Currarino Syndrome

A number sign (#) is used with this entry because of evidence that at least some cases of the Currarino syndrome are caused by heterozygous mutation in the HLXB9 homeobox gene (MNX1; 142994) on chromosome 7q36.

Clinical Features

The Currarino triad involves the association of partial sacral agenesis with intact first sacral vertebra ('sickle-shaped sacrum'), a presacral mass, and anorectal malformation (Currarino et al., 1981). The specific sacral anomaly is distinct to this syndrome. Of 10 affected members in the family reported by O'Riordain et al. (1991), only 4 were symptomatic, 3 of these had the full Currarino syndrome (sacral agenesis, presacral mass, and anorectal malformation), and the fourth had an anterior meningocele with no anorectal problems. All 10 had evidence of partial sacral agenesis on x-ray. Constipation and perianal sepsis are common complaints. Ascending infection resulting in E. coli bacterial meningitis has been reported. Associated malformations include rectovaginal fistula, tethering of the cord, duplex ureter, hydronephrosis, vesicoureteral reflux, bicornuate uterus, and neurogenic bladder. Malignant degeneration of the presacral teratoma has also been reported (Ashcraft and Holder, 1974 and Yates et al., 1983).

Belloni et al. (2000) presented evidence that of the 5 specific categories of sacrococcygeal anomalies (Kalitzki, 1965; Cama et al., 1996), only hemisacrum is caused by mutations in the HLXB9 gene.

Lynch et al. (2000) provided a review of the clinical features and molecular basis of Currarino syndrome.

Kim et al. (2007) reported 2 Korean families with Currarino syndrome. The proband in the first family was a 25-year-old woman with chronic constipation, presacral meningocele, large bony defect of S2 to S5, and rectal dilatation. Two of her sisters and a nephew were also affected. In the second family, a 6-month-old infant girl developed fatal polymicrobial cerebritis and arachnoiditis. She was found to have a presacral mature cystic teratoma with an extension of the spinal canal associated with possible cord tethering to the mass, anterior bony defect of distal sacrum, and left hydroureteronephrosis. Her father had chronic constipation and an anal fistula, and her paternal grandmother had a megacolon. Genetic analysis identified 2 different HLXB9 mutations that segregated with the phenotype in each family; there were a total of 4 asymptomatic mutation carriers in the 2 families, indicating reduced penetrance. Two additional sporadic Korean patients with Currarino syndrome did not have mutations in the HLXB9 gene, suggesting genetic heterogeneity or undetected somatic mosaicism in sporadic cases.

Inheritance

Ashcraft and Holder (1974) obtained clear evidence of autosomal dominant inheritance in this condition which has variable expressivity. They described 2 families with 23 affected members.

Diagnosis

Prenatal Diagnosis

Cretolle et al. (2007) reported prenatal diagnosis of Currarino syndrome by ultrasound in a second pregnancy at 22 weeks' gestation. The mother had a previous pregnancy in which the newborn had complex malformations consistent with Currarino syndrome, including sickle-shaped sacrum, anorectal malformation, and presacral teratoma. The mother had a history of sickle-shaped sacrum, anal atresia with cutaneous fistula, and neonatal intestinal obstruction surgically repaired at age 2 months. Genetic analysis identified a pathogenic mutation in the HLXB9 gene in both the mother and first newborn. The second pregnancy was terminated after ultrasound detected severe ventriculomegaly in association with spinal dysraphism, suggestive of Currarino syndrome, which was confirmed by genetic analysis and postmortem examination.

Mapping

Lynch et al. (1995) demonstrated linkage at 7q36 in the families reported by O'Riordain et al. (1991) and Nour et al. (1989). The region 7q36 was considered a good candidate region because of several case reports describing sacral agenesis in association with 7q deletion. The gene maps to the same region as HPE3 (142945), a gene for autosomal dominant holoprosencephaly. Deletions involving 7q are also associated with holoprosencephaly suggesting that haploinsufficiency at this locus predisposes to both disorders. Both disorders are midline embryonic defects. The authors also pointed to the fact that the incidence of both disorders are increased in infants born to diabetic mothers. Lynch et al. (1995) suggested that these 2 conditions are possibly contiguous gene syndromes or even allelic variants.

