Epiphyseal Dysplasia, Multiple, 4

A number sign (#) is used with this entry because of evidence that autosomal recessive multiple epiphyseal dysplasia-4 (EDM4) is caused by homozygous mutation in the DTDST gene (SLC26A2; 606718) on chromosome 5q32.

Clinical Features

Juberg and Holt (1968) described 3 sisters and a brother with multiple epiphyseal dysplasia (MED). The parents were normal and not related. This family and some previously published families, including some with instances of parental consanguinity, led them to support recessive inheritance for one form of multiple epiphyseal dysplasia. MED with apparent recessive inheritance was also reported by Ribbing (1937), Waugh (1952), Hunt et al. (1967), and Gamboa and Lisker (1974). In some of these families, the differentiation from recessive pseudoachondroplastic spondyloepiphyseal dysplasia (177170) may not be clear. In that disorder, spinal changes may be evident mainly in radiographs taken before puberty. Maroteaux et al. (1975) suggested that the recessive form of MED may differ from the dominant in the presence of flat femoral head and lack of metaphyseal irregularities in the metacarpals and phalanges. Chondrocytes contain inclusions, probably of lysosomal origin, with granular or filamentous material.

Sheffield (1998) reviewed literature on double-layered patella, its relationship to multiple epiphyseal dysplasia, radiographic findings, and clinical implications.

Deere et al. (1995) found linkage of a dominant form of MED, which they classified as the Fairbank type, to 19q (EDM1; 132400), but failed to find linkage to chromosome 19 in a family with unaffected parents in which 3 of 7 sibs were affected. The 2 adult sibs in the latter family were examined radiographically and there appeared to be no phenotypic differences between them.

Superti-Furga et al. (1999) reported a 36-year-old man of tall-normal stature who had requested genetic counseling for a presumed dominant form of multiple epiphyseal dysplasia. Bilateral clubfoot had been surgically corrected in childhood. Lateral knee x-rays at 8 years of age showed bilateral double-layered patellae. Cleft palate, swelling of the ear pinnae, and 'hitch-hiker thumb' were absent. A homozygous mutation in the DTDST gene (R279W; 606718.0002) was found. The authors classified this phenotype as autosomal recessive multiple epiphyseal dysplasia.

Huber et al. (2001) reported 2 unrelated sibships initially thought to have isolated clubfoot. In the first sibship, dizygotic twins had respectively unilateral metatarsus varus and bilateral clubfeet. Subsequently mild epiphyseal dysplasia of the upper femurs was noted. In the second sibship, the 2 children were originally thought to have isolated clubfoot but subsequent examination of x-rays demonstrated delayed ossification of the hip epiphyses and mild flaring of the metaphyses in 1 case and brachymesophalangy and hip subluxation in the second case. A homozygous R279W mutation in the DTDST gene (606718.0002) was found in each case. Huber et al. (2001) noted the absence of double-layered patellae in these cases. The authors suggested that their patients, taken together with the patient of Superti-Furga et al. (1999), added to the view that the clinical spectrum of abnormalities caused by DTDST mutations is broader than originally believed and includes apparently isolated clubfoot.

Makitie et al. (2003) reported 3 patients from 2 families who were born to nonconsanguineous parents and developed signs of hip dysplasia in early childhood. Two had episodes of recurrent patella dislocations. Stature and the feet, ears, and palate were normal. X-rays showed dysplasia of femoral heads, mild generalized epiphyseal dysplasia, abnormal patella ossification, and normal hands and feet. A homozygous mutation in the DTDST gene (C653S; 606718.0011) was detected in each case.

Barreda-Bonis et al. (2018) reported a 14-year-old girl and her maternal grandfather with EDM4. When initially evaluated at the age of 16 months for disproportionate short stature, the girl had bilateral clubfoot, rhizomelic shortening of the extremities, and micrognathia with a high-arched palate. Her height was -3.09 SD and her arm span was severely reduced. Bone age was consistent with chronological age until puberty when it accelerated. At her most recent evaluation at age 14.8 years, her height was -1.9 SD with an advanced bone age of 16 years. Her BMI was 27. Skeletal survey at 20 months showed short, broad femoral necks with delayed ossification centers. Radii and ulna were bowed. She had deformities of both forearms and generalized flattening of the epiphyses. Acromicria was observed, with synostoses between the second and third metatarsals of both feet. She also had a double-layered patella. Her grandfather had short stature (143 cm, -5.33 SD) with shortening of his upper limbs and early joint problems, including bilateral hip pain in his twenties and a hip replacement in his forties, with a subsequent revision on the right hip at age 60. At age 70, surgical intervention of his shoulder joint for osteoarthritis was planned. His radiographic findings were similar to those seen in his granddaughter.

Molecular Genetics

Superti-Furga et al. (1999) reported a homozygous DTDST mutation (R279W; 606718.0002) in a 36-year-old man of tall-normal stature.

Huber et al. (2001) reported homozygous R279W mutations (606718.0002) in the DTDST gene in 2 unrelated sibships initially thought to have isolated clubfoot.

Czarny-Ratajczak et al. (2001) identified the homozygous R279W mutation in 2 probands with multiple epiphyseal dysplasia and multipartite patella.

Of 21 patients from 15 families with recessive multiple epiphyseal dysplasia, Ballhausen et al. (2003) identified homozygosity for the R279W mutation in 18 patients from 12 families. Three of the families were consanguineous. The main clinical findings included foot and hand deformities, joint complaints, and slightly reduced stature on average. The main radiographic findings were flat proximal femoral epiphyses, mild brachydactyly, and double layered patellae.

Makitie et al. (2003) identified a homozygous DTDST mutation (C653S; 606718.0011) in 2 unrelated sibships with early childhood-onset hip dysplasia, recurrent patella dislocation, and normal stature. Abnormal patella ossification was characteristic.

Using a targeted next-generation sequencing skeletal dysplasia panel, Barreda-Bonis et al. (2018) identified mutations in the SLC26A2 gene in a 14-year-old-girl and her maternal grandfather with EDM4. The girl was compound heterozygous for the common R279W mutation (606718.0002), inherited from her mother, and a S522F mutation (606718.0015), inherited from her father. Her grandfather was homozygous for the R279W mutation. The girl's mother was short (-3.53 SD), but was only a carrier of the R279W mutation.