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Other entities represented in this entry:
SNOMEDCT: 715704001, 715707008; ORPHA: 93334, 93335; DO: 1148;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p14.1 | Polydactyly, postaxial, types A1 and B | 174200 | Autosomal dominant | 3 | GLI3 | 165240 |
A number sign (#) is used with this entry because of evidence that postaxial polydactyly type A1 (PAPA1) and type B (PAPB) are caused by heterozygous mutation in the GLI3 (165240) gene on chromosome 7p14.
See also preaxial polydactyly type IV (174700), an allelic disorder.
Polydactyly refers to the occurrence of supernumerary digits and is the most frequent of congenital hand and foot deformities. Based on the location of the extra digits, polydactyly can be classified into preaxial, involving the thumb or great toe; postaxial, affecting the fifth digit; and central, involving the 3 central digits. Postaxial polydactyly (PAP) is further subclassified into 2 types: in type A, a well-formed extra digit articulates with the fifth or a sixth metacarpal, whereas in type B, a rudimentary, poorly developed extra digit is present (summary by Umm-e-Kalsoom et al., 2012).
Genetic Heterogeneity of Postaxial Polydactyly
Other forms of postaxial polydactyly type A include PAPA2 (602085) on chromosome 13q21; PAPA3 (607324) on chromosome 19p13; PAPA4 (608562) on chromosome 7q22; PAPA5 (263450) on chromosome 13q13; PAPA6 (615226), caused by mutation in the ZNF141 gene (194648) on chromosome 4p16; PAPA7 (617642), caused by mutation in the IQCE gene (617631) on chromosome 7p22; PAPA8 (618123), caused by mutation in the GLI1 gene (165220) on chromosome 12q13; PAPA9 (618219), caused by mutation in the FAM98A gene (617273) on chromosome 8q22; and PAPA10 (618498), caused by mutation in the KIAA0825 gene (617266) on chromosome 5q15.
Studies of various pedigrees with postaxial polydactyly indicate that there are 2 phenotypically different forms. In postaxial polydactyly type A, the extra digit is well formed and articulates with the fifth or an extra metacarpal. This type is inherited as a dominant trait with high penetrance. In postaxial polydactyly type B, also known as pedunculated postminimi, the extra digit is not well formed and is frequently in the form of a skin tag (Ventruto et al., 1980).
Sverdrup (1922) studied a large affected kindred; he noted the occurrence of types A and B in the same pedigree and discussed the possibility of a genetic difference between the 2 forms. Odiorne (1943) described a large pedigree with postaxial polydactyly.
Ventruto et al. (1980) studied an Italian family in which some individuals had both types A and B on different limbs. These findings were consistent with a single dominant gene.
Kucheria et al. (1981) observed postaxial polydactyly in 4 generations of an Indian family. The 11 affected males showed type A polydactyly in both hands and feet. The 1 affected female showed polysyndactyly and both types A and B postaxial polydactyly: the left foot showed type A and the right foot type B; the left hand showed type A polydactyly and the right hand showed fusion of otherwise well-formed fifth and sixth fingers and a well-formed seventh finger similar to the usual fifth. The findings suggested a common causal factor for postaxial polydactyly types A and B and polysyndactyly, consistent with an autosomal dominant pattern of inheritance.
Furniss et al. (2007) reported a patient with postaxial polydactyly type B affecting both hands. Her father had unilateral PAPB, and an obligate carrier in the family was unaffected, indicating variable expressivity and reduced penetrance.
Walker (1961) studied a pedigree with postaxial polydactyly of the fifth digit and, owing to lack of penetrance, suggested that the presence of 2 dominant genes would best explain the finding.
Among affected Nigerians, Scott-Emuakpor and Madueke (1976) concluded that postaxial polydactyly showed autosomal dominant inheritance with decreased penetrance (64.9%). They found no phenotypic difference between homozygotes and heterozygotes. Types A and B were found in the same family, suggesting that they are genotypically identical.
