Clinical and molecuar characterization of Brazilian patients with growth hormone gene deletions

Abstract

Genomic DNA from 23 patients with isolated growth hormone (GH) deficiency (12 males and 11 females: heights -4.9 ± 1.4 SDS) was screened for GH gene deletions by restriction endonuclease analysis of polymerase chain reaction amplification products. Three unrelated patients had typical features of severe GH deficiency and deletions (6.7 kb in two and 7.6 kb in one) of the GH gene. The two patients with 6.7-kb deletions developed growth-attenuating anti-GH antibodies whereas the patient with the 7.6-kb deletion continued to grow with GH replacement therapy. Our finding that 3/23 (~13%) Brazilian subjects had GH gene deletions agrees with previous studies of severe isolated GH deficiency subjects in other populations. Two of three subjects (67%) with deletions developed blocking antibodies despite administration of exogenous GH at low doses. Interestingly, only 1/10 of cases with affected relatives or parental consanguinity had GH-1 gene deletions. Correspondence

Type IA isolated growth hormone deficiency (IGHD) consistent with compound heterozygous deletions of 6.7 and 7.6 Kb at the GH1 gene locus

“…To date, several different length deletions within the GH-gene cluster (6.7, 7.0, 7.6, 45, double deletions) have been characterized as molecular defects in IGHD (20)(21)(22)(23)(24), with the 6.7 Kb deletion as the most frequent one (80%). These patients show severe growth retardation early in infancy (first 6 months of age), undetectable GH levels and, in most of the cases, they develop anti-GH antibodies that impair growth response to exogenous GH treatment.…”

Bases Genéticas dos Distúrbios de Crescimento

“…Os pacientes com a deficiência de GH 1A freqüentemente apresentam uma resposta transitória ao tratamento com hormônio de crescimento, seguida do desenvolvimento de altos níveis de anticorpos anti-GH, que impedem o crescimento. Acredita-se que a falta completa de GH durante o período de instalação da tolerância imunológica no feto explique o reconhecimento do GH exógeno como uma proteína estranha, desencadeando a reação imunológica (64). A alteração mais freqüentemente observada é a deleção de 6,7kb, que é facilmente rastreada através de digestão enzimática com a enzima Sma I (64,65).…”

Estudo da etiologia do hipopituitarismo congênito por sequenciamento paralelo em larga escala de um painel gênico

“…A etiologia genética do HC pode ser classificada, de acordo com o mecanismo molecular que resultou na deficiência de GH, em três grandes grupos: [5][6][7][8] . Até o momento, 15 genes foram estudados, utilizando a estratégia de gene candidato, por diversos pesquisadores do serviço (PROP1, SOX3, LHX3, LHX4, GLI2, GH1, GHRH, GHRHR, GHRS, HESX1, HES1, OTX2, FGFR1, PROKR2, NEUROD4) .…”