p.R209H GH1 variant challenges short stature assessment
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.
References (19)
- et al.
Predicting growth in response to growth hormone treatment
Growth Hormon. IGF Res.
(2009) - et al.
Short stature in childhood — challenges and choices
N. Engl. J. Med.
(2013) - et al.
Guidelines for growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency
Horm. Res. Paediatr.
(2016) - et al.
Genetic evaluation of short stature
J. Clin. Endocrinol. Metab.
(2014) Genetics of growth hormone deficiency
Endocrinol. Metab. Clin. N. Am.
(2007)- et al.
Isolated growth hormone deficiency (GHD) in childhood and adolescence: recent advances
Endocr. Rev.
(2014) - et al.
Presence of GH1 and absence of GHRHR gene mutations in a large cohort of Argentinian patients with severe short stature and isolated GH deficiency
Clin. Endocrinol.
(2013) - et al.
Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene
J. Clin. Endocrinol. Metab.
(2007) - et al.
Growth references for weight and height for Argentinian girls and boys from birth to maturity: incorporation of data from the World Health Organisation from birth to 2 years and calculation of new percentiles and LMS values
Arch. Argent. Pediatr.
(2009)
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