The unclear pattern of inheritance of postaxial polydactyly prompted Orioli (1995) to search for evidence of imprinting or change of expression in males and females using material of the Latin American Collaborative Study of Congenital Malformations. The author compared the frequency of affected offspring for 196 fathers with polydactyly with that for 233 mothers with the same condition and stratified the data according to African and non-African ancestry. The postaxial polydactyly prevalence rate among the offspring of affected black fathers (44%) was larger than that in the group of affected black mothers (31%), and no difference between affected nonblack fathers (34%) and affected nonblack mothers (33%) was observed. The sex ratio observed in 631 black propositi (0.51) and in 829 nonblack propositi (0.58) with polydactyly could be a further indication of etiologic heterogeneity for polydactyly between the 2 ethnic groups. The segregation distortion in favor of affecteds among the offspring of affected black fathers could be interpreted as the effect of a sex-linked recessive modifier gene acting during gametogenesis on an autosomal dominant polydactyly gene, this modifier being more frequent in Africans.
In a study based on the Latin American Collaborative Study of Congenital Malformations, comprising 2,030 segregating nuclear families, and a second large migrant northeastern Brazilian population of rural origin comprising 1,040 nuclear families, Feitosa et al. (1998) could find no evidence for a major gene acting on postaxial polydactyly. If the whole larger sample was divided into subsamples, according to black admixture proportions, the same multifactorial picture emerged.
By genomewide linkage analysis of a 5-generation Indian family in which 15 individuals had postaxial polydactyly type A, Radhakrishna et al. (1997) found linkage to chromosome 7p15-q11.23 (maximum lod score of 4.21 at theta = 0.0 for marker D7S801). Haplotype analysis enabled the mapping of the PAPA gene between markers D7S2848 and D7S669.
Lewandowski and Yunis (1977) made the interesting observation that, among the chromosomal syndromes, postaxial polydactyly occurs almost exclusively with trisomy 13, in which about 75% of cases show this feature. In contrast, deletion of 13q leads to oligodactyly (agenesis of the thumb and first metacarpal) and bony syndactyly of the fourth and fifth metacarpals and metatarsals (see 186300). Further analysis suggested that trisomy or deletion of the segment 13q31-q34 is critical for these counter-type features.
In an Indian family with PAPA1 linked to chromosome 7p, Radhakrishna et al. (1997) identified a heterozygous in the GLI3 gene (165240.0004).
In a patient with postaxial polydactyly type B of the hands, Furniss et al. (2007) identified a heterozygous mutation in the GLI3 gene (165240.0015), which was predicted to result in premature termination and shown to be subject to nonsense-mediated mRNA decay. Furniss et al. (2007) postulated that the relatively mild phenotype may be due to nonsense-mediated mRNA decay that eliminates a toxic dominant-negative effect of a mutant protein.
In affected members of a 3-generation nonconsanguineous Saudi Arabian family with broad thumbs, postaxial polydactyly of the hands, and variable cutaneous syndactyly of the hands and feet, Al-Qattan (2012) identified heterozygosity for a 2-bp deletion in the GLI3 gene (165240.0022). Some family members also had broad great toes and PAP of the feet. The PAP was rudimentary in all but 1 family member, who had bilateral PAP type A of both feet. Al-Qattan (2012) noted that although this frameshift predicts truncation in the N-terminal part of the gene with an expected Greig cephalopolysyndactyly (175700) phenotype, none of the family members had craniofacial features.
Postaxial polydactyly is about 10 times more frequent in blacks than in Caucasians (Frazier, 1960).
In Nigeria, Scott-Emuakpor and Madueke (1976) found frequencies of 17.92 and 27.08 per thousand for females and males, respectively. They concluded that the trait is an autosomal dominant with penetrance of 64.9%.
Polydactyly of postaxial type occupies an important place in the history of genetics because in 1756 Maupertuis (1689-1759) published the pedigree of Jacob Ruhe, a surgeon in Berlin, who had 4-limb polydactyly. The trait was inherited from his mother and grandmother and transmitted to 2 sons (out of 6 children). Maupertuis interpreted the pedigree in terms adumbrating mendelism (Glass, 1947; Glass, 1959; Emery, 1988).
