Familial opposable triphalangeal thumbs duplication

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.{{Cite web |title=Preaxial polydactyly type 2 |url=https://rarediseases.info.nih.gov/diseases/5289/index}}

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.{{Cite journal |last1=Heutink |first1=P. |last2=Zguricas |first2=J. |last3=van Oosterhout |first3=L. |last4=Breedveld |first4=G. J. |last5=Testers |first5=L. |last6=Sandkuijl |first6=L. A. |last7=Snijders |first7=P. J. |last8=Weissenbach |first8=J. |last9=Lindhout |first9=D. |last10=Hovius |first10=S. E. |date=March 1994 |title=The gene for triphalangeal thumb maps to the subtelomeric region of chromosome 7q |url=https://pubmed.ncbi.nlm.nih.gov/8012392/ |journal=Nature Genetics |volume=6 |issue=3 |pages=287–292 |doi=10.1038/ng0394-287 |issn=1061-4036 |pmid=8012392|s2cid=5711857 |hdl=1765/57316 |hdl-access=free }}

{{cn span|text=None of the families described in medical literature have had complications associated with their condition.|date=October 2022}}

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.{{Cite journal |last1=Klopocki |first1=E. |last2=Ott |first2=C.-E. |last3=Benatar |first3=N. |last4=Ullmann |first4=R. |last5=Mundlos |first5=S. |last6=Lehmann |first6=K. |date=June 2008 |title=A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome |url=https://pubmed.ncbi.nlm.nih.gov/18178630/ |journal=Journal of Medical Genetics |volume=45 |issue=6 |pages=370–375 |doi=10.1136/jmg.2007.055699 |issn=1468-6244 |pmid=18178630|s2cid=206998781 }}
• Duplications ranging from 131 to 398 kb in intron 5 of the gene, found in affected members of 5 multi-generational Han Chinese families.{{Cite journal |last1=Sun |first1=M. |last2=Ma |first2=F. |last3=Zeng |first3=X. |last4=Liu |first4=Q. |last5=Zhao |first5=X.-L. |last6=Wu |first6=F.-X. |last7=Wu |first7=G.-P. |last8=Zhang |first8=Z.-F. |last9=Gu |first9=B. |last10=Zhao |first10=Y.-F. |last11=Tian |first11=S.-H. |last12=Lin |first12=B. |last13=Kong |first13=X.-Y. |last14=Zhang |first14=X.-L. |last15=Yang |first15=W. |date=September 2008 |title=Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer |url=https://pubmed.ncbi.nlm.nih.gov/18417549/ |journal=Journal of Medical Genetics |volume=45 |issue=9 |pages=589–595 |doi=10.1136/jmg.2008.057646 |issn=1468-6244 |pmid=18417549|s2cid=35291863 }}
• 295T>C transition in intron 5 of the gene, found in 3 un-related British individuals with the condition.{{Cite journal |last1=Furniss |first1=Dominic |last2=Lettice |first2=Laura A. |last3=Taylor |first3=Indira B. |last4=Critchley |first4=Paul S. |last5=Giele |first5=Henk |last6=Hill |first6=Robert E. |last7=Wilkie |first7=Andrew O. M. |date=2008-08-15 |title=A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb |journal=Human Molecular Genetics |volume=17 |issue=16 |pages=2417–2423 |doi=10.1093/hmg/ddn141 |issn=1460-2083 |pmc=2486440 |pmid=18463159}}
• 276 kb duplication in intron 5 of the gene, found in 9 affected members of a Turkish family.{{Cite journal |last1=Wieczorek |first1=Dagmar |last2=Pawlik |first2=Barbara |last3=Li |first3=Yun |last4=Akarsu |first4=Nurten A. |last5=Caliebe |first5=Almuth |last6=May |first6=Klaus J. W. |last7=Schweiger |first7=Bernd |last8=Vargas |first8=Fernando R. |last9=Balci |first9=Sevim |last10=Gillessen-Kaesbach |first10=Gabriele |last11=Wollnik |first11=Bernd |date=January 2010 |title=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 |url=https://pubmed.ncbi.nlm.nih.gov/19847792/ |journal=Human Mutation |volume=31 |issue=1 |pages=81–89 |doi=10.1002/humu.21142 |issn=1098-1004 |pmid=19847792|s2cid=1715146 }}
• 297G>A and 334T>G transitions (respectively) in intron 5 of the gene, found in affected members of 2 un-related French families.{{Cite journal |last1=Albuisson |first1=J. |last2=Isidor |first2=B. |last3=Giraud |first3=M. |last4=Pichon |first4=O. |last5=Marsaud |first5=T. |last6=David |first6=A. |last7=Le Caignec |first7=C. |last8=Bezieau |first8=S. |date=April 2011 |title=Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly |url=https://pubmed.ncbi.nlm.nih.gov/20569257/ |journal=Clinical Genetics |volume=79 |issue=4 |pages=371–377 |doi=10.1111/j.1399-0004.2010.01465.x |issn=1399-0004 |pmid=20569257|s2cid=39562858 }}
• 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.{{Cite journal |last1=VanderMeer |first1=Julia E. |last2=Lozano |first2=Reymundo |last3=Sun |first3=Miao |last4=Xue |first4=Yuan |last5=Daentl |first5=Donna |last6=Jabs |first6=Ethylin Wang |last7=Wilcox |first7=William R. |last8=Ahituv |first8=Nadav |date=August 2014 |title=A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form |journal=Human Mutation |volume=35 |issue=8 |pages=945–948 |doi=10.1002/humu.22581 |issn=1098-1004 |pmc=4110103 |pmid=24777739}}
• c.165A>G and c.297T>C transitions in intron 5 of the gene, found in affected members of 2 un-related Dutch families.{{Cite journal |last1=Potuijt |first1=Jacob W. P. |last2=Hoogeboom |first2=Jeannette |last3=de Graaff |first3=Esther |last4=van Nieuwenhoven |first4=Christianne A. |last5=Galjaard |first5=Robert Jan H. |date=October 2020 |title=Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild triphalangeal thumb phenotypes |journal=Journal of Medical Genetics |volume=57 |issue=10 |pages=660–663 |doi=10.1136/jmedgenet-2019-106685 |issn=1468-6244 |pmc=7525795 |pmid=32179704}}

