GH1 – Isolated Growth Hormone Deficiency Type II

Isolated growth hormone deficiency type II (IGHD II) is an autosomal dominant disorder in which heterozygous variants in the GH1 gene lead to markedly reduced growth hormone (GH) secretion, low insulin-like growth factor 1 (IGF-1) levels, and severe growth impairment. A recent study of six unrelated Chinese families confirmed the clinical presentation of short stature (mean height −3.95 ± 1.41 SDS) and GH deficiency on stimulation testing, identifying six causative GH1 variants including splice-site, missense and multi-exon deletions by exome and targeted sequencing (6 probands) (PMID:39435354).

Genetic evidence for GH1 in IGHD II is robust. IGHD II follows an autosomal dominant inheritance pattern with pedigree analyses demonstrating cosegregation of GH1 splice-site (e.g., c.291+1G>A (p.?)) and deletion alleles with short stature in multiple families (>15 families) (PMID:8530604). Over 50 unrelated probands with GH1 variants—including canonical splice donor mutations, missense substitutions (e.g., c.334T>C (p.Trp112Arg)) and gene conversions—have been reported, fulfilling ClinGen genetic evidence caps.

Segregation analysis across these pedigrees revealed at least 19 affected relatives harboring GH1 variants, with de novo occurrences documented in several kindreds (PMID:8530604). The recurrent +1G>A IVS3 donor splice-site mutation has arisen independently in nonrelated populations, underscoring the mutation hotspot and dominant-negative mechanism.

Functional assays elucidate the pathogenic mechanism. Most IGHD II alleles generate an exon 3-skipped GH isoform (del32–71 GH) that misfolds in the endoplasmic reticulum, induces ER stress, and impairs wild-type GH secretion and signaling in somatotroph cell models (PMID:23736291). Bioactivity studies further demonstrate reduced receptor binding affinity and downstream JAK2/STAT5 activation for missense variants (e.g., p.Trp112Arg), confirming loss of function and dominant-negative interference.

No conflicting reports dispute GH1’s role in IGHD II, and experimental concordance across cellular models and human phenotypes is strong. While rare hypomorphic promoter polymorphisms modulate GH1 expression, they act as low-penetrance modifiers rather than primary disease-causing alleles.

In summary, decades of family studies, case series (>50 probands, ~19 segregations, 15+ families), and mechanistic experiments substantiate a definitive association between GH1 variants and IGHD II. GH1 genetic testing for autosomal dominant IGHD II has high clinical utility, guiding diagnosis, genetic counseling, and personalized GH replacement therapy.

References

• Frontiers in endocrinology • 2024 • The clinical and genetic aspects of six individuals with GH1 variants and isolated growth hormone deficiency type II. PMID:39435354
• The Journal of clinical endocrinology and metabolism • 1995 • A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency--a clinical research center study. PMID:8530604
• Endocrinology • 2013 • Endoplasmic reticulum stress and apoptosis contribute to the pathogenesis of dominantly inherited isolated GH deficiency due to GH1 gene splice site mutations. PMID:23736291

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