Autosomal dominant hypocalcemia type 1: status quo of tailored management and future perspectives

Area of Science:

• Endocrinology
• Genetics
• Pediatrics

Background:

• Infantile hypocalcemia and hypoparathyroidism can lead to severe neurological symptoms like seizures.
• Autosomal dominant hypocalcemia type 1 (ADH1) is a rare genetic disorder affecting calcium homeostasis.
• Standard treatments may be insufficient in managing ADH1 due to complex physiological factors.

Purpose of the Study:

• To investigate the genetic basis of recurrent hypocalcemia and seizures in two infant sisters.
• To identify the underlying cause of treatment resistance in ADH1.
• To explore challenges in managing ADH1 and potential therapeutic avenues.

Main Methods:

• Clinical presentation and biochemical data of two affected infants and their family were analyzed.
• Genetic testing was performed to identify mutations in relevant genes.
• Treatment responses to alfacalcidol and hydrochlorothiazide were evaluated.

Main Results:

• Both sisters presented with severe hypocalcemia, hypoparathyroidism, and recurrent seizures despite treatment.
• Nephrocalcinosis developed in both sisters despite hydrochlorothiazide therapy.
• A pathogenic variant (c.2504C>A [p.Ala835Asp]) in the calcium-sensing receptor (CASR) gene was identified in both sisters and their asymptomatic father, confirming ADH1.
• The identified CASR variant suggests a gain-of-function mutation contributing to hypocalcemia.

Conclusions:

• Genetic variants in the CASR gene are causative for autosomal dominant hypocalcemia type 1 (ADH1).
• Managing ADH1 is complex due to difficulties in stabilizing serum calcium and persistent hypercalciuria.
• Emerging therapies like calcilytics may offer new treatment strategies for ADH1.