IHH gene mutations causing short stature with nonspecific skeletal abnormalities and response to growth hormone therapy

Abstract

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:Westudied 17 familieswith autosomal-dominant short stature by using whole exome sequencing and screened IHHdefects 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 IHHvariants 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 staturewith a frequent finding of shortening of themiddle phalanx of the fifth finger. None of themhave classic features of brachydactyly type A1, whichwas previously associated with IHHmutations. Five patients heterozygous for IHHvariants had a goodresponse to rhGHtherapy. Themeanchange in height standard deviation score in 1 yearwas 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.