Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 205308004, 715710001; ICD10CM: Q74.0; ORPHA: 93336; DO: 0060986;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q36.3 | Triphalangeal thumb | 174500 | Autosomal dominant | 3 | ZRS | 620738 |
| 7q36.3 | Polydactyly, preaxial II | 174500 | Autosomal dominant | 3 | ZRS | 620738 |
A number sign (#) is used with this entry because of evidence that preaxial polydactyly II (PPD2) and isolated triphalangeal thumb (TPT) are caused by heterozygous mutation in the ZRS (620738), a regulatory element of SHH (600725), on chromosome 7q36.
Preaxial polydactyly II (PPD2) is a limb malformation in which duplication, full or partial, of the first digital ray of hands or feet results in extra digits. Triphalangeal thumb is characterized by the presence of 3 phalanges within the thumb. The extra middle phalanx may be fully formed, trapezoidal, or a small triangular 'delta' phalanx; the thumb may be opposable or nonopposable. Preaxial polydactyly and triphalangeal thumb may cosegregate, or each occur in isolation, within families with mutation in the zone of polarizing activity (ZPA) regulatory sequence (ZRS), a regulatory element for the SHH gene (600725) that is contained within intron 5 of the LMBR1 gene (Heutink et al., 1994; Furniss et al., 2008; VanderMeer et al., 2014).
The thumb in this malformation is usually opposable and possesses a normal metacarpal. This form of polydactyly consists of duplication of the distal phalanx, giving a 'duck-bill' appearance. Reported families include the second in the paper by Haas (1939), and those described by Atwood and Pond (1917), Hefner (1940) and Ecke (1962). The proband of a family studied by Temtamy and McKusick (1978) had opposable triphalangeal thumbs, all 3 phalanges being well developed, and duplication of the great toes. The trait had passed through at least 6 generations.
Merlob et al. (1985) described a kindred in which persons in 4 and perhaps 5 generations had opposable triphalangeal thumbs associated with duplication of the great toe. They reviewed syndromes with triphalangeal thumbs and reemphasized the significant distinction between the opposable (true triphalangeal) and nonopposable (finger-like) thumb. The latter condition may require surgical pollicization for satisfactory function.
Heutink et al. (1994) reported 2 Dutch families with triphalangeal thumb-polydactyly syndrome. The 2 families studied came from 'a relatively isolated population' with an estimated prevalence of TPT of 1 in 1,000. Within the families the expression of thumb anomalies was highly variable and ranged from an opposable thumb with a delta phalanx to an extreme form of preaxial polydactyly with a triphalangeal index finger instead of a thumb, 2 extra hypoplastic rays radial to the 'thumb' (septadactyly), hypoplastic thenar muscles, and, occasionally, syndactyly between the fourth and fifth rays. The description suggested that of preaxial polydactyly II. However, Temtamy (1994) was of the opinion that it is distinct from that entity and from nonopposable triphalangeal thumb (190600). She pointed out, furthermore, that dermatoglyphics can help differentiate preaxial polydactyly of a triphalangeal thumb from preaxial polydactyly of an index finger. A duplicate of the 'a' triradius and line is present in the latter. Zguricas et al. (1994) reported the phenotypic features of the families studied by Heutink et al. (1994).
Radhakrishna et al. (1993) described an extensive family from a village in the Rajkot district of Gujarat in India in which many members in 5 generations showed preaxial polydactyly with a well-formed extra digit, triphalangeal thumbs, and duplication of the big toes. They observed that 'the extra digit was functional and flexed like a normal finger.'
Ray (1987) reported a large family from another area of India, Andhra Pradesh, with preaxial polydactyly and, in some persons, bilateral duplication of the big toe. Since the thumb was not triphalangeal, this may have been a different entity (174400).
Nicolai and Hamel (1988) described a large family in which multiple members exhibited a spectrum of pre- and postaxial anomalies of the limbs inherited as an autosomal dominant. In another study of this family, Tsukurov et al. (1994) found that the hand malformations were typically bilateral but usually asymmetric. Both pre- and postaxial polydactyly and syndactyly were present. In all affected individuals the thumb was triphalangeal and the index finger was normal. Malformations of the feet were present in some affected persons but were usually less severe than those observed in the hands. Variable expression of the disease gene was demonstrated by asymmetries in limb deformities of affected individuals and the differences observed between monozygotic twins.
