Calcium-Sensing Receptor Mutation Positive Hypercalcemia with Clinical Features of Primary Hyperparathyroidism

Presentation Number: MON 308
Date of Presentation: April 3rd, 2017

Shailesh Baral*1, Chaitanya Kumar Mamillapalli2, Saba Wasim Aziz3 and Michael G Jakoby IV4
1Southern Illinois University School of Medicine, Springfield, IL, 2Springfield Clinic, Springfield, IL, 3Johnson City Medical Center, Johnson City, TN, 4SIU School of Medicine, Springfield, IL


Background. Heterozygous inactivating mutations of the calcium-sensing receptor (CaSR) are the most common cause of familial hypocalciuric hypocalcemia (FHH). Patients typically have mild, asymptomatic hypercalcemia with normal to modestly elevated parathyroid hormone (PTH) level, 24 hour urine calcium < 200 mg, and a calcium/creatinine clearance ratio (CCCR) < 0.01. We present a case of familial hypercalcemia with CaSR gene mutation and phenotypic features of primary hyperparathyroidism (PHPT).

Case. A 27 year old female was referred for evaluation of persistent hypercalcemia. The patient was incidentally discovered to be hypercalcemic approximately six years before referral. Nine serum calcium measurements ranged from 10.8-11.6 mg/dL (8.5-10.4) from initial discovery of hypercalcemia through end of metabolic evaluation. PTH level on diagnosis of hypercalcemia was 27 pg/mL (12-88), and three additional measurements ranged from 37-50 pg/mL. Three measurements of 25-hydroxyvitamin D level ranged from 22-31 ng/mL. Initial 24 hour urine calcium was 132 mg, though urine creatinine was not measured to allow calculation of CCCR. The patient’s father (deceased), daughter, and a niece had been diagnosed with hypercalcemia, prompting sequencing of the CaSR gene that revealed a heterozygous sequence variant (c.2657G>C) in exon seven predicting a R886P substitution in the receptor. Another 24 hour urine collection yielded a calcium of 272 mg, and CCCR was equivocal (0.016). A DXA scan obtained before referral and following traumatic right hand fracture was notable for marginal Z-scores of the distal third of the radius (-1.7), left femoral neck (-1.9), and left total hip (-1.8). Three serum phosphate levels were low or marginal (2.3-2.6 mg/dL, 2.5-4.5). Approximately 15 months after referral, the patient experienced right nephrolithiasis. No parathyroid adenomas were identified on sestamibi parathyroid scintigraphy. Unfortunately, the patient was lost to follow up.

Conclusion. CaSR mutation positive hypercalcemia may present with biochemical and clinical manifestations that are atypical for FHH. For example, the F881L mutation has been linked to hypercalciuria and nephrolithiasis that benefitted from parathyroidectomy. The R886P mutation found in our patient maps near F881L, and the proband in the initial R886P kindred presented with an elevated PTH level, 24 hour urine calcium > 200 mg, and CCCR > 0.02. However, no PHPT phenotype was described in this kindred. PHPT may also co-occur with CaSR mutations; in a German series of 139 PHPT patients, four had co-existing features of FHH and confirmatory CaSR mutations. Case reports of concurrent FHH and PHPT have also been published, though in our patient parathyroid imaging failed to clearly identify an adenoma. This case demonstrates that familial CaSR mutation positive hypercalcemia may not have the benign course typical of FHH.


Nothing to Disclose: SB, CKM, SWA, MGJ IV