Lessons from monogenic causes of growth hormone deficiency

Area of Science:

• Endocrinology
• Genetics
• Developmental Biology

Background:

• Constitutional hypopituitarism is a complex endocrine disorder.
• Pituitary development is regulated by key transcription factors.
• Understanding the genetic basis is crucial for diagnosis and management.

Purpose of the Study:

• To summarize findings from a large-scale, phenotype-based genetic screening of pituitary development genes.
• To analyze the spectrum of clinical presentations in constitutional hypopituitarism.
• To assess the diagnostic yield of genetic screening in idiopathic hypopituitarism.

Main Methods:

• Screening of 10 transcription factor genes in over 1200 patients with constitutional hypopituitarism.
• Phenotype-based genetic analysis over two decades.
• Evaluation of genotype-phenotype correlations.

Main Results:

• Genetically determined hypopituitarism can present beyond childhood.
• Phenotypes range from pure endocrine deficits to syndromic presentations with visceral malformations.
• Mutations in POU1F1 and PROP1 are associated with syndromic hypopituitarism.
• Genetic screening identifies causative gene alterations in a minority of idiopathic hypopituitarism cases.
• Functional studies have limitations in confirming pathogenicity of variants.

Conclusions:

• Phenotype-based genetic screening provides valuable insights into hypopituitarism.
• The genetic architecture of hypopituitarism is complex and heterogeneous.
• Further research is needed to improve diagnostic yield and functional assessment of genetic variants.