Semerci et al. (2009) reported a large, partially consanguineous 3-generation Turkish family in which 22 individuals had triphalangeal thumb-preaxial polydactyly syndrome affecting only the hands. Eleven individuals were evaluated clinically. There was some intrafamilial variability: all had 3 phalanges in the thumb and 6 metacarpals. Three had triphalangism in an extra digit. Other affected members had an extra hypoplastic digit with 2 phalanges.
Potuijt et al. (2020) reported 2 Dutch families with mild triphalangeal thumb phenotypes. In the first family, the phenotypes of 3 family members genetically confirmed to have the condition were described: the index patient had a bilateral isolated triphalangeal thumb with an additional deltaphalanx, the patient's mother had a triphalangeal thumb with a rudimentary additional thumb on both hands, and the maternal grandfather had broad thumbs, mild thenar hypoplasia, and broad distal phalanges on radiography. In the second family, phenotypes of 4 family members genetically confirmed to have the condition were described: the index patient had bilateral triphalangeal thumb with preaxial polydactyly on the left hand, the patient's father had bilateral triphalangeal thumb without preaxial polydactyly, and the paternal grandfather and paternal aunt had mild thenar hypoplasia and were unable to oppose both thumbs. The authors concluded that the phenotype in affected patients can be remarkably mild and emphasized the importance of clinical examination of family members who might be presumed to be unaffected. The authors also hypothesized that some previous observations of reduced penetrance might instead be due to mild phenotypic expression.
Alvarez et al. (2023) studied an exceptionally large 10-generation Spanish family of 273 individuals with 84 people affected with preaxial polydactyly/triphalangeal thumb. Clinical evaluation was performed in 53 affected and 65 nonaffected individuals. All affected individuals showed an upper limb malformation including triphalangeal thumbs and preaxial polydactyly with hexa- or heptadactyly, or even 8 fingers. Only 4 affected individuals presented polydactyly of both feet, with or without 2-3 toe syndactyly. The family originated in Cervera de Buitrago, a small village 82 kilometers north of Madrid, and the first affected individual of this family was traced back to the mid-1700s. Clinical and radiologic studies of affected members had been performed over the preceding 40 years. The authors noted that this family was the largest with preaxial polydactyly/triphalangeal thumb reported to that time.
In 2 large Dutch kindreds, Heutink et al. (1994) studied the transmission and linkage relationships of triphalangeal thumb. Using microsatellite DNA polymorphisms, they demonstrated that the locus, which they symbolized TPT, maps near the telomere of 7q. The combined maximum lod score for the 2 families was 12.61 at theta = 0.0 with marker D7S559.
Hing et al. (1995) used the designation preaxial polydactyly type II for the disorder they studied in a 6-generation North American Caucasian kindred of presumed English descent. They demonstrated linkage to the 7q36 region and identified a submicroscopic chromosomal deletion segregating with the phenotype, which they symbolized PPD2. Comparison of the haplotypes in this kindred with those in the previously described ones yielded evidence of an independent mutational event. The chromosomal deletion was demonstrated by absence of a parental allele or loss of heterozygosity for the D7S594 marker in PPD2 individuals. To facilitate mapping the boundaries of the chromosome 7 deletion, Hing et al. (1995) constructed human/rodent hybrid cell lines to segregate the human chromosome 7 containing the PPD2 allele (an apparent deletion) from the normal chromosome 7 allele. They concluded that the deletion was in-phase with the anomalous phenotype (and the causative mutation) but not causative of the abnormality.
Zguricas et al. (1999) reported linkage analysis of 12 families of different ethnic origin with preaxial polydactyly. The 2 Dutch families reported by Heutink et al. (1994) and Zguricas et al. (1994) were supplemented by 7 additional Dutch families, a British family, a Turkish family, and 2 Cuban families, 1 of which (Cuban family A) exhibited tibial aplasia in addition to preaxial polydactyly and triphalangeal thumbs (see 188740). Eleven of the kindreds investigated were found to be linked to chromosome 7q36, and haplotype analysis showed recombination events with markers D7S550 and D7S2423, reducing the critical region to 1.9 cM.
Heus et al. (1999) constructed a detailed physical map of the candidate region on 7q36 for preaxial polydactyly II. They used a combination of methods to identify and position 11 transcripts within this map. By recombination analysis on families with preaxial polydactyly, they reduced the candidate region to approximately 450 kb.
