Polydactyly: Causes, Types, and Treatment

• Polydactyly is a malformation during limb development, characterized by having more than the normal number of fingers or toes.
• It is considered a common inherited hand disorder.
• The two main types are non-syndromic polydactyly and syndromic polydactyly.
• Based on the location of the extra digits, types include preaxial, postaxial, and mesoaxial forms.
• Non-syndromic polydactyly often has an autosomal dominant inheritance.
• Defects in anterior-posterior limb development can cause the malformation.
• Many forms exist, including hand and foot extra digit manifestations.
• Upper limbs are more frequently affected than lower limbs, and the left foot is more often affected than the right.
• Treatment involves surgery.
• Research on congenital limb deformities has expanded the list of associated gene mutations.
• Next-generation sequencing helps correlate phenotype and genetic profile, aiding early diagnosis and screening of non-syndromic and syndromic disorders.
• Polydactyly, Gene, Syndromic, Non-syndromic, Preaxial, and Postaxial are key words.

Core Tip

• The molecular basis of syndromic or non-syndromic, is diverse.
• Specific molecular profiles correlate to disorder phenotypes, but some molecular bases are still unclear.
• Gene mutations cause hand and foot polydactyly as an isolated disorder or as part of a syndrome, which determines clinical manifestations.

Introduction

• Non-syndromic or Syndromic polydactyly is often inherited with an autosomal dominant trait with variable penetrance and is related to a disturbance of the anterior-posterior axial limb development.
• This condition is classified into preaxial (radial/tibial digits), axial (central), and postaxial (ulnar/peroneal digits) polydactyly.
• Mirror-image polydactyly and Haas-type polysyndactyly are rare and distinct types that do not fit into the three categories mentioned above.
• Specific phenotypes have been correlated to gene mutations including all types of hand and foot polydactyly have been identified.
• The ability to identify potential syndromes associated with the polydactyly anomaly is important for the clinician.
• It is important to distinguish between syndromic and non-syndromic cases for reasons of genetic counseling.
• Recent progress clinical and molecular manifestations of disorders, and representative syndromes including polydactyly as a phenotype have been reviewed.

