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At a glance

X-Linked Hypophosphatemia (XLH) is characterized by impaired renal phosphate reabsorption and diminished vitamin-D metabolism. In addition, intestinal calcium and phosphate absorption is also impaired.


Familial Hypophosphatemia; Hypophosphatemic Vitamin D-Resistant Rickets Type I; X-Linked Vitamin D-Resistant Rickets; Hereditary Hypophosphatemia Type I; Phosphate Diabetes.


XLH is the most common form of rickets in industrialized countries. It affects males and females in equal numbers; however, males are usually more severely affected than females. Worldwide approximately 1 in 20,000 live births suffers from the disease.

Genetic inheritance

In most cases, XLH is inherited as a dominant X-linked trait. However, autosomal dominant and recessive traits have also been reported. The X-linked defect seems to be the result of a mutation in the PHEX (X-linked phosphate regulating endopeptidase homolog) gene and has been mapped to Xp22.2-22.1. The autosomal dominant form of familial hypophosphatemia (sometimes associated with decreased glucose tolerance) seems to be caused by a mutation of gene 12p13.3.


The two pathogenetic mechanisms involved in this disorder are the failure of the proximal renal tubule to reabsorb phosphate and to convert calcidiol (25-hydroxy-cholecalciferol) to calcitriol (1,25-dihydroxy-choleclaciferol). The defect is characterized by low calcium serum levels in combination with hypophosphatemia not resulting in increased levels of calcitriol. Decreased concentration of inorganic phosphate leads to osteomalacia secondary to impaired function of osteoblasts, since mature bone formation requires the precipitation of hydroxyapatite, which has a high phosphate content.


In the absence of a family history of XLH, the diagnosis is made clinically. Abnormal bowing of the long bones is usually the first sign, but does not appear before 12 to 18 months of age. Elevated serum alkaline phosphatase levels (often the first laboratory sign), mild hypocalcemia, and moderate hypophosphatemia with significant hyperphosphaturia in the absence of severe secondary hyperparathyroidism are typical. Serum calcitriol levels are inappropriately normal. High circulating concentrations of fibroblast growth factor 23 (FGF23). In contrast to ☞Vitamin D Resistant Rickets, aminoaciduria and bicarbonaturia are not present.

Clinical aspects

The clinical signs of XLH are variable. Major symptoms of XLH include skeletal malformations, bone pain, abnormally bowed legs (see below), and generalized, but usually mild muscle weakness. Affected infants may experience failure to thrive resulting in low weight and a short, stocky stature (with an adult height of usually <165 cm). However, most often the symptoms appear at the age of 12 to 18 months and affected infants show a waddling gait, bowing of the legs with coxa vara, genua vara or genus valga (all secondary to the weight-bearing function). Dolichocephaly,☞Arnold Chiari I malformation, and sensorineural hearing loss because of malformation of the inner ear have been reported. Although serum phosphate levels are equally decreased in affected males and females, the degree of bone involvement in males is significantly more severe. Tetany, rachitic rosary, pectus deformity, and severe myopathy are usually not features found in these patients. Besides bowing of the long bones (especially of the lower extremities), radiographic features include rachitic changes such as widening, fraying, and cupping of the growth plates (particularly of the tibia, distal femur, radius, and ulna) and overall mild osteopenia. Later in life, signs of osteoarthritis in the knees and ankles are common and coarsening of the trabecular pattern (consistent with osteomalacia) in combination with Looser transformation zones can be detected and may be associated with fractures and pseudofractures (more common in adults). Dental problems such as cavities because of hypomineralization of the enamel, primary teeth abscesses, but also enlarged pulp chambers and a defect in the calcification of the dentin matrix (called intraglobular dentin) are common findings in these patients. Enthesopathy (the calcification of ligaments, tendons, joint capsules) is common after the age of 40 years and is not only often responsible for the pain, but may also limit joint mobility. Most often this affects elbows, shoulders, hips, (fusion of the sacroiliac joints) or the spine (spinal hyperostosis), where it may result in spinal canal stenosis, scoliosis, and significant disability. Successful treatment consists of oral phosphate supplements along with calcitriol (the active form of vitamin D) to avoid secondary hyperparathyroidism as a consequence of the oral phosphate load. This therapy requires a high compliance from the patient and his/her caregiver, since this means not only taking the medications every 6 hours for many years, but also frequent monitoring. However, phosphate and calcitriol treatment increases the risk of nephrocalcinosis (the risk seems to be correlated with the dose of phosphate administrated) and vitamin D toxicity. Once treatment has been established, growth acceleration and correction of the deformities (to a certain degree) have been described in many patients (with a higher response rate in female patients).

Precautions before anesthesia

Check electrolytes including calcium and phosphate preoperatively and obtain a complete cell blood count. Kidney function should at least be assessed with creatinine. Renal sonography may reveal nephrocalcinosis. Oral phosphate therapy can result in diarrhea (particularly at the beginning of the therapy), if severe, it is important to control the intravascular hydration and acid-base status. Assess spine and neck mobility (possible ankylosis ...

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