Arthrogryposis, Distal, Type 5d

A number sign (#) is used with this entry because of evidence that autosomal recessive distal arthrogryposis type 5D (DA5D) is caused by homozygous or compound heterozygous mutation in the ECEL1 gene (605896) on chromosome 2q36.

Description

This autosomal recessive form of distal arthrogryposis, designated DA5D by McMillin et al. (2013), is characterized by severe camptodactyly of the hands, including adducted thumbs and wrists; mild camptodactyly of the toes; clubfoot and/or a calcaneovalgus deformity; extension contractures of the knee; unilateral ptosis or ptosis that is more severe on one side; a round-shaped face; arched eyebrows; a bulbous, upturned nose; and micrognathia. Notably, these patients do not have ophthalmoplegia.

For a general phenotypic description and discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120).

For discussion of genetic heterogeneity of distal arthrogryposis type 5, see DA5 (108145).

Clinical Features

Dieterich et al. (2013) studied 10 affected individuals from 6 families with distal arthrogryposis (DA) and mutations in the ECEL1 gene (see MOLECULAR GENETICS). All patients exhibited DA with flexion contractures of fingers 3 to 5 and limited knee flexion, while all but 1 had talus valgus deformity of the feet. Lower limbs were more extensively affected than upper limbs. None of the patients had major elbow or shoulder girdle contractures, and no pterygia were present. All but 1 case had hip involvement, consisting of congenital hip dislocation or limited mobility. Other frequent findings included short neck and lower extremity muscle atrophy; mild to severe scoliosis was a common complication, with restrictive pulmonary insufficiency in 4 patients. Three patients had hyperlaxity of distal joints in addition to distal joint contractures. Two frequent and striking features were a spared or less-involved index finger and a central tongue atrophy resulting in a grooved shape. Ptosis was noted in the majority of patients, but oculomotor function was normal, except in 1 patient with Duane syndrome (see 126800). Muscle MRI views in 6 patients showed severe fatty muscle replacement, primarily affecting the thigh and involving the biceps femoris, sartorius, and vastus lateralis muscles, with consistent sparing of the rectus femoris and gracilis muscles. Fatty replacement was also frequent in distal leg muscles and was diffuse and often asymmetric. Muscle biopsies in 4 patients showed no major structural abnormalities of the sarcolemma or signs indicative of denervation; however, type I fiber predominance, variability in fiber size, and moderate lipid storage were observed.

Patil et al. (2014) reported a 5-year-old female, born to consanguineous parents, with features of autosomal recessive distal arthrogryposis type 5D. The patient had congenital joint contractures involving upper and lower limbs with restricted movement of elbow and knee joints, bilateral pes planus, rocker-bottom feet, mild scoliosis, lumbar lordosis, and hip dislocation. In addition, she had a submucosal cleft palate, frontal upsweep of hairs, downslanting palpebral fissures, and furrowing of the tongue. Hands showed ulnar deviation of fingers, webbing, camptodactyly, and adducted thumbs. Ophthalmologic examination revealed ptosis, hyperopic astigmatic refractive error, and exotropia with a lightly pigmented fundus. Cognitive function was normal. The patient had short stature (height -3SD), pterygia, and hypoplastic labia majora. A younger brother, who died at 5 days of age of unknown cause, reportedly had joint contractures. Another brother was unaffected.

Inheritance

The transmission pattern of DA5D in the families studied by McMillin et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

In a family in which 2 sisters and their deceased brother, born of double first-cousin parents, had distal arthrogryposis and unilateral ptosis but no ophthalmoplegia, McMillin et al. (2013) performed parametric linkage analysis and whole-genome sequencing and identified a 16.7-Mb region on chromosome 2q containing 4 candidate genes.

In a consanguineous Malian family segregating autosomal recessive DA, Dieterich et al. (2013) performed homozygosity mapping and identified a locus on chromosome 2q37 with a maximum lod score of 3.1 (theta = 0). Genomewide SNP genotyping in a consanguineous Moroccan family with DA reduced the size of the locus to 5.17 Mb, based on recombination events between rs2396608 and rs6708323 (chr2:229,933,418-235,110,179; GRCh37). Combining multipoint linkage data from the 2 multiplex families confirmed the locus on 2q37 with a maximum lod score of 5.1 (theta = 0).

Molecular Genetics

By analyzing candidate genes in a critical region of 2q identified in a family with autosomal recessive distal arthrogryposis, as well as in 2 additional families with a similar recessive DA phenotype, McMillin et al. (2013) identified homozygous or compound heterozygous variants in only a single gene, ECEL1 (see, e.g., 605896.0001-605896.0002). Screening ECEL1 in 4 more families with this autosomal recessive form of DA revealed homozygous or compound heterozygous mutations in 3 families (see, e.g., 605896.0003-605896.0006). In all, ECEL1 mutations were found in 5 (70%) of 7 families with autosomal recessive DA. McMillin et al. (2013) noted that the clinical characteristics of individuals with DA caused by ECEL1 mutations were indistinguishable from those of individuals without ECEL1 mutations; screening of the highly homologous gene ECE1 (600423) in the latter patients did not reveal any pathogenic mutations. In addition, no heterozygous pathogenic ECEL1 mutations were found in 20 families with autosomal dominant AD that were tested.

Dieterich et al. (2013) analyzed the candidate gene ECEL1 in 20 families with distal arthrogryposis and identified 7 variants in homozygosity or compound heterozygosity in 6 of the families (see, e.g., 605896.0007-605896.0009).

In a 5-year-old female, born of consanguineous parents, with features of DA5D, Patil et al. (2014) identified a homozygous mutation in the ECEL1 gene (A675T; 605896.0010).