Diagnostic methods that can be used to diagnose this condition include the following:{{Cite journal |last1=Saraf |first1=Sanjay |last2=Parihar |first2=Ravi Singh |date=2010-05-01 |title=Polydactyly of triphalangeal thumb |url=https://ijdvl.com/polydactyly-of-triphalangeal-thumb/ |journal=Indian Journal of Dermatology, Venereology and Leprology |language=en |volume=76 |issue=3 |pages=307 |doi=10.4103/0378-6323.62986 |issn=0378-6323 |pmid=20445317|doi-access=free }}

• Physical examination
• Radiography
• Whole genome sequencing

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.{{Cite journal |last1=Hovius |first1=Steven E. R. |last2=Potuijt |first2=Jacob W. P. |last3=van Nieuwenhoven |first3=Christianne A. |date=January 2019 |title=Triphalangeal thumb: clinical features and treatment |journal=The Journal of Hand Surgery, European Volume |volume=44 |issue=1 |pages=69–79 |doi=10.1177/1753193418797922 |issn=1753-1934 |pmc=6297898 |pmid=30223699}}{{Cite journal |last1=Hovius |first1=Steven E. R. |last2=Zuidam |first2=J. Michiel |last3=de Wit |first3=Thijs |date=December 2004 |title=Treatment of the triphalangeal thumb |url=https://pubmed.ncbi.nlm.nih.gov/16518099/ |journal=Techniques in Hand & Upper Extremity Surgery |volume=8 |issue=4 |pages=247–256 |doi=10.1097/00130911-200412000-00008 |issn=1089-3393 |pmid=16518099}}

This treatment method is more effective with milder cases than it is with more severe cases of TPT.

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.

This condition was possibly discovered in 1917 by Atwood and Pond.Atwood, E. S., Pond, C. P. A polydactylous family. J. Hered. 8: 96 only, 1917.

• Brachydactyly
• Heart-hand syndromes

{{Reflist}}

Category:Rare genetic syndromes

Category:Genetic diseases and disorders

Category:Autosomal dominant disorders