Medicine:Familial opposable triphalangeal thumbs duplication

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Familial opposable triphalangeal thumb duplication
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SpecialtyMedical genetics
Usual onsetBirth
DurationLife-long
CausesGenetic mutation
FrequencyRare, less than 1 in 25,000 births.

Familial opposable triphalangeal thumb duplication is a limb malformation syndrome and a type of pre-axial polydactyly, characterized by having duplicated opposable triphalangeal thumbs. This condition can be a symptom of other genetic disorders, such as Holt–Oram syndrome and Fanconi anemia. This trait is autosomal dominant and often runs in families (hence "familial").[1] Sometimes big toe duplication, post-axial polydactyly, and syndactyly of the hand and feet can occur alongside this malformation[2][3] Approximately 20 families with the condition have been described in medical literature.[4]

Signs and symptoms

The most common symptom is a duplication of a triphalangeal thumb in the hands, which would leave the person affected by the condition with two triphalangeal thumbs in each hand, alongside other digital and radiological anomalies, such as duplication of the big toe, hypoplastic duplicated radius bones, etc.[5]

There are multiple phenotypes associated with this condition due to its sometimes incomplete penetrance, this means that, even in the same family, people can have varying degrees of digital anomalies.

This has been observed in various families, one such instance is the 2 families from a relatively remote and isolated region in the Netherlands reported by P Heutink et al. in 1994; even among members of the same families, the phenotype they exhibited was very variable, while some members had an opposable thumb with mild triphalangy manifesting as an underdeveloped delta phalanx, other members had a fully functional extra digit in their hands (not related to the thumb) as well as a fully formed thumb with an outstanding resemblance to an index finger. Other features that could be seen among the same families included duplicated, underdeveloped thumb rays, hypoplasia of the thenar muscle, and syndactyly with metacarpal synostosis affecting the fourth and fifth rays.[6]

Complications

None of the families described in medical literature have had complications associated with their condition.[citation needed]

Genetics

This condition is usually caused by a mutation in a gene located on the 7q36 locus of the seventh chromosome.

The gene that is mutated is usually the LMBR1 gene, this gene encodes a protein called Limb region 1 protein homolog.

The mutation that this gene contains varies among families, most of the point mutations that have been reported have either been transitions or small duplications of material within the gene, which usually aren't any more than 600 kb. Examples of the mutations that have been found in families with the condition include:

  • 589 kb duplication in intron 5 of the gene, found in 9 affected members of a 4-generation German family.[7]
  • Duplications ranging from 131 to 398 kb in intron 5 of the gene, found in affected members of 5 multi-generational Han Chinese families.[8]
  • 295T>C transition in intron 5 of the gene, found in 3 un-related British individuals with the condition.[9]
  • 276 kb duplication in intron 5 of the gene, found in 9 affected members of a Turkish family.[10]
  • 297G>A and 334T>G transitions (respectively) in intron 5 of the gene, found in affected members of 2 un-related French families.[11]
  • c.402T>C transition in intron 5 of the gene, found in a total of 57 affected members of 2 un-related 5-generation Mexican families.[12]
  • c.165A>G and c.297T>C transitions in intron 5 of the gene, found in affected members of 2 un-related Dutch families.[13]

Diagnosis

Diagnostic methods that can be used to diagnose this condition include the following:[14]

Treatment

Treatment for a triphalangeal thumb usually involves the resection of a phalanx in the triphalangic thumb, this can be done with one of various procedures known as an osteotomy.[15][16]

This treatment method is more effective with milder cases than it is with more severe cases of TPT.[16][15]

Prevalence

According to OMIM, between 100 and 200 cases from 20 separate families across the world have been described in medical literature, most of these families were either East Asian or European.[4]

History

This condition was possibly discovered in 1917 by Atwood and Pond.[17]

