medwireNews: A study details the clinical characteristics of patients who have autosomal dominant short stature caused by heterozygous mutations in the aggrecan gene (ACAN).

Patients with the condition frequently have advanced bone age, and joint and back problems are common, the researchers report in The Journal of Clinical Endocrinology & Metabolism.

The team identified 19 mutations among 103 patients from 20 families. Eighteen of the 20 probands (first patient identified in each family) came to medical attention because of short stature but with normal endocrine findings. The other two probands were identified because of skeletal dysplasia observed prenatally or soon after birth.

The 19 mutations comprised 11 truncating and seven missense mutations, plus one splice site mutation, and were “widely scattered over the gene”. But all affected growth, with the height standard deviation score (SDS) of the adult participants being an average of –2.9, with a range of –5.9 to –0.9.

The average height SDS was similar for patients with truncating and missense mutations, suggesting a common mechanism underlying growth impairment, rather than mutation-specific mechanisms, say Andrew Dauber (Cincinnati Children’s Hospital Medical Center, Ohio, USA) and co-researchers.

During childhood, patients’ median height SDS was –2.0, ranging from –4.0 to –0.6, and they stopped growing at a median age of 12 years. They were mostly proportionate, but 20 of 31 children with available data had a bone age that was more than 12 months advanced, with children from six families having “markedly advanced” bone age, by 3–4 years.

This is in marked contrast to children with idiopathic short stature, who often have delayed bone age, say the researchers.

A total of 19 patients were receiving or had received growth hormone (GH) treatment. The five adults who had been treated had a height SDS of –2.5, compared with –3.0 in untreated adults, and treatment resulted in a +1.0 SDS increase over 3 years of treatment in children.

“Both of these observations suggest a modest response to GH with a magnitude similar to that seen in GH treatment of idiopathic short stature”, writes the team. “However, to rigorously assess the efficacy and safety of GH for the treatment of children with short stature due to ACAN mutations, a randomized controlled trial would be required.”

Five patients received gonadotropin-releasing hormone analogues, which halted bone age progression for 9 months and 22 months in two patients with available data.

Early-onset arthritis affected 12 of the 20 families, but there was no clear relationship with specific mutations, implying the contribution of other genetic and environmental factors. And 11 families had members with back pain and probable or confirmed intervertebral disc disease.

“This finding is consistent with aggrecan being the major proteoglycan component of the intervertebral disc and loss of aggrecan being an important pathogenic mechanism for degenerative disc disease”, says the team.

By Eleanor McDermid

J Clin Endocrinol Metab 2016; Advance online publication

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