Familial Hypophosphatemic Rickets

Definition and Clinical Features

Familial hypophosphatemic rickets is a genetic tubulopathy in which an isolated defect of tubular phosphate reabsorption and impaired synthesis of 1,25-dihydroxycholecalciferol (1,25[OH]2D3) lead to major skeletal deformation and growth deficiency. It is inherited as an X-linked trait, in a dominant fashion. Boys have significantly more severe presentations than heterozygous girls. The incidence of familial hypophosphatemic rickets is 1/20,000 births. Hypophosphatemia develops as a result of hyperphosphaturia, which is caused by impaired degradation of fibroblast growth factor 23 (FGF23) and decreased intestinal phosphate absorption due to impaired synthesis of 1,25(OH)2D3.

Bone deformities can manifest at different ages and vary in severity, ranging from minimal to very severe. Varus alignment of the knees with an arcuate curve of the lower limbs is characteristic. The child’s gait is unstable and duck like. Adults aged >40 years may have bone pain and pathologic fractures.

Diagnosis

Persistent hypophosphatemia with hyperphosphaturia, normal serum calcium levels, usually normal or slightly elevated serum parathyroid hormone (PTH) levels, elevated serum alkaline phosphatase (ALP), usually decreased urinary calcium excretion; features of rickets or osteomalacia on bone radiography. Differential diagnosis should include other diseases with growth deficiency, bone deformities, and phosphatonin overproduction or impaired distribution: Fanconi syndrome, distal (type 1) renal tubular acidosis, vitamin D deficiency rickets, vitamin D–dependent rickets, familial hypophosphatemic rickets with hypercalciuria.

Treatment

Use inorganic phosphates dosed 1 to 3 g/d of elemental phosphorus in 4 to 6 portions and biologically active metabolites or analogues of vitamin D. Combined treatment increases phosphate and calcium absorption in the gastrointestinal tract and prevents the development of secondary hyperparathyroidism. Monitor serum and urine calcium levels during treatment to prevent hypercalcemia, hypercalciuria, nephrolithiasis, and nephrocalcinosis. Burosumab is a newly developed agent administered subcutaneously every 2 weeks at a starting dose of 0.4 mg/kg of body weight and uptitrated every 4 to 6 weeks to maintain serum phosphate levels within the low normal range.

Prognosis

Early implementation of appropriate treatment reduces the development of bone deformities and the degree of disability.