Caudal Duplication Anomaly

A number sign (#) is used with this entry because of evidence that caudal duplication anomaly is associated with hypermethylation of the AXIN1 promoter (603816). One such patient has been reported.

Clinical Features

Dominguez et al. (1993) used the term caudal duplication syndrome to describe the occurrence of duplications of different organs in the caudal region. They reported 6 affected patients and reviewed 8 similar previously published cases.

Kroes et al. (2002) described 2 unrelated patients with caudal duplication anomaly. The first patient, a girl who had an unaffected monozygotic twin sister, presented with a duplication of the distal spine from L4, left double ureter, duplication of the vagina and cervix, and duplication of the distal colon. Her psychomotor development was normal at age 1.5 years. The second patient was diagnosed with a duplication of the colon, bladder, vagina, and uterus. Her mental development and growth were normal at age 12 years.

Pathogenesis

Kroes et al. (2002) discussed possible causes of the caudal duplication anomaly, including polytopic primary developmental field defects, disruptive sequences, and somatic or germline mutations in certain developmental genes.

Molecular Genetics

Kroes et al. (2002) noted that 2 genetic mouse models, 'fused' and 'disorganization,' show some resemblance to the caudal duplication anomaly. Because 'fused' results from mutations in the axin gene (603816), they performed DNA analysis of the AXIN1 gene in 1 of their patients and her family but detected no causative mutation.

Caudal duplication anomaly is similar to an anomaly seen in Axin(Fu) mice, which carry a mutation in the Axin locus (Vasicek et al., 1997). Affected mice display bifurcated tails as a result of caudal duplication in the distal region. Axin encodes an inhibitor of the Wnt-signaling pathway and has been shown to regulate embryonic axis formation in mouse and in Xenopus (Zeng et al., 1997). Suppression of wildtype Axin in Xenopus embryos results in the duplication of the body axis. It had been suggested that stochastically or environmentally triggered differences in the epigenetic status of key genes may be responsible for some phenotypic discordance between monozygotic (MZ) twins and, indeed, for much of the burden of complex disease. Using bisulfite sequencing, Oates et al. (2006) examined methylation at the promoter region of the AXIN1 gene in the MZ twins discordant for a caudal duplication anomaly in whom no causative AXIN1 mutation was found (Kroes et al., 2002) and in age-related singleton controls. Methylation of the promoter region in peripheral blood mononuclear cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated (603816.0002) than that of the unaffected twin (P less than 0.0001), which was significantly more methylated than those of the controls (P = 0.02). Oates et al. (2006) confirmed that this CpG island functions as a promoter in vitro and that its activity is inversely proportional to the extent of methylation. This finding raised the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. The authors suggested that this case may be paradigmatic for some cases of MZ discordance.