Key result
Dominant-negative GHR mutations in the intracellular domain cause mild growth hormone insensitivity with substantial growth failure, which improved with rhGH and rhIGF-I combination therapy in one patient.
Case Report
Heterozygous dominant-negative mutations in the intracellular domain of GHR cause mild growth hormone insensitivity and substantial growth failure, which may respond to combination rhGH and rhIGF-I therapy.
Context: Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype. Objective: To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients. Results: All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation. Conclusion: Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
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Vairamani et al. (2017) conducted a case report in Primary growth hormone insensitivity (GHI) syndrome and IGF-I deficiency. Dominant-negative GHR mutations was evaluated on Growth hormone insensitivity phenotype and in vitro protein expression. Dominant-negative GHR mutations in the intracellular domain cause mild growth hormone insensitivity with substantial growth failure, which improved with rhGH and rhIGF-I combination therapy in one patient.
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