Growth hormone insensitivity syndrome caused by a heterozygous GHR mutation: phenotypic variability owing to moderation by nonsense-mediated decay.

OBJECTIVES: Growth hormone insensitivity syndrome (GHIS) is characterized by extreme short stature and resistance to the actions of growth hormone (GH). The heterogeneity ranges from the most severe form, known as Laron syndrome, to less severe phenotypes like idiopathic short stature and partial GH insensitivity. Here, we aimed to identify and characterize the molecular cause of severe short stature in a patient with resistance to GH treatment.

PATIENT: We describe a male patient born small for gestational age [38 weeks gestation, length 38·5 cm; -7·8 standard deviation score (SDS), weight 1350 g; -4·84 SDS]. At the age of 7 years (109·7 cm; -2·89 SD), he received GH treatment (1 mg/m(2)/day) for 1 year without any increase in height SDS, IGF-I or IGFBP-3 levels. Double-GH-dose treatment for another year did not result in any improvement in growth factor level either. The patient does not have the typical Laron craniofacial and somatic features.

RESULTS: Analysis of GHR showed a heterozygous nonsense mutation (c.703C>T; p.Arg217X). Extensive mutation screening as well as copy number variation analysis of other candidate genes in the GH-IGF-I axis excluded any additional genetic defects. Analysis of the patient's fibroblasts showed that growth hormone receptor (GHR) messenger ribonucleic acid (mRNA) expressed from the mutant allele was degraded by a mechanism called nonsense-mediated mRNA decay (NMD).

CONCLUSIONS: GHIS in this patient is because of a heterozygous nonsense mutation in GHR. Our study is the first to demonstrate that NMD is involved in the phenotypic variability of GHIS caused by GHR mutations.