Missense Mutation in the CASR Gene, Unexpected Diagnosis of Autosomal Dominant Hypocalcemia in a Middle Aged Woman

Introduction : Autosomal dominant hypocalcemia is a condition caused by mutations in the calcium-sensing receptor (CASR) gene.  Normally characterized by hypocalcemia with parathyroid hormone (PTH) that is inappropriately low in concentration.  Half of affected individuals have no associated health problems.  Severe manifestations often present in infancy or childhood, sometimes only during periods of illness and can be associated with: imbalances of electrolytes (hypomagnesemia or hyperphosphatemia) resulting in carpopedal spasms, paresthesia, neuromuscular irritability, seizures, nephrocalcinosis, and nephrolithiasis.

Case Description : In this report, we describe identification of a heterozygous missense mutation in the CASR Gene in an autosomal dominant pattern.  Genetic testing was carried out by a reputable source; Athena Diagnostics, via whole blood DNA sequence testing finding a substitution of c.2042A >G; p.Gln681arg.  Assessment using both SIFT and PolyPhen-2.2.2 predicted that this variant is pathogenic.  Patient's family, including 4 children, had not yet completed testing at the time of this submission.  

This condition was not discovered until patient started routine bloodwork monitoring in early adulthood which demonstrated persistently low normal calcium levels despite oral calcium therapy by her Primary Care Doctor (PCP). This continued for more than 20 years before a new PCP reviewed her yearly labs and referred her for Endocrinology evaluation.  Clinical manifestation of this condition was limited to muscle soreness or cramping in her hips down to her toes during heavy exertion, even during pregnancy and breast feeding her four children.  No cognitive impairment or extrapyramidal signs common to the condition were present in this patient despite calcifications in the globus pallidus bilaterally on CT brain without contrast.  Laboratory analysis revealed hypocalcemia to 7.1 when corrected for albumin, ionized calcium of 0.91, high normal phosphorus at 4.5, low normal magnesium at 1.8, and low normal parathyroid hormone at 25.4.  No nephrocalcinosis or nephrolithiasis was discovered.

Discussion : After 1.5 years of therapy with calcium and calciferol supplementation patient had improvement in her calcium levels to 8 when corrected for albumin with resolution of her manifesting symptoms.  No nephrocalcinosis or nephrolithiasis was ever discovered nor did the patient ever manifest neurological symptoms.

Family members of the patient are currently undergoing genetic screening for this condition.