A Previously Unreported Mutation of the Calcium Sensing Receptor Causing Familial Hypocalciuric Hypercalcemia

Presentation Number: MON 306
Date of Presentation: April 3rd, 2017

Sonia K Hans* and Steven N Levine
Louisiana State University Health Sciences Center, Shreveport, LA


Background: Evaluation of genomic databases indicate that there are >150 different mutations of the calcium sensing receptor (CASR) gene which cause the autosomal dominant disorder familial hypocalciuric hypercalcemia type 1 (FHH1). Greater than 85% of cases are due to missense substitutions while <15% result in nonsense, deletion, insertion and splice-site mutations that lead to truncated CASR proteins.

Clinical Case: A 61 year old male with chronic hyperparathyroidism, with asymptomatic, mild hypercalcemia and chronic kidney disease (CKD) stage 4 was diagnosed with FHH1 due to a mutation of the CASR gene which has not been described in prior studies, p.Lys584Ter (K584X).

The patient was initially diagnosed with tertiary hyperparathyroidism due to CKD and treated with cinacalcet. An ultrasound of the neck revealed no enlarged parathyroid glands and a sestamibi parathyroid scan showed no adenoma. The patient was then referred to our Endocrinology clinic. He was asymptomatic, with no history of nephrolithiasis or medication which could result in hypercalcemia. Family history was significant for a brother and sister with chronic hypercalcemia and no nephrolithiasis history.

Biochemical studies included calcium 9.3 mg/dL (8.5-10.1), albumin 3.4 g/dL (3.4-5.0), corrected calcium 9.8 mg/dL, PTH 662.1 pg/mL (12.4-76.8), vitamin D 25-OH 27.6 ng/mL (30-100), creatinine 3.08 mg/dL (0.70-1.30), eGFR 25. His 24 hour urine calcium excretion measured on two separate occasions was <5 mg/24h.

Genetic analysis identified a novel heterozygous mutation of the CASR gene at coding region c.1750 A>T, variant p.Lys584Ter (K584X). The variant is predicted to cause a protein truncation which could result in pathology, however no RNA studies have yet confirmed this hypothesis. This variant has not been published as benign or pathogenic. It has not been observed in 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing project, indicating it is not common in these populations. Evaluation of the Exome Aggregation Consortium and CASR database resulted in no reports of this mutation.

Conclusion: We describe a patient with FHH1 with a newly discovered mutation of the CASR gene predicted to cause protein truncation. Most mutations are caused by missense substitutions while <15% are nonsense, deletion, insertion and splice-site mutations resulting in the FHH1 phenotype.


Nothing to Disclose: SKH, SNL