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It is the most common form of hereditary hypophosphatemia with a prevalence of approximately 1/47,000 worldwide. The disease affects both sexes equally.

X-linked hypophosphatemia (XLH) manifests during childhood with typical clinical features of rickets such as short stature, bone pain, and skeletal deformities (bowed legs, genu varum, rachitic rosary...). Dental abnormalities (recurrent abscesses, abnormal enamel) are observed in children and adults. Cranial anomalies are also observed due to thickness of parietal and frontal bones and craniosynostosis. In adults, musculoskeletal symptoms are the main feature of the disease with a heavy burden on the patient's quality of life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathy, and muscle weakness.

The disease is caused by various variants in the PHEX gene (Xp22.1) which encodes an endopeptidase expressed predominantly in bone and teeth. Although the mechanism is unknown, the PHEX variants lead to increased circulating levels of FGF-23, a phosphate-regulating hormone. Through its action on sodium-phosphate cotransporter genes in the proximal renal tubule, as well as CYP271B and CYP24A1, increased FGF-23 ultimately results in reduced renal phosphate reabsorption, and decreased intestinal phosphate and calcium absorption, consequently leading to abnormal bone mineralization.

Diagnosis is based on clinical and biochemical findings, and typical rickets/osteomalacia radiographic features. Biochemical findings include elevated circulating levels of FGF-23 associated with hypophosphatemia, hyperphosphaturia, normal serum levels of calcium, increased or normal plasma levels of parathyroid hormone, and increased levels of alkaline phosphatase. Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate. Molecular genetic testing confirms the diagnosis.

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

XLH is transmitted as an X-linked dominant trait with complete penetrance, but variable expressivity. Genetic counseling should be recommended to affected patients.

Multidisciplinary care by experts in the field of XLH is recommended. Current conventional treatment consists of active vitamin D analogs and phosphate supplementation which respectively enhances digestive absorption of phosphate and compensates renal phosphate wasting. This treatment can be effective in treating rickets and osteomalacia and their associated symptoms, as well as improve dental mineralization; however, it does not correct renal phosphate wasting. Potential complications include hyperparathyroidism and/or nephrocalcinosis. In adults, the benefit of continuing conventional treatment remains debated. Burosumab, an anti-FGF23 humanized antibody approved in Europe and the USA, is an alternative treatment to the conventional treatment that lowers circulating FGF-23 levels and thus corrects renal phosphate wasting, rickets and osteomalacia. Management also includes regular dental and orthodontic care in all patients, neurosurgery in certain cases, possible orthopedic interventions, hearing aids, physiotherapy and nutritional follow-up.

With optimal treatment and multidisciplinary care initiated early in life, prognosis can be good. Skeletal deformities can be avoided or corrected by medical treatment and if necessary corrective orthopedic surgery (preferably at the end of growth). Final height remains compromised. In adults who did not receive optimal care, chronic musculoskeletal symptoms lead to physical disabilities and impaired quality of life.

Last update: August 2022 - Expert reviewer(s): Pr Agnès LINGLART | Endo-ERN* - Dr Anya ROTHENBUHLER | Endo-ERN*

* European Reference Network