ESPE Abstracts

Background: Familial growth hormone deficiency (GHD) with an autosomal dominant inheritance pattern (isolated GHD type II) due to multiple different mutations in the GH1 gene have been described.

Objective and hypotheses: Describe the clinical characteristics and mutation analysis of affected individuals in a family with growth hormone deficiency inherited in an autosomal dominant pattern.

Method: Medical record review.

Results: GHD was first identified in the female proband at 6 years 1 month, Height SDS – 3.21 with a peak stimulated GH of 4.9 ng/ml. GHD was subsequently identified in her female sibling (6 years 0 month, Ht SDS – 1.67, peak GH 2.9 ng/ml) and female maternal half-sibling (3 years 1 month, Ht SDS – 1.68, peak GH 6.6 ng/ml). The mother had previously been diagnosed with GHD at age 7 years. Due to the family history, sequencing of the GH1 gene was performed and identified a heterozygous change in the gh1 gene (c.178G>A) resulting change in the GH protein (p.Ala60Thr) in all four affected individuals. This genetic variant has not been recorded in the Broad ExAc dataset representing >60,000 children without severe childhood onset disease. This amino acid is weakly conserved. The amino acid change is not predicted to cause a significant structural change in the protein. However heterozygous mutation of the gene leading to changes in the adjacent amino acid (P59), lead to a bio-inactive GH protein that has lower GHR binding affinity and impaired Jak2-STAT5 signaling.

Conclusion: The presence of the heterozygous gh1 gene variant (c.178G>A, p.Ala60Thr) in four individuals with GHD inherited in an autosomal dominant pattern suggests this novel mutation is likely pathogenic and causes GHD. Functional studies of the mutant GH (p.Ala60Thr) are needed to confirm the negative impact of this mutation on protein function.