Hypophosphatasia

ALPL-related tissue-nonspecific alkaline phosphatase deficiency — perinatal, infantile, juvenile, adult and odontohypophosphatasia forms.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Hypophosphatasia is an inborn error of metabolism in which deficient activity of a cell-membrane ectoenzyme, tissue-nonspecific alkaline phosphatase, prevents normal mineralisation of bone and teeth. The central clinical concept is that the disease is defined by low enzyme activity, rather than low phosphate: PPi, a natural inhibitor of hydroxyapatite crystallisation, accumulates in the extracellular space and inhibits mineralisation, while circulating PLP rises because it is not dephosphorylated [2, 5]. The spectrum is unusually broad: it ranges from a fetus with no mineralised skeleton, who dies of respiratory failure, to an adult with chronic musculoskeletal pain, slowly healing metatarsal fractures and femoral pseudofractures, through to a child whose only sign is early loss of deciduous incisors with intact roots [2, 12].

The disease was recognised as a distinct clinical entity by Rathbun in 1948, although patients had previously been described without serum ALP measurement [13, 14]. Rathbun described an infant with skeletal abnormalities, growth retardation and seizures, and the eponym “Rathbun syndrome” persisted in the literature [15]. In 1957, Fraser published an estimated incidence of 1:100,000 live births, based on paediatric hospital records in Ontario, which remained the sole population reference for decades [2, 13, 16]. Nyhan's Atlas also describes the evolution of classification into phenotypes of decreasing severity — neonatal or prenatal, childhood, adult and odontohypophosphatasia — and the finding of asymptomatic adults identified because ALP was included in a routine biochemical panel or because urinary amino acid chromatography revealed phosphoethanolamine [13]. The term pseudohypophosphatasia designated patients with a typical presentation and normal serum ALP; the coexistence of these patients and typical cases within the same family led the Atlas to interpret the phenomenon as assay variation rather than a distinct disease, whereas the skeletal dysplasia atlas describes an enzyme with defective activity towards natural substrates and preserved activity towards the artificial assay substrate [12, 13].

Identification of the gene, localised to 1p36.1–34 by linkage analysis in 1990 and characterised as the cDNA of the liver/bone/kidney isoenzyme in 1986, clarified the heterogeneity: the most severe form is recessive, whereas classic mild hypophosphatasia, some asymptomatic adults with phosphoethanolaminuria and some cases of odontohypophosphatasia show dominant expression of a variant in a single allele [13]. In 1992, Henthorn and colleagues demonstrated distinct missense variants at the TNSALP locus in mild and severe recessive forms [17], and in 2001 Lia-Baldini and colleagues presented the molecular basis of dominance through the dominant-negative effect of certain variants [18, 19].

The second major turning point was therapeutic. Asfotase alfa — recombinant human TNSALP fused to the Fc fragment of immunoglobulin G1 and to an aspartic acid decapeptide that targets it to hydroxyapatite — corrected the disease in mice lacking Alpl and, in 2012, the first trial in infants and young children with life-threatening hypophosphatasia showed radiological healing of rickets and improvement in respiratory and physical function [13, 20]. Authorisation in Japan, the European Union and the United States in 2015 transformed perinatal and infantile disease into a condition in which most treated patients survive, and gave rise to a new phenotype of “treated perinatal and infantile hypophosphatasia” [2, 21]. In parallel, the global patient registry and population genetic studies revealed that most diagnosed patients are adults, have a single variant and present with extraskeletal manifestations — pain, fatigue, weakness — that the classic classification, centred on the child's skeleton, failed to capture [15, 22].

2. Molecular Genetics and Pathophysiology

2.1. The gene and enzyme

ALPL is located at 1p36.12 and encodes TNSALP, the isoenzyme found in the liver, kidney and bone. The gene has 12 exons spanning approximately 50 kb, according to the Atlas [2, 13]. Tissue-specific alkaline phosphatases — intestinal, placental and germ-cell — are encoded by genes clustered at 2q34–37 and are unaffected, which explains why intestinal and placental activity remains normal in patients [5, 12, 13]. TNSALP accounts for approximately 95% of total ALP activity; it functions as a homodimer, anchored to the outer surface of the osteoblast membrane by glycosylphosphatidylinositol (GPI), and requires three metal sites, two occupied by zinc and one by magnesium, with an additional calcium-binding site [5]. This dependence explains a relevant analytical artefact: EDTA and oxalate in collection tubes chelate magnesium and artificially lower measured activity [5].

2.2. The three substrates and their consequences

PPi is the substrate that best explains the mineral phenotype. Its accumulation alters the phosphate/PPi ratio and prevents hydroxyapatite crystal growth, causing rickets in children and osteomalacia in children and adults [5, 7]. Several decades ago, Fraser and Yendt showed that slices of rachitic cartilage from vitamin D-deficient rats calcify in normal serum or in serum from patients with hypophosphatasia, but cartilage from patients with hypophosphatasia does not calcify in normal serum — a classic argument that the defect is local, at the mineralisation site [13]. The same excess of PPi favours calcium pyrophosphate dihydrate crystal formation and the joint inflammatory response (chondrocalcinosis, pseudogout), and is associated with acellular cementum hypoplasia and abnormal dentine in exfoliated teeth [12, 22]. Because the skeleton does not incorporate calcium and phosphate, severely affected infants develop hypercalcaemia, hyperphosphataemia and hypercalciuria, with parathyroid hormone (PTH) suppression and a risk of nephrocalcinosis [5, 12].

PLP is the circulating form of vitamin B6. To cross membranes, including the blood–brain barrier, it must be dephosphorylated to pyridoxal by TNSALP and rephosphorylated inside the cell [5, 23]. In hypophosphatasia, extracellular PLP accumulates while the intracellular compartment, particularly in the brain, becomes deficient; reduced synthesis of PLP-dependent neurotransmitters, particularly gamma-aminobutyric acid (GABA), lowers the seizure threshold [12, 24]. The Saudubray chapter emphasises that ubiquitous intracellular PLP deficiency does not manifest as severe anaemia, unlike other vitamin B6 disorders, and that neurotransmitter abnormalities have been documented only in isolated patients [24]. TNSALP also participates in neural stem cell proliferation and differentiation, myelination, axonal growth and synaptic maturation, which has been invoked to explain vitamin B6-independent neurological manifestations [5]. PEA is not a proven direct substrate; its elevation may result from GPI anchor degradation or changes in PLP-dependent hepatic processing [22].

Other proposed mechanisms — imbalance between pro-inflammatory ATP and anti-inflammatory adenosine due to deficient nucleotide hydrolysis, interference with phosphorylated osteopontin, altered detoxification of intestinal lipopolysaccharides and muscle mitochondrial respiration — remain hypotheses unconfirmed in patients and have no diagnostic application [22, 25]. In a murine model, maximal muscle mitochondrial respiration was 37% of wild-type levels, independently of the skeletal phenotype, and mitochondria with branched cristae have been described in human muscle biopsy; these data are preclinical and small-scale [25].

Bone histology shows broad, irregular zones of proliferative cartilage and a lack of osteoid calcification, resembling rickets; osteoclasts lack membrane ALP activity but are morphologically normal [2, 13]. In teeth, cementum is reduced in proportion to severity, and all hard tissues of the dentoalveolar complex — enamel, dentine, cementum and alveolar bone — may be affected [2].

2.3. Variant spectrum and disease mechanisms

More than 400 pathogenic variants have been described, predominantly missense; frameshift variants, small insertions–deletions, splicing variants, nonsense variants and large deletions also occur [1, 2, 5]. Molecular consequences may coexist in the same variant: loss or reduction of catalytic activity, inability to form homodimers and protein retention in intracellular compartments, preventing arrival at the membrane [2]. Site-directed mutagenesis and three-dimensional modelling have distinguished severe alleles, moderate alleles with significant residual activity and alleles with a dominant-negative effect; the latter produce an abnormal monomer that reduces the activity of the heterodimer formed with the normal monomer to below 50% or sequesters it in the Golgi apparatus [2, 26]. These tools do not always predict severity [2].

The ALPL variant reclassification consortium, using functional testing, showed among 100 variants of uncertain significance reassessed since 2021 that 72% of the 40 functionally tested variants had less than 30% residual activity and that, among these, 48% exhibited a dominant-negative effect; all variants with less than 15% activity had this effect, and none with more than 20% did. The process reclassified 11 variants as pathogenic, 62 as likely pathogenic, 3 as likely benign and 1 as benign, while retaining 23 as variants of uncertain significance [27].

A dominant-negative effect does not explain all affected heterozygotes. In the Global HPP Registry, 75% of 814 patients had a single variant; among heterozygotes with a previously tested variant, only 42% had a proven dominant-negative effect [15]. In another analysis of 608 heterozygotes from the same registry, 27% had a variant with a dominant-negative effect, 37% had a variant without this effect and 36% had an untested variant [26]. In the European cohort of 424 patients studied by Mornet and colleagues, 60% of adults were heterozygous for a variant without a dominant-negative effect, suggesting haploinsufficiency; these adults were less severely affected than carriers of dominant-negative variants and were proposed as an entity of “mild hypophosphatasia with non-specific signs” [28]. Other explanations under investigation include regulatory or deep intronic variants, an undetected second allele, modifier genes and hormonal or epigenetic regulation; the c.787T>C variant, classified as benign, may cause subclinical disease in homozygosity or contribute in combination with another variant, and COL1A2 has been speculatively suggested as a modifier [22, 26].

2.4. Inheritance and genotype–phenotype correlation

Perinatal and infantile forms are typically autosomal recessive; milder forms, particularly adult and odontohypophosphatasia, may be recessive or dominant depending on the variant effect [2]. In the registry, 72% of patients with onset before 6 months had two variants, and 83% of patients with onset after 6 months had only one [15]. The skeletal dysplasia atlas summarises the practical rule: severe forms are almost exclusively recessive, mild forms — including benign prenatal disease — may be dominant, and compound heterozygosity for two mild dominant alleles may be lethal [12]. Siblings with the same two variants tend to have similar severity, with less variability at the severe than at the mild end of the spectrum [2]. Nevertheless, intrafamilial variability is the rule when heterozygotes and biallelic carriers coexist: in one published example, a mother diagnosed with the dominant form (c.331G>A variant) and a father with poor dentition and the c.1426G>A variant had a daughter with both variants who died at 31 days from respiratory failure [26]. The Atlas had already recorded that severe neonatal and mild juvenile forms do not coexist within the same family, an observation now interpreted in terms of allele number and type [13].

Some variants have predictive value. The following tables use transcript NM_000478.6 and protein NP_000469.3; conversions were confirmed using VariantValidator, and historical names, which number the protein without the signal peptide, were confirmed in ClinVar [4, 29].

The c.571G>A variant illustrates the difficulty of interpreting heterozygotes. In the Global Registry, 4.4% of heterozygotes with a clinical diagnosis had this variant; in UK Biobank, only 2 of 14 heterozygotes with repeated measurements (14%) had persistently low ALP, implying that disease frequency in these carriers is even lower [26]. In Vanderbilt's BioVU biobank, among 37,147 genomes from unselected individuals, 0.3% (1:341) carried pathogenic or likely pathogenic variants, of which 67.9% were c.571G>A; of the 70 carriers with electronic health records, 65.7% had low ALP and only 12.9% fulfilled the consensus diagnostic criteria, while 3.4% of controls without a variant fulfilled them [32]. ClinVar therefore retains conflicting classifications for c.571G>A, whereas c.1001G>A and c.1559del are classified as pathogenic/likely pathogenic or pathogenic without conflicts [29].

GeneReviews recognises no other allelic phenotypes of germline ALPL variants beyond the hypophosphatasia spectrum [2]. In the GeneGuidance database, ClinGen assigns definitive validity to both inheritance patterns and classifies clinical actionability as moderate in paediatric and adult settings [3].

3. Clinical Spectrum and Manifestations by System

3.1. Clinical classification and its limitations

The traditional classification orders the disease by age at first manifestations and severity. GeneReviews recognises seven forms; Orphanet describes six; Smith lists six, including the benign prenatal form; and the skeletal dysplasia atlas groups findings into lethal perinatal, infantile, late-onset and benign perinatal forms [1, 2, 12, 14]. All sources emphasise that this is a continuum and that categories overlap. Table 3.1 summarises the cardinal features of each form.

Table 3.1. Features by clinical form, according to GeneReviews, based on the Global HPP Registry (NCT02306720). AR, autosomal recessive; AD, autosomal dominant [2].

In 2025, the Global Registry, with more than 1,500 patients from 12 countries, proposed a simplified classification into early onset (before 6 months) and late onset (from 6 months), based on two observations: patients with onset before 6 months have life-threatening manifestations and more often two variants, and disease burden in late-onset disease is high regardless of age and variant number [15]. Two terms were also proposed for people without clinical manifestations: “asymptomatic carrier”, with a variant but neither biochemical nor clinical abnormalities, and “subclinical hypophosphatasia”, with a variant and biochemical signature (persistently low ALP without another cause and substrate accumulation) but no overt manifestations [15, 26]. Seefried and colleagues likewise argue that the disease should be viewed as systemic and lifelong, and criticise labels centred on a single organ, such as “odonto”-HPP [22].

3.2. Severe perinatal form

It is usually identified on prenatal ultrasound and may result in fetal death. The skull is soft and globular (“caput membranaceum”), appearing boneless on radiographs: the base is relatively calcified, the frontal bones tend to be spared, and the remaining vault shows only islands of bone [12, 13]. The limbs are short, deformed and flaccid, with skin dimples over the bowing and sometimes bony spurs in the midshaft of the ulna and fibula (“Bowdler spurs”), which may perforate the skin [12–14]. Polyhydramnios, a small thorax with short, thin and fractured ribs, and restrictive respiratory failure occur; the latter is the most frequent cause of death [2, 12]. Radiology distinguishes this form from all other bone diseases: generalised rarefaction, irregular metaphyseal ossification defects extending into the diaphyses, vertebrae with absent neural arch ossification and alternating ossified and unossified vertebral bodies (“skip lesions”), relatively preserved clavicles and scapulae and, at the extreme, complete absence of ossification (“boneless fetus”) [12–14]. Hypercalcaemia is common and may be associated with apnoea and seizures; vitamin B6-dependent seizures may precede skeletal manifestations, with a severely abnormal electroencephalogram and sometimes a burst-suppression pattern [2, 24]. Before enzyme replacement therapy (ERT), these neonates died within hours or days, or later from pulmonary infection; the Atlas describes fever, vomiting, seizures and intense crying suggestive of pain even in very young infants [12, 13].

3.3. Benign perinatal form

Ultrasound shows short, bowed long bones with normal or slightly reduced mineralisation; bowing, with osteochondral spurs and no metaphyseal ossification defects, improves spontaneously in the third trimester or after birth, and the child develops a less severe form [2, 12, 33]. Wenkert and colleagues identified 17 cases among 178 paediatric patients and reviewed 24 published cases: postnatal severity ranged from infantile to the odonto phenotype; 63% of the cumulative 41 cases were autosomal recessive; and, in dominant cases, transmission was maternal in 11 of 13 probands, suggesting an intrauterine maternal effect. They concluded that normal fetal crowding, fetal mineralisation and thoracic circumference, together with heterozygosity, suggest the benign form, but that bowing with recessive inheritance, specific variants or poor mineralisation before the third trimester does not reliably predict lethality [33]. Smith mentions spontaneous prenatal improvement, and Oxford recommends consulting the literature before counselling and considering parental ALP measurement [14, 34].

3.4. Infantile form

There may be no signs at birth. Between birth and 6 months, growth retardation, episodic vomiting, anorexia, constipation, fever, irritability, hypotonia, sometimes blue sclerae and pyridoxine-dependent seizures develop [2, 12]. Cranial sutures appear wide and the fontanelle bulging, with prominent scalp veins, but hypomineralised bone tends to fuse prematurely; craniosynostosis, with intracranial hypertension, exophthalmos and a risk of secondary brain injury, is a classic complication [2, 12, 13]. The thorax is rachitic, with a rachitic rosary and widened bone ends, and clinical severity depends primarily on the degree of respiratory failure: before ERT, 50% died from respiratory failure resulting from rib hypomineralisation [2, 14]. Hypercalcaemia (with vomiting and feeding refusal) and hypercalciuria may lead to nephrocalcinosis; proteinuria, casts and renal impairment are described in the youngest patients [12, 13]. In a natural history study of untreated patients with infantile onset, craniosynostosis occurred in 61.3% and nephrocalcinosis in 51.6% between birth and 5 years [8]. If the infant survives, clinical features tend to improve spontaneously and bowed bones straighten, but rickets-like changes, delayed walking, abnormal gait, genu valgum and limb pain become evident [12]. Serial radiographs in the skeletal dysplasia atlas show this evolution: short, bowed and undermineralised tubular bones at 3 months and almost normally modelled bones, without visible metaphyseal defects, at 7 years in an untreated patient [12].

3.5. Childhood forms (severe juvenile and mild)

The severe juvenile form has a variable initial presentation but frequently progresses to rickets. More severely affected children have short stature, delayed walking and a waddling myopathic gait, bone and joint pain, and diaphyseal and metaphyseal fractures [2]. Radiographs show irregular, frayed metaphyses with large “punched-out” radiolucent defects projecting into the diaphyses, distorted trabeculation and thin cortices; the notched appearance of bone ends resembles metaphyseal dysplasia more than the cupping of nutritional rickets, and subperiosteal new bone formation also distinguishes the two conditions [12, 13]. Focal radiolucent “tongue-shaped” metaphyseal defects are fairly specific to childhood hypophosphatasia [2]. Craniosynostosis may give the skull a “beaten copper” appearance [12, 13].

The mild childhood form presents later, without rickets, with low bone mineral density for age and unexplained fractures. Premature loss of deciduous teeth before 5 years, usually beginning with the incisors, with the root still attached to the tooth, is the characteristic sign [2]. Bone and joint pain is atypical in this form, but attention deficit hyperactivity disorder and sleep disturbances are overrepresented in children with hypophosphatasia [2].

3.6. Adult form

There may be a history of transient childhood rickets or early loss of deciduous teeth [2, 13]. It is usually recognised in middle age, with stress fractures and pseudofractures of the lower limbs as cardinal findings: foot pain due to recurrent, slowly healing metatarsal fractures, and thigh or hip pain due to pseudofractures (Looser zones) in the lateral cortex of the femoral shaft [2, 13]. Chondrocalcinosis, pseudogout due to calcium pyrophosphate dihydrate crystal deposition, arthropathy, periarticular calcifications and spinal ligament ossification (syndesmophytes) accumulate with age [12, 13]. The skeletal dysplasia atlas describes increasing osteomalacia and fractures after menopause [12]. Osteomalacia distinguishes the adult form from odontohypophosphatasia [2]. Early loss of permanent dentition is common but not universal [2].

The global registry changed perceptions of this form. Among 304 untreated adults (median age 48.6 years; 74% women), 62% had a history of at least one fracture or pseudofracture, 38% reported five or more manifestations, and patient-reported pain, disability and quality of life did not differ significantly between paediatric and adult onset, except for disability (HAQ-DI) and BPI-SF “worst pain”, which were higher with paediatric onset [35]. Only 44% of children and 43% of adults in the registry had a history of overt skeletal manifestations [15]. In a retrospective review of 82 patients, fatigue (66%), headache (61%), sleep disturbances (51%), gait disturbances (44%), vertigo (43%), depression (39%) and anxiety (35%) were frequent [5]. In a cohort of 49 patients from Central and Eastern Europe, with clinical data for 34 from five countries, chronic musculoskeletal pain (73%), fractures (44%), tooth loss (26%) and bone deformities (18%) were the most frequent findings, and only one patient was receiving asfotase alfa [36]. Seefried and colleagues describe generalised musculoskeletal pain, weakness, exercise intolerance with prolonged recovery, headache, neuropathic pain, “brain fog” and gastrointestinal and periodontal complaints, often emerging after 40 years, as “non-canonical” manifestations [22].

Interpreting this presentation requires caution: many of these complaints are non-specific and common in the population, and the frequency of hypophosphatasia in heterozygotes does not make every symptom in a carrier causal. The Vanderbilt biobank study found mild symptoms, mainly neurological, in all 70 carriers with clinical records, but only 12.9% fulfilled the consensus criteria; compared with non-carriers, they had a higher probability of progression of mobility problems (median age 73 versus 82 years), without differences in fatigue, arthritis or dental problems [32]. Conversely, 43 individuals with low ALP, an ALPL variant and no symptoms — median age 29 years, 79% heterozygotes, 19 with elevated PLP or PEA, including five carriers of in vitro dominant-negative variants — illustrate that the biochemical signature alone does not define disease [37].

3.7. Odontohypophosphatasia and dental manifestations

Odontohypophosphatasia presents with premature exfoliation of deciduous teeth and/or severe caries, without skeletal manifestations; incisors are most often lost [2]. Dental abnormalities are also part of the other forms: anterior mandibular alveolar bone loss, large pulp chambers, cementum hypoplasia and, in some cases, abnormal dentine; enamel hypoplasia and tooth mobility have been described in adolescents and adults [2, 12]. Some patients diagnosed with isolated dental disease in childhood subsequently develop childhood or adult skeletal forms [2]. The International Working Group adds that deciduous tooth loss typically occurs by 4 years and that the exfoliated tooth may have an abnormal shape, colour and structure [5].

3.8. Manifestations by system

Table 3.2. Manifestations by system.

4. Clinical Recognition and Warning Signs

Recognition depends on a simple habit: viewing low ALP as a meaningful finding, rather than considering only high ALP. GeneReviews advocates routine ALP activity measurement in infants and children with poor weight gain, growth deficiency, unexplained seizures and suspected non-accidental skeletal injury [2]. Clinical clues highlighted by the International Working Group include recurrent or slowly healing fractures, chondrocalcinosis, nephrocalcinosis, enthesopathies with calcification of tendon and ligament insertions, musculoskeletal pain, abnormal gait, early loss of deciduous teeth with intact roots and abnormal tooth colour or shape [5].

Table 4.1. Warning signs by context.

Three pitfalls deserve emphasis. The first is the apparently wide fontanelle or suture in an infant, which reflects hypomineralisation rather than delayed closure: this bone tends towards early synostosis [2]. The second is “low-normal” ALP measured during pregnancy, liver disease, after an acute fracture or surgery, situations in which ALP rises transiently; serial measurements may be needed, and bone ALP (heat-labile) can be separated from liver ALP (heat-stable) [2]. The third is the adult who has already received antiresorptives, whose low ALP may result from the drug itself; most patients with suppressed ALP on bisphosphonates do not have hypophosphatasia [5, 22]. The German S3 guideline on rare dental diseases (approved in 2024; English summary published in 2026) recommends, by expert consensus and with strong recommendation strength, that idiopathic early tooth loss, particularly in the deciduous dentition, should trigger medical investigation for hypophosphatasia [40].

Diagnostic delay documents the problem. In the registry, the median interval between first symptoms and diagnosis was 24.5 years in adults with symptoms since childhood and 8.4 months in children presenting symptoms between 1 and 18 years, despite approximately half of patients having a family history [15]. Another registry analysis, cited by the International Working Group, showed a median of 5.7 years (n = 194) between first signs and diagnosis [5]. Diagnoses peak in the first 6 months (13%), early childhood (18%) and middle age (26%); from late adolescence onwards, women predominate, accounting for approximately 75% of adult diagnoses [15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Alkaline phosphatase activity

Serum ALP persistently below the age- and sex-specific reference range is the mandatory criterion; in children, values should be compared with age-specific (or bone age-specific, if delayed) and sex-specific references, because any condition reducing linear growth lowers ALP [5, 22]. Total ALP is suitable for initial assessment because the bone and liver isoforms, both encoded by ALPL, normally account for more than 90% of circulating activity; in the third trimester of pregnancy, in some tumours or in inflammatory bowel disease, phosphatases from other genes may contribute and isoenzyme analysis becomes useful [22]. The sample should be collected in a lithium heparin tube, avoiding EDTA, citrate and oxalate, and haemolysis should be excluded [5]. Serum ALP does not correlate directly with clinical severity or reflect enzyme function in tissues [13, 22]. Table 5.1 lists causes of low ALP that must be excluded.

Table 5.1. Causes of low ALP to exclude, according to the International Working Group [5, 22].

The French national protocol (PNDS, 2021) adds practical details: measurement uses a tube without EDTA; in adults, the cited reference range is 40 to 170 IU/L, and in children it proposes lower limits derived from the Canadian CALIPER study — above 90 IU/L up to 15 days, 134 IU/L from 15 days to 1 year, 156 IU/L from 1 to 10 years, 141 IU/L from 10 to 13 years and, subsequently, sex-specific values (13–15 years: 62 IU/L in girls and 127 IU/L in boys; 15–17 years: 54 and 89 IU/L; 17–19 years: 48 and 59 IU/L) — always interpreted according to each laboratory's method [43]. The reduction may not be detectable at the first measurement, dental or mild forms may have ALP near the lower limit, and profound vitamin D deficiency may raise ALP and mask the diagnosis, so 25-hydroxyvitamin D is checked [43]. In children, low ALP is accompanied by hypercalcaemia, hypercalciuria, hyperphosphataemia and suppressed PTH, sometimes with elevated magnesium; in adults, hypercalcaemia is rare (approximately 15%) [43]. The protocol also includes Wilson disease, corticosteroid therapy and adynamic bone disease of chronic kidney disease among causes of low ALP, and vitamin D intoxication, neonatal subcutaneous fat necrosis, Williams syndrome and idiopathic infantile hypercalcaemia among causes of hypercalcaemia with low PTH that mimic the biochemistry of hypophosphatasia [43].

5.2. Substrates

PLP (frequently reported by laboratories as “vitamin B6”) is the most widely used substrate. Pyridoxine supplements, multivitamins or calcium supplements containing vitamin B6 must be discontinued for one week before sampling, and the sample must be protected from light [2, 5, 22]. In the registry, 89% of untreated children and 78% of untreated adults with available data had PLP above the upper limit, and the proportion of patients in whom PLP was actually measured ranged from 18% to 61% by region [15]. The PLP/pyridoxal ratio has been studied as an indicator of severity, without sufficient precision [22].

Urinary PEA, normalised to creatinine, is useful but has limitations: it may be elevated in other metabolic bone diseases, normal in affected patients or elevated in asymptomatic heterozygotes [2, 13]. In the registry it was elevated in 79% of tested children and 71% of tested adults, but in only 44% of European adults [15]. The Atlas indicates that normal values decrease with age, with ranges of 83–222 µmol/g creatinine below 15 years, 42–146 from 16 to 30 years, 38–155 from 31 to 41 years and 48–93 in older individuals, and that hydroxyproline excretion is low, unlike vitamin D-resistant rickets [13]. Plasma PPi is the most sensitive and specific substrate and the main cause of the mineralisation defect, but requires complex preanalytical processing and is unavailable in North American clinical laboratories; it remains restricted to specialised centres and trials [2, 22]. Asymptomatic heterozygotes may also have elevated urinary PPi and reduced ALP [2].

Other parameters guide differential diagnosis and complication assessment: calcium and ionised calcium are usually normal but sometimes elevated in the first year; serum and urinary phosphate are normal or elevated (phosphate elevated in approximately 50% of children and adults, according to the skeletal dysplasia atlas); hypercalciuria, particularly in the first year; normal 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and PTH [2, 12]. Table 5.2 compares hypophosphatasia biochemistry with other metabolic bone diseases.

Table 5.2. Comparative biochemistry, according to Khan et al. 2024 [5].

5.3. Imaging

A skeletal survey identifies rickets or craniosynostosis in children; radiographs show fractures, pseudofractures, delayed healing (classically in the metatarsals) and calcium pyrophosphate deposition in joints; scintigraphy, magnetic resonance imaging or computed tomography (CT) may be required to characterise pseudofractures, and renal ultrasound detects nephrocalcinosis or stones [5]. When skull shape is abnormal, GeneReviews suggests three-dimensional CT to assess craniosynostosis [2]. Densitometry (DXA) is not a reliable marker of severity or bone health in hypophosphatasia: quality and mineralisation may be impaired despite normal or high density, and patients with a canonical phenotype sometimes have particularly high lumbar density [22, 44]. Bone biopsy is no longer advised because of the risk of worsening fragility [44].

5.4. International Working Group diagnostic criteria (2024)

The International HPP Working Group, established in 2021 with experts from Europe and North America and supported by McMaster University methodologists using a GRADE approach, conducted systematic reviews of 93 paediatric and 119 adult articles and defined major criteria when pooled prevalence exceeded 50% or the criterion was recommended by more than 50% of studies [5, 45, 46]. The criteria apply only to patients with persistently low ALP without another cause, and diagnosis requires two major criteria or one major and two minor criteria [5].

Table 5.3. Diagnostic criteria for patients with persistently low ALP [5].

The group's paediatric paper describes an arrangement of three major and six minor criteria in its abstract; the final consensus table published by Khan and colleagues, reproduced by GeneReviews, includes the variant and substrates among four major and five minor criteria. The final table is used here [2, 5, 45]. The panel excluded family history as a minor criterion to avoid promoting “solely biochemical or molecular” diagnoses in people without manifestations, and plans to review the criteria within 5 to 6 years [5, 45]. GeneReviews adopts the same criteria, distinguishing clinical diagnosis (two major, or one major and two minor, excluding the variant) from molecular diagnosis (one major or two minor associated with biallelic loss-of-function variants or a heterozygous variant with a dominant-negative effect) [2].

External validation in a Spanish cohort of 83 adults with persistently low ALP (47 genetically positive and 36 negative) showed that 97.9% of positives and 2.8% of negatives fulfilled the criteria; the two-major-criteria branch had sensitivity of 95.7% and specificity of 100%, and the one-major-and-two-minor branch had sensitivity of 44.7% and specificity of 97.2%. The substrate criterion alone had sensitivity of 97.9% but specificity of 33.3%. Without genetic testing, only 51.1% of confirmed patients fulfilled the criteria; without substrates, 44.7%; and using clinical features alone, 6.4% [47]. These figures apply to adults already selected for low ALP at a Spanish centre and do not estimate sensitivity in the general population.

5.5. Genetic testing and its limitations

Confirmation of an ALPL variant is considered standard care and should be undertaken early, but is not mandatory for diagnosis: it should not delay treatment of a severely affected infant, is unavailable in some regions and has a yield below 100% [5, 22].

Table 5.4. Molecular tests; ~95% refers to detection of biallelic variants in patients of European ancestry with severe forms; in other phenotypes, the proportion is difficult to estimate [2].

The proportion of variants detectable by a method is not the clinical sensitivity of the test: in a mild form with a single variant, yield depends on phenotype, population and coverage of intronic and regulatory regions. Skeletal dysplasia panels, exome and genome sequencing are alternatives when the phenotype is non-specific; genome sequencing covers non-coding regions, but interpreting these variants is difficult [2, 26]. An apparent homozygote with only one carrier parent requires consideration of a deletion undetected by sequencing or uniparental isodisomy [2]. The report should indicate the gene, transcript with version (NM_000478.6), HGVS nomenclature, zygosity, ACMG/AMP classification and limitations; a variant of uncertain significance neither confirms nor excludes the diagnosis, and the Johannes Kepler University ALPL databases include functional testing of residual activity and dominant-negative effects that may support reclassification [2, 27]. In the Global Registry genetic analysis, phase data were unavailable to distinguish variants in cis or in trans in patients with more than one variant, limiting interpretation of these genotypes [15].

5.6. Practical algorithm

1. Clinical suspicion (signs in section 4) or low ALP on a routine panel: repeat ALP in a lithium heparin tube, using age- and sex-specific references, and exclude the causes in Table 5.1 [5].
2. Persistently low ALP: PLP (without B6 supplements for at least one week) and urinary PEA; calcium, phosphate, magnesium, PTH, 25-hydroxyvitamin D, creatinine and urinary calcium/creatinine [2, 5].
3. Targeted imaging: skeletal survey and skull in children; foot, femur and joint radiographs in adults; renal ultrasound [2, 5].
4. ALPL sequencing with deletion/duplication analysis, or panel/exome according to the differential diagnosis [2].
5. Apply IWG major/minor criteria and, for a variant of uncertain significance, use functional testing and family studies as investigative tools, without converting partial segregation into proof of pathogenicity [5, 27].
6. In a severely affected neonate, substantiated suspicion (radiology, undetectable ALP, hypercalcaemia) justifies immediate referral for ERT without awaiting the molecular result [18, 22].

5.7. Prenatal diagnosis

In severe forms, ultrasound from the 14th week shows absent calvarial ossification and short, bowed limbs; the Atlas reports ultrasound diagnosis of the fetal head at 16 weeks, and Smith mentions second-trimester ultrasound and measurement of the liver/bone/kidney isoenzyme in chorionic villi at 10–12 weeks [12–14]. ALP measurement in amniotic fluid, amniocytes and villi is prone to misinterpretation, particularly when distinguishing unaffected heterozygotes; molecular testing is preferred when familial variants are known [2, 13]. Recurrence of the severe perinatal form is reliably identified by ultrasound, but isolated bowing does not diagnose lethality: in pregnancies without known risk with short, bowed bones, when molecular investigation was performed, 50% of fetuses had a single variant, excluding the severe perinatal form [2]. Functional classification of variants improved prenatal discrimination: in 46 perinatal cases with classifiable variants, imaging alone diagnosed lethal disease in 35, but in 11 it could not distinguish lethal from benign disease [48]. Trio sequencing (fetus and parents) increases yield when the skeletal differential diagnosis is broad [26].

6. Differential Diagnosis

The differential diagnosis depends on the age at which hypophosphatasia is considered. Three elements help at any age: prenatal and immediate postnatal bone hypomineralisation, elevated serum calcium and phosphorus in infants and persistently low ALP [2]. Oxford notes in several chapters that ALP is reduced or absent in hypophosphatasia and normal or elevated in osteogenesis imperfecta, and that reduced bone density is common to both [18, 49].

6.1. Prenatal and neonatal period

Table 6.1. Prenatal and neonatal differential diagnosis. Fetal or neonatal radiographs usually resolve uncertainty; when it persists, ALP, PLP and PEA suggest the diagnosis, to be confirmed molecularly [2].

6.2. Infants and children

Irritability, feeding refusal, growth deficiency, hypotonia and seizures place the infantile form within a broad differential diagnosis including inborn errors of energy metabolism, organic acidaemias, primary and secondary rickets, neglect and non-accidental trauma [2]. Intractable seizures may precede any biochemical or radiological sign of rickets; among vitamin B6-dependent epilepsies, hypophosphatasia is distinguished from antiquitin and PNPO deficiencies by very low ALP, hypercalcaemia and elevated PEA, with markedly elevated pretreatment plasma PLP [2, 24]. At the opposite extreme, hyperphosphatasia with intellectual disability syndrome (Mabry syndrome; PIGV, less often PIGO or PGAP2), a GPI anchor synthesis defect, causes seizures and moderately elevated ALP [24].

Table 6.2. Childhood differential diagnosis [2].

6.3. Adult and odontohypophosphatasia

In adults, the most dangerous confusion is with osteoporosis because it leads to bisphosphonate prescription; osteoarthritis and pseudogout secondary to calcium pyrophosphate deposition may themselves be the presenting features of hypophosphatasia [2]. Wilson disease (ATP7B) may cause low ALP, fatigue, neurological symptoms and hepatic osteodystrophy [2, 5]. Hypochondroplasia (FGFR3), periodontal forms of Ehlers-Danlos syndrome (C1R, C1S; loss of teeth with roots but normal ALP), aggressive periodontitis, Papillon-Lefèvre and Haim-Munk syndromes (CTSC, with palmoplantar keratoderma), and periodontitis in ELANE-associated neutropenias complete the dental differential diagnosis; gingival inflammation is unusual in odontohypophosphatasia, and ALP measurement is reasonable whenever these diseases are considered [2]. Adult pseudohypophosphatasia retains normal serum ALP [2]. Vitamin D insufficiency may coexist with hypophosphatasia and should be excluded by measuring 25-hydroxyvitamin D, alongside the other causes of low ALP in Table 5.1 [5].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no cure. Management combines targeted therapy — enzyme replacement with asfotase alfa — and multidisciplinary supportive care adapted to age and manifestations [2]. Seefried and colleagues describe this care as individually combined “building blocks”: metabolic and musculoskeletal treatment, dental care, neurological and neurosurgical surveillance, pain management, physiotherapy and psychological support [22]. Before ERT, no treatment had convincing benefit: phosphate supplements, bone marrow transplantation and symptomatic measures for fractures, deformities and craniosynostosis were the options described in the Atlas [13].

7.2. Asfotase alfa (Strensiq®)

Mechanism and formulation. Asfotase alfa is a soluble glycoprotein produced in Chinese hamster ovary cells, comprising two identical chains of 726 amino acids, each with the catalytic domain of human TNSALP, the Fc domain of human IgG1 and an aspartic acid decapeptide targeting it to hydroxyapatite; the chains are joined by two disulphide bridges [7, 8]. It replaces deficient activity, reduces PPi and PLP and enables mineralisation [7]. Treated perinatal/infantile and juvenile patients had reductions in plasma PPi and PLP within 6 to 12 weeks, without correlation between these reductions and clinical outcomes, and biopsies showed reduced osteoid volume and thickness [7]. It is an injectable solution for subcutaneous administration, stored between 2 °C and 8 °C, protected from light, without freezing or shaking, and administered within 3 hours of removal from the refrigerator [7, 8].

Table 7.1. US label (version 18, effective 12 Dec 2025) and European label (product information published 18 Mar 2026) [7, 8, 55].

The weight-based dosing tables in both labels convert these regimens into volumes: for example, at 2 mg/kg 3×/week, a child weighing 10 kg receives 20 mg (0.5 mL of 40 mg/mL) per injection [7, 8]. GeneReviews summarises practice as a total dose up to 9 mg/kg/week in infants and 6 mg/kg/week in adolescents and adults, the most common regimens being 1 mg/kg 6×/week or 2 mg/kg 3×/week [2]. Elimination half-life after subcutaneous administration is approximately 5 days in the US label; the European population pharmacokinetic analysis estimated 2.28 ± 0.58 days, bioavailability of 60.2% and linearity up to 28 mg/kg/week, the maximum dose used in studies [7, 8]. Injection-site reactions may limit the six-injections-per-week regimen [7].

Adverse effects and management. In trials (99 patients aged 1 day to 58 years, most treated for more than 2 years), the most common effects were injection-site reactions (63%), lipodystrophy (28%), ectopic calcifications (14%) and hypersensitivity reactions (12%) [7]. Frequencies were higher in juvenile disease: injection-site reactions in 90%, lipodystrophy in 70% and ectopic calcifications in 55% [7]. The European SmPC, covering 112 patients, reports injection-site reactions in approximately 74%, mostly mild, self-limiting and starting within the first 12 weeks, and classifies headache, erythema, limb pain, pyrexia, irritability and contusion as very common [8]. Anaphylaxis occurred within minutes of injection, both at initiation and after more than a year of treatment; for a severe reaction, discontinue, treat with adrenaline and consider re-exposure individually, which the European SmPC permits under medical supervision and with premedication [7, 8]. Site rotation and injection technique prevent lipodystrophy, and antihistamine plus paracetamol or ibuprofen premedication is used in patients with mild to moderate local reactions [7, 44]. Rare effects (<1%) included hypocalcaemia, kidney stones, chronic hepatitis and reduced vitamin B6 [7]. Serum PTH may rise, particularly during the first 12 weeks, and calcium and oral vitamin D supplements may be needed; in the 2012 trial, rising PTH accompanied skeletal healing and often required dietary calcium supplementation [8, 20]. In an observational study of adults with paediatric onset, injection-site reactions and lipodystrophy affected 86% and 82% of 22 patients [44].

Immunogenicity. Of 109 patients with post-initiation data, 97 (89%) had anti-asfotase alfa antibodies and, among these, 55 (57%) had neutralising antibodies; antibodies reduce systemic exposure [7, 8]. In postmarketing experience, some initially responding patients deteriorated biochemically and radiologically, sometimes with neutralising antibodies; no commercial antibody tests exist, and the US label advises contacting the marketing authorisation holder to obtain testing [7]. In the study of 69 children aged 5 years or younger, radiological non-responders (28%) had more severe disease at baseline and more neutralising antibodies at the last assessment [56]. A sponsor phase 4 study to mitigate immune-mediated loss of response with methotrexate, rituximab and bortezomib was registered and subsequently withdrawn without enrolling patients [57].

Laboratory interference. Asfotase alfa raises measured ALP to thousands of U/L, so serum ALP can no longer guide clinical decisions; it also interferes with immunoassays using ALP as a detection reagent (hormones, antigens, antibodies), so the laboratory should be informed and use alternative platforms [7, 8]. An unexplained reduction in ALP during ERT may indicate poor adherence or antibodies [44].

7.3. Trial evidence

Table 7.2. Asfotase alfa trials. RGI-C, Radiographic Global Impression of Change (−3 to +3); 6MWT, 6-minute walk test.

The limitations of this evidence must be explicit. No paediatric trial was placebo-controlled; survival and growth outcomes compare treated patients with historical cohorts, and the US label itself reports no comparative RGI-C data in the perinatal/infantile form and insufficient data to assess the effect on fractures (18 perinatal/infantile patients and 8 of 20 juvenile patients developed new fractures during treatment) [7]. European authorisation under exceptional circumstances specifically reflects the impossibility of obtaining comprehensive information in a rare disease [8]. Adult efficacy rests on small studies, some using below-standard doses during the first year, and observational data; GeneReviews notes that adult trials were limited to disease documented in childhood, already in the remodelling phase, and that outcomes, duration and long-term effects in this setting remain unknown [2, 60]. Real-world studies and the registry suggest improvements in walking, pain and quality of life in adults and in children treated after 2 years, with injection-site reactions the most frequent event, but the injection-site reaction rate reported in the registry (12% in 216 adults) differs from trial rates and requires validation [15, 44]. Discontinuation is harmful: six adults who stopped treatment for 15–48 months deteriorated and, upon restarting, not all returned to their previous levels [44].

7.4. Whom to treat

Sources agree on the indication for perinatal- and infantile-onset forms, in which ERT changes survival, and differ across the remaining spectrum. Dahir and Dunbar state that there are no evidence-based recommendations on when to start; they proposed 26 criteria in three categories (severity, genotype and manifestations), of which 9 favour and 4 discourage treatment, leaving a grey area for isolated pain, dental problems, stones or abnormal gait, and expressly note that this is an expert opinion-based decision [44]. NICE funding criteria, revised in 2023 with managed access agreement data (HST23, replacing 2017 HST6), translate the same logic into a European jurisdiction [61]:

Table 7.3. NICE criteria (England), published on 1 Mar 2023 [61].

Seefried and colleagues emphasise that, for patients with non-canonical, non-life-threatening manifestations, larger placebo-controlled or crossover studies would be required, with less burdensome administration [22]. Cost also matters: based on 2024 US retail prices, Dahir and Dunbar estimate approximately 1.8 million dollars per year for an 80 kg adult at the standard dose, and note that insurance coverage usually follows the restriction to paediatric onset [44]. In France, the 2021 PNDS (French National Diagnosis and Care Protocol) indicates asfotase alfa for children with poor-prognosis forms as early as possible, citing 5-year survival of 84% on treatment versus 27% in controls, and excludes benign perinatal disease and odontohypophosphatasia; in adults, with limited efficacy data, it reserves treatment for patients whose first signs occurred before 18 years and who have progressive bone manifestations, such as unhealed fractures or fissures and prolonged non-union [43]. The indication is established by an expert at a reference or competence centre and approved at an OSCAR network multidisciplinary meeting; initial prescribing is hospital-based at a reference centre, renewable at a competence centre, for 3-month periods, with inclusion in the Phenodent and ALX-HPP-501 registries recommended [43]. The protocol uses 2 mg/kg 3 times weekly or 1 mg/kg 6 times weekly and adjusts the dose to weight and to blood and urinary calcium–phosphate balance (no maximum dose defined in the PNDS; the European SmPC sets the maximum at 6 mg/kg/week [8]), seeking to limit hypercalcaemia, hypercalciuria and hyperphosphataemia and using suppressed PTH as a marker of chronic hypercalcaemia; it notes that ALP on treatment, often in the several thousands, allows adherence to be monitored but not the dose to be adjusted [43]. This titration by calcium–phosphate parameters diverges from the position of Dahir and Dunbar, who advise against adjusting the dose according to biochemical markers [44]. Practical instructions include storage at 2–8 °C, removing the vial from the refrigerator at least 15 minutes beforehand but injecting within the following hour, rotating injection sites (abdomen, thighs, deltoids), massaging for at least 1 minute and not exceeding 1 mL per site; injection-site reactions occurred in 73%, cases of anaphylaxis have been described, and safety in pregnancy and breastfeeding has not been established [43].

The consulted sources provided no information on reimbursement or access in Portugal (INFARMED) or Brazil (ANVISA/CONITEC); absence from these sources does not demonstrate an absence of national decisions.

7.5. Supportive care and non-pharmacological interventions

Critical and respiratory care. Severely affected neonates frequently need ventilation; early ERT is decisive, and comfort care remains an option where ERT is unavailable [2, 22]. In studies ENB-002-08/003-08 and ENB-010-10 (80 patients), 29 required ventilatory support at baseline: of 16 receiving invasive ventilation, 7 were weaned and 3 died while ventilated; of 13 receiving non-invasive ventilation, 10 discontinued all support and the remaining 3 died [8]. Monitoring recommendations include a sleep study before discharge and safety assessment before air travel in perinatal/infantile disease [44].

Seizures. Vitamin B6-dependent seizures require pyridoxine; Seefried and colleagues specify parenteral pyridoxine hydrochloride in severely affected neonates at risk [2, 22]. Pyridoxine response is variable and inconsistent, worsening seizures with pyridoxine have been described, and whether ERT corrects central nervous system manifestations is questionable because asfotase alfa does not cross the blood–brain barrier [24]. No pyridoxine dose is given here because it is absent from the hypophosphatasia-specific sources consulted.

Hypercalcaemia and hypercalciuria. In untreated infants, hypercalcaemia responds to dietary calcium restriction and/or glucocorticoids, according to the skeletal dysplasia atlas; GeneReviews notes that it is usually resistant to hydration and furosemide, that optimal management is uncertain and that bisphosphonates are contraindicated [2, 12]. In the case in section 10, hydrochlorothiazide and magnesium citrate resolved hypercalciuria-associated stones [31].

Craniosynostosis. This requires neurosurgical surveillance with fundoscopy for papilloedema and imaging, and vault remodelling surgery when intracranial hypertension occurs [2, 22]. Worsening pre-existing craniosynostosis and Chiari malformation were reported in trials in children younger than 5 years, without an established causal relationship with the drug [8].

Pain. Non-steroidal anti-inflammatory drugs are the mainstay; naproxen had a positive effect in children, and in adults as-needed ibuprofen at the lowest effective dose appears to have a favourable benefit–risk ratio; opioids have limited usefulness [2, 22]. GeneReviews recommends referral to pain specialists [2].

Physiotherapy, exercise and orthoses. Physiotherapy and supervised exercise, with a home programme, are recommended for everyone, regardless of age, severity and ERT indication; varied activities are preferable to monotonous or exhausting isometric training, which causes prolonged pain and fatigue [22]. Orthoses, particularly custom-made devices, help prevent planovalgus feet, genu valgum and scoliosis in children and relieve adult pain; GeneReviews suggests foot orthoses for tarsal fractures and pseudofractures [2, 22].

Orthopaedic surgery. Temporary guided-growth hemiepiphysiodesis is often sufficient for deformities; severe deformities may require corrective osteotomy [12, 22]. For complete fractures and symptomatic or progressive pseudofractures, load-sharing devices such as rigid intramedullary nails are recommended, avoiding unnecessary removal because of recurrence risk; joint replacement is technically feasible with pharmacological preparation and careful implant selection [2, 12, 22].

Dental care. Paediatric dental assessment by the first year and every six months thereafter; preserve the deciduous dentition for nutrition and preserve or replace the permanent dentition [2]. The German S3 guideline on rare dental diseases includes two recommendations for hypophosphatasia, both of strong strength and based on expert consensus: idiopathic early tooth loss, particularly in the deciduous dentition, should prompt medical investigation for hypophosphatasia; and, in the deciduous dentition, mobile teeth causing pain should be extracted [40]. The published summary adds that teeth that are already mobile generally cannot be preserved, that space maintainers should be considered in the deciduous dentition, always with regular appointments monitoring disease progression, oral function and prosthesis stability, and that prevention of caries, gingivitis and periodontitis (dietary counselling to reduce sugar, oral hygiene, professional cleaning and fluoride application) is a priority [40]. According to the same authors, the available data suggest that patients with hypophosphatasia benefit from adjusted systemic therapy when they receive treatments involving the alveolar bone (orthodontics, periodontal therapy, implants), and the duration of orthodontic and implant treatment should be extended to allow time for bone remodelling [40]. The evidence base is scarce: the systematic search from 2000 to 2022 found only case reports and case series outside amelogenesis imperfecta, and hypophosphatasia was, together with X-linked hypophosphataemia, the condition with the fewest publications [40]. The French PNDS requests an initial assessment at a reference-centre dental service (OSCAR and O-RARES networks), with follow-up tailored to severity and, in patients receiving asfotase alfa, dental examination at least every six months, a baseline assessment before treatment and scheduling of orthodontics or implants after enzyme therapy has been started; adults usually require periodontal therapy [43]. If started early and maintained, ERT may improve oral health in children with infantile onset [2].

Nutrition, vitamin D and minerals. Sources differ here, and the divergence is explained by context. The skeletal dysplasia atlas, centred on hypercalcaemic infants, states that vitamin D and mineral supplements increase hypercalcaemia risk and should be avoided [12]. GeneReviews limits the precaution to excess vitamin D in hypercalcaemic infants and allows calcium and vitamin D in adults under specialist monitoring to prevent secondary hyperparathyroidism [2]. Seefried and colleagues consider vitamin D supplementation no different from general-population recommendations, discourage low-phosphate diets without evidence and found no benefit from zinc or magnesium [22]. During ERT, the European SmPC and the 2012 trial indicate that rising PTH may require calcium and vitamin D [8, 20]. In practice, decisions depend on measured calcium, phosphate, PTH and 25-hydroxyvitamin D and the treatment phase. Infants with persistent nausea and vomiting may require nutritional support and gastrostomy; the SmPC recommends dietary supervision because of disproportionate weight gain [8, 22].

Osteoanabolic drugs. Teriparatide (PTH fragment 1–34), which stimulates osteoblastic TNSALP, has case reports of improved healing, pain and mineralisation in adults; it is off-label use, without prospective studies, and is contraindicated in children [2]. The anti-sclerostin antibody BPS804 increased ALP, formation markers and lumbar density in an open-label phase 2 study of 8 adults, with 3 escalating intravenous doses [62]. Seefried and colleagues consider these agents safe and feasible in adults with concomitant osteoporosis, with a defined objective and maintenance strategy, but without fracture data [22]. Orphanet includes teriparatide in adult supportive treatment [1].

French protocol (PNDS 2021). For vitamin B6-dependent seizures in severely affected neonates, the PNDS specifies pyridoxine hydrochloride at a loading dose of 100 mg by slow intravenous infusion over 20 minutes, followed by 50 to 100 mg intravenously once daily, and allows systematic preventive pyridoxine for several months in severe neonatal forms [43]. In hypercalcaemia, vitamin D is stopped, low-calcium milk and hyperhydration are used, and early asfotase alfa controls it; bisphosphonates are not recommended and prolonged use is contraindicated [43]. The protocol considers long-term benefit from growth hormone in infantile forms unproven, recommends decompressive surgery for symptomatic craniosynostosis with intracranial hypertension (with craniocervical junction MRI before anaesthesia) and systematic screening for Chiari malformation in children; in adults, no antiresorptive should be administered, calcium and vitamin D deficiencies are treated to avoid secondary hyperparathyroidism, and teriparatide may be discussed with a reference centre for non-union, never before growth plate closure [43]. It advises non-contact physical activity, such as swimming, and weight monitoring [43].

7.6. Agents and circumstances to avoid

Table 7.4. Agents to avoid.

Distinguishing hypophosphatasia from osteoporosis before prescribing antiresorptives is therefore a safety measure. Seefried and colleagues note that hypophosphatasia does not increase major osteoporotic fracture risk (vertebrae, hip and humeral metaphyses) or have a causal association with low density, so osteoporosis in a mildly affected adult should be viewed as the coincidence of two diseases [22]. The International Working Group notes that atypical femoral pseudofractures also occur in hypophosphatasia without bisphosphonate exposure [5].

7.7. Investigational therapies and recent developments (October 2025 to October 2026)

Table 7.5. Investigational therapies. Millán's review discusses the need for therapies targeting extraskeletal manifestations [71].

Table 7.6. Efzimfotase alfa phase 3 programme (196 patients, 22 countries), with fixed doses of 20, 35 or 50 mg by weight bands, subcutaneously every 2 weeks [9, 75].

The evidence hierarchy of these data must be clear. Efzimfotase alfa phase 3 results were released by AstraZeneca on 31 March 2026 as an inside-information announcement, and MULBERRY and CHESTNUT figures appear in the half-year report of 27 July 2026 as a presentation at the June 2026 ICCBH congress; no peer-reviewed articles reporting these results were identified by the cut-off date [9, 72]. The same half-year report lists a regulatory submission in Japan; it lists no acceptance of an application in the USA or EU, and there is no CHMP opinion or authorisation [72]. HICKORY is a negative trial for its primary endpoint: subgroup benefits and the fatigue parameter are exploratory and do not replace the absence of a demonstrated effect in the overall population, which included adult-onset patients. CHESTNUT was designed for safety, not to demonstrate superiority over asfotase alfa. No data allow efzimfotase alfa and asfotase alfa to be ranked for efficacy through comparison of different trials.

7.8. Special populations

Pregnancy and lactation. Asfotase alfa use in human pregnancy has not been extensively studied, and fetal risk is unknown [2]. The US label has no human data and describes animal studies without embryofetal toxicity; the European SmPC considers animal studies insufficient, reports transplacental transfer in mice and does not recommend the drug during pregnancy or in women of childbearing potential without contraception [7, 8]. ALP rises physiologically in the third trimester, which may mask low ALP [2, 22]. Maternal transmission predominated in dominant benign prenatal disease, suggesting a maternal intrauterine effect and justifying maternal assessment [33].

Children and transition. Teriparatide is contraindicated in children [2]. Transition to adult care merits planning: many patients experience a lower disease burden in late puberty and early adulthood, but disease frequently re-emerges with ageing, particularly as pseudofractures [22].

Perioperative care and anaesthesia. The consulted sources contain no specific anaesthetic recommendations; available surgical recommendations concern fracture fixation and arthroplasty [22].

8. Reproductive Options and Family Counselling

Counselling begins with identifying the variant(s) in the proband and testing the parents, because reliable recurrence-risk assessment depends on the inheritance pattern in the specific family [2]. Coexisting recessive and dominant inheritance, reduced penetrance and variable expressivity make hypophosphatasia one of the most difficult monogenic disorders for counselling; Orphanet emphasises that de novo mutations are exceptional and that penetrance appears low in the dominant form [1, 2].

Table 8.1. Recurrence risks [2].

Parental assessment includes targeted clinical and laboratory history alongside molecular testing: a parent may be affected but undiagnosed because of lack of recognition, reduced penetrance or a mild phenotype [2]. Oxford recommends molecular analysis and parental ALP measurement, noting that parents of severely affected children may have no symptoms or only very mild symptoms [18]. The Atlas recorded the historical usefulness of combining ALP and PEA to detect heterozygotes, since neither marker was sufficient alone [13]; today, carrier testing in at-risk relatives requires prior identification of familial variants [2]. In Japan, most c.1559del carriers had normal ALP and PEA, so only molecular testing detects them reliably [76].

Asymptomatic relatives with the familial variant(s) warrant longitudinal follow-up to enable early treatment of those who develop disease [2]. This recommendation must be reconciled with low-penetrance data in carriers of pathogenic variants identified in biobanks and the risk of overdiagnosis and unnecessary treatment highlighted in the study of asymptomatic carriers with a biochemical signature [32, 37]. GeneReviews recommends offering genetic and reproductive counselling to affected, heterozygous or at-risk young adults and, according to the American Academy of Pediatrics, introducing it in an age-appropriate manner during adolescence [2].

The French PNDS considers a genetics consultation essential, offers prenatal diagnosis (targeted molecular testing after chorionic villus sampling from 12 weeks of amenorrhoea) and preimplantation diagnosis to couples at risk of severe forms — recessive, lethal perinatal and complicated juvenile — discussed at a multidisciplinary prenatal diagnosis centre, and recalls that, following an ultrasound sign, genotype–prognosis correlation is difficult because benign prenatal forms exist [43]. Complete ALPL analysis of a heterozygote's partner is not performed routinely because of the difficulty interpreting rare variants and the low risk of severe recessive disease in offspring, and counselling should consider the availability of treatment [43]. The optimal time for counselling is before pregnancy. When familial variants are known, prenatal diagnosis, particularly molecular analysis following chorionic villus sampling, and preimplantation genetic testing are possible [1, 2]. Ultrasound reliably identifies recurrence of severe perinatal disease, but long-bone bowing has been observed in affected siblings and children of patients with juvenile or adult forms, and may represent benign prenatal disease that improves during pregnancy and results in non-lethal disease; functional variant information helps distinguish prenatal forms [2, 48]. In a pregnancy without known risk, prognosis based solely on ultrasound is difficult [2]. Views on prenatal and preimplantation testing vary among professionals and families, and the decision is personal [2].

ACMG includes hypophosphatasia among conditions for which expanded carrier screening should be offered to all pregnant women and those planning pregnancy [2, 77]. Newborn screening does not include hypophosphatasia in the US recommended uniform screening panel; ongoing genomic newborn screening studies (Generation Study in England, a large study in China, GUARDIAN, BabySeq, BeginNGS) include it among the conditions assessed [26]. When a molecular diagnosis is not obtained, GeneReviews suggests considering storage of the proband's DNA [2].

9. Special Considerations: Population Diversity and Epidemiology

Frequency estimates concern different entities and are not interchangeable. Table 9.1 specifies the population and form to which each figure applies.

Table 9.1. Frequencies by entity and population.

Founder effects explain most recurrent variants [26]. In Canadian Mennonites, c.1001G>A homozygosity — originally described as Gly317Asp — causes lethal perinatal disease; the same variant occurs in compound heterozygosity with c.571G>A in Mennonite families with very different phenotypes [26, 30]. In the Japanese population, c.1559del is the founder variant associated with the lethal form; in the global registry, 69% of Japanese patients had two variants, unlike other regions, where 69–86% had only one [15]. In Europe, Mornet and colleagues observed that many recurrent variants have a regional “anchor”, consistent with founder effects, and Oxford cites evidence for a founder effect for c.571G>A (E174K) [28, 41].

The most recent European data come primarily from clinical cohorts rather than population studies. The cohort of 49 patients from Central and Eastern Europe (five countries with clinical data) showed underdiagnosis and limited access to ERT [36]; the Spanish criteria-validation cohort included 83 adults with persistently low ALP [47]; and Mornet's French series underpin the European prevalence estimates [6, 28]. In the global registry, sponsored by the asfotase alfa marketing authorisation holder, women account for approximately 75% of diagnoses made in adulthood [15]. The same company, in the notes to its March 2026 announcement, estimates that approximately 80% of people with hypophosphatasia are adults and cites a US diagnosed-prevalence estimate of 2.8 per 100,000; this is sponsor information, without the original study among the sources consulted [9]. A hospital series or registry does not measure population prevalence, and the female predominance may reflect healthcare-seeking and ascertainment patterns; the role of sex hormones in ALPL expression remains unknown [26].

No data from Portugal or Brazil were found in the consulted sources; this absence does not demonstrate that no studies exist in these countries.

10. Illustrative Clinical Case

10.1. Perinatal hypophosphatasia requiring a higher-than-recommended dose (Croatia, 2025)

Petković Ramadža and colleagues, from Zagreb, described a girl with perinatal hypophosphatasia homozygous for c.1402G>A, p.(Ala468Thr) [NM_000478.6; NP_000469.3], in whom standard-dose asfotase alfa was insufficient both during the critical respiratory period and, years later, to control rickets [4, 31]. She was the fourth child of healthy parents reported as non-consanguineous. Her eldest sister had neonatal seizures and was diagnosed with infantile hypophosphatasia only at 5 months because of growth retardation, hypotonia and rickets, with ALP of 4 U/L and hypercalcaemia; without specific treatment available, she died at 8 months from respiratory failure following bilateral pneumonia. The carrier parents received genetic counselling and declined prenatal testing [31].

The pregnancy was complicated by premature rupture of membranes, oligohydramnios and threatened preterm labour at 27 weeks, without overt signs of skeletal dysplasia on fetal ultrasound. Delivery occurred at 37 weeks (2,490 g; length 46 cm; head circumference 30.5 cm, 5th percentile; Apgar 9/8/10). At birth, wide cranial sutures, bowed forearms and corneal opacity were noted; ALP was below 5 U/L and ophthalmological examination showed bilateral corneal oedema and ocular hypertension, consistent with congenital glaucoma. Molecular investigation confirmed her sister's variant [31]. The radiograph on the second day of life, showing wide sutures and short, bowed forearm bones, is available in Figure 1 of the article.

