SNOMEDCT: 721972001; ORPHA: 69085;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q28 | Limb-mammary syndrome | 603543 | Autosomal dominant | 3 | TP63 | 603273 |
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).
Limb-mammary syndrome (LMS) is an autosomal dominant disorder characterized by variable expressivity of severe hand and/or foot anomalies (deficiencies, duplications, and fusion/separation defects) and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal duct atresia, nail dysplasia hypohidrosis, hypodontia, and cleft palate with or without bifid uvula (Van Bokhoven et al., 1999).
Van Bokhoven et al. (1999) described a 'new' syndrome, which they designated limb-mammary syndrome, in a large 9-generation Dutch family, in which van Bokhoven and Brunner (2002) reported mutation in the TP63 gene. Consistent 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.
Van Bokhoven et al. (2001) reported 2 unrelated patients (BX and DW) with LMS and mutation in the TP63 gene. Patient BX had bilateral split-hand/foot malformations (SHFM), isolated cleft palate, and normal hair, skin, and teeth, but absent nipples. Patient DW had bilateral SHFM, absence of the lacrimal punctae, bilateral ear pits, submucous cleft palate, and absent nipples, as well as anteriorly placed anus.
Guazzarotti et al. (2008) described a 14-year-old girl with LMS, previously reported by van Bokhoven et al. (2001) as patient BX, 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.
Clinical Variability
Mathorne et al. (2020) reported 6 affected individuals over 2 generations of a Danish family who had features consistent with LMS but without limb anomalies, and mutation in the TP63 gene. The affected individuals were 4 sibs, their father, and their paternal uncle. All 6 affected family members had nipple abnormalities, including supernumerary, split, small, bean-shaped, and widely spaced nipples. Lacrimal duct atresia was present in 4 of the 6 patients, and dental anomalies, including tooth agenesis, severe decay, and moderate to severe attrition, were observed in 3 patients. The 2 affected sisters had mammary gland and nipple hypoplasia, ovarian agenesis, and uterine hypoplasia. No ovaries were detected by MRI. With estrogen treatment, the uterine size increased to normal or near-normal and the sisters had menstrual periods; thus, the authors considered the uterine hypoplasia to be secondary to ovarian insufficiency. The father had hypoplastic toenails, 1 brother was born with cleft palate, and the paternal uncle also had anteriorly placed anus. None of the affected individuals exhibited split hand/foot or syndactyly.
The transmission pattern of LMS in the family reported by van Bokhoven et al. (1999) was consistent with autosomal dominant inheritance.
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. The maximum lod score obtained was 12.014 at a recombination fraction of 0 for marker D3S3530. Haplotype analysis reduced the critical region to a 3-cM interval on chromosome 3q27 between D3S1580 and D3S1314.
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.
Exclusion Studies
In a large Dutch family with LMS, van Bokhoven et al. (1999) noted 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 chromosome 7q (EEC1; 129900). However, allelism with UMS and EEC1 was excluded by linkage studies with markers from the relevant chromosomal regions.
Van Bokhoven et al. (2001) sequenced the TP63 gene in 2 unrelated patients with LMS (patients BX and DW) as well as in the large Dutch family originally reported by van Bokhoven et al. (1999). Patient BX was heterozygous for a 2-bp deletion in exon 13 of the TP63 gene (603273.0012), whereas patient DW was heterozygous for a 2-bp deletion in exon 14 (603273.0013). No mutation in the TP63 gene was identified in the original Dutch family with LMS mapping to 3q27; the authors suggested that their mutation was likely to reside outside the P63 coding region, in an intron or regulatory region of the gene.
Van Bokhoven and Brunner (2002) stated that a G76W substitution in exon 4 of the TP63 gene, just upstream of the TA domain, had been found in the large 9-generation Dutch family with LMS that was originally described by van Bokhoven et al. (1999).
