Synpolydactyly (SPD) is caused by mutations in the transcription factor gene HOXD13. Such mutations include polyalanine expansion (PAE), but further study is required for the phenotypic spectrum characteristics of HOXD13 PAE. We investigated four unrelated Chinese families with significant limb malformations. Three PAEs were found in the HOXD13 polyalanine coding region: c.172_192dup (p.Ala58_Ala64dup) in Family 1, c.169_192dup (p.Ala57_Ala64dup) in Family 2, and c.183_210dup (p.Ala62_Ala70dup) in Family 3 and Family 4. Interestingly, we identified a new manifestation of preaxial polydactyly in both hands in a pediatric patient with an expansion of seven alanines, a phenotype not previously noted in SPD patients. Comparing with the wild-type cells and mutant cells with polyalanine contractions (PACs), the HOXD13 protein with a PAE of nine-alanine or more was difficult to enter the nucleus, and easy to form inclusion bodies in the cytoplasm, and with the increase of PAE, the more inclusion bodies were formed. This study not only expanded the phenotypic spectrum of SPD, but also enriched our understanding of its pathogenic mechanisms.

Synpolydactyly is a rare congenital anomaly characterized by syndactyly and polydactyly in the central hand. Limited treatment guidelines exist for this complex condition. A retrospective review of synpolydactyly patients was conducted at a large, tertiary pediatric referral center to describe our surgical experience and evolution of management. The Wall classification system was used to categorize cases. Eleven patients (21 hands) with synpolydactyly were identified. Most of the patients were White and had at least one first-degree relative who also had synpolydactyly. The Wall classification yielded the following results: 7 type 1A hands, 4 type 2B hands, 6 type 3 hands, and 4 uncategorizable hands. Each patient had an average of 2.6 surgeries and an average follow-up time of 5.2 years. The rates of postoperative angulation and flexion deformities were 24% and 38%, respectively, with many of these cases also demonstrating preoperative alignment abnormalities. These cases often required additional surgeries including osteotomies, capsulectomies, and/or soft tissue releases. The rate of web creep was 14% with 2 of these patients requiring revision surgery. Despite these findings, at the time of final follow-up, most patients had favorable functional outcomes, were able to engage in bimanual tasks, and were able to perform activities of daily living independently. Synpolydactyly is a rare congenital hand anomaly with a significant degree of variability in clinical presentation. The rates of angulation and flexion deformities as well as web creep are not insignificant. We have learned to prioritize correcting contractures, angulation deformities, and skin fusion, over simply trying to delete the "extra" number of bones as this may destabilize the digit(s).

Synpolydactyly (SPD) is a digital malformation with the typical clinical phenotype of the webbing of 3/4 fingers and/or 4/5 toes, and combined with polydactyly. In this study, we investigated a Chinese family with SPD and genetic analysis found that all of the affected individuals in the family carry a heterozygous 11,451 bp microdeletion at chr2:176933872-176945322 (GRCh37), which is located upstream of HOXD13 gene, the known disease gene for SPD1. All the affected individuals in the family carry the heterozygous deletion variant, and the variant co-segregated with SPD in the family. Thus, we speculate that the 11,451 bp microdeletion is the disease-causing variant in the family. To date, the microdeletion associating with SPD1 which we identified is the smallest deletion upstream of the HOXD13 gene and not altering the sequence of the HOXD13 gene.

Connective tissue disorders are a spectrum of diseases that affect the integrity of tissues including skin, vasculature, and joints. They are often caused by variants that disrupt genes encoding components of extracellular matrix (ECM). The fibulin glycoproteins are ECM proteins important for integrity of tissues including dermis, retina, fascia, and vasculature. The fibulin family consists of seven members (fibulins-1 to -7) and is defined by a fibulin-type domain at the C-terminus. The family is associated with human diseases, for instance a variant in FBLN1, encoding fibulin-1, is associated with synpolydactyly, while one in EFEMP1, encoding fibulin-3, causes Doyne honeycomb degeneration of the retina. Loss-of-function of fibulins-4 and -5 causes cutis laxa, while variants in fibulins-5 and -6 are associated with age-related macular degeneration. Of note, EFEMP1 is not currently associated with any connective tissue disorder. Here we show biallelic loss-of-function variants in EFEMP1 in an individual with multiple and recurrent abdominal and thoracic herniae, myopia, hypermobile joints, scoliosis, and thin translucent skin. Fibroblasts from this individual express significantly lower EFEMP1 transcript than age-matched control cells. A skin biopsy, visualised using light microscopy, showed normal structure and abundance of elastic fibres. The phenotype of this individual is remarkably similar to the Efemp1 knockout mouse model that displays multiple herniae with premature aging and scoliosis. We conclude that loss of EFEMP1 function in this individual is the cause of a connective tissue disorder with a novel combination of phenotypic features, and can perhaps explain similar, previously reported cases in the literature.

Syndactyly type II (synpolydactyly, SPD) is a rare autosomal dominant inherited disease with higher incomplete penetrance. Currently, several variants in HOXD13 and one deletion in FBLN1 have been associated with SPD. However, the causative variants in several SPD families and their etiological mechanism are still largely unknown. Whole exome and PCR-sanger sequencing followed by two-point linkage analysis were performed to identify the pathogenic variant in a six-generation Chinese pedigree. Homology modeling in combination with the RNAi and qRT-PCR experiments was used for revealing the pathogenic mechanism of the TTC30B variant. A six-generation SPD family was reported. The affected subjects in this family had no other clinical malformation beyond SPD. A rare missense variant c.1157C>T [p.Ala375Val] (chr2:178416368, hg19) in TTC30B was demonstrated to be responsible for this SPD family. The modeling structure indicated that the Ala375 was evolutionarily and structurally conserved. The variant p.Ala375Val was predicted to be deleterious for protein structure and/or stability. Two-point linkage analysis resulted in a maximum LOD score of 3.1444 (P = 0.000071). Furthermore, we found that TTC30B was regulated by the Shh signaling pathway and the abnormal expression of TTC30B will affect the activation of the Shh signaling pathway in human retinal pigment epithelial cells. This study demonstrates for the first time that an IFT (intraflagellar transport) - related gene TTC30B is implicated with SPD.