X-linked hypophosphatemia (XLH) is a rare, X-linked dominant multisystem disorder caused by PHEX gene mutations (Xp22.1), leading to elevated FGF23, renal phosphate wasting, impaired 1,25-dihydroxyvitamin D hydroxylation, and consequent rickets, osteomalacia, and dental disease. Prevalence is ~15–48 per 1 million globally, with an incidence of 1 in 20,000 reported in Japan. Symptoms begin between 1 and 2 years of age but diagnosis is typically delayed until 2–3 years due to phenotypic variability. Existing international guidelines focus on Western populations and do not adequately address APAC resource limitations (medication access, diagnostic testing, multidisciplinary expertise) or pediatric-to-adult transition of care.
A core panel of 15 pediatric and adult endocrinologists from nine APAC countries/regions (Australia, China, Hong Kong, Japan, Malaysia, Singapore, South Korea, Taiwan, Thailand) was convened. A PubMed search (January 2012–September 2021) using MeSH and free-text terms addressing 16 clinical questions yielded 2171 abstracts, narrowed to 164 full-text articles and finally 92 reports for evidence extraction. Evidence quality was appraised using GRADE criteria. Draft statements were refined at an advisory meeting (November 20, 2021) and subjected to a two-round Delphi process involving 38 XLH experts from 15 countries/regions (12 APAC, 3 EU). Consensus was defined a priori as ≥70% agreement; strength was rated as strong (>90%), moderate (70–90%), or weak (<70%). The recommendations were endorsed by 17 regional endocrine, metabolic, and bone/mineral societies.
Among 2171 records identified, 92 articles (mostly observational, <15% from APAC, predominantly Chinese) informed 16 statements across four themes: screening/diagnosis (Statements 1–3), multidisciplinary management (4–12), transition of care (13–15), and medical education/training (16). All statements achieved strong consensus after round 2 (range 92.11%–100%; Statement 12 reached 100% in round 1).
SCREENING AND DIAGNOSTIC CRITERIA INCLUDE
reduced growth velocity, short stature (33%–92% of children), lower limb deformities (genu varum/valgum in >90%), radiographic rickets (100% pre-treatment, >70% despite treatment), dental pathology (up to 100% of children; ~82% of adults), low serum phosphate (95%–100%), reduced TmP/GFR (~100%), elevated ALP (83%–100% of children >1 year), and PHEX mutations (~90%–100% of clinically diagnosed cases). Differential features distinguishing nutritional rickets, hypophosphatasia, and Fanconi syndrome are detailed.
PHARMACOLOGIC RECOMMENDATIONS
Conventional therapy comprises oral phosphate (children: 20–60 mg/kg elemental phosphorus in 4–6 daily doses; adults: 750–2000 mg in 2–4 doses) plus active vitamin D (children: calcitriol 20–40 ng/kg twice daily or alfacalcidol 30–50 ng/kg daily; adults: 0.50–0.75 μg calcitriol or 0.75–1.5 μg alfacalcidol daily). Conventional therapy adverse effects include gastrointestinal discomfort (56%), hyperparathyroidism (17%–47.5% in children; 15.6%–45% in adults), nephrocalcinosis (11.3%–68% in children; 15.6%–25% in adults), nephrolithiasis (2%–14%), and renal impairment (7.1% of children; 8%–9.5% of adults). Early initiation (<1 year) yields better height outcomes (median SDS −0.7 vs −2.0, p=0.009).
Burosumab, a fully human anti-FGF23 monoclonal antibody, is approved for XLH from age 1 year (children: 0.8 mg/kg subcutaneously every 2 weeks; adults: 1.0 mg/kg every 4 weeks). In a pediatric phase 3 RCT (N=61), burosumab outperformed conventional therapy at 64 weeks on height (mean difference 0.14, p<0.05), rickets severity score (mean difference −1.2, p<0.0001), and lower limb deformity (mean difference 1.0, p<0.0001). In an adult phase 3 RCT (N=134), 94.1% versus 7.6% achieved serum phosphate normalization at 24 weeks (p<0.001). Adverse events with possible relation occurred in 38.5%–59% of children and 64%–71.4% of adults, most commonly mild injection site reactions. Burosumab is not recommended during pregnancy/lactation; conventional therapy may be continued with monitoring at least every 3 months.
Multidisciplinary referral includes orthopedics, dentistry/endodontics, neurosurgery, physiotherapy/occupational therapy, audiology, genetics counseling, psychology, and dietetics. Monitoring schedules are stratified by age: children and adolescents reviewed every 1–3 months initially then 3-monthly; adults every 3–12 months. Telemedicine is supported where legally approved but does not replace in-person evaluation when imaging or examination is required.
Transition of care recommendations include introducing transition 2–4 years before actual transfer (typically ages 14–18 in APAC), use of validated questionnaires (TRxANSITION Index, STARx, TRAQ), transition clinics ideally co-led by pediatric and adult endocrinologists, and a comprehensive transfer letter/checklist capturing patient information, XLH history, treatment history (medical and surgical), complications, and advocacy contacts.
**Clinical Implications**
These 16 statements provide APAC-tailored guidance to reduce diagnostic delay, standardize multidisciplinary management across age groups, and ensure structured pediatric-to-adult transition of care. They highlight critical regional gaps—particularly limited burosumab access, restricted commercial availability of oral phosphate solutions, lack of validated translated transition questionnaires, and the need for XLH centers of excellence and APAC-specific registries. The recommendations emphasize that optimized XLH care requires coordinated effort among pediatric and adult endocrinologists, orthopedic surgeons, dentists, neurosurgeons, allied health professionals, genetic counselors, and patients/families to minimize lifelong disability and improve quality of life.