Family History Predicts Primary Hyperparathyroidism Regardless of Genetic Predisposition

Area of Science:

• Endocrinology
• Genetics
• Metabolic Bone Disease

Background:

• Primary hyperparathyroidism (PHPT) has a significant genetic component, yet only 10% of cases have identified genetic predispositions.
• Identifying predictors of PHPT is crucial for early diagnosis and management, especially in individuals with a family history or suspected genetic links.

Purpose of the Study:

• To determine predictors of PHPT occurrence in patients undergoing genetic assessment.
• To compare clinical and genetic findings between PHPT patients and non-PHPT individuals.
• To evaluate the impact of pathogenic variants (PVs) in PHPT-related genes on disease presentation and outcomes.

Main Methods:

• Prospective study enrolling patients assessed for PHPT or endocrine neoplasia syndromes.
• Collection and comparison of demographic, clinical, biochemical, and genetic data.
• Multivariable analysis to identify independent predictors of PHPT.

Main Results:

• 31.7% of 249 patients had PHPT; 26.1% carried PVs, notably GCM2 p.Y394S (7%) and MEN1 (4%).
• PHPT patients with a family history (FH) were younger, had higher recurrence risk, and increased osteoporotic fractures.
• MEN1 and GCM2 PV carriers showed more parathyroid glands involved; GCM2 PV carriers exhibited a wide spectrum of PHPT severity.

Conclusions:

• Family history is a robust predictor of PHPT, independent of pathogenic variant status, suggesting other genetic or epigenetic factors.
• The GCM2 p.Y394S variant is prevalent and associated with diverse clinical presentations, highlighting its significance in PHPT genetic evaluations.