Recent Advances in Syndactyly: Basis, Current Status and Future Perspectives

Abstract

A comprehensive summary of recent knowledge in syndactyly (SD) is important for understanding the genetic etiology of SD and disease management. Thus, this review article provides background information on SD, as well as insights into phenotypic and genetic heterogeneity, newly identified gene mutations in various SD types, the role of HOXD13 in limb deformities, and recently introduced modern surgical techniques for SD. This article also proposes a procedure for genetic analysis to obtain a clearer genotype–phenotype correlation for SD in the future. We briefly describe the classification of non-syndromic SD based on variable phenotypes to explain different phenotypic features and mutations in the various genes responsible for the pathogenesis of different types of SD. We describe how different types of mutation in HOXD13 cause various types of SD, and how a mutation in HOXD13 could affect its interaction with other genes, which may be one of the reasons behind the differential phenotypes and incomplete penetrance. Furthermore, we also discuss some recently introduced modern surgical techniques, such as free skin grafting, improved flap techniques, and dermal fat grafting in combination with the Z-method incision, which have been successfully practiced clinically with no post-operative complications.

A novel homozygous missense variant in LRP4 causing Cenani‐Lenz syndactyly syndrome and literature review

“…In 2022, Zaib et al. summarized the classification of non‐syndromic syndactyly (Zaib et al., 2022). According to the specific phenotype, syndactyly deformities are divided into nine categories, most SD are autosomal dominant (AD), only types VII and IX are autosomal recessive (AR).…”

“…Type VII SD is CLSS, the most serious type in SD and very rare (Zaib et al., 2022), with syndactyly, shortening and fusion of radius and ulna, and abnormal development of metacarpal and metatarsal bones as typical clinical features. Most CLSS is caused by missense mutations in LRP4 (Afzal et al., 2017; Alrayes et al., 2020; Hettiaracchchi et al., 2018; Steel et al., 2020; Zaib et al., 2022). It is one of the most severe types of syndactyly known to date (Harpf et al., 2005; Malik, 2012).…”

“…According to the specific phenotype, syndactyly deformities are divided into nine categories, most SD are autosomal dominant (AD), only types VII and IX are autosomal recessive (AR). Type VII SD is CLSS, the most serious type in SD and very rare (Zaib et al., 2022), with syndactyly, shortening and fusion of radius and ulna, and abnormal development of metacarpal and metatarsal bones as typical clinical features. Most CLSS is caused by missense mutations in LRP4 (Afzal et al., 2017; Alrayes et al., 2020; Hettiaracchchi et al., 2018; Steel et al., 2020; Zaib et al., 2022).…”

“…Exome sequencing revealed a novel homozygous c.282C > A variant in the LRP4 (OMIM 604270; NM_002334.4) causing p. (Asn94Lys) change in the encoded protein. (Zaib et al, 2022). According to the specific phenotype, syndactyly deformities are divided into nine categories, most SD are autosomal dominant (AD), only types VII and IX are autosomal recessive (AR).…”

“…Syndactyly can manifest alone or as a feature of a complex genetic disorder or syndrome. According to the specific phenotype, syndactyly deformities are divided into nine categories, Cenani‐Lenz syndactyly syndrome (CLSS; OMIM 212780) is type VII syndactyly and is also the most severe type in SD (Zaib et al., 2022).…”