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J Clin Endocrinol Metab. 2018 Feb 1;103(2):604-614. doi: 10.1210/jc.2017-02026.

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

Author information

1
Unidade de Endocrinologia Genetica (LIM/25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
2
Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM/42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
3
Laboratorio de Imunologia, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
4
Institute of Medical and Molecular Genetics, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.
5
Centro de Investigacion Biomedica em Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
6
Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Madrid, Spain.
7
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan.
8
Unidade de Genetica Clinica, Instituto da Criança do Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
9
Centro de Pesquisa sobre o Genoma Humano e Células Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
10
Departamento de Epidemiologia da Faculdade de Saude Publica, Universidade de São Paulo, São Paulo, Brazil.

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:

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.

PMID:
29155992
DOI:
10.1210/jc.2017-02026
[Indexed for MEDLINE]

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