Al-Qattan, M. M. A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with/without big toes, postaxial polydactyly and variable syndactyly of the hands/feet. (Letter) Clin. Genet. 82: 502-504, 2012. [PubMed: 22428873] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01866.x]
Castilla, E., Paz, J. E., Mutchinick, O., Munoz, E., Giorgiutti, E., Gelman, Z. Polydactyly: a genetic study in South America. Am. J. Hum. Genet. 25: 405-412, 1973. [PubMed: 4716659]
Emery, A. E. H. Pierre Louis Moreau de Maupertuis (1698-1759). J. Med. Genet. 25: 561-564, 1988. [PubMed: 3050101] [Full Text: https://doi.org/10.1136/jmg.25.8.561]
Feitosa, M. F., Castilla, E. E., da Garcia Dutra, M., Krieger, H. Lack of evidence of a major gene acting on postaxial polydactyly in South America. Am. J. Med. Genet. 80: 466-472, 1998. [PubMed: 9880210] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19981228)80:5<466::aid-ajmg6>3.0.co;2-d]
Frazier, T. M. A note on race-specific congenital malformation rates. Am. J. Obstet. Gynec. 80: 184-185, 1960. [PubMed: 13824672] [Full Text: https://doi.org/10.1016/s0002-9378(16)36439-0]
Furniss, D., Critchley, P., Giele, H., Wilkie, A. O. M. Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3. Am. J. Med. Genet. 143A: 3150-3160, 2007. [PubMed: 18000979] [Full Text: https://doi.org/10.1002/ajmg.a.32097]
Glass, B. Maupertuis, pioneer of genetics and evolution. In: Glass, B.; Temkin, O.; Straus, W. L., Jr.: Forerunners of Darwin: 1745-1859. Baltimore: Johns Hopkins Press (pub.) 1959. Pp. 51-83.
Glass, H. B. Maupertuis and the beginnings of genetics. Quart. Rev. Biol. 22: 196-210, 1947. [PubMed: 20264553] [Full Text: https://doi.org/10.1086/395787]
Kucheria, K., Kenue, R. K., Taneja, N. An Indian family with postaxial polydactyly in four generations. Clin. Genet. 20: 36-39, 1981. [PubMed: 7296946] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb01803.x]
Lewandowski, R. C., Jr., Yunis, J. J. Phenotypic mapping in man. In: Yunis, J. J.: New Chromosomal Syndromes. New York: Academic Press (pub.) 1977. Pp. 369-394.
Mohan, J. Postaxial polydactyly in three Indian families. J. Med. Genet. 6: 196-200, 1969. [PubMed: 5801468] [Full Text: https://doi.org/10.1136/jmg.6.2.196]
Odiorne, J. M. Polydactylism in related New England families. J. Hered. 34: 45-56, 1943.
Orioli, I. M. Segregation distortion in the offspring of Afro-American fathers with postaxial polydactyly. Am. J. Hum. Genet. 56: 1207-1211, 1995. [PubMed: 7726178]
Radhakrishna, U., Blouin, J.-L., Mehenni, H., Patel, U. C., Patel, M. N., Solanki, J. V., Antonarakis, S. E. Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis. Am. J. Hum. Genet. 60: 597-604, 1997. [PubMed: 9042919]
Scott-Emuakpor, A. B., Madueke, E. D. N. The study of genetic variation in Nigeria. II. The genetics of polydactyly. Hum. Hered. 26: 198-202, 1976. [PubMed: 955643] [Full Text: https://doi.org/10.1159/000152803]
Sverdrup, A. Postaxial polydactylism in six generations of a Norwegian family. J. Genet. 12: 217-240, 1922.
Umm-e-Kalsoom, Basit, S., Kamran-ul-Hassan Naqvi, S., Ansar, M., Ahmad, W. Genetic mapping of an autosomal recessive postaxial polydactyly type A to chromosome 13q13.3-q21.2 and screening of the candidate genes. Hum. Genet. 131: 415-422, 2012. [PubMed: 21877132] [Full Text: https://doi.org/10.1007/s00439-011-1085-7]
Ventruto, V., Theo, G., Celona, A., Fioretti, G., Pagano, L., Stabile, M., Cavaliere, M. L. A and B postaxial polydactyly in two members of the same family. Clin. Genet. 18: 342-347, 1980. [PubMed: 7460370] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb02294.x]
Walker, J. T. A pedigree of extra-digit-V polydactyly in a Batutsi family. Ann. Hum. Genet. 25: 65-68, 1961. [PubMed: 13782730] [Full Text: https://doi.org/10.1111/j.1469-1809.1961.tb01498.x]