Limb-Mammary Syndrome

A number sign (#) is used with this entry because of evidence that limb-mammary syndrome is caused by heterozygous mutation in the TP63 gene (603273) on chromosome 3q28.

Allelic disorders with overlapping features include EEC3 (604292), AEC syndrome (106260), ADULT syndrome (103285), Rapp-Hodgkin syndrome (RHS; 129400), and SHFM4 (605289).

Van Bokhoven et al. (1999) described a 'new' syndrome, which they designated limb-mammary syndrome, in a large Dutch family. The features were severe hand/foot anomalies and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings included lacrimal-duct atresia, nail dysplasia, hypohidrosis, hypodontia, and cleft palate with or without bifid uvula. Phenotypic overlap with the ulnar mammary syndrome (UMS; 181450), which is caused by mutation in the TBX3 gene (601621) on 12q24.1, as well as with the syndrome of ectrodactyly, ectodermal dysplasia, and clefting (EEC), 1 form of which maps to 7q (EEC1; 129900), was noted. Allelism with UMS and EEC1 was excluded by linkage studies with markers from the relevant chromosomal regions.

Guazzarotti et al. (2008) described a 14-year-old girl with LMS, previously found by van Bokhoven et al. (2001) to carry a 2-bp deletion in the TP63 gene (603273.0012), who presented with primary amenorrhea and was found to have absence of the uterus and ovaries on abdominal MRI. She had normal development of external genitalia and pubic hair, and normal morphology of the lower vaginal tract; hormonal evaluation revealed hypergonadotropic hypogonadism with a very low plasma estrogen level. Guazzarotti et al. (2008) stated that this was the first report of female gonadal dysgenesis in the group of EEC and related conditions.

By genomewide screening with polymorphic markers in a large Dutch family with LMS, van Bokhoven et al. (1999) localized the genetic defect to the subtelomeric region of chromosome 3q. Haplotype analysis reduced the critical region to a 3-cM interval on chromosome 3q27. Van Bokhoven et al. (1999) pointed to the SOX2 gene (184429) at 3q27 as an excellent candidate gene for LMS because the gene product stimulates expression of fibroblast growth factor-4 (FGF4; 164980), an important signaling molecule during limb outgrowth and development. However, they found no mutations in the SOX2 open reading frame.

To investigate the possibility that EEC syndrome is allelic to LMS, Celli et al. (1999) used polymorphic markers from the 3q27 region for a linkage analysis in 5 families with EEC syndrome. Positive lod scores were obtained with markers from within the LMS interval for each of these families. The added Zmax across these families was 8.03 at marker D3S3530 at a recombination fraction theta = 0. Recombination events were observed between markers that define the LMS interval, D3S1580 and D3S1314, and the disease locus, indicating that these 5 EEC syndrome families map to the same 3-cM region of 3q27 that had been found for the LMS family reported by van Bokhoven et al. (1999). This colocalization and the overlapping clinical features of these disorders strongly suggested that the same gene is involved in this form of EEC syndrome (EEC3; 604292) and LMS. The critical region for EEC3/LMS was reduced to a 2.3-cM interval by a recombination event between marker D3S3530 and the genetic defect in EEC3 family Bri-1 (64:1 odds). Analysis of the p63 gene (TP63; 603273), a homolog of p53 located in the critical LMS/EEC3 interval, revealed heterozygous mutations in 9 unrelated EEC3 families. No mutations were identified in the LMS family and several other EEC3 families mapping to chromosome 3q27. Celli et al. (1999) suggested that these mutations most likely reside in other parts of the TP63 gene not yet analyzed, including exons 1 to 4 and 15.

Because of the phenotypic similarity between a family with the ADULT syndrome (103285) described by Propping and Zerres (1993) and a family with LMS syndrome mapping to chromosome 3q27, Propping et al. (2000) genotyped 21 members of the family with ADULT syndrome with 19 polymorphic markers from the 3q27 chromosome region. Their studies placed the ADULT locus in the same chromosome region as the LMS locus, suggesting that these 2 conditions are allelic.

Van Bokhoven et al. (2001) demonstrated mutations in the TP63 gene (603273.0012-603273.0013) in 2 small kindreds with LMS.