[Hypogonadotropic hypogonadism due to pathogenic variants in the POLR3B gene]

Area of Science:

• Genetics
• Endocrinology
• Neurology

Background:

• Congenital hypogonadotropic hypogonadism (CHH) results from impaired gonadotropin-releasing hormone (GnRH) synthesis or secretion.
• Over twenty genes are linked to CHH, with most cases involving GnRH neuron development, migration, or survival.
• Pathologies in GnRH signal action/transmission are less common causes of CHH.

Purpose of the Study:

• To describe a rare form of CHH caused by pathogenic variants in the POLR3B gene.
• To investigate the genetic basis of CHH and associated comorbid conditions.

Main Methods:

• Genetic analysis to identify pathogenic variants.
• Clinical evaluation for associated conditions.

Main Results:

• Identified a rare variant of CHH (1.1% of cases) due to POLR3B gene pathogenic variants.
• This variant is associated with hypomyelinating leukodystrophy 4H, encompassing hypomyelination and hypodontia.
• Genetic identification confirmed the cause of CHH and diagnosed comorbid conditions.

Conclusions:

• Pathogenic variants in the POLR3B gene represent a rare but significant cause of CHH.
• POLR3B-related CHH is part of a broader syndrome including hypomyelination and hypodontia.
• Genetic diagnosis is crucial for understanding CHH etiology and identifying associated disorders.