Endocrine Abstracts

Background: Most patients consulting an endocrinologist for hypercalcemia suffer from primary hyperparathyroidism. Rarely, toxic vitamin D levels can also induce hypercalcemia while suppressing parathyroid hormone (PTH) levels. Infantile hypercalcemia can be caused by mutations in CYP24A1 (24-hydroxylase), which are inherited in an autosomal recessive manner (1). This enzyme is responsible for the inactivation of 25-OH-vitaminD (25-OHD) and 1,25(OH)₂vitaminD₃ (1,25(OH)₂D₃). A loss of function in CYP24A1 can result in toxic vitamin D levels causing hypercalcemia and hypercalciuria. Several cases have been described in which hypercalcemia due to often more mild CYP24A1 mutation has not been discovered until adult age, and these patients usually present with recurrent nephrolithiases (2–4).

Case: A 44-year old male was first referred to the outpatient endocrinology clinic in the year 2016. He had a medical history of recurrent nephrolithiasis, with a first episode occurring at the age of 22. At the age of 33, a blood work-up showed hypercalcemia (2.8 mmol/l (ref 2.1–2.65)) with normophosphatemia (1.03 mmol/l (ref 0.75–1.45)) and suppression of PTH (5 ng/l (ref 12–72)). Calciuria was increased (9.2 mmol/24h (ref <7.5 mmol/24h)). 25-OHD was in the high normal range (66.2 μg/l (ref 11–60)) and 1,25(OH)₂D₃ was normal (44.6 ng/l (ref 29–65)). Thyroid function was normal and there was no evidence of cortisol deficiency. Granulomatous and malignant diseases were excluded by negative imaging (FDG-PET, bone scintigraphy), protein electrophoresis and Mantoux test. The diagnosis was a non-PTH mediated hypercalcemia of unknown etiology. Kidney function at that time was at the lower limit of normal (serum creatinine: 1.2 mg/dl (ref 0.7–1.2)), corresponding to an eGFR (CKD-EPI) of 79 ml/min per 1.73 m². Eleven years later at the age of 44, hypercalcemia was confirmed (2.90 mmol/l), but PTH was no longer suppressed (31.6 ng/l). Neck ultrasound and parathyroid scintigraphy were normal. Choline-PET scintigraphy suggested two hotspots possibly suggestive for parathyroid adenomas. Further biochemical analysis showed elevated 25-OHD (67 μg/l), high-normal 1,25(OH)₂D₃ (65.2 ng/l), but very low levels of 24,25(OH)₂D₃ (<0.2 ng/ml), suggestive for reduced breakdown of 25-OHD and 1,25(OH)₂D₃. Genetic analysis revealed a homozygous inactivating mutation in the CYP24A1 gene (c.1186C>T (p.Arg396Trp) confirming the diagnosis of congenital 24-hydroxylase deficiency. A high phosphate diet (to lower the fractional gastrointestinal calcium absorption), bisphosphonates (to lower the calcium flux from the bone), itraconazole (P450 inhibitor) and cinacalcet (to suppress PTH and to directly increase calciuria) either failed to lower serum calcium levels or were not tolerated. Hypercalcemia persisted and kidney function deteriorated (eGFR nadir 41 ml/min per 1.73 m²). Ultrasound of the kidneys confirmed bilateral nephro-ureterolithiasis. A kidney biopsy showed extensive interstitial fibrosis, tubular atrophy and interstitial calcium-phosphate deposits (nephrocalcinosis). Given the severity of the condition and the failure of other treatment options, a subtotal parathyroidectomy was performed. Two out of four glands showed hyperplasia on pathological examination. PTH levels decreased from 48 to 12 ng/l two months after surgery, along with normalization of the serum calcium levels and calciuria (resp. 2.28 mmol/l and 3.1 mmol/24 h. 25-OHD and 1,25(OH)₂D₃ levels also diminished (resp. 53.9 μg/l and 38,3 ng/l). Kidney function partially recovered (eGFR 51 ml/min per 1.73 m²).

Discussion: In patients with recurrent episodes of nephrolithiasis at early adult age, hypercalcemia and hypercalciuria with low PTH levels, a problem of CYP24A1 inactivation needs to be ruled out. 25-OHD/24,25(OH)₂D₃ ratio should be measured, followed by confirmatory genetic analysis when the ratio is high. These patients should also carefully be monitored for kidney dysfunction, which may occur as a consequence of nephrocalcinosis. Effective treatment of this condition is however challenging. To the best of our knowledge this is the first case of patient with a CYP24A1 mutation where a subtotal parathyroidectomy resulted in normal serum calcium levels, along with an improved kidney function.

References: 1. Mutation in CYP24A1 and Idiopathic Infantile Hypercalcemia. Schlingmann KP, Kaufmann M, Weber S, Irwin A, Goos C, John U et al. NEJM 2011, 365(5): 410–21.

2. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study. Cools M, Goemaere S, Baetens D, Raes A, Desloovere A, Kaufman JM et al. Bone 2015, 81: 89–96.

3. 1,25-(OH)₂D-24 Hydroxylase (CYP24A1) Deficiency as a Cause of Nephrolithiasis. Nesterova G, Malicdan MC, Yasuda K, Sakaki T, Vilboux T, Ciccone C et al. Clin J Am Soc Nephrol 2013, 8(4): 649–57.

4. A lifetime of Hypercalcemia and Hypercalciuria, Finally Explained. Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann KP, Shapses S and Bilezikian JP. J Clin Endocrinol Metab 2014, 99(3): 708–12.