Spectrum of mutations and genotype–phenotype analysis in Currarino syndrome

Abstract

The triad of a presacral tumour, sacral agenesis and anorectal malformation constitutes the Currarino syndrome which is caused by dorsal-ventral patterning defects during embryonic development. The syndrome occurs in the majority of patients as an autosomal dominant trait associated with mutations in the homeobox gene HLXB9 which encodes the nuclear protein HB9. However, genotype ± phenotype analyses have been performed only in a few families and there are no reports about the specific impact of HLXB9 mutations on HB9 function. We performed a mutational analysis in 72 individuals from nine families with Currarino syndrome. We identified a total of five HLXB9 mutations, four novel and one known mutation, in four out of four families and one out of five sporadic cases. Highly variable phenotypes and a low penetrance with half of all carriers being clinically asymptomatic were found in three families, whereas affected members of one family showed almost identical phenotypes. However, an obvious genotype ± phenotype correlation was not found. While HLXB9 mutations were diagnosed in 23 patients, no mutation or microdeletion was detected in four sporadic patients with Currarino syndrome. The distribution pattern of here and previously reported HLXB9 mutations indicates mutational predilection sites within exon 1 and the homeobox. Furthermore, sequence homology to Drosophila homeobox genes suggest that some of these mutations located within the homeobox may alter the DNA-binding specificity of HB9 while those in sequences homologous to a recently identified NLS motif of the human homeobox gene PDX-1 may impair nuclear translocation of the mutated protein. European Journal of Human Genetics (2001) 9, 599 ± 605.

A tail of sacral agenesis: delayed presentation of meningocele in sacral agenesis

“…The gene associated with Currarino Syndrome has been identified as HLXB9, a homeodomain-containing transcription factor, encoding for nuclear protein HB9 which, when mutated, is thought to cause a loss of function [10][11][12]. HLXB9 is a homeobox gene encoding the nuclear protein HB9.…”

“…HLXB9 is a homeobox gene encoding the nuclear protein HB9. Homeobox genes are essential for normal morphogenesis and are known to function in the regulation of human embryonic development [10,12]. This mutation has been shown in association with SA both in familial and approximately 30 % of sporadic cases [10][11][12].…”

Sindrome de currarino associada ao Tailgut Cyst: ressecção abdômino-sacral

“…Kennedy em 1926 e Ashcraft & Holder em 1974 também caracterizaram esta condição 12 . Entretanto, somente em 1981, Currarino a reconheceu como síndrome caracterizada como anomalia de embriogênese 9,10,12 . No período compreendido entre 1926 a 2003 foram descritos mais de 200 casos.…”

Currarino syndrome as an etiology of a neonatal Escherichia coli meningitis

“…Impairments associated with CS are frequent. First, bacterial meningitis can be the first symptom of neurological malformation (7-11% of cases) 9 and reveal the possibility of communication between the spinal canal and the presacral tumor. 1,2 Therefore, as reported for patients III2 and IV2, the CSF is often polymicrobial and the digestive origin of the incriminated germs is frequent.…”

“…10 Hydrocephalus, intra-or extraspinal lipomas (patients III2 and IV2) and neurological symptoms can be observed as a result of the presacral mass. Investigation into malformation of the urogenital tract (vesicourethral reflux) is recommended, as it is sometimes responsible for recurrent urinary tract infections 9 and Mü llerian duplications. 1,8 The digestive system is often affected as severe constipation is the primary symptom of the disease (patients II2, III2 and IV2).…”