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

Author(s):Show less -

Vasques, Gabriela A. ^[1] ; Funari, Mariana F. A. ^[2] ; Ferreira, Frederico M. ^[3] ; Aza-Carmona, Miriam ^{[4, 5, 6]} ; Sentchordi-Montane, Lucia ^{[4, 5]} ; Barraza-Garcia, Jimena ^{[4, 5, 6]} ; Lerario, Antonio M. ^{[7, 1]} ; Yamamoto, Guilherme L. ^{[8, 9]} ; Naslavsky, Michel S. ^[9] ; Duarte, Yeda A. O. ^[10] ; Bertola, Debora R. ^[8] ; Heath, Karen E. ^{[4, 5, 6]} ; Jorge, Alexander A. L. ^[1]

Affiliation

^[1] Univ Sao Paulo, Hosp Clin, Fac Med, Unidade Endocrinol Genet LIM 25, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Hosp Clin, Lab Hormonios & Genet Mol LIM 42, Fac Med, Unidade Endocrinol Desenvolvimento, BR-0540301 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Fac Med, Inst Coracao, Lab Imunol, BR-05403900 Sao Paulo - Brazil

^[4] Univ Autonoma Madrid, IdiPAZ, Inst Med & Mol Genet, E-28049 Madrid - Spain

^[5] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029 - Spain

^[6] Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit, Madrid 28046 - Spain

^[7] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[8] Univ Sao Paulo, Hosp Clin, Fac Med, Inst Crianca, Unidade Genet Clin, BR-05403000 Sao Paulo - Brazil

^[9] Univ Sao Paulo, Inst Biociencias, Ctr Pesquisa Genoma Humano & Celulas Tronco, BR-05508090 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Fac Saude Publ, Dept Epidemiol, BR-03178200 Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 103, n. 2, p. 604-614, FEB 2018.
• Web of Science Citations: 13

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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine
• Grantee: Berenice Bilharinho de Mendonça
• Support Opportunities: Research Projects - Thematic Grants