Phenotypic and genotypic analysis of pediatric patients with congenital isolated growth hormone deficiency resulting from biallelic variants in the GHRHR gene: a Belgian registry study.

Pathogenic variants in the growth hormone releasing hormone receptor (GHRHR) gene cause severe isolated growth hormone deficiency (IGHD). Over 82 distinct variants have been described, mostly in South and East Asia and Northern Brazil. This study characterizes the phenotypic and genotypic variability of children harboring (likely) pathogenic GHRHR variants, included in the Belgian and Luxembourg Registry for Growth Hormone Treated Children. We retrospectively reviewed clinical, biochemical, genetic and neuroimaging data from seven children with severe IGHD carrying biallelic GHRHR variants. Peak growth hormone (GH) concentrations were measured following insulin and glucagon-induced hypoglycemia. Auxological parameters at diagnosis and pituitary magnetic resonance imaging (MRI) findings were obtained from medical records. Three children of Syrian origin from two consanguineous families carried a novel likely pathogenic c.367G > T, p.(Glu123*) variant in a homozygous state. Among the four Belgian-origin patients, one was homozygous for a pathogenic c.674_677delinsGCTGTTGGCAGAAG, p.(Val225Gly*fs165) variant, while two siblings were compound heterozygous including this particular variant and an additional pathogenic c.271dupG, p.(Ala91Glyfs*13) frameshift variant. The other Belgian patient was compound heterozygous for the well described likely pathogenic c.431 T > A, p.(Leu144His) variant and a previously undescribed c.150C > A, p.(Asn50Lys) variant. IGHD was diagnosed between 7 months and 7 years. Height SDS at presentation ranged from - 4.6 to - 3.4. Peak GH levels after stimulation were markedly reduced (0.35-3.4 ng/ml), confirming severe growth hormone deficiency (GHD). No dysmorphic features were observed. Anterior pituitary hypoplasia at MRI was seen in six patients.

conclusionThis series expands the geographic spectrum of biallelic GHRHR variants causing severe IGHD. Targeted GHRHR genotyping should be considered in children with early-onset severe IGHD, particularly when anterior pituitary hypoplasia is present and dysmorphic features are absent. WHAT IS KNOWN: • Biallelic GHRHR variants cause severe congenital IGHD with early onset growth failure and markedly reduced GH/IGF-1 (Insulin-like growth factor 1) levels. WHAT IS NEW: • This first Belgian registry series broadens the phenotypic and genotypic spectrum of biallelic GHRHR variants. • Identification of a novel likely pathogenic homozygous c.367G > T, p.(Glu123*) variant in two unrelated Syrian families, suggesting a potential founder effect in the Syrian population, as this variant has not been reported elsewhere.