First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing...

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Primary pigmented nodular adrenocortical disease (PPNAD) is a rare endocrine disorder causing ACTH-independent Cushing syndrome.
• PPNAD is often associated with Carney complex (CNC), a genetic disorder characterized by multiple tumors.
• Germline inactivating PRKAR1A gene defects are common in CNC, and mosaicism is increasingly recognized as a factor in disease development.

Purpose of the Study:

• To investigate the genetic basis of PPNAD in a patient with ACTH-independent Cushing syndrome.
• To explore the role of PRKAR1A gene mutations and mosaicism in the development of adrenal adenomas.

Main Methods:

• A patient with ACTH-independent Cushing syndrome underwent adrenalectomy for a left adrenal adenoma.
• DNA analysis using Sanger sequencing and deep next-generation sequencing (NGS) was performed on tumor and blood/saliva samples.
• PRKAR1A gene variants were identified in the adrenal adenoma and low-level mosaicism was detected in blood and saliva.

Main Results:

• The adrenal adenoma showed two different PRKAR1A variants, c.682C>T and c.974-2A>G.
• Deep NGS revealed low-level mosaicism for the c.682C>T PRKAR1A variant in the patient's blood and saliva.
• This suggests the adenoma formed due to a combination of germline mosaicism and an adrenal-specific somatic mutation.

Conclusions:

• This is the first reported case of PPNAD and an adenoma caused by PRKAR1A mosaicism combined with a somatic mutation leading to complete gene inactivation in adrenal tissue.
• The identification of mosaicism has significant implications for genetic counseling and the need for ongoing tumor surveillance.
• Understanding mosaicism in PRKAR1A is crucial for diagnosing and managing patients with Cushing syndrome and CNC.