Oral Presentation ANZBMS-MEPSA-ANZORS 2022

An unusual cause of hypercalcemia in two siblings (#53)

Lucy Collins 1 , Emma Boehm 1 2 , Catherine Luxford 3 , Roderick Clifton-Bligh 3 4 , Vivian Grill 1 2
  1. Department of Endocrinology and Diabetes, Western Health, Melbourne, Victoria
  2. University of Melbourne, Melbourne, Victoria
  3. Kolling Institute, Royal North Shore Hospital, Sydney, NSW
  4. Department of Endocrinology, Royal North Shore Hospital, Sydney, New South Wales

A 53 year old man was investigated for symptomatic hypercalcemia. His medical history included hypertrophic cardiomyopathy with previous septal myomectomy, paroxysmal atrial fibrillation, ischaemic heart disease and obstructive sleep apnoea. He denied previous nephrolithiasis and minimal trauma fractures. Corrected calcium was 3.08 mmol/L (2.15-2.65), Parathyroid hormone (PTH) 2.5 pmol/L (1.5-7.6), Phosphate 1.0 mmol/L (0.8-1.4), Creatinine 102 umol/L (45-90), 25-hydroxyvitamin D (25(OH)D) 52 nmol/L (> 50) and 1,25-dihydroxyvitamin D (1,25(OH)2D) 330 pmol/L (78-190). Urine Calcium excretion was 15.9 mmol/24h (2.0-7.5). Serum Angiotensin-Converting Enzyme (ACE) was normal, serum and urine monoclonal proteins were absent. Chest, renal imaging and whole-body bone scan were unremarkable. A parathyroid 99Tc-MIBI uptake study led to a focused left upper parathyroidectomy (180mg adenoma).   

 

Hypercalcemia, hypercalciuria with low normal PTH levels persisted post-operatively. An 18FDG-PET/CT study was negative. A repeat parathyroid 99Tc-MIBI uptake study led to a right inferior parathyroidectomy (170mg adenoma). After the second parathyroidectomy, hypercalcemia (2.86 mmol/L), hypercalciuria (8.3 mmol/24hour) persisted but PTH became undetectable (< 0.3 pmol/L) and 1,25(OH)2D was 130 pmol/L. 

 

A new presentation with PTH-independent hypercalcemia in a sibling (Case 2) signalled the underlying cause.

 

 

Case 2

 

A 62 year old woman presented with PTH-independent hypercalcemia during hospitalisation for a subarachnoid hemorrhage. Her medical history included diet-controlled T2DM, fibromyalgia, anxiety and depression. She had a distant history of nephrolithiasis and a family history of hypercalcemia in her brother (Case 1). Corrected calcium was 2.96 mmol/L (2.15-2.65), PTH 0.5 pmol/L (1.5-7.6), Phosphate 1.02 mmol/L (0.75-1.5), Creatinine 61 umol/L (40-90), 25(OH)D 76 nmol/L (> 50) and 1,25(OH)2D 179 pmol/L (50-190). Urinary calcium excretion was 10.3 mmol/24h (2.0-7.5). Serum ACE, PTH-related Protein (PTHrP), serum and urine monoclonal proteins were absent. Chest, renal imaging and whole-body bone scan were unremarkable. Bone Mineral Density (BMD) measurement showed the following: total lumbar spine (L1-L4) T score -3.6, femoral neck T score -1.8 and distal radius T score -4.1 (Hologic Horizon).

 

In the absence of available assays for 24,25-dihydroxyvitamin D (24,25(OH)2) levels, Sanger sequencing found her to be homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W) of CYP24A1(NM_000782.4).

 

Cascade testing identified the same mutation in her brother (Case 1).