Dobbs et al. (2000) performed linkage analysis in 2 Iowa kindreds with triphalangeal thumb and found a maximum lod score of 6.23 at marker D7S559 on chromosome 7q36.
Lettice et al. (2003) showed that chromosome 7q36-associated preaxial polydactyly II results from point mutations in the ZPA regulatory sequence (ZRS; 620738), an SHH (600725) regulatory element. SHH, normally expressed in the zone of polarizing activity (ZPA) posteriorly in the limb bud, is expressed in an additional ectopic site at the anterior margin in mouse models of PPD. Lettice et al. (2003) identified the enhancer element ZRS and showed that it drives normal SHH expression in the ZPA. ZRS lies within intron 5 of the LMBR1 gene, 1 Mb from the target gene SHH. The ZRS contained point mutations that segregated with polydactyly in 3 unrelated families with PPD2 (620738.0001, 620738.0003, and 620738.0004) and in 1 family with tibial hypoplasia with polydactyly (see 188740 and 605522.0002) as well as in the Hx mouse mutant.
Gurnett et al. (2007) studied 4 families with triphalangeal thumb and preaxial polydactyly, 2 of which were previously reported by Dobbs et al. (2000), and identified 2 heterozygous mutations in 3 families (620738.0005 and 620738.0006). At least 1 affected member in each of the 3 families with mutations had preaxial polydactyly in addition to triphalangeal thumb; the affected mother and son in the fourth family had only triphalangeal thumb. A genotype/phenotype correlation was suggested by the 5-generation family, which showed reduced penetrance with 4 unaffected carriers who had affected offspring, and a milder phenotype with 18 of 19 affected members manifesting only triphalangeal thumb.
Furniss et al. (2008) identified a mutation in the ZRS (295T-C; 620738.0007) in the LMBR1 gene in 3 unrelated probands from southern England with bilateral triphalangeal thumb, 1 of whom also had unilateral preaxial polydactyly. The mutation was found in heterozygous state in all affected individuals except for the mother of 1 proband, who was homozygous for the mutation, and it was also detected in 4 unaffected obligate carriers and 1 unaffected individual at 50% prior risk; it was not found in 381 ethnically matched controls. Analysis of the 3 pedigrees demonstrated a common haplotype at 4 flanking microsatellite loci, indicating a likely founder effect for the 295C allele. Furniss et al. (2008) concluded that 295T-C is a dominant mutation with reduced penetrance and is a common cause of triphalangeal thumb in southern England.
In affected members of a 3-generation Turkish family with triphalangeal thumb-preaxial polydactyly syndrome affecting only the hands, Semerci et al. (2009) detected a heterozygous mutation in the ZRS (620738.0008). One affected individual, born of consanguineous affected parents, was homozygous for the mutation but did not have a more severe phenotype.
In affected members of 2 unrelated French families with preaxial polydactyly II, Albuisson et al. (2011) identified 2 different heterozygous mutations in the ZRS region of the LMBR1 gene (297G-A; 620738.0009 and 334T-G; 620738.0010, respectively) that occurred in highly conserved nucleotides within predicted binding sites for the transcription factors SOX9 (608160) and PAX3 (606597), respectively. The mutations were fully penetrant in both families. In mouse, both Sox9 and Pax3 are concomitantly expressed with Shh in the embryonic developing limb bud at the time of digit patterning. Albuisson et al. (2011) suggested that SOX9 and PAX3 may regulate SHH from the ZRS.
VanderMeer et al. (2014) studied 2 large unrelated 5-generation Mexican kindreds segregating autosomal dominant triphalangeal thumb and and/or preaxial polydactyly. In the first family, 31 affected individuals had isolated triphalangeal thumb, 14 had preaxial polydactyly with triphalangeal thumbs, and the proband had tibial and radioulnar hypoplasia with preaxial polydactyly of the hands and feet as well as short triphalangeal thumbs. In the second family, 6 affected individuals had isolated triphalangeal thumbs, 2 had preaxial polydactyly, 2 had preaxial polydactyly and triphalangeal thumbs, and 2 had mild radioulnar synostosis. In both families, affected individuals were heterozygous for a point mutation in the ZRS region of LMBR1 (402C-T; 620738.0013) except for the more severely affected proband in the first family, who was homozygous for the mutation, suggestive of a dosage effect.
