Knowledge on rare diseases and orphan drugs

To date, fewer than 15 families have been reported worldwide.

The first clinical signs appearing in childhood are broad knees and flat nasal bridge, followed in late childhood and adolescence by short 3rd and 4th metatarsals (not always present), joint pain in knees and hips and later osteoarthritis of the spine, shoulder, hips, and knees. Shortening of the metacarpals may also be present. Vertebral abnormalities include mild platyspondyly, irregular end plates, and reduced intervertebral distances. Stature is within average range. Brachydactyly is restricted to metatarsals III, IV and, more variably, V. Progressive hearing loss may be associated and typically starts in early adulthood, although subclinical hearing impairment for high frequencies may be detected in children.

The disorder is due to the R275C mutation in the geneCOL2A1 (12q13.11).

Disorder is suspected based on family history and clinical presentation, but this may be difficult to detect in early childhood. Skeletal radiographs showing platyspondyly and shortened metatarsals and metacarpals may be helpful in the diagnosis work up. Diagnosis is confirmed by genetic testing for the R275C mutation in COL2A1.

Disorders with early-onset osteoarthritis and polyarticular arthritis form the main differential diagnoses and include juvenile idiopathic osteoarthritis and mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis. Whilst COL2A1 mutations are involved in a spectrum of skeletal dysplasias, this specific disorder is typically distinguished by the absence of cleft palate, ophthalmologic pathology and short stature.

Genetic prenatal diagnosis is possible when the mutation has been previously identified in a family member.

The pattern of inheritance is autosomal dominant. The risk of transmission to offspring is 50% and there is full disease penetrance.

Treatment is symptomatic and frequently includes hip replacement (often by the age of 40), hearing aids for hearing loss, and anti-rheumatic medication for osteoarthritis. Appropriate surveillance of hearing loss and progression of osteoarthritis is required.

The disorder is associated with early-onset, progressive arthritis that is typically associated with significant joint pain and restricted mobility that can adversely impact quality of life. Early joint replacements are often recommended. Longevity does not appear to be different to that of the general population.

Last update: January 2020 - Expert reviewer(s): Dr Lindsay BURRAGE