Epiphyseal Chondrodysplasia, Miura Type

A number sign (#) is used with this entry because of evidence that the Miura type of epiphyseal chondrodysplasia (ECDM) is caused by heterozygous mutation in the NPR2 gene (108961) on chromosome 9p13.

Clinical Features

Miura et al. (2012) described a 15-year-old boy, born to nonconsanguineous Japanese parents, with tall stature, scoliosis, long hands and feet with arachnodactyly, and markedly long and broad great toes. His height was greater than 3 SD at birth and at age 15. Bone formation and resorption markers (bone-specific alkaline phosphatase, osteocalcin, cross-linked C-terminal telopeptide of type I collagen, urinary cross-linked N-telopeptide of type I collagen) were elevated. The z score for spine was low (-3.9 corrected for his height). His mother and maternal grandmother had a similar phenotype.

Hannema et al. (2013) described a 61-year-old patient with tall stature (+5.2 SD), long fingers, mild scoliosis, and broad but not elongated great toes. He had undergone epiphysiodesis of the distal femur and proximal tibia and fibula. Echocardiogram was normal. He had mild hip dysplasia with normal bone mineral density.

Miura et al. (2014) reported a 4-generation Korean family in which 11 affected individuals had tall stature (up to greater than 3 SD), macrodactyly of the great toe, long and slender fingers and toes, and scoliosis. Echocardiogram and ophthalmologic examinations were normal. Bone formation and resorption markers were increased. All affected family members showed coxa valga deformity with dysplasia of the femora capital epiphyses; 2 family members had slipped capital femoral epiphyses. Vertebral bodies were tall and showed endplate irregularities.

Inheritance

The transmission pattern of epiphyseal chondrodysplasia in the families studied by Miura et al. (2012) and Miura et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

By screening of 4 candidate genes in a nonconsanguineous family segregating epiphyseal chondrodysplasia, Miura et al. (2012) identified a heterozygous missense mutation in the NPR2 gene (V883M; 108961.0005) that segregated with the disorder in the family. Transfection experiments in HEK293A cells showed a gain of function, with increased cGMP. Transgenic mice expressing V883M-mutant NPR2 in chondrocytes displayed a skeletal phenotype similar to that observed in the patients, with severe bone deformities, including elongation of the spine, metatarsal bones, and distal phalanges, as well as severe kyphosis.

In a patient with tall stature (+5.2 SD), long fingers, mild scoliosis, and broad but not particularly long halluces, Hannema et al. (2013) identified a heterozygous mutation in the NPR2 gene (R655C; 108961.0006). Ex vivo studies using fibroblasts from this patient as well as transfected HEK293A cells expressing mutant NPR2 showed markedly increased cGMP production, stimulated by C-type natriuretic peptide (CNP, NPPC; 600296). Coimmunoprecipitation of FLAG-tagged wildtype NPR2 and Myc-tagged mutant NPR2 confirmed a tight interaction, suggesting an activating effect.

In affected members of a 4-generation Korean kindred with tall stature, macrodactyly of the great toes, scoliosis, and coxa valga with epiphyseal dysplasia, Miura et al. (2014) identified a heterozygous missense mutation in the NPR2 gene (A488P; 108961.0007). NPR2 encodes a receptor for CNP which, upon binding with the ligand, leads to increase of intracellular cGMP. Serum NT-proCNP was not elevated in the proband. An in vitro functional assay indicated that A488P is a gain-of-function mutation. Transfection experiments with HEK293A cells showed comparable expression of both wildtype and mutated allele, but only the latter showed production of cGMP.