HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype

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Fang, Qing ; Benedetti, Anna Flavia Figueredo ; Ma, Qianyi ; Gregory, Louise ; Li, Jun Z. ; Dattani, Mehul ; Sadeghi-Nejad, Abdollah ; Arnhold, Ivo J. P. ; Mendonca, Berenice Bilharinho ; Camper, Sally A. ; Carvalho, Luciani R.

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL ENDOCRINOLOGY; v. 85, n. 3, p. 7-pg., 2016-09-01.

Resumo

IntroductionMutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation. Patients and ResultsWe report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH. ConclusionThese three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype. (AU)

• Processo FAPESP: 13/00073-8 - Análise molecular do gene LHX3 em pacientes portadores de deficiência isolada ou combinada de GH
• Beneficiário: Anna Flávia Figueredo Benedetti
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica