The packet lists PHEX, located on the X chromosome, as the single known gene, with a ClinGen validity of DEFINITIVE, and lists X-linked inheritance. GeneReviews states that XLH is inherited in an X-linked manner, that hemizygous males and heterozygous females are similarly affected, and that penetrance is 100% with no difference between males and females.

For parents of an affected male, GeneReviews states that the father will not have the disorder and will not be hemizygous for the PHEX pathogenic variant. The mother of an affected male in a family with more than one affected individual is described as an obligate heterozygote. In a simplex case, the mother may be a heterozygote or have germline mosaicism, or the affected male may have a de novo germline or postzygotic PHEX pathogenic variant.For a female proband, a PHEX pathogenic variant may be inherited from either parent or arise de novo.

The packet does not supply a diagnostic methods list or newborn screening information. GeneReviews describes XLH as suspected on the basis of clinical, radiographic, laboratory and family history findings. Clinical findings in children include rickets resistant to treatment with regular vitamin D, progressive lower extremity bowing, decreased height velocity after the start of ambulation, epiphyseal swelling, Harrison groove, rachitic rosary, craniosynostosis or craniotabes, and dental abscesses. Radiographic findings include widened, frayed or cupped metaphyses in growing children, Looser zones or pseudofractures, and radiographically dense bones, in contrast to nutritional or vitamin D deficiency-related rickets.

Laboratory findings listed by GeneReviews are low serum phosphate for age (although milder manifestations may be normophosphatemic), high alkaline phosphatase for age, and reduced tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR), with normal serum calcium and 25-hydroxyvitamin D.Its differential diagnosis distinguishes nutritional rickets, in which bone appears osteopenic and 25-hydroxyvitamin D is low in vitamin D deficiency, from XLH, in which bone is dense.

The packet lists one FDA-approved option with market status ACTIVE: Crysvita (burosumab), a BLA approved on 2018-04-17. GeneReviews describes burosumab as a recombinant human monoclonal antibody that targets fibroblast growth factor 23 (FGF23), administered subcutaneously, and reports approval by regulatory agencies including the FDA and EMA for XLH in children from age one year, adolescents and adults. In clinical trials, burosumab is reported to have improved radiographic signs of rickets, lower limb deformity and height z scores in children compared with phosphate plus active vitamin D, with a significant improvement in the six-minute walking test at 64 weeks but not at 40 weeks. In adults, compared with placebo, it is reported to have improved joint stiffness, physical function, pseudofracture healing and histologic signs of osteomalacia.

GeneReviews also describes conventional therapy consisting of oral phosphate with active vitamin D analogs such as alfacalcidol or calcitriol, noting that superiority of burosumab over this approach has been demonstrated in children, and that conventional therapy can aggravate renal phosphate wasting and urinary calcium excretion with a risk of nephrocalcinosis. It states that the goals of targeted therapy are to improve osteomalacia and rickets, improve pain, promote fracture healing, and, in children, stimulate growth and correct or prevent bone deformation.GeneReviews describes current guidelines as supporting multidisciplinary team care at tertiary referral centers with attention to the transition from pediatric to adult care. The packet also lists several orphan drug designations; designation is not approval, and one designation in the packet's orphan drug list refers to a different indication.

The packet does not supply a certified survival or life expectancy estimate. GeneReviews states that XLH significantly impairs health-related quality of life. Persistent lower extremity deformities are described as possible after insufficient pharmacologic therapy during childhood and adolescence, and some individuals are reported to have persistent bowing and torsion despite apparently adequate therapy, with surgical treatment frequently pursued for misalignment. Dental complications and enthesopathy are described as progressive with age.

The packet reports 7 clinical trial records, all counted as active. NCT06525636 is a Phase 1 first-in-human study of KK8123 in adults with XLH, sponsored by Kyowa Kirin Co., Ltd. (recruiting; start 2024-10-09, listed completion 2029-05-21). NCT03651505 is an XLH disease monitoring program sponsored by Ultragenyx Pharmaceutical Inc (active, not recruiting; start 2018-07-16). NCT03193476 is a registry for patients with XLH sponsored by Kyowa Kirin Pharmaceutical Development Ltd (recruiting; start 2017-09-12). NCT03745521 is a longitudinal observation study of X-linked hypophosphatemic rickets and osteomalacia with Asian partners, sponsored by Kyowa Kirin Co., Ltd. (active, not recruiting; start 2018-05-01). NCT06921720, sponsored by Hospices Civils de Lyon, is a phosphorus-31 spectroscopy study (phase not applicable; recruiting; start 2025-05-16). Intervention types in the trial summary are drug therapy and other interventions, with no gene therapy trials flagged. The packet's research landscape digest classifies 136 publications, with epidemiology and natural history the dominant type.