Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 205135003; ICD10CM: Q69.1; ORPHA: 93339;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.3 | Polydactyly, preaxial I | 174400 | Autosomal recessive | 3 | GLI1 | 165220 |
A number sign (#) is used with this entry because of evidence that preaxial polydactyly I (PPD1) is caused by homozygous mutation in the GLI1 gene (165220) on chromosome 12q13. One such family has been reported.
Homozygous mutation in the GLI1 gene has also been reported to cause postaxial polydactyly type A8 (PAPA8; 618123).
Preaxial polydactyly, i.e., polydactyly on the radial side of the hand, is a heterogeneous category. Four types are: (1) thumb polydactyly, (2) polydactyly of triphalangeal thumb, (3) polydactyly of index finger, and (4) polysyndactyly. Preaxial polydactyly I, 'thumb polydactyly,' involves duplication of 1 or more of the skeletal components of a biphalangeal thumb. Severity varies from mere broadening of the distal phalanx with slight bifurcation at the tip to full duplication of the thumb including the metacarpals. This type is the most frequent form of polydactyly in many populations (Handforth, 1950).
Digby (1645) reported preaxial polydactyly, presumably of this type, in females in 5 generations. Pott (1884) observed 10 affected (6 females and 4 males) in 3 generations. Sinha (1918) found irregular segregation in a family with affected persons in 3 generations. In 1 generation, only 1 of 13 persons at risk were affected. Sobbota and De Marinis (1957) observed a girl with bilateral thumb polydactyly whose mother had radial deviation of the terminal phalanx (a feature that Pott also considered a manifestation of the same trait). No male-to-male transmission seems to have been documented.
Bingle and Niswander (1975) found that polydactyly is about twice as frequent in the American Indian as in Caucasians. Preaxial polydactyly type I was 3 to 4 times more frequent than in Caucasians or Blacks. More females than males were affected. It showed a strong predilection for the hands and was always unilateral, whereas postaxial polydactyly type B was bilateral in more than half of affected persons. Although the evidence suggests that polydactyly is in large part genetically determined, it was difficult to choose between a single autosomal dominant gene with reduced penetrance and a multigenic threshold model involving a few major genes.
Kelly (1982) observed a family in which symmetric duplication of the thumbs and great toes was observed over 5 or 6 generations with frequent examples of male-to-male transmission.
Graham and Hoefnagel (1982) and Graham et al. (1985, 1987) suggested that a minor expression of thumb polydactyly is aplasia or hypoplasia of the thumb musculature and that this trait may more often be autosomal dominant than one would realize from a study of polydactyly alone. They referred to this minor change as Fromont anomaly, after the French anatomist who described it (Fromont, 1895); see Haller (1977).
Ray (1987) reported a family in Andhra Pradesh, India with preaxial polydactyly in 15 males and 5 females in 6 generations. Bilateral duplication of the big toe showed reduced penetrance and variable expressivity. Duplication of the thumb was a less consistent feature.
Castilla et al. (1997) concluded from epidemiologic studies that hand postaxial polydactyly differs from foot postaxial polydactyly. This prompted Orioli and Castilla (1999) to test whether thumb and hallux duplication also had different clinical and epidemiologic characteristics, depending on the limb involved. They studied 920 newborns with first digit duplication, ascertained among 3,444,374 births by the Latin-American Collaborative Study of Congenital Malformations, from 1967 to 1995. Since biphalangeal thumb duplication or hallux duplication can occur in families with triphalangeal thumb or polysyndactyly propositi, these groups were also analyzed. The 715 isolated (nonsyndromal) cases (prevalence 2.08 per 10,000) were subdivided into 5 groups: (1) thumb duplication (n = 568; prevalence = 1.65/10,000); (2) hallux duplication (n = 82; prevalence = 0.24); (3) thumb and/or hallux duplication plus syndactyly (polysyndactyly) (n = 37; prevalence = 0.11); (4) triphalangeal thumb (n = 24; prevalence = 0.07); and (5) thumb duplication plus hallux duplication (n = 4; prevalence = 0.01). Both the thumb and hallux duplication groups showed a significant excess of males, and right-sidedness was also more frequent in both forms though without statistical significance for hallux duplication. Thumb duplication was more often unilateral (94.7% vs. 81.5% for hallux duplication), and its prevalence was higher in Bolivia (3.37/10,000) than in the other 10 Latin-American countries included in this study (1.62/10,000).
