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.
The Currarino triad is a hereditary transmitted syndrome, originally defined by Currarino as ASP-association, consisting of an anorectal malformation, a sacral bony defect and a presacral mass. In most cases autosomal dominant transmission is suggested. In family members one or two features of the syndrome may be missing, indicating an incomplete form of this complex. We describe two unrelated girls at the age of 8 and 9 months respectively with ASP-association. Family screening in both patients showed 8 additional cases with a complete or incomplete Currarino triad, four of them being asymptomatic. A review of the literature up to 1991 revealed 48 patients with ASP-association. In more than 80% of cases, this complex is diagnosed in the first decade, whereas incomplete Currarino syndrome is diagnosed predominantly in adults. Most frequently the presacral mass in ASP-association was reported to be an anterior meningocele (47%) and a benign teratoma (40%). The number of patients with Currarino syndrome has been underestimated so far. We recommend anorectal examination, pelvic ultrasound and pelvic x-rays in all patients with a history of chronic constipation since early childhood. Positive findings should lead to further investigations such as barium enema, MRI, myelography and family screening. Close cooperation between pediatric surgeons and neurosurgeons is required to ensure adequate surgical treatment, considering both the risk of malignant degeneration as well as the risk of intraoperative nerve damage. Thus, radical excisional surgery is not obligatory in every case of Currarino syndrome.
Purpose: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features.Experimental Design: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion.Results: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement.Conclusions: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.
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