See also

References

  1. ↑ "Orphanet: Polydactyly of a triphalangeal thumb". https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93336. 
  2. ↑ Merlob, P.; Grunebaum, M.; Reisner, S. H. (1985). "Familial opposable triphalangeal thumbs associated with duplication of the big toes". Journal of Medical Genetics 22 (1): 78–80. doi:10.1136/jmg.22.1.78. PMID 3981586. 
  3. ↑ Zguricas, J.; Snijders, P. J.; Hovius, S. E.; Heutink, P.; Oostra, B. A.; Lindhout, D. (1994). "Phenotypic analysis of triphalangeal thumb and associated hand malformations". Journal of Medical Genetics 31 (6): 462–467. doi:10.1136/jmg.31.6.462. PMID 8071973. 
  4. ↑ 4.0 4.1 "Entry - #174500 - POLYDACTYLY, PREAXIAL II; PPD2 - OMIM" (in en-us). https://omim.org/entry/174500#5. 
  5. ↑ "Preaxial polydactyly type 2". https://rarediseases.info.nih.gov/diseases/5289/index. 
  6. ↑ Heutink, P.; Zguricas, J.; van Oosterhout, L.; Breedveld, G. J.; Testers, L.; Sandkuijl, L. A.; Snijders, P. J.; Weissenbach, J. et al. (March 1994). "The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q". Nature Genetics 6 (3): 287–292. doi:10.1038/ng0394-287. ISSN 1061-4036. PMID 8012392. https://pubmed.ncbi.nlm.nih.gov/8012392/. 
  7. ↑ Klopocki, E.; Ott, C.-E.; Benatar, N.; Ullmann, R.; Mundlos, S.; Lehmann, K. (June 2008). "A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome". Journal of Medical Genetics 45 (6): 370–375. doi:10.1136/jmg.2007.055699. ISSN 1468-6244. PMID 18178630. https://pubmed.ncbi.nlm.nih.gov/18178630/. 
  8. ↑ Sun, M.; Ma, F.; Zeng, X.; Liu, Q.; Zhao, X.-L.; Wu, F.-X.; Wu, G.-P.; Zhang, Z.-F. et al. (September 2008). "Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer". Journal of Medical Genetics 45 (9): 589–595. doi:10.1136/jmg.2008.057646. ISSN 1468-6244. PMID 18417549. https://pubmed.ncbi.nlm.nih.gov/18417549/. 
  9. ↑ Furniss, Dominic; Lettice, Laura A.; Taylor, Indira B.; Critchley, Paul S.; Giele, Henk; Hill, Robert E.; Wilkie, Andrew O. M. (2008-08-15). "A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb". Human Molecular Genetics 17 (16): 2417–2423. doi:10.1093/hmg/ddn141. ISSN 1460-2083. PMID 18463159. 
  10. ↑ Wieczorek, Dagmar; Pawlik, Barbara; Li, Yun; Akarsu, Nurten A.; Caliebe, Almuth; May, Klaus J. W.; Schweiger, Bernd; Vargas, Fernando R. et al. (January 2010). "A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb". Human Mutation 31 (1): 81–89. doi:10.1002/humu.21142. ISSN 1098-1004. PMID 19847792. https://pubmed.ncbi.nlm.nih.gov/19847792/. 
  11. ↑ Albuisson, J.; Isidor, B.; Giraud, M.; Pichon, O.; Marsaud, T.; David, A.; Le Caignec, C.; Bezieau, S. (April 2011). "Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly". Clinical Genetics 79 (4): 371–377. doi:10.1111/j.1399-0004.2010.01465.x. ISSN 1399-0004. PMID 20569257. https://pubmed.ncbi.nlm.nih.gov/20569257/. 
  12. ↑ VanderMeer, Julia E.; Lozano, Reymundo; Sun, Miao; Xue, Yuan; Daentl, Donna; Jabs, Ethylin Wang; Wilcox, William R.; Ahituv, Nadav (August 2014). "A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form". Human Mutation 35 (8): 945–948. doi:10.1002/humu.22581. ISSN 1098-1004. PMID 24777739. 
  13. ↑ Potuijt, Jacob W. P.; Hoogeboom, Jeannette; de Graaff, Esther; van Nieuwenhoven, Christianne A.; Galjaard, Robert Jan H. (October 2020). "Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes". Journal of Medical Genetics 57 (10): 660–663. doi:10.1136/jmedgenet-2019-106685. ISSN 1468-6244. PMID 32179704. 
  14. ↑ Saraf, Sanjay; Parihar, Ravi Singh (2010-05-01). "Polydactyly of triphalangeal thumb" (in en). Indian Journal of Dermatology, Venereology and Leprology 76 (3): 307. doi:10.4103/0378-6323.62986. ISSN 0378-6323. PMID 20445317. https://ijdvl.com/polydactyly-of-triphalangeal-thumb/. 
  15. ↑ 15.0 15.1 Hovius, Steven E. R.; Potuijt, Jacob W. P.; van Nieuwenhoven, Christianne A. (January 2019). "Triphalangeal thumb: clinical features and treatment". The Journal of Hand Surgery, European Volume 44 (1): 69–79. doi:10.1177/1753193418797922. ISSN 1753-1934. PMID 30223699. 
  16. ↑ 16.0 16.1 Hovius, Steven E. R.; Zuidam, J. Michiel; de Wit, Thijs (December 2004). "Treatment of the triphalangeal thumb". Techniques in Hand & Upper Extremity Surgery 8 (4): 247–256. doi:10.1097/00130911-200412000-00008. ISSN 1089-3393. PMID 16518099. https://pubmed.ncbi.nlm.nih.gov/16518099/. 
  17. ↑ Atwood, E. S., Pond, C. P. A polydactylous family. J. Hered. 8: 96 only, 1917.



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