In 2 Dutch families with autosomal dominant inheritance of triphalangeal thumb phenotypes, Potuijt et al. (2020) identified heterozygous mutations in the ZRS region of LMBR1: a novel c.165A-G transition in 1 family and a previously identified c.295T-C transition (620738.0007) in the other family. The phenotype in these families varied but included mild findings (e.g., broad thumbs, mild thenar hypoplasia, broad distal phalanges, and inability to oppose thumbs).
In a large Spanish family with 84 affected individuals with preaxial polydactyly and triphalangeal thumb, Alvarez et al. (2023) identified a 396C-T transition (620738.0008) in the ZRS segregating with the phenotype. The phenotype was similar in heterozygous and homozygous individuals. Only 4 affected individuals presented polydactyly of both feet, with or without 2-3 toe syndactyly. The disorder was documented to have segregated for at least 10 generations in the town of Cervera de Buitrago, 82 kilometers north of the city of Madrid.
Albuisson, J., Isidor, B., Giraud, M., Pichon, O., Marsaud, T., David, A., Le Caignec, C., Bezieau, S. Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly. Clin. Genet. 79: 371-377, 2011. [PubMed: 20569257] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01465.x]
Alvarez, L. F. G., Tenorio-Castano, J., Poletta, F. A., Santos-Simarro, F., Arias, P., Gallego, N., Orioli, I. M., Mundlos, S., Castilla, E. E., Martinez-Glez, V., Martinez-Frias, M. L., Ruiz-Perez, V. L., Nevado, J., Lapunzina, P. A large, ten-generation family with autosomal dominant preaxial polydactyly/triphalangeal thumb: historical, clinical, genealogical, and molecular studies. Am. J. Med. Genet. 191A: 100-107, 2023. [PubMed: 36308343] [Full Text: https://doi.org/10.1002/ajmg.a.62994]
Atwood, E. S., Pond, C. P. A polydactylous family. J. Hered. 8: 96 only, 1917.
Dobbs, M. B., Dietz, F. R., Gurnett, C. A., Morcuende, J. A., Steyers, C. M., Murray, J. C. Localization of dominantly inherited isolated triphalangeal thumb to chromosomal region 7q36. J. Orthop. Res. 18: 340-344, 2000. [PubMed: 10937618] [Full Text: https://doi.org/10.1002/jor.1100180303]
Ecke, H. Beitrag zu den Doppelmissbildungen im Bereich der Finger. Bruns Beitr. Klin. Chir. 205: 463-468, 1962.
Furniss, D., Lettice, L. A., Taylor, I. B., Critchley, P. S., Giele, H., Hill, R. E., Wilkie, A. O. M. A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Hum. Molec. Genet. 17: 2417-2423, 2008. [PubMed: 18463159] [Full Text: https://doi.org/10.1093/hmg/ddn141]
Gurnett, C. A., Bowcock, A. M., Dietz, F. R., Morcuende, J. A., Murray, J. C., Dobbs, M. B. Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am. J. Med. Genet. 143A: 27-32, 2007. [PubMed: 17152067] [Full Text: https://doi.org/10.1002/ajmg.a.31563]
Haas, S. L. Three-phalangeal thumbs. Am. J. Roentgen. 42: 677-682, 1939.
Hefner, R. A. Hereditary polydactyly: associated with extra phalanges in the thumb. J. Hered. 31: 25-27, 1940.
