Endocrine Abstracts (2008) 17 P34

Hereditary vitamin D resistant rickets (HVDRR), diagnostic and therapeutic challenges

K Ali1, J Allgrove2 & F Ryan1

1Children’s Hospital, Oxford, UK; 2Barts and the London NHS Trust, London, UK.

Case history: A 2 year old Pakistani boy born of consanguineous parents was referred for a dermatological opinion as he had total alopecia. He was born with a full crop of hair, which was shaved at 7 days of age as per religious custom and had not grown back. His motor milestones were delayed such that he started crawling at 14 months and was unable to walk independently. His weight was on the 0.4th centile and his height (72 cm) was far below the 0.4th centile. His anterior fontanelle was open and his wrists were swollen.

Investigations: Bone profile was consistent with rickets: Corrected calcium 1.34 mmol/l (2.12–2.62); phosphate 1.32 mmol/l (1.0–2.0); alkaline phosphatase 2829 IU/l (200–1100); parathyroid hormone (PTH) 56.1 pmol/l (1.3–7.6); 25OHD 13.9 nmol/l (deficiency <50 nmol/l) and 1,25(OH)2D >550 pmol/l (43–144). DNA analysis revealed a homozygous splice acceptor mutation in intron 2 of the vitamin D receptor, confirming HVDRR.

Treatment: Alfacalcidol and calcium supplements were commenced. Biochemistry remained unchanged after 7 months (corrected calcium 1.43 mmol/l, phosphate 1.62 mmol/l, alkaline phosphatase 2954 IU/l, PTH 51.9 pmol/l) despite increasing oral treatment to 8 mcg/d of alfacalcidol and >8 mmol/kg per day of calcium. In view of his poor response to oral treatment he was commenced on intravenous (IV) calcium infusions. Ten days after starting IV calcium and magnesium, total (ionised) calcium have risen from 1.39 (0.82) to 2.39 (1.37) mmol/l and PTH and alkaline phosphatase are falling.

Comment: Rickets in association with alopecia is suggestive of HVDRR. His significantly elevated 1,25(OH)2 vitamin D supports this diagnosis. His low 25OH vitamin D levels could be secondary to co-existent nutritional vitamin D deficiency. HVDRR is a very rare form of rickets with fewer than 50 known affected kindreds. It is associated with end organ resistance to 1,25(OH)2D, usually caused by mutations in the gene encoding the vitamin D receptor. Alopecia is present in about two-thirds of cases and is due to lack of vitamin D receptor action within keratinocytes. It is a marker of disease severity, usually associated with a ligand-binding defect. The individual response to oral treatment is difficult to predict because the severity of the receptor defect varies among patients. Long term infusion of calcium into a central vein becomes necessary if there is a poor response to oral therapy.

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