Isolated Growth Hormone Deficiency (GHD) in Childhood and Adolescence: Recent Advances

Abstract

The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes

“…In our 4-year follow-up cohort seven of 22 patients with hypothalamic-pituitary genetic defects progressed to MPHD (32%), predominantly those with PROP1 mutations, but also two patients with GH1 mutation. Development of MPHD in patients with GH1 mutation was not entirely unexpected as patients with IGHD and autosomal dominant heterozygous GH1 mutations have been reported to develop additional pituitary hormone deficiencies (20). Patients who developed MPHD during GH therapy were shorter at baseline and had more severe GHD than those who continued to have IGHD, reflecting the high prevalence of patients with history of intracranial tumour and known genetic defects of pituitary development in the MPHD group.…”

Análise molecular dos genes NEUROD4, FGFR1 e PROKR2 em pacientes com hipopituitarismo congênito

“…(8,9) . Deficiência Isolada do Hormônio do Crescimento -(DIGH): a deficiência isolada do hormônio do crescimento é a deficiência hipofisária mais comum, com uma incidência relatada de 1 a cada 4000-10000 nascidos vivos, e pode ter origem congênita ou adquirida (10) .…”

“…Embora teoricamente possível, ate o momento não foram relatadas mutações no GHRH (10,11) . Raramente a DIGH pode resultar de mutações nos genes HESX1, GHSR, OTX2, GLI2, SOX3 e BTK (os dois últimos de herança ligada ao X) alguns dos quais também implicados nos casos de DHHM (10,12,13) .…”

“…Embora teoricamente possível, ate o momento não foram relatadas mutações no GHRH (10,11) . Raramente a DIGH pode resultar de mutações nos genes HESX1, GHSR, OTX2, GLI2, SOX3 e BTK (os dois últimos de herança ligada ao X) alguns dos quais também implicados nos casos de DHHM (10,12,13) . Mutações nos genes que codificam proteínas responsáveis pela diferenciação hipofisária foram avaliadas em várias coortes e identificadas em aproximadamente 11% dos pacientes (9,10) .…”

“…Raramente a DIGH pode resultar de mutações nos genes HESX1, GHSR, OTX2, GLI2, SOX3 e BTK (os dois últimos de herança ligada ao X) alguns dos quais também implicados nos casos de DHHM (10,12,13) . Mutações nos genes que codificam proteínas responsáveis pela diferenciação hipofisária foram avaliadas em várias coortes e identificadas em aproximadamente 11% dos pacientes (9,10) . parece apresentar papel fundamental e específico na maturação e função dos somatotrofos (14) .…”