Heus, H. C., Hing, A., van Baren, M. J., Joosse, M., Breedveld, G. J., Wang, J. C., Burgess, A., Donnis-Keller, H., Berglund, C., Zguricas, J., Scherer, S. W., Rommens, J. M., Oostra, B. A., Heutink, P. A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36. Genomics 57: 342-351, 1999. [PubMed: 10329000] [Full Text: https://doi.org/10.1006/geno.1999.5796]
Heutink, P., Zguricas, J., van Oosterhout, L., Breedveld, G. J., Testers, L., Sandkuijl, L. A., Snijders, P. J. L. M., Weissenbach, J., Lindhout, D., Hovius, S. E. R., Oostra, B. A. The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q. Nature Genet. 6: 287-292, 1994. [PubMed: 8012392] [Full Text: https://doi.org/10.1038/ng0394-287]
Hing, A. V., Helms, C., Slaugh, R., Burgess, A., Wang, J. C., Herman, T., Dowton, S. B., Donis-Keller, H. Linkage of preaxial polydactyly type 2 to 7q36. Am. J. Med. Genet. 58: 128-135, 1995. [PubMed: 8533803] [Full Text: https://doi.org/10.1002/ajmg.1320580208]
Lettice, L. A., Heaney, S. J. H., Purdie, L. A., Li, L., de Beer, P., Oostra, B. A., Goode, D., Elgar, G., Hill, R. E., de Graaff, E. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Molec. Genet. 12: 1725-1735, 2003. [PubMed: 12837695] [Full Text: https://doi.org/10.1093/hmg/ddg180]
Merlob, P., Grunebaum, M., Reisner, S. H. Familial opposable triphalangeal thumbs associated with duplication of the big toes. J. Med. Genet. 22: 78-80, 1985. [PubMed: 3981586] [Full Text: https://doi.org/10.1136/jmg.22.1.78]
Nicolai, J.-P. A., Hamel, B. C. J. A family with complex bilateral polysyndactyly. J. Hand Surg. Am. 13: 405-407, 1988. [PubMed: 2837505] [Full Text: https://doi.org/10.1016/s0363-5023(88)80019-4]
Potuijt, J. W. P., Hoogeboom, J., de Graaff, E., van Nieuwenhoven, C. A., Galjaard, R. J. H. Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes. J. Med. Genet. 57: 660-663, 2020. [PubMed: 32179704] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106685]
Radhakrishna, U., Multani, A. S., Solanki, J. V., Shah, V. C., Chinoy, N. J. Polydactyly: a study of a five generation Indian family. J. Med. Genet. 30: 296-299, 1993. [PubMed: 8487274] [Full Text: https://doi.org/10.1136/jmg.30.4.296]
Ray, A. K. A pedigree with bilateral preaxial polydactyly from India. J. Genet. Hum. 35: 267-274, 1987. [PubMed: 3655751]
Semerci, C. N., Demirkan, F., Ozdemir, M., Biskin, E., Akin, B., Bagci, H., Akarsu, N. A. Homozygous feature of isolated triphalangeal thumb-preaxial polydactyly linked to 7q36: no phenotypic difference between homozygotes and heterozygotes. Clin. Genet. 76: 85-90, 2009. [PubMed: 19519794] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01192.x]
Temtamy, S. A., McKusick, V. A. The Genetics of Hand Malformations. New York: Alan R. Liss (pub.) 1978. P. 376.
Temtamy, S. A. Personal Communication. Cairo, Egypt 4/25/1994.
Tsukurov, O., Boehmer, A., Flynn, J., Nicolai, J.-P., Hamel, B. C. J., Traill, S., Zaleske, D., Mankin, H. J., Yeon, H., Ho, C., Tabin, C., Seidman, J. G., Seidman, C. A complex bilateral polysyndactyly disease locus maps to chromosome 7q36. Nature Genet. 6: 282-286, 1994. [PubMed: 8012391] [Full Text: https://doi.org/10.1038/ng0394-282]
VanderMeer, J. E., Lozano, R., Sun, M., Xue, Y., Daentl, D., Jabs, E. W., Wilcox, W. R., Ahituv, N. A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form. Hum. Mutat. 35: 945-948, 2014. [PubMed: 24777739] [Full Text: https://doi.org/10.1002/humu.22581]
Zguricas, J., Heus, H., Morales-Peralta, E., Breedveld, G., Kuyt, B., Mumcu, E. F., Bakker, W., Akarsu, N., Kay, S. P. J., Hovius, S. E. R., Heredero-Baute, L., Oostra, B. A., Heutink, P. Clinical and genetic studies on 12 preaxial polydactyly families and refinement of the localisation of the gene responsible to a 1.9 cM region on chromosome 7q36. J. Med. Genet. 36: 32-40, 1999. [PubMed: 9950363]
Zguricas, J., Snijders, P. J. L. M., Hovius, S. E. R., Heutink, P., Oostra, B. A., Lindhout, D. Phenotypic analysis of triphalangeal thumb and associated hand malformations. J. Med. Genet. 31: 462-467, 1994. [PubMed: 8071973] [Full Text: https://doi.org/10.1136/jmg.31.6.462]