Genetic variations, clinical presentation and treatment outcome of isolated growth hormone deficiency type I and II: case series and review of the literature.

Abstract

To report a case series of four patients with isolated growth hormone deficiency (IGHD) type I from two Chinese pedigrees and to elucidate phenotype-genotype correlation of IGHD type I and II with GH1 gene alterations in the literature. Whole exome sequencing (WES) was performed and a literature review was conducted. Four patients presented with extreme growth retardation (height -4.74 to -6.50 SDS) and undetectable peak growth hormone (GH) during GH stimulating test. WES revealed a novel homozygous nonsense mutation, c.316delC (p.L106Cfs*35), in GH1 gene in the the first pedigree. Deletions of exon 1-5 in GH1 gene were identified in the second pedigree. Ideal catch-up growth after GH treatment was achieved. 94 patients with IGHD type I and 240 patients with IGHD type II were included in literature review. Patients with IGHD type I exhibited younger age (3.2 vs 6.0 years, P < 0.001), more severe growth retardation (median height -6.50 vs -3.84 SDS, P < 0.001), lower peak GH levels (0.05 vs 1.70 ng/ml, P < 0.001) and a higher dosage of GH (0.22 vs 0.17 mg/kg/week, P = 0.012) compared to patients with IGHD type II. Gross deletions constituted 72.3% of IGHD type I cases, while splicing mutations and missense mutations comprised 54.2% and 45.0% of IGHD type II cases. In patients with IGHD type I harboring gross deletion, an early age of diagnosis correlated with both a higher height SDS at diagnosis and a better response after GH treatment. Height SDS after GH treatment in patients with IGHD type II carrying splicing mutations was negatively correlated with age at diagnosis. We identified two GH1 gene mutations, c.316delC (p.L106Cfs*35) and deletions of exon 1-5 in four Chinese patients with IGHD type I. They had a good response to GH treatment and gained satisfactory height improvement. Early diagnosis and initiating treatment may lead to a better prognosis.