XLH Point-Of-Care Resource: Diagnosis & Treatment

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XLH Point-of-Care Resource: Diagnosis & Treatment Overview X-linked hypophosphatemia (XLH) is a disease caused by inactivating mutations in the PHEX gene, which functions to regulate phosphate reabsorption. It is inherited in an X-linked dominant manner and is the most prevalent form of heritable rickets, estimated to occur in 1/20,000 live births.

Table 1: Clinical Features of XLH

Children and Adolescents Adults Evidence of rickets: wide-based gate, coxa vara, Osteomalacia: defective mineralization, fractures/ genu varum pseudofractures, bone pain Growth retardation Enthesopathy Dental abnormalities Degenerative osteoarthropathy Craniosynostosis and/or intracranial hypertension Spinal stenosis Hearing loss, tinnitus, vertigo Dental abscesses

Differential Diagnosis of Adult XLH

Rheumatologic/ Hereditary Disease Other Medical Conditions Orthopedic

• Autosomal dominant • Osteoporosis, osteopenia • Hypophosphatasia, renal hypophosphatemic rickets (ADHR) • Ankylosing spondylitis insufficiency, liver disease, primary, • Autosomal recessive • Rheumatoid arthritis hypoparathyroidism hypophosphatemic rickets (ARHR) • Osteoarthritis • Renal Fanconi syndrome • Hereditary hypophosphatemic • Systemic lupus erthematosus • Vitamin D deficiency rickets with hypercalciurua • Diffuse idiopathic skeletal (HHRH) hyperostosis • Skeletal dysplasia • Blount disease • Fibrous dysplasia of bones • Tumor-induced osteomalacia (TIO)

Measure: Age-Specific Phosphate Reference Mean Upper 97.5% Lower 2.5% Serum: fasting phosphate, calcium, alkaline 7.0 phosphatase, parathyroid hormone (PTH), 25(OH) vitamin D, 1,25(OH)2 vitamin D, and 6.0 creatinine 5.0 Urine: calcium, creatininecalculate the tubular maximum reabsorption of phosphate per 4.0 glomerular filtration rate (TmP/GFR) 3.0

Serum fibroblast growth factor 23 (FGF23) Serum Phos (mg/dL) 2.0 0 5 10 15 20 Diagnostic Assessment of XLH Diagnostic confirmation of XLH by genetic analysis of the PHEX gene Age (Years)

© 2021 PRIME Education, LLC. All Rights Reserved. www.primeinc.org X-Linked Hypophosphatemia (XLH) Point-of-Care Resource: Conventional Therapy Overview Early treatment in children promotes growth, reduces bone pain, progressively corrects leg deformities, and improves dental health. In symptomatic adults, therapy reduces osteomalacia and improves oral health.

Symptomatic Treatment Treatment Monitoring Nephrocalcinosisdecrease or Combination therapy (children): discontinue phosphate and/or calcitriol 3 Phosphorus: 20-60 mg/kg Serum and urinary calcium; serum phosphate – divided in 4-6 doses daily Hypercalcemia/ 3 Calcitriol: 20-30 ng/kg hypercalciuriadiscontinue – divided in 2 doses daily 25-OHD

Combination therapy (Adults)*: Decrease phosphate and/or 3 Phosphorus: 20-40 mg/kg increase calcitriol Increased PTH – divided in 4-6 doses daily 3 Calcitriol: 20-40 ng/kg Ensure adequate dietary Ca2+ – divided in 2 doses daily Renal ultrasound *DO NOT treat to serum phosphorous levels, treat to Bow defects, torsion, epiphyseal X-ray

Conventional Medical Therapy symptoms Skeletal outcomes

Alkaline phosphatase: balance phosphate and/or calcitriol Dental examinations/TX

Burosumab Overview Disease-modifying therapy indicated for XLH in adult and pediatric patients 6 months of age and older. Burosumab is a human monoclonal antibody that binds to and inhibits excess circulating levels of fibroblast growth factor 23 (FGF23), restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.

Disease-Modifying Treatment Treatment Monitoring:

Children and Adolescents: 3 Fasting serum phosphate levels and TmP/GFR • Radiographic evidence of overt bone disease – Titration period: 7–11 days after last injection to and refractory or inability to adhere to detect hyperphosphataemia conventional therapy – Every 4 weeks during the following 3 months and 3 Burosumab: 0.8mg/kg SC Q2W thereafter as appropriate – Titrate every four weeks to raise fasting serum – Once stable, assess directly before injections to phosphate levels within age-specific reference detect under dosing range (maximum dose of 90 mg) Exclusion Criteria: Adults: x Baseline phosphate levels within normal age-

Burosumab Therapy Burosumab • Osteomalacia-related bone/ joint pain or fractures/ pseudofractures limiting daily activities; appropriate reference range and refractory to conventional therapy x Concurrent conventional treatment 3 Burosumab: 1.0 mg/kg SC Q4W x Severe renal impairment – maximum dose 90 mg

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