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Autosomal dominant hypophosphatemic rickets (ADHR) is extremely rare, to date approximately 50 cases have been reported in the literature.

Clinical manifestations depend on the age of onset (childhood, adolescence, even adulthood) and on the severity of hypophosphatemia. During childhood, the disease manifests with signs and symptoms of rickets. When the disease manifests during adolescence or adulthood, clinical findings include bone pain, muscle weakness, and pseudo fractures. Some patients are asymptomatic throughout life, some patients alternate between symptomatic and non-symptomatic.

The disease is caused by activating mutations in the FGF23 gene (12p13) encoding fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone. These mutations render FGF23 resistant to cleavage and thus cause an increase in circulating levels. Increased FGF23 levels leads to reduced renal phosphate reabsorption and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.

Diagnosis is based on clinical findings, and biochemical and X-ray examination. Biochemical findings can include significant hypophosphatemia, hyperphosphaturia (that can disappear with age), elevated circulating levels of FGF23 associated with normal serum levels of calcium, increased plasma levels of alkaline phosphatase. Radiological findings include typical signs of rickets and/or osteomalacia. Molecular genetic testing confirms the diagnosis.

Differential diagnosis includes X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome, vitamin D deficiency, and tumor-induced osteomalacia.

Transmission is autosomal dominant with incomplete penetrance.

Treatment aims at improving growth, bone or joint pain, enhancing mineralization of bones, and preventing skeletal deformities caused by rickets. It consists of daily oral administration of phosphate and calcitriol and is associated with frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum concentrations, as well as urinary calcium and creatinine. Corrective surgery of skeletal deformities may be required in some cases. Sometimes, nephrocalcinosis and hyperparathyroidism can be observed as complications of the therapy; frequent follow-up is therefore necessary. The efficacy of burosumab (an anti-FGF23 humanized antibody), a recently developed therapy that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, has not yet been evaluated in ADHR patients.

With treatment, prognosis is very good: growth is normalized and skeletal deformities can be corrected.