Hypophosphatasia

The estimated prevalence ranges from 1/300,000 in severe forms to 1/6,300 in mild forms in European populations.

Hypophosphatasia shows a broad range of inheritance patterns, reflecting the underlying ALPL variant-dependent loss of enzyme activity. Severe perinatal and infantile forms are typically associated with biallelic pathogenic variants, whereas milder childhood and adult forms may occur with monoallelic variants and display autosomal dominant inheritance with variable expressivity and reduced penetrance. Accordingly, hypophosphatasia may be considered a semidominant disorder with a continuum of phenotypes depending on residual enzyme activity. Each child of an affected individual with the autosomal dominant form has a 50% risk of inheriting the pathogenic variant. For biallelic disease, each sibling of an affected individual carries a 25% recurrence risk.

Diagnosis is based on clinical, biochemical, and radiological findings and is supported by the , which combine major and minor criteria for children and adults. These criteria incorporate the identification of a pathogenic variant in ALPL as a major or minor diagnostic feature, depending on the clinical context. Fulfilment of these criteria establishes the clinical diagnosis.

Main differential diagnoses include:

• and other causes of impaired bone mineralisation or osteomalacia: including inherited bone fragility disorders and metabolic conditions, typically with normal or increased serum ALP activity.
• Rheumatological conditions: chronic musculoskeletal pain and functional impairment may mimic hypophosphatasia, but these disorders are not associated with persistently reduced serum ALP activity
• Other causes of persistently reduced alkaline phosphatase activity: including nutritional deficiencies (e.g., zinc or magnesium deficiency), malabsorption, endocrine disorders (e.g., hypothyroidism), medication effects (e.g., antiresorptive therapy), and laboratory artefacts.

• Where hypophosphatasia is suspected, molecular genetic testing can confirm the underlying diagnosis by identifying pathogenic variants in ALPL and may fulfil a major or minor diagnostic criterion within the established clinical framework. Establishing the genetic diagnosis may end a diagnostic odyssey in some cases and enables accurate risk assessment, predictive testing of at-risk relatives, and informed reproductive planning.
• The identified genetic finding supports further clinical management, including condition-specific surveillance and treatment decisions, which are determined by the treating physicians in consultation with the affected individual.

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• Khan AA, Brandi ML, Rush ET, Ali DS, Al-Alwani H, Almonaei K, et al. Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults. Osteoporos Int. 2024;35(3):431-438. doi:10.1007/s00198-023-06844-1. PMID: . PMCID: PMC10866785.
• Seefried L, Genest F, Hofmann C, Brandi ML, Rush E. Diagnosis and treatment of hypophosphatasia. Calcif Tissue Int. 2025;116(1):46. doi:10.1007/s00223-025-01356-y. PMID: . PMCID: PMC11885340.