A 2-year-old girl is being evaluated for bilateral leg pain and muscle weakness with associated growth delay. She is able to sit but unable to stand or walk without support due to pain. Physical examination shows patchy alopecia, frontal bossing, wrist widening, and lateral bowing of the tibia and fibula. Skeletal imaging reveals generalized osteopenia with cupping and fraying at the metaphyseal ends of the long bones of the upper and lower extremities. Further evaluation reveals a homozygous inactivating mutation in the gene encoding the vitamin D receptor. A serum sample would most likely show which of the following findings?

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This patient with bone pain and deformity (eg, frontal bossing, lower extremity bowing, abnormal mineralization of metaphyseal bone) has rickets. Dermal abnormalities (eg, alopecia) also are common due to keratinocyte dysfunction. The most common cause of rickets is vitamin D deficiency, but less common causes include hereditary vitamin D-resistant rickets (HVDRR), which is caused by inactivating mutations of the vitamin D receptor. Most vitamin D is stored in the form of 25-hydroxyvitamin D, which has only weak activity. In response to parathyroid hormone (PTH), it is converted to 1,25-dihydroxyvitamin D, the primary active form, by 1-alpha-hydroxylase in the kidneys. The action of 1,25-dihydroxyvitamin D is mediated by the vitamin D receptor; prominent effects include increases in intestinal calcium absorption, renal calcium and phosphate reabsorption, and bone mineralization. In patients with HVDRR, as in those with severe nutritional vitamin D deficiency, lack of vitamin D effect leads to hypocalcemia (decreased intestinal absorption); the compensatory rise in PTH causes increased bone resorption and renal calcium reabsorption to partially correct the circulating calcium deficit but causes renal phosphorus wasting as well. The high levels of PTH also induce greater 1-alpha-hydroxylase activity, leading to elevated 1,25-dihydroxyvitamin D levels. (Choice A) Catabolism of vitamin D is initiated by CYP24A1 (ie, 24-hydroxylase), which inactivates both the 25- and 1,25-hydroxylated vitamin D forms. Expression of this enzyme is induced by carbamazepine and other anticonvulsants (eg, phenytoin), increasing the risk of vitamin D deficiency. (Choice B) Patients with vitamin D-deficiency rickets, the more common type, have clinical features resembling HVDRR, including hypocalcemia and hypophosphatemia. However, 25-hydroxyvitamin D is low, reflecting reduced whole-body stores (1,25-dihydroxyvitamin D may sometimes be normal due to upregulation of PTH). (Choice D) Primary hyperparathyroidism presents with mild or moderate hypercalcemia. Serum phosphorus is low due to renal phosphate wasting, and 1,25-dihydroxyvitamin D is elevated due to increased activity of 1-alpha-hydroxylase. 25-hydroxyvitamin D levels are generally unaffected. (Choice E) Granulomatous diseases (eg, sarcoidosis, tuberculosis) can be associated with extrarenal expression of 1-alpha-hydroxylase by macrophages. This leads to increased production of 1,25-dihydroxyvitamin D, hypercalcemia, and hyperphosphatemia. Total vitamin D stores (25-hydroxyvitamin D) are generally normal. Educational objective: Lack of vitamin D effect (eg, vitamin D deficiency, vitamin D receptor mutation) causes hypocalcemia due to inadequate calcium absorption. The compensatory rise in parathyroid hormone (PTH) causes increased bone resorption, renal calcium reabsorption, and renal phosphorus wasting. PTH also induces 1-alpha-hydroxylase activity, leading to elevated 1,25-dihydroxyvitamin D levels.

A 2-Year-Old Girl Is Being Evaluated for Bilateral Leg Pain