A Review of the Phenotype of Synpolydactyly Type 1 in Homozygous Patients: Defining the Relatively Long and Medially Deviated Big Toe with/without Cupping of the Forefoot as a Pathognomonic Feature in the Phenotype

Abstract

Synpolydactyly type 1 (SPD1, OMIM 186000) is inherited as autosomal dominant and is caused by HOXD13 mutations. The condition is rare and is known for its phenotypic heterogeneity. In the homozygous state, the phenotype is generally more severe and is characterized by three main features: a more severe degree of syndactyly, a more severe degree of brachydactyly, and the frequent loss of the normal tubular shape of the metacarpals/metatarsals. Due to the phenotypic heterogeneity and the phenotypic overlap with other types of syndactyly, no pathognomonic feature has been described for the homozygous phenotype of SPD1. In the current communication, the author reviews the literature on the phenotypes of SPD1 in homozygous patients. The review documents that not all homozygous patients show a severe hand phenotype. The review also defines the “relatively long and medially deviated big toe with/without cupping of the forefoot” as a pathognomonic feature in the phenotype. Illustration of this feature is done through a demonstrative clinical report in a multigeneration family with SPD1 and HOXD13 polyalanine repeat expansion. Finally, the pathogenesis of the clinical features is reviewed.

A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

“…HOXD13 is an important genetic factor of SPD. There is variable and asymmetrical expressivity of clinical phenotypes caused by HOXD13 mutations ( Malik and Grzeschik, 2010 ; Al-Qattan, 2020 ) and studies on genotype–phenotype correlation are limited.…”

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

“…Previously, it has been reported that families inheriting a homozygous mutation in the HOXD13 have a severe form of SPD [86] but, recently, this has been demonstrated not to be true in all cases of SPD1 patients with homozygous mutations [87]. Studies have also reported HOXD13 mutations in families with different syndactyly types, e.g., SD1-a, SD1-c, and SD5 (Table 3), which gives a clear indication that HOXD13 has a critical role in limb formation and that it may also interact with other limb-formation genes during the process.…”