In affected members of a Danish family with features of LMS but without limb anomalies, Mathorne et al. (2020) identified heterozygosity for a nonsense mutation in the TP63 gene (R643X; 603273.0035). The mutation segregated with disease in the family and was not found in the gnomAD database.
Exclusion Studies
In a large Dutch family with LMS mapping to chromosome 3q27, van Bokhoven et al. (1999) considered the SOX2 gene to be an excellent candidate gene because the gene product stimulates expression of fibroblast growth factor-4 (FGF4; 164980), an important signaling molecule during limb outgrowth and development. However, Southern blot analysis excluded a large deletion as the cause of the disorder, and screening the gene by SSCP analysis and sequencing both DNA strands did not reveal any mutations in the SOX2 open reading frame.
Celli, J., Duijf, P., Hamel, B. C. J., Bamshad, M., Kramer, B., Smits, A. P. T., Newbury-Ecob, R., Hennekam, R. C. M., Van Buggenhout, G., van Haeringen, A., Woods, C. G., van Essen, A. J., de Waal, R., Vriend, G., Haber, D. A., Yang, A., McKeon, F., Brunner, H. G., van Bokhoven, H. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99: 143-153, 1999. [PubMed: 10535733] [Full Text: https://doi.org/10.1016/s0092-8674(00)81646-3]
Guazzarotti, L., Caprio, C., Rinne, T. K., Bosoni, M., Pattarino, G., Mauri, S., Tadini, G. L., van Bokhoven, H., Zuccotti, G. V. Limb-mammary syndrome (LMS) associated with internal female genitalia dysgenesia: a new genotype/phenotype correlation? Am. J. Med. Genet. 146A: 2001-2004, 2008. [PubMed: 18627043] [Full Text: https://doi.org/10.1002/ajmg.a.32371]
Mathorne, S. W., Ravn, P., Hansen, D., Beck-Nielsen, S. S., Gjorup, H., Sorensen, K. P., Fagerberg, C. R. Novel phenotype of syndromic premature ovarian insufficiency associated with TP63 molecular defect. Clin. Genet. 97: 779-784, 2020. [PubMed: 32067224] [Full Text: https://doi.org/10.1111/cge.13725]
Propping, P., Friedl, W., Wienker, T. F., Uhlhaas, S., Zerres, K. ADULT syndrome allelic to limb mammary syndrome (LMS). Am. J. Med. Genet. 90: 179-182, 2000. [PubMed: 10607963]
Propping, P., Zerres, K. ADULT-syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia. Am. J. Med. Genet. 45: 642-648, 1993. [PubMed: 8456838] [Full Text: https://doi.org/10.1002/ajmg.1320450525]
van Bokhoven, H., Brunner, H. G. Splitting p63. Am. J. Hum. Genet. 71: 1-13, 2002. Note: Erratum: Am. J. Hum. Genet. 72: 779 only, 2003. [PubMed: 12037717] [Full Text: https://doi.org/10.1086/341450]
van Bokhoven, H., Hamel, B. C., Bamshad, M., Sangiorgi, E., Gurrieri, F., Duijf, P. H., Vanmolkot, K. R., van Beusekom, E., van Beersum, S. E., Celli, J., Merkx, G. F., Tenconi, R., and 13 others. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-foot malformation suggest a genotype-phenotype correlation. Am. J. Hum. Genet. 69: 481-492, 2001. [PubMed: 11462173] [Full Text: https://doi.org/10.1086/323123]
van Bokhoven, H., Jung, M., Smits, A. P. T., van Beersum, S., Ruschendorf, F., van Steensel, M., Veenstra, M., Tuerlings, J. H. A. M., Mariman, E. C. M., Brunner, H. G., Wienker, T. F., Reis, A., Ropers, H.-H., Hamel, B. C. J. Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. Am. J. Hum. Genet. 64: 538-546, 1999. [PubMed: 9973291] [Full Text: https://doi.org/10.1086/302246]