Ullah et al. (2019) reported a consanguineous Pakistani family in which 2 cousins exhibited bilateral preaxial polydactyly of the hands. The authors stated that x-ray showed duplication of the distal phalanx of the thumb (Figure 1 appears to show bifid distal phalanx of the thumb).
By genotyping highly polymorphic microsatellite markers in a consanguineous Pakistani family in which 2 cousins exhibited bilateral preaxial polydactyly of the hands, Ullah et al. (2019) established linkage to the GLI1 locus on chromosome 12q13.3.
In a consanguineous Pakistani family in which 2 cousins exhibited bilateral preaxial polydactyly mapping to chromosome 12q13.3, Ullah et al. (2019) identified homozygosity for a missense mutation in the GLI1 gene (L506Q; 165220.0004) that segregated fully with disease in the family and was not found in 70 unrelated Pakistani controls.
Associations Pending Confirmation
For discussion of a possible association between preaxial polydactyly and mutation in the STKLD1 gene, see 618530.0001.
Bingle, G. J., Niswander, J. D. Polydactyly in the American Indian. Am. J. Hum. Genet. 27: 91-99, 1975. [PubMed: 1155454]
Castilla, E. E., da Graca Dutra, M., Lugarinho da Fonseca, R., Paz, J. E. Hand and foot postaxial polydactyly: two different traits. Am. J. Med. Genet. 73: 48-54, 1997. [PubMed: 9375922] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<48::aid-ajmg10>3.0.co;2-r]
Digby, K. The Immortality of Reasonable Souls. London: John Williams (pub.) 1645.
Fromont, (NI). Anomalies musculaires multiples de la main, absence du flechisseur propre du ponce; absence des muscles de l'eminence thenar; lombricaux supplementaire. Bull. Soc. Anat. Paris 70: 395-401, 1895.
Graham, J. M., Jr., Brown, F. E., Hall, B. D. Thumb polydactyly as part of the range of genetic expression for thenar hypoplasia. (Abstract) Am. J. Hum. Genet. 37: A132 only, 1985.
Graham, J. M., Jr., Brown, F. E., Hall, B. D. Thumb polydactyly as a part of the range of genetic expression for thenar hypoplasia. Clin. Pediat. 26: 142-148, 1987. [PubMed: 3816011] [Full Text: https://doi.org/10.1177/000992288702600308]
Graham, J. M., Jr., Hoefnagel, D. Thumb polydactyly as part of the range of genetic expression for preaxial limb deficiency. (Abstract) Clin. Res. 30: 133A only, 1982.
Haller, P. Hereditary abductor--opponens agenesis: report of a family with congenital muscle defects of the thenar eminence. J. Neurol. 214: 235-238, 1977. [PubMed: 65459] [Full Text: https://doi.org/10.1007/BF00316155]
Handforth, J. R. Polydactylism of hand in southern Chinese. Anat. Rec. 106: 119-125, 1950. [PubMed: 15405667] [Full Text: https://doi.org/10.1002/ar.1091060202]
Kelly, T. E. Personal Communication. Charlottesville, Va. 1/28/1982.
Orioli, I. M., Castilla, E. E. Thumb/hallux duplication and preaxial polydactyly type I. Am. J. Med. Genet. 82: 219-224, 1999. [PubMed: 10215544]
Pott, R. Ein Beitrag zu den symmetrischen Missbildungen der Finger und Zehen. Jahrb. Kinderheilk. 21: 392-407, 1884.
Ray, A. K. A pedigree with bilateral preaxial polydactyly from India. J. Genet. Hum. 35: 267-274, 1987. [PubMed: 3655751]
Sinha, S. Polydactylism and tooth color. J. Hered. 9: 96 only, 1918.
Sobbota, A., De Marinis, F. On the inheritance and development of preaxial and postaxial types of polydactylism. Acta Genet. Med. Gemellol. 6: 85-93, 1957. [PubMed: 13394081] [Full Text: https://doi.org/10.1017/s1120962300020096]
Ullah, A., Umair, M., Majeed, A. I., Abdullah, Jan, A., Ahmad, W. A novel homozygous sequence variant in GLI1 underlies first case of autosomal recessive pre-axial polydactyly. Clin. Genet. 95: 540-541, 2019. [PubMed: 30620395] [Full Text: https://doi.org/10.1111/cge.13495]