ORPHA: 2440; DO: 0090023;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q28 | Split-hand/foot malformation 4 | 605289 | Autosomal dominant | 3 | TP63 | 603273 |
A number sign (#) is used with this entry because split-hand/foot malformation-4 (SHFM4) is caused by heterozygous mutation in the tumor protein p63 gene (TP63; 603273) on chromosome 3q28.
Split-hand/split-foot malformation is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients with SHFM4 have been found to have mental retardation, ectodermal findings, and orofacial clefting (Elliott and Evans, 2006).
For additional phenotypic information and a discussion of genetic heterogeneity in this disorder, see SHFM1 (183600).
Spranger and Schapera (1988) described an instructive South African family in which 3 unaffected sibs with normal parents had each produced affected offspring. An offspring of 1 of the unaffected sibs, himself unaffected, produced affected children. Once originated in the family, the disorder was transmitted, in 2 branches of the family, through 3 generations as a regular dominant. Premutation of an autosomal dominant gene or cosegregation of an epistatic gene linked to the gene for split-hand was suggested. The spectrum of clinical manifestations in this family was broad, ranging from the presence of a split hand in 1 individual to bilateral monodactyly and unilateral aplasia of the right lower extremity with a split left foot in another individual. No family members had any significant abnormalities other than those of the extremities.
Ianakiev et al. (2000) described a family with SHFM that also came from Cape Province, South Africa. The phenotype in this family ranged from severe 'lobster claw' malformations of the feet in 1 individual, to minor 3/4 syndactyly of the left foot appearing as the only manifestation in another individual. The daughter of the latter individual had distal duplications of her thumbs bilaterally with absence of the second and third phalanges of the right hand and an absent second phalanx with 3/4 syndactyly of the left hand. No members of the family had significant abnormality of the face, palate, skin, teeth, hair, or nails. No abnormalities of the mammary glands or nipples were noted.
In a literature review including 48 SHFM1 patients, 40 SHFM3 (246560) patients, 45 SHFM4 patients, and 20 SHFM5 (606708) patients, Elliott et al. (2005) found that preaxial involvement of the upper extremities was a significant locus discriminator, most commonly seen in patients with SHFM3 (60% of patients). Preaxial involvement occurred in approximately 40% of SHFM5, 4% of SHFM4, and 2% of SHFM1 patients. In further analysis of the previously studied SHFM patients, Elliott and Evans (2006) identified phenotypic patterns involving mental retardation, ectodermal and craniofacial findings, and orofacial clefting associated with the mapped genetic SHFM loci.
In a cohort of 56 families with SHFM, Klopocki et al. (2012) identified 17p13.3 duplications (SHFLD3; 612576) in 17 (30%) of the families, 10q24 duplications (SHFM3; 246560) in 11 (20%), and TP63 mutations in 5 (9%).
The transmission pattern of SHFM1 in the families reported by Ianakiev et al. (2000) was consistent with autosomal dominant inheritance.
In 2 multigenerational families with SHFM in which segregation analysis had excluded linkage to all previously identified autosomal regions, Ianakiev et al. (2000) identified heterozygous missense mutations in the TP63 gene (603273.0005 and 603273.0006, respectively). One of the families had previously been reported by Spranger and Schapera (1988).
Elliott, A. M., Evans, J. A. Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients. Am. J. Med. Genet. 140A: 1419-1427, 2006. [PubMed: 16688749] [Full Text: https://doi.org/10.1002/ajmg.a.31244]
Elliott, A. M., Reed, M. H., Roscioli, T., Evans, J. A. Discrepancies in upper and lower limb patterning in split hand foot malformation. Clin. Genet. 68: 408-423, 2005. [PubMed: 16207208] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00511.x]
Ianakiev, P., Kilpatrick, M. W., Toudjarska, I., Basel, D., Beighton, P., Tsipouras, P. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am. J. Hum. Genet. 67: 59-66, 2000. [PubMed: 10839977] [Full Text: https://doi.org/10.1086/302972]
Klopocki, E., Lohan, S., Doelken, S. C., Stricker, S., Ockeloen, C. W., Thiele de Aguiar, R. S., Lezirovitz, K., Netto, R. C. M., Jamsheer, A., Shah, H., Kurth, I., Habenicht, R., and 11 others. Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion. J. Med. Genet. 49: 119-125, 2012. [PubMed: 22147889] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100409]
Spranger, M., Schapera, J. Anomalous inheritance in a kindred with split hand, split foot malformation. Europ. J. Pediat. 147: 202-205, 1988. [PubMed: 3366140] [Full Text: https://doi.org/10.1007/BF00442225]