Hypophosphatemic Rickets

The observed abnormality is decreased proximal renal tubular resorption of phosphate, resulting in renal phosphate wasting and hypophosphatemia. This defect is due to circulating factors called phosphatonins. The principle phosphatonin in hereditary hypophosphatemic rickets is fibroblast growth factor-23 (FGF-23). Decreased intestinal calcium and phosphate absorption also occurs. Deficient bone mineralization is due to low phosphate levels and osteoblast dysfunction rather than to the low calcium and elevated parathyroid hormone (PTH) levels as in calcipenic rickets ( see Vitamin D Deficiency and Dependency). Because 1,25-dihydroxyvitamin D3 levels are normal to slightly low, a defect in conversion is presumed; hypophosphatemia would normally cause elevated 1,25-dihydroxyvitamin D3 levels.

There are several forms of hypophosphatemic rickets (see table Forms of Hereditary Hypophosphatemic Rickets). A form of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is known to occur due to mutations in the proximal tubule type 2c sodium-phosphate cotransporter (NaPi2c). Defective phosphate transport and hypophosphatemia in this case result in appropriately increased 1,25-dihydroxyvitamin D3 levels, thus leading to hypercalciuria.

The disease manifests as a spectrum of abnormalities, from hypophosphatemia alone to growth retardation and short stature to severe rickets or osteomalacia. Children usually present after they begin walking, with bowing of the legs and other bone deformities, pseudofractures (ie, x-ray findings in osteomalacia that may represent areas of prior stress fractures that have been replaced by inadequately mineralized osteoid vs areas of bony erosions), bone pain, and short stature. Bony outgrowth at muscle attachments may limit motion.

Patients with HHRH may present with nephrolithiasis and/or nephrocalcinosis.

• Serum levels of calcium, phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D3, parathyroid hormone (PTH), FGF-23, and creatinine

• Urinary phosphate and creatinine levels (for calculation of the tubular reabsorption of phosphate)

• Bone x-rays

• Often genetic testing

In calcipenic rickets, hypocalcemia is present, hypophosphatemia is mild or absent, and urinary phosphate is not elevated.

Bone x-rays are typically done.

The different forms of hypophosphatemic rickets are diagnosed based on a combination of family history, clinical presentation, laboratory tests (blood and urine), and imaging tests (see table Forms of Hereditary Hypophosphatemic Rickets). Genetic testing using specific gene panels or whole exome sequencing, often in consultation with a genetic specialist, is helpful to confirm the diagnosis.

Because forms with elevated serum levels of FGF-23 are worsened by iron deficiency, complete blood count and iron tests are indicated in patients with those forms.

Family members of patients with hypophosphatemic rickets may be carriers or potentially affected. Full siblings of patients who have an autosomal recessive disorder have a 25% chance of having the disorder. Boys born to a mother with a pathogenic PHEX variant have a 50% chance of having X-linked hypophosphatemia (XLH), and all children born to a parent affected by autosomal dominant hypophosphatemic rickets (ADHR) have a 50% chance of having ADHR.

Prenatal and preimplantation genetic screening can be offered to families where a member is known to have hypophosphatemic rickets.

Forms of Hereditary Hypophosphatemic Rickets).

• Oral phosphate and calcitriol

• Burosumab for X-linked hypophosphatemia

Treatment of hypophosphatemic rickets consists of neutral phosphate solution or tablets. Starting dose in children is 10 mg/kg (based on elemental phosphorus) 4 times a day. Phosphate supplementation lowers ionized calcium concentrations and further inhibits calcitriolcalcitriol can be detrimental.

Phosphate dose may need to be increased to achieve bone growth or relieve bone pain. Diarrhea may limit oral phosphate dosage. Increase in plasma phosphate and decrease in alkaline phosphatase concentrations, healing of rickets, and improvement of growth rate occur. Hypercalcemia, hypercalciuria, and nephrocalcinosis with reduced renal function may complicate treatment. Patients undergoing treatment need frequent follow-up evaluations.

1). Dosing in children < 10 kg is started at 1 mg/kg (rounded to nearest 1 mg) subcutaneously every 2 weeks. For children 6 months to < 18 years and > 10 kg, starting dose is 0.8 mg/kg (rounded to the nearest 10 mg) subcutaneously every 2 weeks. For adults ≥ 18 years, starting dose is 1 mg/kg (rounded to the nearest 10 mg) subcutaneously every 4 weeks. The dose may be titrated upwards according to the manufacturer’s instructions to a maximum of 2 mg/kg or 90 mg as needed to normalize serum phosphate.

Iron deficiency upregulates expression of bone FGF-23 and can exacerbate conditions with high FGF-23 levels/impaired FGF cleavage. Therefore, repletion of iron is essential for patients with iron deficiency in the setting of high FGF-23 hypophosphatemic conditions.

The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.

1. Manufacturer’s instructions: Dosing, administration, and storage information for burosumab