IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy.

CONTEXT: Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders.

OBJECTIVE

To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy.

PATIENTS AND

METHODS

We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants.

RESULTS

We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P < 0.001). Identified IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6.

CONCLUSION

Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH.