Introduction

Hypophosphatasia (HPP) is a rare metabolic bone disease characterized by impaired mineralization of bone and teeth resulting from deficient alkaline phosphatase (ALP) activity. The clinical spectrum is broad, ranging from severe, life-threatening disease in infancy to milder forms presenting in childhood or adulthood with musculoskeletal pain, fractures, or dental abnormalities. Disease severity may vary substantially even among affected relatives, suggesting contributions from both genetic heterogeneity and additional modifying factors [1–7]. Determining the true prevalence of HPP remains challenging due to its marked phenotypic variability and substantial underdiagnosis. Severe forms are estimated to occur in approximately 1 per 100,000 to 900,000 live births in Japanese cohorts and around 1 per 300,000 in Europe and 1 per 100,000 in North America [4, 6, 8–13]. In contrast, milder forms, including adult-onset disease, are likely more common, with an estimated prevalence of approximately 1 in 6,000 in European populations [6, 10, 11, 14, 15]. Increasing evidence suggests that HPP is frequently overlooked in routine clinical practice, particularly in adults, where nonspecific symptoms and persistently low ALP levels are often unrecognized or misinterpreted. Early diagnosis is critical, as appropriate management may prevent complications, avoid inappropriate therapies such as anti-resorptive agents, and enable timely initiation of disease-specific treatment. However, significant challenges remain in identifying affected individuals and translating biochemical and genetic findings into clinical decision-making, emphasizing the need for improved diagnostic strategies and clearer guidance for clinicians.

Methods (literature search strategy)

A comprehensive, non-systematic literature search was conducted to summarize current evidence on the pathophysiology, clinical manifestations, diagnosis, and management of HPP. A structured literature search was performed in PubMed/MEDLINE, Scopus, and Google Scholar to identify relevant publications from January 2000 to March 2026. Search terms included combinations of the following keywords: “hypophosphatasia,” “ALPL,” “tissue-nonspecific alkaline phosphatase,” “low alkaline phosphatase,” “diagnosis,” “clinical manifestations,” “enzyme replacement therapy,” and “asfotase alfa.” Boolean operators (AND/OR) were applied where appropriate.

Studies were eligible for inclusion if they were peer-reviewed articles, including original research studies, clinical trials, observational studies, systematic and narrative reviews, and international consensus or guideline papers relevant to HPP. Particular emphasis was placed on recent publications, high-quality evidence, and studies addressing diagnostic strategies, disease monitoring, and therapeutic outcomes. Articles were excluded if they were non-peer-reviewed reports, conference abstracts without full text, or publications lacking sufficient clinical or methodological detail. Additional relevant studies were identified through manual screening of reference lists of selected articles. Given the narrative nature of this review, formal systematic review methodology (e.g., PRISMA) was not applied; however, efforts were made to ensure a comprehensive and balanced representation of the available literature.

Genetic basis and genotype-phenotype correlations in HPP

HPP is caused by pathogenic variants in the ALPL gene, located on chromosome 1p36.1-p34, which encodes tissue non-specific alkaline phosphatase (TNSALP) [6, 13]. To date, more than 500 pathogenic variants have been identified, the majority of which are missense mutations, although nonsense, splice-site, and small insertion/deletion variants have also been reported. An international database of ALPL mutations is available (https://alplmutationdatabase.jku.at/) [16]. Inheritance may be autosomal recessive or autosomal dominant [3]. In general, autosomal recessive forms are associated with more severe disease due to near-complete loss of enzyme activity, whereas autosomal dominant variants, including those exerting dominant-negative effects, are more often associated with milder phenotypes [12, 13]. However, genotype-phenotype correlations remain inconsistent, and clinical severity cannot be reliably predicted from genetic findings alone. This variability suggests that additional factors may modify disease expression. Potential modifiers include residual enzyme activity associated with specific variants, compound heterozygosity, epigenetic influences, and environmental factors such as nutritional status, vitamin D levels, and mechanical loading, which may influence skeletal manifestations and timing of symptom onset [2, 4, 6, 8, 12, 13, 17].

Genetic testing helps confirm the diagnosis and determine the pattern of inheritance but is not mandatory, as some patients with clinically confirmed HPP may have negative or inconclusive results. In selected cases, evaluation of additional genes involved in phosphate metabolism and skeletal mineralization, such as runt-related transcription factor 2 (RUNX2) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), may be considered in the context of differential diagnosis [16, 18]. Biochemical abnormalities also tend to correlate with clinical severity. Patients with severe perinatal or infantile forms typically exhibit markedly reduced serum ALP activity and significantly elevated circulating PLP levels, whereas individuals with milder childhood or adult-onset disease may show only modest biochemical alterations in PLP levels [1–6, 11, 15, 18, 19]. The clinical heterogeneity of HPP reflects the combined effects of genetic variants, residual enzyme activity, and additional modifying factors, which limits the ability to predict disease severity based on genetic findings alone. These alterations result in reduced TNSALP activity and drive the biochemical and pathophysiological changes mediating the clinical manifestations of this condition [5, 18, 19].

Pathophysiology of HPP: skeletal and extra-skeletal mechanisms

HPP results from deficient TNSALP activity, leading to impaired hydrolysis of extracellular phosphate-containing substrates. TNSALP is the predominant circulating isoenzyme and is widely expressed in bone, liver, kidney, lungs, and developing teeth [10–13, 20–26]. Its primary physiological substrates include inorganic pyrophosphate (PPi), phosphoethanolamine (PEA), and pyridoxal-5-phosphate (PLP), the major circulating form of vitamin B6 [5–7, 9, 11, 20–24] (Figure 1A). The accumulation of PPi, a potent inhibitor of hydroxyapatite crystal formation, is the primary driver of defective mineralization. Consequently, reduced hydrolysis of PPi impairs skeletal mineralization, manifesting as osteomalacia and rachitic changes [9–13, 24–27]. Furthermore, elevated PPi concentrations may promote calcium pyrophosphate dihydrate crystal deposition in articular and periarticular tissues, contributing to the extra-skeletal manifestations of the disease in adults [1, 2, 6, 20, 24] (Figure 1B).

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Figure 1. Tissue non-specific alkaline phosphatase (TNSALP)-mediated regulation of bone mineralization. (A) Under normal conditions, TNSALP hydrolyzes inorganic pyrophosphate (PPi), increasing local inorganic phosphate (Pi) availability in the extracellular matrix, which combines with calcium to form hydroxyapatite crystals that deposit on type I collagen. (B) In hypophosphatasia (HPP), reduced TNSALP activity leads to PPi accumulation, inhibition of hydroxyapatite formation, and defective bone mineralization.

TNSALP also plays a critical role in central nervous system function by regulating PLP metabolism. Under normal conditions, phosphorylated PLP cannot cross the blood–brain barrier; therefore, TNSALP-mediated dephosphorylation to pyridoxal (PL) is required to enable its transport into the brain [28–30] (Figure 2A). Once intracellular, PL is rephosphorylated to PLP, which serves as an essential cofactor for the synthesis of neurotransmitters, including gamma-aminobutyric acid (GABA), serotonin, and dopamine. In HPP, impaired dephosphorylation of PLP reduces PL availability within the central nervous system, thereby disrupting neurotransmitter synthesis. In severe infantile forms, this deficiency commonly manifests as vitamin B6-responsive seizures [3, 6, 13, 20, 30]. In contrast, adult patients may present with more subtle neuropsychiatric manifestations, such as fatigue, depression, and anxiety [10, 12, 13]. Consequently, circulating PLP levels are typically elevated and represent a sensitive biochemical marker of TNSALP deficiency (Figure 2B).

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Figure 2. Role of non-specific alkaline phosphatase (TNSALP) in vitamin B6 metabolism and neurotransmitter synthesis. (A) TNSALP converts pyridoxal-5-phosphate (PLP) to pyridoxal (PL), allowing transport across the blood–brain barrier and re-phosphorylation to PLP within the brain. (B) In hypophosphatasia (HPP), impaired dephosphorylation of PLP limits PL availability in the brain, contributing to reduced neurotransmitter synthesis. GABA: gamma-aminobutyric acid.

Classification of HPP

HPP is classified into six clinical subtypes based on age at onset and disease presentation, reflecting a broad phenotypic spectrum that ranges from severe perinatal forms, typically inherited in an autosomal recessive manner, to milder adult presentations [2, 3, 9, 12, 30]. With the exception of odontohypophosphatasia (odonto-HPP), all forms are characterized by impaired skeletal mineralization and low ALP levels adjusted for age and sex [3, 9, 31] (Table 1).

The perinatal lethal form is characterized by profound skeletal hypomineralization, severe chest wall deformities, and pulmonary hypoplasia, leading to respiratory failure and early mortality [9, 22]. In contrast, the prenatal benign form presents with skeletal abnormalities detected in utero that may improve during late gestation, although residual limb deformities can persist at birth [6, 10, 20, 22]. Infantile HPP typically manifests within the first months of life with rickets, fractures, and growth impairment, and may be associated with neurological complications, including vitamin B6-dependent seizures, as well as abnormalities in cranial development [10, 17, 22].

Childhood and adult forms are generally milder but highly variable. Common manifestations include premature loss of teeth with intact roots, musculoskeletal pain, fractures, and fatigue, with symptom recurrence often observed in adulthood [10, 20, 22, 30, 32]. In adults, recurrent metatarsal fractures, femoral pseudofractures, and calcium pyrophosphate deposition disease (CPPD) are characteristic features [10, 20]. Neuropsychiatric symptoms and metabolic abnormalities, including hypercalcemia and nephrocalcinosis, may also occur [10, 33].

The odonto-HPP subtype is characterized by isolated dental manifestations without overt skeletal involvement [20, 22, 34]. Defective cementum mineralization leads to premature loss of primary teeth, particularly the mandibular incisors [10, 20, 22, 25]. Additional dental abnormalities, including defective dentin, alveolar bone loss, enlarged pulp chambers, enamel defects, and altered crown morphology, are frequently observed before the age of five and should raise clinical suspicion of HPP. Children with odonto-HPP may experience speech difficulties and impaired nutrition due to early loss of their primary teeth [10, 20, 25, 34]. Adults typically report a history of early tooth loss extending into adulthood, often accompanied by caries and periodontal disease [10, 20]. Although odonto-HPP represents the mildest end of the clinical spectrum, current genotype-phenotype correlations remain incomplete, and no specific ALPL genotype reliably predicts disease confined to the dentition. The mechanisms responsible for the apparent restriction of disease manifestations to the dentition also remain incompletely understood [20, 22, 34]. Longitudinal follow-up is recommended, as some patients may later develop skeletal manifestations [34].

Diagnosis of HPP

The diagnosis of HPP requires integration of clinical features, biochemical findings, and imaging studies, reflecting the marked heterogeneity of the disease.

Case-finding and screening strategies

Systematic approaches using laboratory databases to identify persistently low ALP levels have improved case detection, particularly when combined with targeted symptom screening. Diagnostic yield appears higher when ALP levels are < 25 IU/L in the presence of musculoskeletal symptoms [15, 54, 55]. Biochemical algorithms have been developed to identify individuals with ALPL variants among patients with persistent hypophosphatasemia [55, 56]. In addition, predictive modeling and machine-learning approaches that integrate biochemical markers such as ALP and PLP with clinical variables have demonstrated promising preliminary results for identifying affected individuals within large datasets [57–61]. However, these approaches remain largely exploratory, with limited external validation and few prospective studies assessing real-world clinical performance. In current practice, careful evaluation of persistently low ALP values in the appropriate clinical context remains the most practical strategy for improving early detection of HPP. Increased clinician awareness and accurate interpretation of biochemical abnormalities therefore remain essential to reducing diagnostic delay and improving patient outcomes [54–57].

Clinical assessment and disease evaluation in HPP

A recent expert consensus developed using a modified Delphi methodology proposed a structured framework for defining clinical severity and disease progression in adult patients with HPP. Seven consensus-based markers were identified to characterize clinical burden, together with multiple statements describing patterns of progression. Importantly, the panel distinguished between ambulatory patients and those who are non-ambulatory or functionally impaired, recognizing differences in clinical manifestations and trajectories over time [62]. Evaluation of these parameters is essential for guiding management and monitoring treatment response. The seven markers include recurrent or poorly healing fractures (particularly metatarsal fractures), fractures occurring with minimal trauma, dental manifestations such as premature loss of teeth, impaired mobility requiring assistive devices, gait abnormalities, pain, and histological evidence of osteomalacia. Progression is defined by clinically meaningful changes over time. In ambulatory adult patients, this may include low-trauma fractures, recurrent fractures, delayed or impaired fracture healing, the development of ectopic calcifications (articular, renal, or ocular), and worsening functional status with impairment in daily activities. In patients who are non-ambulatory or have significant functional impairment, progression may present with new fractures, additional calcifications, and further decline in functional capacity, including loss of independence in transfers or activities of daily living. In advanced stages, progressive loss of mobility and autonomy may be observed. Standardized functional assessments may help capture these changes longitudinally [62].

Functional assessment tools complement clinical evaluation by providing objective measures of functional status and treatment response. Validated instruments in HPP include the 6-minute walk test (6MWT) and the Lower Extremity Functional Scale (LEFS) [63, 64]. Other assessments, such as the Timed Up and Go test (TUG), Chair Stand Test (CST), and Short Physical Performance Battery (SPPB), may also be informative, although they have not been specifically validated in HPP. In addition, quality-of-life instruments, including the Short Form-36 version 2 (SF-36v2), the Health Assessment Questionnaire (HAQ), and the Brief Pain Inventory (BPI), are useful for evaluating patient-reported outcomes and monitoring changes over time [62–65].

Therapeutic management and monitoring of HPP

Management of HPP requires a multidisciplinary approach involving metabolic bone specialists, dentists, orthopedic surgeons, physiotherapists, and genetic counsellors. Patients with severe infantile forms often require specialized care in an intensive care setting. In addition, supportive measures, including pain management, rehabilitation, and psychosocial support, remain essential to improve function and quality of life across the disease spectrum [6, 9, 62, 65]. Although HPP is frequently misdiagnosed as osteoporosis or osteopenia, persistently low serum ALP should prompt evaluation for HPP before initiating antiresorptive therapy, as bisphosphonates and denosumab should generally be avoided because they may exacerbate the underlying skeletal pathology and increase the risk of atypical femoral fractures [20, 62].

Novel emerging strategies in HPP

Novel therapeutic strategies are being explored for HPP, including next-generation enzyme replacement approaches and emerging regenerative and gene-based therapies.

Conclusions

HPP is a rare and clinically heterogeneous metabolic disorder that can present at any stage of life. The wide variability in clinical manifestations, ranging from severe skeletal and neurological disease to milder adult presentations, contributes to persistent underdiagnosis and diagnostic delay. Although recently proposed diagnostic criteria and increased clinical awareness may improve recognition, many affected individuals remain unidentified. Systematic screening strategies, including evaluation of persistently low ALP levels and the development of data-driven approaches such as artificial intelligence-assisted case finding, may help reduce diagnostic delay and improve detection in clinical practice. Biochemical and genetic testing remain central to establishing the diagnosis, particularly in individuals with suggestive clinical features. Earlier recognition is essential to facilitate timely access to appropriate care while avoiding therapies that may be unsuitable for patients with HPP. Optimal management requires a multidisciplinary approach involving metabolic bone specialists, dentists, orthopedic surgeons, and genetic counseling. ERT with AA has significantly improved outcomes in patients with pediatric-onset disease, including skeletal mineralization, physical function, and quality of life. However, important knowledge gaps remain regarding long-term outcomes, optimal treatment initiation, and disease monitoring in adults. In parallel, novel therapeutic strategies, including next-generation enzyme replacement therapies, gene-based approaches, and cell-based platforms, are under active investigation. These approaches seek to address current therapeutic limitations through complementary mechanisms, with the goal of improving long-term outcomes and expanding treatment options for patients with HPP. While early results are encouraging, their long-term efficacy, safety, and place in clinical practice remain to be established. Looking further ahead, continued advances in precision genomic medicine may ultimately enable mutation-specific therapeutic strategies, particularly for selected dominant-negative ALPL variants. Future research, including large international registries and long-term real-world studies, will be essential to better define the natural history of adult HPP, optimize diagnostic and therapeutic strategies, and determine whether emerging precision medicine approaches can be translated into effective therapies for HPP.