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The semilethal skeletal malformation syndrome campomelic dysplasia (CD) with or without XY sex reversal is caused by mutations within the SOX9 gene on 17q24.3 or by chromosomal aberrations (translocations, inversions or deletions) with breakpoints outside the SOX9 coding region. The previously published CD translocation breakpoints upstream of SOX9 fall into two clusters: a proximal cluster with breakpoints between 50-300 kb and a distal cluster with breakpoints between 899-932 kb. Here, we present clinical, cytogenetic and molecular data from two novel CD translocation cases. Case 1 with karyotype 46,XY,t(1;17)(q42.1;q24.3) has characteristic symptoms of CD, including mild tibial bowing, cryptorchidism and hypospadias. By standard fluorescence in situ hybridization (FISH) and by high-resolution fiber FISH, the 17q breakpoint was mapped 375 kb from SOX9, defining the centromeric border of the proximal breakpoint cluster region. Case 2 with karyotype 46,X,t(Y;17)(q11.2;q24.3) has the acampomelic form of CD and complete XY sex reversal. By FISH and somatic cell hybrid analysis, the 17q breakpoint was mapped 789 kb from SOX9, defining the telomeric border of the distal breakpoint cluster region. We discuss the structure of the 1 Mb cis-control region upstream of SOX9 and the correlation between the position of the 14 mapped translocation breakpoints with respect to disease severity and XY sex reversal.

Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited disorder characterized by ear, anal, limb, and renal malformations, and results from mutations in the gene SALL1. All SALL1 mutations previously found in TBS patients create preterminal termination codons. In accordance with the findings of pericentric inversions or balanced translocations, TBS was initially assumed to be caused by SALL1 haploinsufficiency. This assumption was strongly contradicted by a Sall1 mouse knock-out, because neither hetero- nor homozygous knock-out mutants displayed a TBS-like phenotype. A different mouse mutant mimicking the human SALL1 mutations, however, showed a TBS-like phenotype in the heterozygous situation, suggesting a dominant-negative action of the mutations causing TBS. We applied quantitative real time PCR to detect and map SALL1 deletions in 240 patients with the clinical diagnosis of TBS, who were negative for SALL1 mutations. Deletions were found in three families. In the first family, a 75 kb deletion including all SALL1 exons had been inherited by two siblings from their father. A second, sporadic patient carried a de novo 1.9-2.6 Mb deletion including the whole SALL1 gene, and yet another sporadic case was found to carry an intragenic deletion of 3384 bp. In all affected persons, the TBS phenotype is rather mild as compared to the phenotype resulting from point mutations. These results confirm that SALL1 haploinsufficiency is sufficient to cause a mild TBS phenotype but suggest that it is not sufficient to cause the severe, classical form. It therefore seems that there is a different contribution of SALL1 gene function to mouse and human embryonic development., (2006 Wiley-Liss, Inc.)

Familial reciprocal translocations are generally without phenotypic effect, although there is some evidence for a small excess of mental retardation and congenital malformations (MR/CM) in children carrying familial reciprocal translocations. Possible mechanisms whereby such translocations could have a phenotypic effect include cryptic unbalanced rearrangements, uniparental disomy, and disruption of putative genes at the breakpoints, unmasking recessive alleles on the normal homologs. Mosaicism for a supernumerary derivative chromosome in a carrier of a familial reciprocal translocation has not yet been described. We report a boy presenting with MR/CM and a familial reciprocal translocation, t(17;22)(q24.2;q11.23), inherited from the mother. Cytogenetic analysis of peripheral blood lymphocytes showed a balanced karyotype in all 32 analyzed metaphase spreads. Molecular genetic analysis was consistent with biparental origin of the normal homologs. In metaphase spreads from skin fibroblasts a supernumerary chromosome was found in all 24 cells analyzed and could be identified as der(22)t(17;22)(q24.2;q11.23). Several possible segregation modes at meiosis I followed by meiosis II or postzygotic nondisjunction of the der(22) might have led to this unusual chromosomal mosaicism. We propose hidden mosaicism as a possible cause for MR/CM in patients who apparently carry a balanced familial reciprocal translocation., (Copyright 2001 S. Karger AG, Basel)

A case of a prenatal diagnosis at the second trimester is presented showing a normal karyotype in 12 metaphases from chorionic villi. In all cultured amniotic cells, however, and also in all fetal fibroblasts analyzed after abortion a structural anomaly (46,XY;del 4(pter----p15.2) was detected. Prenatal diagnosis was performed because of intrauterine growth retardation, cleft lip and esophagus atresia by ultrasound. The fetal stigmata are compatible with the Wolf Hirschhorn syndrome. We conclude that amniocentesis may be indicated notwithstanding a normal CV-diagnosis in those rare pregnancies with a characteristically abnormal ultrasound.