Long-Term Outcomes, Genetics, and Pituitary Morphology in Patients with Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiencies: A Single-Centre Experience of Four Decades of Growth Hormone Replacement

Abstract

<b><i>Background:</i></b> Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. <b><i>Aims:</i></b> Using a combined retrospective and cross-sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. <b><i>Methods:</i></b> The files of 96 GH-deficient children were reviewed. In a subset of 50 patients, re-assessment in adulthood was performed, including GHRH-arginine testing, pituitary magnetic resonance imaging (MRI), and mutational screening for the growth hormone-1 gene <i>(GH1)</i> and the GHRH receptor gene <i>(GHRHR)</i> in isolated GHD (IGHD), and <i>HESX1</i>, <i>PROP1</i>, <i>POU1F1</i>, <i>LHX3</i>, <i>LHX4</i>, and <i>GLI2</i> in multiple pituitary hormone deficiency (MPHD) patients. <b><i>Results:</i></b> GH was started at a height SDS of -3.2 ± 1.4 in IGHD patients and of -4.1 ± 2.1 in MPHD patients. Relative height gain was 0.3 SDS/year, absolute gain 1.6 SDS, and 1.2/2.6 SDS in IGHD/MPHD, respectively. Mid-parental target height was reached in 77%. Initial height SDS, bone age retardation and duration of GH replacement were correlated with height SDS gain. GHD persisted into adulthood in 19 and 89% of subjects with IGHD and MPHD, respectively. In 1/42 IGHD patients a <i>GH1</i> mutation was detected; <i>PROP1</i> mutations were found in 3/7 MPHD subjects. Anterior pituitary hypoplasia, combined with posterior pituitary ectopy and pituitary stalk invisibility on MRI, was an exclusive finding in MPHD patients. <b><i>Conclusions:</i></b> GH replacement successfully corrects the growth deficit in children with GHD. While the genetic aetiology remains undefined in most cases of IGHD, <i>PROP1</i> mutations constitute a major cause for MPHD. Persistence of GHD into adulthood is related to abnormal pituitary morphology.