Clinical and Molecular Manifestations of Non-Syndromic Hand and Foot Polydactyly

• Preaxial polydactyly is the second most common phenotype behind postaxial.
• A prevalence of approximately 0.8 to 2.3 in 10000 live births is reported.
• This condition is characterized by an extra digit on the tibial/radial side of the limb..
• The following classification has been suggested:
  • Preaxial polydactyly type I, which is thumb polydactyly (OМІМ 174400), is characterized by duplication of one or more skeletal elements of a biphalangeal thumb.
  • Preaxial polydactyly type II is polydactyly of a triphalangeal thumb (OMIM 174500).
  • Preaxial polydactyly type III, which is polydactyly of the index finger, characterized by the presence of one or two triphalangeal digits (OMIM 174600).
  • Preaxial polydactyly type IV and syndactyly of various degrees involving the middle and ring finger/second and third toe (OMIM 174700) or hallux polydactyly (OMIM 601759).
• Preaxial polydactyly type I, or Thumb polydactyly is usually observed unilaterally.
• In bilateral cases, hands are more often affected and the left hand is also more often affected than the right.
• It follows an autosomal dominant inheritance model.
• A recent study in a Pakistani family revealed a rare autosomal recessive preaxial polydactyly linked to a novel variant (c.1517T>A; p. Leu506Gln) in the GLI1 gene on chromosome 12q13.3.
• Wassel classification is the most commonly used classification, which divides thumb duplication into six subtypes according to the level and extent of duplication (partial or complete) and Hallux polydactyly is also known as a predominant presentation or an isolated disorder.
• Hallux duplication incidence is 2.4/100000 compared to thumb polydactyly incidence in South America, which is 1.65/10000.
• Preaxial type I polydactyly is caused by sequence variants in the sonic hedgehog (SHH) enhancer, called zone of polarizing activity (ZPA) regulatory sequence (ZRS), regulated by the LMBR1 gene.
• Mutations in CEP290, RPGRIP1, TMEM216, FBN1, CEP1, and MEGF8 genes have been isolated and suspected to play a role in Wassel III and Wassel IV manifestations.
• A mutation in the STKLD1 gene, located on chromosome 9q34.2, was found and correlated with the disease phenotype in all members of the studied family.
• A molecular study of the SHH/GLI signaling axis, identified the HES1 gene as a downstream modifier, which can cause preaxial polydactyly.
• Next-generation sequence analysis in a four-generation family revealed a new ZRS mutation (g.101779T>A), which can cause the disease phenotype and genetic analysis identified two novel mutations in a Chinese patient with preaxial polydactyly in genes GLI3 gene (c.G2844A) and EVC gene (c.1409_1410del) Mutations in the KIAA0586 gene, related with ciliopathies (OMIM 610178) were also detected.Preaxial polydactyly type II: Preaxial polydactyly type II is characterized by the presence of a usually opposable triphalangeal thumb with or without one or more skeletal duplications of the thumb.
• The thumb appearance can differ widely in shape or it can be deviated in the radio-ulnar plane.
• It can also be associated with Holt-Oram syndrome and Fanconi anemia.
• LMBR1 and its related pathways Wnt/Notch and Hedgehog play a significant role in the development of the disorder.
• The disease gene locus was mapped to chromosome 7q36.
• SHH mutations in the SHH regulatory factor were also reported. Mutation near the ZRS (739A>G transition) and a 621C>G mutation in the ZRS of the LMBR1 gene were also identified.
• Triphalangeal thumb-polysyndactyly can manifest as a syndrome. It is an isolated limb deformity characterized by pre- and postaxial polysyndactyly of hands and feet with mutations in ZRS.
• Preaxial polydactyly type III is an autosomal dominant disorder characterized by a malformation of fingers, where the thumb is replaced by one or two triphalangeal digits with dermatoglyphic pattern specific for the index finger. It can occur unilaterally and bilaterally and there is no know responsible gene.
• Preaxial polydactyly type IV is described as mild duplication of the thumb, syndactyly, duplication of the first or second toes, and toes syndactyly and Patients may only have foot malformations. Mutations in GLI3 gene are associated to genetic analysis in two families with the phenotype was heterozygous for p.L1216PfsX31 and p.R290X mutations in the GLI3 gene.
• Postaxial polydactyly is a common congenital hand malformation characterized by fifth digit duplications in hands/feet with a prevalence estimated between 1/630 and 1/3300 in Caucasian race and between 1/100 and 1/300 in Black race.
• Type A is formed and articulates with the fifth or an extra metacarpal and type B is rudimentary represented by an extra skin tag and can be be inherited by autosomal dominant/recessive.
• Postaxial polydactyly type A1 the extra digit well-formed and articulates with the fifth or a sixth metacarpal/metatarsal. GLI3 gene mutations are associated to a family phenotype mapped to 7pl5-q11.23.
• A mutation in the C- and N-terminal or the zinc finger domain of the GLI3 gene causes isolated postaxial polydactyly type A1 and the post-zinc finger region is incriminated for Pallister-Hall syndrome.
• In a Chinese family the isolated postaxial polydactyly revealed a new mutation of GLI3. The DACH1 gene mutation identified a ptient with a bilateral postaxial polydactyly that was subject whole exome sequencing with new mutation of genes incriminated for postaxial polydactyly.
• Postaxial polydactyly type A2 consists of phenotypes an extra digit and revealed mapped disease to 13q21-q32.
• Postaxial polydactyly type A3 it manifests in hands and feet and was found to map phenotypes disease gene locus which was mapped to 19p13.2-p13.1.
• Postaxial polydactyly type A4 is characterized two to three syndactyly mapping 7q21-q34.
• Postaxial polydactyly type A5 is characterized feet minor syndactyly, found in two Italian families.
• Postaxial polydactyly type A6 the phenotype is characterized an extra functionally developed digit.
• Polydactyly, and exome in Pakistani family a function protein
• Postaxial polydactyly the and gene neurovascular aspects mutations are associated.
• Central one in three other is the feet or duplication.
• Mesoaxial, and is with.
• Complex with syndrome.
• Haas-type total affected with and
• Syndrome.

Clinical and Molecular Manifestations of Syndromic Hand and Foot Polydactyly

• Bardet-Biedl syndrome (OMIM 209900) is an autosomal or digenic recessive disorder presenting with vision loss, obesity, hand/foot polydactyly, intellectual disabilities, and hypogonadism and has mutations in at least 20 genes.
• McKusick-Kaufman Syndrome, contains Genitourinary malformations Postaxial hand/foot and rarely cardiac defects and are are recessive trait.
• Carpenter with head finger/toes feet finger genetics are inheritance.
• Hand first and dominant.
• Poland, is and polydactyly with are are.
• Greig is with preaxial common with associated with the correlated with.
• Pallister Hall which often with and considered autosomal.
• Jeune with one DYNC2H1 for that.
• Smith multimalformation.

Conclusion

• Genetic mechanisms which combine epigenetic and environmental factors play a significant role in foot and hand polydactyly manifestations
• Proper genotype-phenotype correlations might help in future genetic testing and enhance our knowledge about identified diseases and their associated genes.
• Recent genetic analysis techniques of extra foot or hand digit formation highlight the existence of nongradual transitions in phenotypes, suggesting a distinction between continuous and discontinuous variation in evolution.
• Genome sequencing will probably lead to the discovery of a number of new gene mutations responsible for non-syndromic or syndromic polydactyly.
• Clinical manifestation and genetic profile correlation of polydactyly types will be further established by use of bioinformatics analysis of gene mutations.
• Progress of prenatal diagnosis, which is still mostly postnatal, prenatal operative treatment planning, and potential future gene modification treatment will be enhanced and unknown molecular background of diseases, which is to date unclear, will be elucidated.