Variable hand and foot abnormalities in family with congenital vertical talus and CDMP-1 gene mutation

Headnote

Abstract

Isolated foot anomalies, including congenital vertical talus, were shown recently to occur in heterozygous carriers of CDMP-1 (cartilage-derived morphogenetic protein-1) gene mutations. Six families with isolated congenital vertical talus with apparent autosomal dominant inheritance were ascertained. DNA was isolated from 17 affected individuals and 24 unaffected individuals from these families and subjected to mutational analysis of the CDMP-1 gene. A missense mutation was identified ( 1312C>T) that results in an R438C substitution in the CDMP-1 active domain. This segregated with disease in one Northeren American family. Phenotypic variability in this family includes brachydactyly type C, clinodactyly, calcaneo valgus deformity, and congenital vertical talus. Metacarpophalangeal profiles (MCPPs) confirm incomplete penetrance in one family member. Hence, CDMP-1 mutations may be found in individuals with apparently isolated CVT, although careful examination of family members may reveal additional, subtle hand and foot abnormalities. However, mutations in CDMP-1 do not appear to be a frequent cause of isolated congenital vertical talus.

© 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.

Keywords: Vertical talus; CDMP-1: Hand anomalies; Foot anomalies

Introduction

Congenital vertical talus (CVT) is an uncommon primary dislocation of the talonavicular joint. This foot deformity, also known as rocker bottom flatfoot and congenital convex pes valgus, occurs most frequently in the context of a syndrome or chromosomal disorder such as aneuploidy of chromosome 13, 15 and 18. CVT has also been described in Rasmussen syndrome (external auditory canal atresia, vertical talus, and hypertelorism) [10] and in a single individual with split hand and split foot malformation associated with a deletion of chromosome 7q2I.l-q21.3 [8].

CVT also occurs as an isolated abnormality and may be inherited as an autosomal dominant condition in 1220% of patients [9,11]. Incomplete penetrance has been described in some families with variable expressivity [16], manifesting as flatfoot, cavus foot, and metatarsus adductus. Co-existence of congenital vertical talus and talipes equinovarus has only been reported once within a single family [3,11]. This family, included in that study, had two members with bilateral vertical talus and one individual with vertical talus involving the left foot and talipes equinovarus on the right.

Patients with homozygous and compound heterozygous CDMP-I (cartilage-derived morphogenetic protein-1) mutations present with severe limb abnormalities in Grebe and Hunter-Thompson forms of...