Clinical Guidance

The clinical presentation of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to craniosynostosis and/or severe lower extremity bowing. The diagnosis is typically made in the first two years of life, when lower extremity bowing becomes evident with the onset of weight-bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood. Overall, XLH significantly impairs health-related quality of life (more so than, for example, axial spondylarthritis ), posing a significant socioeconomic and psychosocial burden . Table 3. X-Linked Hypophosphatemia: Frequency of Select Features

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . Suggestive Findings X-linked hypophosphatemia (XLH) should be suspected in an individual with the following clinical, radiographic, laboratory, and family history findings. Note: XLH generally affects males and females similarly. Clinical findings in children • Clinical signs of rickets resistant to treatment with regular vitamin D • Progressive lower extremity bowing • Decrease in height velocity after the child starts ambulating • Epiphyseal swelling • Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward) • Rachitic rosary (visibly prominent costochondral joints) • Craniosynostosis and/or craniotabes (softening of the skull bone) • Dental abscesses Clinical findings in adults • Short stature, sometimes disproportionate with short legs • Joint pain, enthesopathy, and decreased joint mobility, particularly at the hips, spine (which may cause spinal stenosis), and shoulders • Insufficiency fractures • Dental abscesses • Fatigue, chronic pain, muscle atrophy, weakness , and sleep disturbances • Sensorineural hearing loss • Chiari I malformations (mostly asymptomatic in children) Radiographic findings • Rickets in growing children. Metaphyses may be widened, frayed, or cupped (most often affecting lower limbs, but any metaphysis can be involved); excessive limb bowing in adults may indicate presence of rickets during skeletal growth. • Rachitic rosary or beading of the ribs from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage • Insufficiency fractures • Looser zones or pseudofractures • Calcification of the tendons, ligaments, and joint capsules in adults • Radiographically dense bones (in contrast to nutritional, calcipenic, or vitamin D deficiency-related rickets, or osteomalacia). Diffuse osteosclerosis may be seen particularly in the axial skeleton at the late stage. Laboratory findings • Low serum phosphate concentration for age (although individuals with milder manifestations may be normophosphatemic ) • High alkaline phosphatase (ALP) for age (bone-specific ALP or total ALP in the absence of liver disease) is a biochemical indicator of rickets/osteomalacia. • Reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR). The age-related normal ranges for TmP/GFR are shown in . The tubular resorption of phosphate (TRP) must first be calculated as follows (see TmP/GFR calculator): • TRP = 1 - [(urine phosphate plasma phosphate) x (plasma creatinine urine creatinine)] In those with TRP 0.86, the TmP/GFR can be calculated directly as follows: • TmP/GFR = TRP x plasma phosphate Note: Historically, the nomogram-based method described by was used to determine the TmP/GFR. However, it may overestimate values in children . Table 1. Age-Related Normal Range of TmP/GFR

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia (XLH), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

X-Linked Hypophosphatemia: Recommended Evaluations Following Initial Diagnosis

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 8. X-Linked Hypophosphatemia: Recommended Surveillance