Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family

Abstract

Proximal symphalangism (SYM1B) (OMIM 615298) is an autosomal dominant developmental disorder affecting joint fusion. It is characterized by variable fusions of the proximal interphalangeal joints of the hands, typically of the ring and little finger, with the thumb typically being spared. SYM1 is frequently associated with coalition of tarsal bones and conductive hearing loss. Molecular studies have identified two possible genetic aetiologies for this syndrome, NOG and GDF5. We herein present a British caucasian family with SYM1B caused by a mutation of the GDF5 gene. A mother and her three children presented to the orthopaedic outpatient department predominantly for feet related problems. All patients had multiple tarsal coalitions and hand involvement in the form of either brachydactyly or symphalangism of the proximal and middle phalanx of the little fingers. Genetic testing in the eldest child and his mother identified a heterozygous missense mutation in GDF5 c.1313G>T (p.R438L), thereby establishing SYM1B as the cause of the orthopaedic problems in this family. There were no mutations identified in the NOG gene. This report highlights the importance of thorough history taking, including a three generation family history, and detailed clinical examination of children with fixed planovalgus feet and other family members to detect rare skeletal dysplasia conditions causing pain and deformity, and provides details of the spectrum of problems associated with SYM1B.

Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family

“…Proximal symphalangism (SYM1; MIM# 185800) is a rare condition characterized by ankylosis of proximal interphalangeal joints (PIP, those between the first (also called proximal) and second (intermediate) phalanges) in fingers and toes, due to carpal and tarsal bone fusion [1]. In some affected individuals, fusions are concomitant with conductive hearing loss [2–5], hypermetropia [6–8], deformed facies [7], absence of digit flexion creases [1, 9], curtate metacarpals, and semideveloped distal phalanges [7, 10–12].…”

GDF5 mutation case report and a systematic review of molecular and clinical spectrum: Expanding current knowledge on genotype-phenotype correlations

“…Interestingly, some missense mutations are associated with brachydactyly in homozygous state [48,64] and mild anomalies in heterozygous state [29], putatively resulting, when combined, in a signaling decrease comparable to that of a null allele. Mutations with a gain-of-function effect have also been reported, all of them in heterozygosity, as causative of Proximal Symphalangism type 1B or Multiple Synostoses syndrome type 2 [34][35][36][37]41,65,66]. These phenotypes are also caused by mutations in NOG, the main GDF5 inhibitor [67,68].…”

Identification of an unknown frameshift variant of NOG in a Han Chinese family with proximal symphalangism

“…The typical features of SYM1 are reduced proximal interphalangeal joint space, symphalangism of the 4th and/or 5th finger [2,3]. The estimated prevalence of SYM1 is less than 1/1000000 with autosomal dominant inherited pattern [4,5]. And the first family with ankylosis of the proximal interphalangeal joints was reported and named as symphalangism in 1916 [6].…”