Elsevier

Growth Hormone & IGF Research

Volume 50, February 2020, Pages 23-26
Growth Hormone & IGF Research

p.R209H GH1 variant challenges short stature assessment

https://doi.org/10.1016/j.ghir.2019.11.002Get rights and content

Highlights

  • Growth hormone provocative tests have many limitations.

  • Phenotype between GHD and GHI may overlap.

  • Genetic evaluation is an additional tool towards a definitive diagnosis of GHD.

  • GH1 p.R209H variant has markedly variable clinical and biochemical consequences.

  • It is advisable to explore GH1 in short children with low IGF-I and IGFBP-3, despite normal GHPT.

Abstract

Objective: to describe the marked variability in clinical and biochemical patterns that are associated with a p.R209H GH1 missense variant in a large Argentinean pedigree, which makes the diagnosis of GHD elusive. Design: We describe a non-consanguineous pedigree composed by several individuals with short stature, including 2 pediatric patients with typical diagnosis of isolated growth hormone deficiency (IGHD) and 4 other siblings with severe short stature, low serum IGF-1 and IGFBP-3, but normal stimulated GH levels, suggesting growth hormone insensitivity (GHI) in the latter group. Results: Patients with classical IGHD phenotype carried a heterozygous variant in GH1: c.626G>A (p.R209H). Data from the extended pedigree suggested GH1 as the initial candidate gene, which showed the same pathogenic heterozygous GH1 variant in the four siblings with short stature and a biochemical pattern of GHI. Conclusions: We suggest considering GH1 sequencing in children with short stature associated to low IGF-1 and IGFBP-3 serum levels, even in the context of normal response to growth hormone provocative testing (GHPT).

Introduction

Endocrine causes of short stature include defects in the growth hormone (GH)-insulin-like growth factor (IGF) system and main discrimination must be done between growth hormone deficiency (GHD) and GH insensitivity (GHI) [1]. Patients with GHD usually present severe postnatal short stature, low IGF-I and IGF binding protein-3 (IGFBP-3) levels, subnormal response to GH provocative tests (GHPT) and typical clinical features. GHI is generally characterized by pre- and/or postnatal growth retardation, low IGF-I levels, and normal or even increased circulating GH concentrations, additional features may vary according to its pathogenesis. Nevertheless, confirming the diagnosis of GHD and GHI is a challenge since clinical and biochemical features may overlap between these entities.

GHPT are a useful biochemical tool and have been the gold standard to confirm the diagnosis of GHD. Many limitations still exist such as weak grade of evidence for the cut-off values used and poor test specificity and reproducibility [2]. With the expansion of genomics, genetic evaluation has become an additional tool in aiding the process of obtaining a definitive diagnosis [3].

Isolated GHD (IGHD) of genetic origin is mostly caused by GH1 gene pathogenic variants, and less commonly by variants in GHRH receptor (GHRHR) or Ghrelin receptor (GHSR) genes [[4], [5], [6]]. GH1 variants inherited with an autosomal dominant pattern are classified as type II IGHD. Most of them affect GH1 splicing and result in exon 3 skipping, but missense mutations have also been described, usually with a milder phenotype [5,7].

The aim of our study was to describe marked variability in clinical and biochemical pattern due to a p.R209H GH1 missense variant, previously described as p.R183H, in a large Argentinean pedigree, making the diagnosis of IGHD elusive.

Section snippets

Auxological variables

Height, weight and head circumference were measured and expressed in SDS for age and sex, according to Argentinean reference growth charts [8]. Length and height were determined using an infantometer or a wall mounted stadiometer according to age.

Hormonal studies

Serum levels of GH, IGF-I and IGFBP-3 were determined by chemiluminescent immunometric assays (Immulite 2000, Siemens Healthcare Diagnostics, Llamberis, Gwynedd, UK). GH provocative tests were performed with arginine (0.5 g/kg) and clonidine (0.100 mg/m

Results and discussion

Gene panel NGS analysis revealed a heterozygous c.626G > A transition in exon 5 of the GH1 gene in GHD patient IV.3, which was confirmed by Sanger sequencing. This variant predicts the change of an arginine for a histidine in position 209 (p.R209H). Her father was heterozygous for the GH1 p.R209H variant, and her paternal grandmother was homozygous for this variant.

Sanger sequencing revealed that GHD patient IV.2 and his mother were also heterozygous for p.R209H.

Data from the extended pedigree

Conclusion

The identification of short stature disorders requires the integration of all clinical, biochemical and radiological data and it is critical to ascertain an extended family history. The wide spectrum of clinical and biochemical presentation in individuals carrying the p.R209H GH1 variant could hinder the diagnosis of GHD, therefore misleading the genetic diagnosis approach. We suggest considering GH1 sequencing in children with short stature associated to low IGF-I and IGFBP-3 serum levels,

Funding

Funding was provided by National Institute of Health HD30428 (SAC), Agencia Nacional de Promoción Científica y Tecnológica PICT 2017-0002, PICT 2016-2913 (MIPM), Consejo Nacional de Investigaciones Científicas y Técnicas P-UE 2292016010-0131 (NS, DB, PS, AK, MGB, MGR, HJ, HD, RAR, IB).

Declaration of Competing Interest

None of the authors has conflicts of interest to disclose.

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