Isolated GH deficiency with dominant inheritance: new mutations, new insights

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Pediatric Growth Disorders

Background:

• Isolated growth hormone (GH) deficiency, particularly autosomal dominant forms, is often linked to mutations in the GH-1 gene.
• Understanding these mutations is crucial for diagnosing and managing growth failure in affected individuals.

Purpose of the Study:

• To investigate the genetic basis of isolated GH deficiency type II in familial and sporadic cases.
• To correlate specific GH-1 mutations with clinical phenotypes and disease severity.

Main Methods:

• Direct sequencing of PCR-amplified genomic DNA from 17 patients (16 familial, 1 sporadic).
• Ectopic transcript analysis of lymphocyte mRNA to detect splicing defects.
• Clinical data analysis, including age at diagnosis, height, body mass index, and adult final height.

Main Results:

• Identified two previously reported and one novel splice site mutation in GH-1 intron III, causing exon 3 skipping.
• Discovered a novel missense mutation (G6191 to T) in GH-1 exon 4, altering valine 110 to phenylalanine, likely affecting protein structure.
• Splice site mutations were associated with earlier onset and more severe growth failure compared to the missense mutation; phenotype variability was observed even within families.

Conclusions:

• GH-1 splice site and missense mutations are significant causes of isolated GH deficiency.
• Clinical presentation, including growth failure severity, varies depending on the mutation type.
• Genetic testing for GH-1 mutations is recommended for children with severe GH and IGF-I deficiencies and normal adenohypophysis size.