Endocrine Abstracts

We present a 67 years old male originally from Cyprus who presented with Hypercalcemia. He had renal calculi twice and required Laparoscopic procedure. In his family history his 3 siblings had confirmed raised calcium and PTH and 2 other siblings had renal calculi. One of his brother, had surgery for primary hyperparathyroidism twice but no parathyroid adenoma was found and his calcium remained high. Patients’ calcium was 2.81 mmol/l (2.15–2.50), 25 HVD 82 nmol/l (75–200), 1,25 hydroxy vitamin D was 119 pmol/l (43–143) and PTH on 2 occasions was <0.7 pmol/l (1.1–6.9). He had hypercalciuria. His parathyroid imaging was normal. His genetic test did not identify mutations in dominant HPT panel. He had Homozygous mutations in CYP24A1C.1186C>T_p.Arg396Trp. CYP24A1 is an enzyme that inactivates vitamin D. Loss-of-function mutations in this enzyme is rare but clinically, two distinct phenotypes have been recognised from this mutation: 1) Infants with CYP24A1mutations present with infantile idiopathic hypercalcaemia, often precipitated byrophylactic vitamin D supplementation. 2) A separate phenotype of nephrolithiasis, hypercalciuria and nephrocalcinosis often presents in adulthood. CYP24A1 mutation should be suspected when a classical biochemical profile of high active vitamin D metabolites, high or normal serum calcium, high urine calcium and low parathyroid hormone is detected. 65% of patients with hypercalciuric nephrolithiasis may have a positive family history with polygenic or monogenic inheritance. CYP24A1 mutation is now included as a new monogenic etiology of hypercalciuric nephrolithiasis with hypercalcemia and normal/low PTH. 25-OH-D3:24, 25-(OH)2D3 ratio greater than 50, and usually greater than 80, is indicative of inactivating CYP24A1 mutations. Restriction of vitamin D and sun protection might protect affected patients. Vitamin D supplementation can be deleterious in these patients. Ketoconazole/fluconazole, a nonspecific inhibitor of P450 enzymes can reduce 1, 25-(OH) 2D3 levels by inhibiting 1α-hydroxylase, the enzyme responsible for its production. Although CYP24A1mutations are rare, early recognition can prompt definitive diagnosis, ensure treatment and avoid parathyroidectomy. We suggest that it is clinically important to identify patients with this phenotype.

References: Schlingmann KP1, Kaufmann M, Weber S, Irwin A, Goos C et al.; Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011365(5): 410-21.

A. Molin R. Baudoin M. Kaufmann J. C. Souberbielle et al.; CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait. The Journal of Clinical Endocrinology & Metabolism, 100(10), 1 October 2015.