E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

An unusual cause of parathyroid hormone-independent hypercalcaemia and hypercalciuria (#116)

Emma Boehm 1 , Catherine Luxford 2 , Roderick Clifton-Bligh 3 , Vivian Grill 1
  1. Dept Endocrinology and Diabetes, Western Health, Melbourne, Vic
  2. Kolling Institute, Royal North Shore Hospital, Sydney, NSW
  3. Dept Endocrinology, Royal North Shore Hospital, Sydney, NSW

Case

 A 62-year-old postmenopausal woman was referred to the Metabolic Bone Disorders clinic for evaluation of hypercalcaemia noted during a recent hospitalisation for a subarachnoid haemorrhage from a posterior communicating artery aneurysm. She had a history of diet-controlled Type 2 Diabetes, fibromyalgia, anxiety and depression. The patient also had a distant history of nephrolithiasis, and no previous clinical minimal trauma fractures. She had partial dentures after unexplained teeth loss in her early adulthood. She took no regular medications.

Albumin corrected serum calcium was 2.96 mmol/L (2.15 – 2.65 mmol/L) (Albumin 37g/L), Phosphate 1.02 mmol/L (0.75 – 1.50 mmol/L), eGFR >90 mL/min, PTH 0.5 pmol/L (2.0 – 8.5 pmol/L) and 25(OH)D 76nmol/L. A 24 hour urinary calcium excretion was 10.3 mmol/24h (2.0-7.5 mmol). PTHrP was undetectable (<2 pmol/L). TSH was 1.27 mIU/L (0.50 – 4.00 mIU/L). Serum 1,25(OH)2D was 179 pmol/L (50 – 190 pmol/L). Angiotensin Converting Enzyme was 46.1 U/L (8.0 – 75.0 U/L). CT Chest was normal, as was a whole body bone scan.

Bone Mineral Density measurement showed T scores of -3.6 at L1-4, -1.8 at the Femoral Neck and -4.1 at the Distal Radius (Hologic Horizon). There were no vertebral fractures on spinal X-rays. There was no evidence of either nephrolithiasis or nephrocalcinosis on renal tract ultrasound.

A family history of hypercalcaemia in a sibling, persisting after excision of a parathyroid adenoma and unexplained despite extensive investigations came to light. The patient has one adult daughter following an uneventful pregnancy. 

In the absence of available assays for 24,25 (OH)2D levels, Sanger sequencing of CYP24A1 was performed at the Kolling Institute. Our patient was found to be homozygous for the pathogenic variant c.1186C>T, p.Arg396Trp (R396W). Cascade testing is being offered to her contactable siblings.

 

Discussion

Hypercalcaemia is a relatively common disorder most frequently attributable to either primary hyperparathyroidism or malignancy. Hypercalcemia due to a disorder of Vitamin D metabolism is less common, but neither a history of Vitamin D intoxication, nor a granulomatous disorder or a lymphoma were found in our patient, as an explanation for the relatively high 1,25(OH)D level associated with hypercalcemia and a suppressed PTH.

Inactivating mutations in the gene encoding CYP24A1 constitute a mechanism which can lead to a syndrome of hypercalcaemia, hypercalciuria and nephrolithiasis due to reduced catabolism of 1,25(OH)2D. The pathogenic nature of CYP24A1 variants was first described in 2011, wherein five different variants in either homozygous or compound heterozygous form were associated with idiopathic infantile hypercalcaemia. Vitamin D supplementation exacerbates the hypercalcemia in this condition (1).  Adult cases of CYP24A1 mutation have subsequently been described in women with hypercalcemia identified during pregnancy (2,3), or in males presenting with hypercalcaemia and complications of hypercalciuria (4-8).

We describe a rare case of CYP24A1 variant in a postmenopausal female presenting with hypercalcemia and hypercalciuria outside of pregnancy.

The R396W variant identified in our patient might be associated with a milder phenotype. This variant was described in a family of compound heterozygotes (8) and in a homozygous female with a normal serum calcium after 25 years of follow-up (3).

The impact of an inactivating CYP24A1 variant on bone is not well understood. Osteopaenia, osteoporosis and normal Bone Mineral Density have been seen in adult males with CYP24A1 variants (7,8). Animal studies of Cyp24a1-/- mice revealed defective mineralisation throughout the skeleton at birth (9). The mandible of infant mice is most severely affected, which is of interest given our patient’s history of early dental loss.

Possible treatments to manage the risk of hypercalcaemia in patients with CYP24A1 deficiency include avoidance of vitamin D over-supplementation and consideration of inhibition of CYP450 enzymes with ketoconazole (4, 8) or rifampicin (10). The long-term safety of ketoconazole and rifampicin for this purpose, however, needs to be established.

Conclusion

This case illustrates that mutation of CYP24A1 should be considered in cases of unexplained hypercalcemia associated with normal or elevated 1,25(OH)2D and kidney stones.

 

Take Home Messages

  • Consider genetic disorders of vitamin D metabolism in the differential diagnosis of hypercalcaemia in patients of all ages
  • Genetic testing is further developing our understanding of disease and should be further studied to de-label other “idiopathic” conditions

 

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  2. Arnold, N., O’Toole, V., Huynh, T., Smith, H., Luxford, C., Clifton-Bligh, R. and Eastman, C., 2019. Intractable hypercalcaemia during pregnancy and the postpartum secondary to pathogenic variants in CYP24A1. Endocrinology, Diabetes & Metabolism Case Reports, 2019.
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