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X-linked hypophosphatemia

What's new

Two international expert group guidelines have recently been published for the diagnosis and management of X-linked hypophosphatemia in children and adults. Burosumab is the preferred treatment for symptomatic patients, particularly those with fractures, pseudofractures, or inadequate response or intolerance to conventional therapy with phosphate and active vitamin D. Conventional therapy remains an option when burosumab is unavailable, but it should not be used concurrently with burosumab. Management should be guided by a multidisciplinary team, with individualized monitoring to optimize skeletal outcomes, minimize complications, and ensure appropriate dental, orthopedic, and neurological care. .

Background

Overview

Definition
X-linked hypophosphatemia is a rare inherited disorder of phosphate metabolism caused by mutations in the PHEX gene, leading to renal phosphate wasting and impaired bone mineralization.
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Pathophysiology
Mutations in the PHEX gene result in increased circulating levels of fibroblast growth factor 23, a phosphaturic hormone that reduces renal phosphate reabsorption and suppresses 1α-hydroxylase activity, decreasing production of active vitamin D (1,25-dihydroxyvitamin D). The resulting hypophosphatemia leads to defective mineralization of bone and cartilage, manifesting as rickets in children and osteomalacia in adults. Impaired skeletal growth, enthesopathy, and dental abnormalities are common consequences of chronic phosphate deficiency.
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Epidemiology
X-linked hypophosphatemia is the most common inherited form of rickets, with an incidence of approximately 3.9 per 100,000 live births and a prevalence ranging from 1.7 to 4.8 per 100,000 individuals. It affects both males and females due to its X-linked dominant inheritance pattern. While most cases have a positive family history, 20-30% arise from de novo PHEX mutations.
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Risk factors
X-linked hypophosphatemia is inherited in an X-linked dominant pattern, affecting both males and females, though males may present with more severe manifestations. A positive family history is the primary risk factor, although de novo mutations can also occur.
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Disease course
X-linked hypophosphatemia typically presents in early childhood, often within the first two years of life, with signs of rickets, bone pain, and progressive leg deformities (such as genu varum or valgum), and delayed walking. Growth is impaired, leading to disproportionate short stature. Premature fusion of cranial sutures may occur, along with dental complications such as enamel hypomineralization, recurrent tooth abscesses, and periodontitis, even in the absence of dental caries. As the disease progresses into adulthood, patients may develop osteomalacia-related pseudofractures, fractures, osteoarthritis, enthesopathies, and spinal stenosis. Hearing loss, depression, and reduced QoL are also commonly reported.
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Prognosis and risk of recurrence
With appropriate and early treatment, many individuals with X-linked hypophosphatemia can achieve improved growth, reduced skeletal complications, and better QoL. However, long-term complications such as osteoarthritis, dental disease, and enthesopathy may persist and require multidisciplinary management.
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Guidelines

Key sources

The following summarized guidelines for the evaluation and management of X-linked hypophosphatemia are prepared by our editorial team based on guidelines from the Expert Group on X-Linked Hypophosphatemia (XLH-EG 2025) and the International Working Group on X-Linked Hypophosphatemia (XLH-IWG 2025).
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Screening and diagnosis

Diagnosis: as per XLH-EG 2025 guidelines, consider the diagnosis of X-linked hypophosphatemia in children and growing adolescents presenting with or having a history of clinical, biochemical, and/or radiological signs of rickets, impaired growth velocity, and serum phosphate levels below the age-related reference range associated with isolated renal phosphate wasting, in the absence of vitamin D or calcium deficiency, particularly with a positive family history.
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  • Differential diagnosis

Diagnostic investigations

History and physical examination: as per XLH-EG 2025 guidelines, obtain a detailed clinical evaluation to assess for evidence of rickets, growth failure, dental abnormalities, and signs of craniosynostosis and/or intracranial hypertension.
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  • Laboratory tests

  • Genetic testing

  • Skeletal survey

  • Bone mineral density testing

  • Dental assessment

Medical management

General principles, children
As per XLH-EG 2025 guidelines:
Consider ensuring multidisciplinary patient care and organizing the management plan by an expert in metabolic bone diseases.
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Discuss treatment plans in a multidisciplinary team setting before performing any orthopedic, neurosurgical, or dental surgery.
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  • General principles (adults)

  • Burosumab (children, initiation and administration)

  • Burosumab (children, monitoring)

  • Burosumab (adults, initiation and administration)

  • Burosumab (adults, monitoring)

  • Vitamin D and phosphate salts (children)

  • Vitamin D and phosphate salts (adults)

  • GH therapy

  • Dental care (children)

  • Dental care (adults)

  • Management of tertiary hyperparathyroidism (general principles)

  • Management of tertiary hyperparathyroidism (calcimimetics)

  • Management of tertiary hyperparathyroidism (surgery)

  • Management of hypercalciuria

  • Management of musculoskeletal symptoms

  • Management of bone deformities (children, nonoperative management)

  • Management of bone deformities (children, surgery)

  • Management of bone deformities (adults, surgery)

  • Management of hearing impairment

  • Management of neurosurgical complications

Nonpharmacologic interventions

Lifestyle advice: as per XLH-EG 2025 guidelines, support and adapt physical activity in patients with X-linked hypophosphatemia to their abilities. Allow all sports unless individual contraindications exist.
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Specific circumstances

Pregnant patients, monitoring: as per XLH-IWG 2025 guidelines, provide genetic counseling to all women of childbearing age, including adolescents, regarding the inheritance of X-linked hypophosphatemia and the risk of transmission.
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  • Pregnant patients (management)

Follow-up and surveillance

Follow-up, children
As per XLH-EG 2025 guidelines:
Consider scheduling follow-up visits for children and adolescents demonstrating a satisfactory response to treatment and/or in a stable condition at least every 6 months. Schedule more frequent visits, such as every 3 months, during periods of expected rapid growth or after initiation of therapy.
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Obtain the following in the follow-up of children with X-linked hypophosphataemia:
measurements of height, weight, head circumference (until the age of 5 years), intercondylar and intermalleolar distances, and BP
calculation of BMI and annual height velocity
documentation of head shape and history of headaches, dental abscesses or maxillofacial cellulitis, bone pain, fatigue, and level of physical function
orthopedic assessment of the musculoskeletal system in the presence of lower-limb deformity (varus or valgus or anteroposterior)
assessment for evidence of hearing loss, spine deformity, and scoliosis, as well as manifestations related to craniosynostosis, Chiari 1 malformation, intracranial hypertension, and maxillary dysmorphosis
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  • Follow-up (adults)

  • Follow-up (all patients)