the hom eobox gene fam ily (H arrison et a l , 1994; Saha et a l , 1997) and will be discussed in m ore detail in chapter 7.

O ther chrom osom es involved in caudal dysgenesis. 7q36 deletions account for only a portion o f cases of caudal dysgenesis and it seems likely that other genes are also involved. Nagai et al. (1994) described a patient with Currarino triad o f symptoms and partial trisomy of chrom osom es 13q and 20p, indicating that the Currarino phenotype is genetically heterogeneous. It is o f interest that HPE has also been associated with 13q (Chen et al., 1997).

Similarly, A nderson-Shotwell and W ilson (1989) reported a patient with short stature, unusual facial features, a single central incisor, partial agenesis of the sacrum and spinal cord abnorm alities. The patient show ed an

ISp deletion. It is possible that the single incisor represents a m ild form of H PE and that this case represents another exam ple o f HPE associated with sacral agenesis. Interestingly, other HPE patients with ISp deletions have been identified (Chen et a l, 1997). If there is an HPE gene on ISp, this either gives rise to the sacral agenesis phenotype in addition to HPE, or is in a

conserved cluster with a separate gene that can give rise to sacral agenesis. Sacral agenesis and anal atresia have also been described in patients w ith a wide range of symptoms and abnormalities of chrom osom es 6q and 3p (M cLeod et a l , 1990; Asai et al., 1992; M eng et al., 1992; Schinzel et al.,

1998). Thus, it is clear that although some im portant advances have been m ade in determ ining the genetic basis o f sacral agenesis and its associated disorders, more genes rem ain to be discovered.