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X-linked hypophosphatemia (XLH) is a hereditary renal phosphate-wasting disorder characterized by hypophosphatemia, rickets and/or osteomalacia, and diminished growth.
ORPHA:89936Classification level: Disorder
It is the most common form of hereditary hypophosphatemia with a prevalence of approximately 1/ 20,000. The disease affects both sexes equally.
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 (abscesses, cavities, abnormal enamal) are observed in children and adults. Cranial anomalies are also observed due to thickness of parietal and frontal bones. In adults, osteoarthritis of the lower limbs, mineralizing enthesopathy and osteophyte formation commonly occur and, in some rare cases, hearing loss has been observed. Muscle weakness and hypotonia are absent.
The disease is caused by various mutations in the PHEX gene (Xp22.1) and is transmitted as an X-linked dominant trait with complete penetrance, but variable expressivity. PHEX encodes an endopeptidase expressed predominantly in bone and teeth that regulates fibroblast growth factor 23 (FGF-23) synthesis through unknown mechanisms. PHEX mutations lead to increased circulating levels of FGF-23, a phosphate-regulating hormone (phosphatonin), that leads to reduced renal phosphate reabsorption and consequently abnormal bone mineralization.
Diagnosis is based on clinical and biochemical findings, and typical rickets/osteomalacia radiographic feautures (in children: fraying and cupping of metaphyseal regions; in adults: pseudofactures and enthesopathies). Biochemical findings include elevated circulating levels of FGF-23 associated with hypophosphatemia, hyperphosphaturia, normal serum levels of calcium and parathyroid hormone, increased or normal plasma levels of alkaline phosphatise, normal plasma calcidiol concentration and inappropriately normal or low serum levels of calcitriol. Phosphate excretion can be evaluated by measuring the maximum tubular reabsorption per glomerular filtration rate. Iliac bone biopsy reveals osteomalacia and hypomineralized periosteocytic lesions. Molecular genetic testing confirms the diagnosis.
Differential diagnosis includes autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), fibrous dysplasia of bones, renal Fanconi syndrome (see these terms), vitamin D deficiency and tumor-induced osteomalacia.
Management and treatment
Treatment aims at improving growth, bone or joint pain, and preventing skeletal deformities caused by rickets. Patients do not respond to vitamin D supplementation. For children, treatment consists of systematic oral administration of phosphate and calcitriol associated with frequent monitoring of height, serum calcium, alkaline phosphatase, parathyroid hormone, phosphate serum concentrations, and urinary calcium and creatinine. Calcitriol helps prevent secondary hyperparathyroidism that can be induced by phosphate administration. In adulthood, therapy is usually continued in symptomatic patients and generally aims at reducing bone pain. 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. Several forms of adjuvant therapy are being tested to prevent/reduce complications of the current therapy.
With consistent treatment, prognosis is good and skeletal deformities can be normalized, but growth rates usually remain subnormal.
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