E034

The Intersection of Genetics and Endocrinology:  Idiopathic Infantile Hypercalcemia from CYP24A1 deficiency and a Decade-long Missed Diagnosis.

L Eltayieb, F Hussain, B Bhatt, S.Mukadam, A Mota, B Bhatt, HC Wong, M Bashir, B Hossain,

M Dram, Z Khan, G Mlawa.

Barking, Havering and Redbridge University Hospitals NHS Trust, Romford, United Kingdom.

Abstract

Introduction

Hypercalcemia is commonly caused by primary hyperparathyroidism, malignancy, or medications. Idiopathic infantile hypercalcemia (IIH) is a rare autosomal recessive condition due to an inactivating mutation or deletion in the CYP24A1gene on chromosome 20, which results in loss of function of the enzyme vitamin D 24-hydroxylase, leading to impaired inactivation of active vitamin D metabolites. Although classically presenting in infancy, adult cases are increasingly recognized.

Case Presentation

We report a 72-year-old male with an 11-year of recurrent hospital admission due to persistent hypercalcemia, nephrolithiasis, and haematuria. He was referred by his GP to the endocrinology clinic for further assessment. Routine investigations repeatedly showed elevated calcium 2.89 mmol/L with suppressed/normal PTH. Ultrasound, technetium-99m sestamibi scanning, CT CAP, and PET imaging were all normal. He was referred for genetic testing which eventually confirmed a CYP24A1 mutation which reduces the activity of the vitamin D 24-hydroxylase enzyme, an enzyme responsible for vitamin D breakdown. The diagnosis of (IIH) was made. He was commenced on fluconazole 50 mg daily and cinacalcet 30 mg twice daily, resulting in normalisation of calcium levels to 2.50 mmol/L. Three first-degree relatives tested positive for the same mutation. Since treatment initiation, he has remained normocalcemic without further renal colic episodes.

Discussion

CYP24A1 mutations lead to reduced vitamin D breakdown, resulting in elevated levels of active vitamin D and persistent hypercalcemia with suppressed PTH. Although typically diagnosed in childhood, adult presentations may occur after years of unexplained hypercalcemia. Previously, a diagnosis of (IIH) was made only after exclusion of more common causes of hypercalcemia. Standard acute management follows conventional hypercalcemia treatment. Long-term therapy includes placing patients on low-calcium and vitamin D–free diets. In addition, antifungals such as fluconazole—which inhibit 1α-hydroxylase and 25-hydroxylase involved in vitamin D activation—can be used. Patients with persistent hypercalciuria and recurrent nephrolithiasis may be treated with thiazide diuretics, which reduce urinary calcium excretion.

Conclusion

Early recognition of (IIH) prevents complications including nephrolithiasis, nephrocalcinosis, and renal impairment. Genetic screening is recommended for relatives due to autosomal recessive inheritance.

This case highlights that CYP24A1-related IIH can present in adulthood after prolonged unexplained hypercalcemia. Genetic testing should be considered in patients with PTH-independent hypercalcemia and recurrent renal stones. Targeted treatment with fluconazole and cinacalcet can successfully normalise calcium levels and prevent complications.