(4.11) Rare Calcium sensing gene mutation in Familial hypocalciuric hypercalcemia associated with Parathyroid Adenoma and Primary Hyperparathyroidism with rising PTH: Long-term Follow-up.

A 67-year-old male patient we first reported in 2018 presented with a 3-year duration of persistent hypercalcemia. He denied any symptoms from hypercalcemia, any family history of hypercalcemia kidney stones or renal failure. His laboratory evaluation showed the following results: Serum calcium 10.7- 11.5 mg/dL (nl 8.4-10.2); Ionized calcium 1.46 mmol/L (nl 1.12-1.30); Intact PTH 44-56 pg/ml (nl 8-53); 25-OH Vitamin D 62 ng/ml (nl 30-100); Phosphorus 3.5 mg/dl (nl 2.6-4.9); Alkaline Phosphatase 63 IU/L (nl 38-126); 24-hour urine calcium 25 mg/24 hours (nl 100-300). DXA scan: Osteoporosis in bilateral hips with a T score of -4.2. Technetium sestamibi scan was consistent with a right superior parathyroid adenoma, which was confirmed after right superior parathyroidectomy.

Postoperative calcium levels were persistently mildly elevated. PTH levels remained within normal limits for 47 months, then began to rise.  The calcium creatinine clearance ratio was 0.001, consistent with FHH. Genetic testing uncovered a heterozygous CaSR gene mutation c.893c >T with a rare variant p.Ala298Val.

Laboratory results 6 years after surgery showed serum calcium 9.4- 10.4 mg/dl ( nl 8.4-10.2); ionized calcium 1.38 mmol/L( nl 1.12-1.32); Intact PTH 103-200 pg/ml ( nl 8-53) and low urine calcium. Neck imaging has been negative. He required bilateral hip replacements secondary to arthritis, but otherwise remains asymptomatic and has no reported fractures or kidney stones.

Discussion :

Discussion

CaSR gene mutation c.893c >T with a rare variant p.Ala298Val has been classified as Variant of Uncertain Significance( VUS). Among at least reported 21 cases of FHH1 and parathyroid adenoma or abnormality, 4 cases (including ours) carry the p.Ala298Val protein variant.  The persistent increase in PTH over the past 2 years in our patient raises a controversial question of whether the reduced CaSR expression or function may lead to parathyroid cell proliferation.

Conclusion

The CaSR gene mutation c.893c >T with the variant p.Ala298Val could be classified as a likely pathogenic mutation in FHH1 based on our patient’s progressive PTH rise. This requires continued monitoring for parathyroid lesions and efforts to screen family members for this mutation and parathyroid disease.