Lynch et al. (1995) obtained a maximum lod score of 4.38 at theta = 0.0 with marker D7S559.

Nagai et al. (1994) described a Japanese male with typical Currarino triad who showed partial trisomy of 13q and 20p inherited from his mother, suggesting that the disorder may be heterogeneous and that a second locus may be present on 13q or 20p.

Cytogenetics

Wang et al. (1999) reported a family in which the presence of sacral dysgenesis in sibs and their maternal uncle prompted specific cytogenetic investigation of chromosome 7. Cytogenetic analysis showed that the mother of the 2 affected children carried a balanced translocation between chromosome 7q36 and 12q24. Both children were monosomic for 7q36, as they had inherited the deleted chromosome 7 from their mother.

Pathogenesis

Ross et al. (1998) were prompted to investigate the sacral expression of HLXB9 (142994) in cases of sacral agenesis by a report of tailbud expression of the homolog in Xenopus laevis. Ross et al. (1998) found that HLXB9 was detectable in the sacral region during embryogenesis, albeit predominantly in the anterior horn regions of the spinal cord. Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies in Currarino syndrome.

Molecular Genetics

Ross et al. (1998) demonstrated mutations in the homeobox gene HLXB9 (142994) as the cause of the Currarino syndrome. In the families they studied, some individuals had the typical scimitar, or sickle-shaped, hemisacrum but were asymptomatic, whereas others had the full Currarino syndrome.

Hagan et al. (2000) identified mutations in the HLXB9 gene in 20 of 21 patients with familial Currarino syndrome and in 2 of 7 patients with sporadic Currarino syndrome. In 3 of the patients, pathogenesis was due to a microdeletion that encompassed HLXB9 in the D7S637-D7S594 interval. All 3 of the microdeletion patients also had developmental delay, and 1 of them had a single maxillary incisor, a feature associated with holoprosencephaly. Hagan et al. (2000) stated that FISH analysis of this patient revealed a deletion in the SHH gene (600725) as well.

In affected members of a 3-generation family segregating Currarino syndrome, Urioste et al. (2004) identified a frameshift mutation in the HLXB9 gene (142994.0009). The mutation was identified in the proband, a 22-year-old male in whom malignant transformation of a presacral teratoma was observed, as well as in 8 other family members, 3 of whom were asymptomatic but were subsequently found to have presacral teratomas. Of 9 family members with the mutation, 7 had confirmed teratomas, 1 had a presacral 'tumor' removed 15 years previously, and 1 refused removal of a presacral mass. Only 2 affected members displayed the complete triad.

In 6 affected members of a 4-generation family with Currarino syndrome, Wang et al. (2006) identified heterozygosity for a nonsense mutation in the HLXB9 gene (142994.0010). All manifestations of the Currarino syndrome were seen in mutation carriers, ranging from a severely affected girl with anorectal duplication, constipation, presacral lipoma, anterior meningocele, hypoplastic sacrum, and recurrent urinary tract infections with hydronephrosis, to an anatomically normal man whose only manifestation was constipation. The mutation was not found in 5 asymptomatic family members.

Genotype/Phenotype Correlations

Kochling et al. (2001) analyzed the genotype-phenotype correlation in 23 patients from 9 families with mutations in the homeobox gene HLXB9. Although 10 of the patients were asymptomatic, radiologic investigation revealed characteristic phenotypic features in all patients. The complete triad, consisting of a presacral mass, anorectal malformation, and sacral agenesis, was found only in 8 of the 23 patients. There was a remarkable variability of the sacral agenesis. A highly variable phenotype was seen within most families, and a detailed clinical investigation failed to identify any obvious genotype-phenotype correlation.