 

Discussion

 

Hypervitaminosis D as a cause of hypercalcemia may be due to vitamin D intoxication, granulomatous diseases or abnormalities of vitamin D metabolism. CYP24A1 gene encodes the 24-hydroxylase enzyme responsible for the catabolism of 25(OH)D and 1,25(OH)2D (1). Loss-of-function mutations in CYP24A1 can result in elevated concentrations of 1,25(OH)2D causing hypercalcemia, hypercalciuria, low/undetectable PTH, nephrolithiasis and nephrocalcinosis in children and adults. CYP24A1 loss-of-function mutations were first reported as an underlying cause of idiopathic infantile hypercalcemia in ten paediatric patients presenting with failure to thrive, vomiting, dehydration and nephrolithiasis/nephrocalcinosis (2). Whilst the majority of documented cases in the literature are consistent with an autosomal recessive inheritance, an autosomal dominant inheritance pattern with incomplete penetrance has been postulated (3).

 

In clinical practice CYP24A1 loss-of-function mutations should be considered in patients presenting with PTH-independent hypercalcemia, hypercalciuria and 1,25(OH)2D levels in the upper normal or elevated range. Whilst in our case assays of 24,25(OH)2D were not available, calculation of the 25(OH)D:24,25(OH)2D ratio can assist in the diagnostic process. In unaffected individuals, the levels of 25(OH)D and 24,25(OH)2D are proportional, and the ratio is typically less than 25 (4, 5). However, in individuals harbouring a CYP24A1 loss-of-function mutation, 25(OH)D is elevated in comparison to 24,25(OH)2D, leading to an increased ratio, typically greater than 80 (4, 5).

 

Other isolated case reports have identified both hyperplastic parathyroid glands and discrete parathyroid adenomas in patients also harbouring CYP24A1 loss-of-function mutations. It is not clear whether there is an underlying association between these two conditions, or merely a random coincidence (6, 7).

 

Possible treatments to manage the risk of hypercalcemia in patients with CYP24A1 loss-of-function mutations include avoidance of vitamin D over-supplementation and excessive sun exposure, hydration and bisphosphonate therapy. Treatment with ketoconazole, fluconazole and rifampicin have also been described as potential therapeutic options, but their long-term efficacy and safety for this purpose requires further evaluation (3, 8). 

 

Take Home Messages

  • A loss-of-function mutation of CYP24A1 should be considered in cases of unexplained hypercalcemia with inappropriately normal or elevated 1,25(OH)2D.
  • Concurrent Primary Hyperparathyroidism and a CYP24A1 loss-of-function mutation is very rare and of unclear mechanistic association.
  • Future possible treatment options include ketoconazole, fluconazole and rifampicin.
  1. Miller WL. Genetic disorders of vitamin D biosynthesis and degradation. J Steroid Biochem Mol Biol 2017; 165(Pt A): 101–108.
  2. Schlingmann KP. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med 2011; 365(5): 410-421.
  3. Tebben PJ, Milliner DS, Horst RL et al. Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to cyp24a1mutations: Effects of ketoconazole therapy. J Clin Endocrinol Metab 2012; 97(3): 423-427.
  4. Kaufmann M, Gallagher JC, Peacock M et al. Clinical utility of simultaneous quantitation of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D by LC-MS/ms involving derivatization with DMEQ-tad. J Clin Endocrinol Metab 2014; 99(7): 2567–2574.
  5. Molin A, Baudoin R, Kaufmann M et al. CYP24A1Mutations in a Cohort of Hypercalcemic Patients: Evidence for a Recessive Trait. J Clin Endocrinol Metab 2015; 100(10): 1343-1352.
  6. David K, Khalil R, Hannon H et al. Therapy-Resistant Hypercalcemia in a Patient with Inactivating CYP24A1 Mutation and Recurrent Nephrolithiasis: Beware of Concomitant Hyperparathyroidism. Calcif Tissue Int 2020; 107(5): 524-528.
  7. Loyer C, Leroy C, Molin A et al. Hyperparathyroidism complicating CYP 24A1 mutations. Ann Endocrinol (Paris) 2016; 77(5): 615-619.
  8. Hawkes C, Li D, Hakonarson H et al. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients with CYP24A1 Mutations. J Clin Endocrinol Metab 2017; 102(5): 1440-1446.