Hypophosphatasia results from deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). According to GeneReviews, the condition is caused by pathogenic variants in the gene encoding TNSALP, with biallelic variants typically resulting in more severe disease than heterozygous variants exhibiting dominant-negative effects. GeneReviews documents that most affected individuals have unique pathogenic variants, limiting reliable genotype-phenotype correlation predictions. Variants producing significant residual enzymatic activity are associated with less severe phenotypes. Reduced TNSALP activity leads to accumulation of natural substrates including inorganic pyrophosphate (PPi), which inhibits hydroxyapatite crystal formation and bone mineralization. Seven disease subtypes are documented in this packet, including infantile hypophosphatasia, childhood hypophosphatasia, adult hypophosphatasia, moderate hypophosphatasia, odontohypophosphatasia, ALPL-related autosomal dominant hypophosphatasia, and ALPL-related autosomal recessive hypophosphatasia.

According to GeneReviews, clinical diagnostic criteria for hypophosphatasia have been published. Hypophosphatasia is suspected in individuals with persistently low serum alkaline phosphatase (ALP), which must be interpreted using age-specific reference ranges, as pediatric ALP is physiologically elevated. Diagnostic features documented in GeneReviews include clinical features of infantile rickets in young patients, premature loss of deciduous teeth before age five, and bone hypomineralization on imaging. Laboratory findings include elevated serum concentrations of natural TNSALP substrates: phosphoethanolamine (PEA), pyridoxal-5-phosphate (PLP), and inorganic pyrophosphate (PPi). Molecular genetic testing of the TNSALP-encoding gene, guided by a published variants database referenced in GeneReviews, provides definitive genetic confirmation. Differential diagnosis documented in GeneReviews varies by age of presentation and includes other causes of bone hypomineralization, rickets, and premature tooth loss.

Asfotase alfa (STRENSIQ) holds FDA approval (BLA, October 2015) for hypophosphatasia and carries active market status in this packet, representing the only enzyme replacement therapy (ERT) with active FDA approval documented here. According to GeneReviews, there is no cure for hypophosphatasia, and medical management guidelines for treatment with asfotase alfa have been published. GeneReviews documents that asfotase alfa ERT has demonstrated improvement in pulmonary function outcomes in treated individuals. GeneReviews documents bisphosphonates as relatively contraindicated based on structural similarity to inorganic pyrophosphate, the natural TNSALP substrate. According to GeneReviews therapies under investigation section, efzimfotase alfa (ALXN1850) — featuring enhanced TNSALP catalytic activity, alternate Fc regions, and bone-targeting modifications — is in Phase 1 clinical evaluation. Two NORD patient assistance programs (HPP Medical Assistance and HPP Emergency Relief) are documented in this packet as currently accepting applications.

According to GeneReviews, clinical severity in hypophosphatasia spans an extremely wide spectrum from lethal perinatal disease to asymptomatic subclinical biochemical findings. Biallelic variants producing little to no residual enzymatic activity are associated with the most severe perinatal and infantile forms. GeneReviews documents intrafamilial clinical variability as a consistent feature, with affected family members showing widely differing severity depending on variant type and zygosity. Penetrance may be incomplete in the autosomal dominant form, as documented in GeneReviews. With enzyme replacement therapy, improvements in survival and pulmonary function outcomes have been documented in severely affected patients, per GeneReviews. Long-term outcomes depend on disease severity at presentation, age of onset, and treatment access.

Three clinical trials currently recruiting patients with hypophosphatasia are documented in this packet. NCT05596539 is a prospective longitudinal observational registry of adult patients with hypophosphatasia (REG-HYPO), sponsored by Assistance Publique - Hopitaux de Paris, with enrollment ongoing and planned completion September 2031. NCT07179640 is a Phase 1 study assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of ALE1, a novel investigational compound, in healthy adults and adults with hypophosphatasia, sponsored by Alesta Therapeutics, with enrollment beginning September 2025 and planned completion January 2027. NCT07390240 examines the effect of monoallelic ALPL gene variants on the natural course of hypophosphatasia in Russia, sponsored by AstraZeneca, beginning December 2025 with planned completion June 2027. GeneReviews additionally documents efzimfotase alfa as a modified ERT under investigation with completed and ongoing Phase 1 studies.