Synpolydactyly: Clinical and molecular advances

Zentrum für Humangenetik, Philipps-Universität Marburg, Bahnhofstr. 7, Marburg, Germany.
Clinical Genetics (Impact Factor: 3.93). 03/2008; 73(2):113-20. DOI: 10.1111/j.1399-0004.2007.00935.x
Source: PubMed


Synpolydactyly (SPD) is a rare limb deformity showing a distinctive combination of syndactyly and polydactyly. Of the nine non-syndromic syndactylies, it is clinically and genetically one of the most heterogeneous malformation. SPD families may show clinical features consistent with the Temtamy and McKusick criteria as well as additional phenotypic variants, which vary from case to case. In certain instances, these variants predominate in a given family, while the typical SPD features remain less explicit. We have reviewed all the clinical variants occurring in well-documented SPD families. We conclude that typical SPD features can be delineated from minor clinical variants. Then, we propose to lump all the phenotypic variants, manifesting themselves in SPD families into three categories: (i) typical SPD features, (ii) minor variants, and (iii) unusual phenotypes. Next, we discuss the likely reasons for the occurrence of minor variants and the obvious lack of penetrance in SPD families. Finally, we show that for the SPD phenotype associated with HOXD13 mutations, a straightforward genotype-phenotype correlation is weak. Our lumping and splitting scheme for SPD phenotypic variants could be useful for the understanding of this interesting malformation.

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Available from: Sajid Malik, Jun 23, 2015
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    • "The most common type of HOXD13 mutations are expansions of the 15-residue N-terminal alanine repeat [Muragaki et al., 1996]. Expansions of þ7 to þ14 alanines have been reported in over 40 families with varying penetrance and expressivity of the SPD phenotype [Malik and Grzeschik, 2008], which increases in severity with the length of the alanine expansion [Goodman et al., 1997]. It has been shown that the polyalanine-tract expansions lead to cytoplasmatic retention and aggregation of mutant HOXD13 protein. "
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    ABSTRACT: Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2015 · American Journal of Medical Genetics Part A
    • "There is little published information in the surgical literature about the phenotypic variations, and there is no widely accepted classification system. As Malik and Grzeschik noted, 'it may not be possible to develop the ultimate classification system for synpolydactyly; however, different patterns of lumping and splitting may be useful for the clinicians, the pathologist, or the geneticist/molecular biologist' (Malik and Grzeschik, 2008). More careful analysis of larger numbers of synpolydactyly cases, however, might provide for a classification scheme that would aid communication, guide surgical intervention, and allow for improved reporting of treatment and outcomes. "
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    ABSTRACT: Synpolydactyly is an uncommon congenital anomaly characterized by polydactyly with syndactyly in the central hand. The purpose of this investigation was to develop and assess the reliability of a radiographic classification system for synpolydactyly. We identified 56 hands with central synpolydactyly and developed a radiographic classification system that categorizes by the location within the hand, the bony level of polydactyly, and the presence of a delta phalanx. Four paediatric hand surgeons independently reviewed each radiograph to establish reliability. There was exact agreement among raters in 40 cases (71%). The inter-rater reliability was 0.97 and intra-rater reliability was at least 0.87. Seven of 16 bilateral cases had symmetric deformity classification. The most common presentations were types 1A and 2A. We present a new, reliable radiographic classification system for synpolydactyly that will allow improved communication between clinicians and serve as a foundation for future investigations. 2. © The Author(s) 2015.
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    • "We re-examined the proposed genotype-phenotype correlation for HOXD13 (Figure 3 and Table 3). The polyalanine repeat expansions and frameshift deletion mutations usually give rise to typical SPD phenotypes, and the homeodomain missense mutation cluster for brachydactyly types [38]. Close genotype-phenotype correlations were also observed between different types of HOXD13-Syndactyly. "
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    ABSTRACT: Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Its four subtypes (a, b, c, and d) are defined based on variable phenotypes, but the responsible gene is yet to be identified. SD1-a has been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and, to our knowledge, no gene loci have been identified. In two Chinese families with SD1-c, linkage and haplotype analyses mapped the disease locus to 2q31-2q32. Copy number variation (CNV) analysis, using array-based comparative genomic hybridization (array CGH), excluded the possibility of microdeletion or microduplication. Sequence analyses of related syndactyly genes in this region identified c.917G>A (p.R306Q) in the homeodomain of HOXD13 in family A. Analysis on family B identified the mutation c.916C>G (p.R306G) and therefore confirmed the genetic homogeneity. Luciferase assays indicated that these two mutations affected the transcriptional activation ability of HOXD13. The spectrum of HOXD13 mutations suggested a close genotype-phenotype correlation between the different types of HOXD13-Syndactyly. Overlaps of the various phenotypes were found both among and within families carrying the HOXD13 mutation. Mutations (p.R306Q and p.R306G) in the homeodomain of HOXD13 cause SD1-c. There are affinities between SD1-c and synpolydactyly. Different limb malformations due to distinct classes of HOXD13 mutations should be considered as a continuum of phenotypes and further classification of syndactyly should be done based on phenotype and genotype.
    Full-text · Article · May 2014 · PLoS ONE
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