medwireNews: Heterozygous mutations in the Indian hedgehog gene (IHH) are a potential cause of idiopathic short stature (ISS), say researchers who report that children with these mutations appear to respond well to treatment with recombinant human growth hormone (rhGH).

The researchers say their work has “extended the known phenotype of IHH defects”.

Mutations in this gene are reported to be associated with relatively severe skeletal disorders, such as acrocapitofemoral dysplasia and brachydactyly type A1, but in this study the team found mutations in patients who had ISS but no or only mild skeletal abnormalities.

Alexander Jorge (Universidade de São Paulo, Brazil) and colleagues first identified these genetic variants when conducting whole exome sequencing of 17 Brazilian families who had autosomal dominant short stature but no notable clinical or laboratory findings. Three of these families had heterozygous IHH mutations, despite lacking obvious signs of skeletal dysplasia or brachydactyly.

Eight of the 12 affected children had mildly disproportionate short stature, and 10 had delayed bone age, although two had advanced bone age. Six children had mildly abnormal findings on hand radiographs and the researchers also found some abnormalities in foot radiographs.

The team then identified another two heterozygous IHH mutations among 130 children with short stature of unknown cause and another five among a further 160 patients with short stature and mild skeletal dysplasia or brachydactyly.

This gave a total of 10 heterozygous mutations, nine of which were not previously reported; two were frameshift mutations and eight were missense variants. These rare variants were present in around 1.5% of the cohorts with short stature, compared with just 0.017% of people with normal stature.

Five of the Brazilian children from the original 17 families were trialled on rhGH. Excluding a child who entered puberty during the first year of treatment, the average gain in height standard deviation score during the first year was 0.6, with growth velocities ranging from 8.0 to 10.8 cm/year.

The researchers stress that only a comprehensive genetic analysis lead to the identification of the IHH mutations in their patients, because of the “subtle” clinical and radiological findings.

“Thus, we have expanded the phenotype associated with heterozygous IHH mutations and established a novel […] cause of growth disorder, with a preliminary good response to rhGH”, they conclude in The Journal of Clinical Endocrinology & Metabolism.

By Eleanor McDermid

J Clin Endocrinol Metab 2017; Advance online publication

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