Novel gain of function mutations of the calcium-sensing receptor in two patients with PTH-deficient hypocalcemia

Area of Science:

• Endocrinology
• Medical Genetics

Background:

• Idiopathic hypocalcemia is a rare condition characterized by low serum calcium levels without a clear cause.
• The calcium-sensing receptor (CaSR) plays a crucial role in calcium homeostasis.

Observation:

• This study investigated 15 patients diagnosed with parathyroid hormone (PTH)-deficient idiopathic hypocalcemia.
• Two patients presented with novel missense mutations in the calcium-sensing receptor (CaSR) gene.

Findings:

• Patient 1 exhibited a de novo heterozygous missense mutation (A844P) in the CaSR transmembrane domain, leading to severe neonatal hypocalcemia and seizures.
• Patient 2 carried a heterozygous missense mutation (E228G) in the CaSR extracellular domain, resulting in asymptomatic hypocalcemia.

Implications:

• These findings highlight the importance of CaSR gene mutations in the etiology of idiopathic hypocalcemia.
• Genetic testing for CaSR mutations should be considered in the diagnostic workup of idiopathic hypocalcemia, especially in the neonatal period.