Asfotase alfa was started at 2 months on compassionate grounds at 2 mg/kg three times weekly; markedly elevated PLP and PEA fell after one month, but respiratory function deteriorated and signs of rickets emerged. The dose increased to 3 mg/kg three times weekly after 6 weeks of treatment and, following progression to mechanical ventilation, to 4 mg/kg three times weekly (12 mg/kg/week) one month later. Three months of intensive care followed, with pneumonia, atelectasis, tracheobronchomalacia, pulmonary hypertension treated with sildenafil, high-frequency ventilation, tracheostomy and sepsis; the patient was subsequently weaned from the ventilator [31]. At 9 months she underwent trabeculectomies for glaucoma; corneal calcifications, present before treatment, regressed, which the authors interpret as a manifestation of disease rather than a drug effect. At 2 years she had bilateral kidney stones (<3 mm) with hypercalciuria (6.7 mg/kg/day) and hyperphosphaturia, resolving within 18 months with hydrochlorothiazide and magnesium citrate [31].

Once stable, the child “grew out” of the high dose and remained on 6 mg/kg/week from 3 years, when she began walking independently. At 6 years she deteriorated: she could walk only with support and flexed knees, her Rickets Severity Score (RSS) was 10 and lumbar spine mineral content had a Z-score of −6.3, despite normal calcium and PLP within the reference range; anti-asfotase alfa antibody testing was unavailable, adherence appeared adequate and injection sites showed no abnormalities. CT showed cranial demineralisation and craniosynostosis, but neurosurgery was not considered indicated at that age [31]. Knee and wrist radiographs at this stage appear in Figure 2, and the “beaten copper” skull in Figure 3. After a humeral fracture from a fall, the dose increased to 10 mg/kg/week: the fracture healed with conservative treatment, the patient resumed independent walking after 3 months, RSS fell to 3.5 within 14 months (Figure 4) and lumbar Z-score improved to −3.7, without adverse effects attributed to the higher dose [31]. However, a neurodevelopmental disorder persisted: at 8 years she had severe delay, undeveloped speech and autism spectrum disorder; she never had seizures. She lost deciduous incisors prematurely with their roots, and permanent teeth had enamel discolouration [31].

10.2. Critical interpretation

The case brings together several lessons. Her sister's history shows the natural course of severe disease without ERT, consistent with the 50% mortality of untreated infantile disease [2]. Absence of ultrasound signs did not exclude severe disease in a fetus with a known familial genotype, and prenatal molecular testing was a parental decision, as provided for in counselling [2, 31]. The total dose of 12 mg/kg/week in infancy and 10 mg/kg/week at 6 years exceeded both the European SmPC maximum (6 mg/kg/week) and the US label maximum (9 mg/kg/week): this is use outside authorised indications, supported by a case report rather than a trial, and should not become a general rule [7, 8, 31]. Deterioration despite normal PLP confirms that biomarkers do not faithfully reflect bone disease during ERT, consistent with the recommendation not to titrate doses by biochemical parameters — although here the decision to increase the dose was clinical and radiological [31, 44]. Finally, unfavourable neurological progression without seizures and with normalised PLP reinforces that asfotase alfa does not cross the blood–brain barrier and that TNSALP's role in neurodevelopment extends beyond vitamin B6 [5, 24, 31]. Congenital glaucoma, not previously described in hypophosphatasia according to the authors, has an unresolved aetiology [31].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Without treatment, severe perinatal disease is almost always fatal within days or weeks, and infantile mortality, primarily from respiratory complications, was approximately 50%; historical control series showed 5% survival among infants requiring ventilatory support and 27% at 5 years in patients with onset before 6 months [1, 2, 15, 59]. With asfotase alfa, 5-year survival was 84% and, in long-term follow-up in the US label, 69 of 78 perinatal/infantile patients (88%) were alive at last contact, up to 7 years [7, 59]. Unfavourable outcomes may occur despite prompt diagnosis, and radiological non-responders cluster among the most severe cases and those with neutralising antibodies [2, 56]. Life expectancy does not appear affected in childhood, adult and odontohypophosphatasia forms, according to Orphanet, but adult pain, disability and impaired quality-of-life burden is high and independent of onset age or variant number [1, 35, 80]. In the registry analysis of 685 patients with onset after 6 months, carriers of two or more variants had more skeletal (52.1% vs 32.6%), dental (73.5% vs 56.0%), muscular (36.8% vs 23.6%) and neurological manifestations (22.2% vs 8.8%), but pain, disability and quality of life were similar [80]. Without treatment, some surviving infants improve spontaneously, but rickets, abnormal gait and craniosynostosis become apparent, and final height may be considerably below average [12]. Throughout life, mineralisation may improve in adolescence and decline again in middle age [2].

11.2. Initial assessment after diagnosis

In the perinatal form, GeneReviews recommends serum calcium, phosphorus and magnesium (risk of hypercalcaemia-related apnoea or seizures), pulmonary function assessment (prognosis and distinction between severe and benign forms), orthopaedic assessment with skeletal survey and skull radiography, neurological, craniofacial/neurosurgical and renal assessment (urea, creatinine, nephrology), family support and genetic counselling [2]. In older patients, it adds 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and PTH to exclude comorbidity, ophthalmological examination for ectopic calcifications, renal ultrasound for hypercalciuria and nephrocalcinosis, and dental assessment by the first year [2].

11.3. Surveillance

Table 11.1. Monitoring patients receiving asfotase alfa, according to Dahir and Dunbar's (2025) update of the 2017 guidance by Kishnani and colleagues, adapted to each centre's resources [44, 81]. TUG, Timed Up and Go; 5TSTS, 5-times sit-to-stand.

GeneReviews proposes a slightly different laboratory schedule, also derived from the 2017 guidance: ALP activity at baseline, 3, 6 and 12 months and then every six months in infants, and at baseline, 2 weeks, 3, 6 and 12 months and then annually in children and adults; PLP, urinary PEA, ionised calcium and phosphorus at baseline, 1, 3, 6 and 12 months and annually in infants; blood count and liver function; urea, creatinine and urinary calcium/creatinine every 3 months in infants; and estimated glomerular filtration rate in adults [2]. Regardless of treatment, it recommends annual renal ultrasound and ophthalmological examination, six-monthly dental assessment from the first year and neurosurgical surveillance for intracranial hypertension in infantile disease [2]. The European SmPC adds periodic fundoscopy for papilloedema below 5 years and PTH and calcium monitoring [8]. The French PNDS has its own schedule. Without enzyme therapy, it proposes six-monthly paediatric visits (every three months during treatment) and annual orthopaedics; calcium, phosphorus, PTH, 25-hydroxyvitamin D, ALP, blood count, electrolytes, liver and renal function, and urinary calcium, phosphorus and creatinine at least annually; PLP at diagnosis; radiographs every 1–3 years (EOS technique from 5 years); brain CT at 6 months in infantile forms; MRI including the craniocervical junction every 12–24 months until 4 years and then every 2–5 years; fundoscopy at least annually for 3–4 years; renal ultrasound every 1–3 years; and, in adults, densitometry every 2–3 years if fragility is present and slit-lamp ophthalmological examination every 1–3 years, with transition consultation at 17–18 years and adult follow-up every 2–3 years (4–6 months during treatment) [43]. During asfotase alfa: blood tests at 1, 3, 6 and 12 months in the perinatal period and early childhood and then at least every six months, or at 2 weeks, 3, 6 and 12 months and then every six months in children and adults; anti-asfotase alfa IgG antibodies annually and upon deterioration; wrist and knee radiographs every six months for 2 years and then annually; densitometry every 2–3 years; junctional MRI every 12–24 months in treated infantile forms until stabilisation (at least 10 years); functional tests and polysomnography before school entry and at 6, 10 and 15 years in infantile forms; and ophthalmological examination with fundoscopy and slit lamp every six months until 3 years and then at least annually [43]. Dahir and Dunbar caution that substrates have limited practical value — PPi is not commercially available, PLP may continue to be dephosphorylated in the tube by asfotase alfa itself, and biomarker variation has not been shown to alter outcomes — so doses should not be titrated by biochemical parameters; DXA is unreliable, bone biopsy is not advised and ALP during ERT does not reflect endogenous activity [44].

11.4. Resources and networks

ERN BOND (European Reference Network on Rare Bone Diseases) is the European reference network for rare bone diseases and devoted a webinar series to hypophosphatasia in 2026 [11]. Orphanet lists specialised centres, networks, tests, registries and patient organisations [1]. GeneReviews lists Hypophosphatasie Europe, Soft Bones (USA) and Soft Bones Canada, the MAGIC Foundation, NORD and UCLA's International Skeletal Dysplasia Registry [2]; in Germany, Hypophosphatasie Deutschland participated in developing the S3 guideline on rare dental diseases [40]. The Global HPP Registry (NCT02306720; EUPAS13514), sponsored by the marketing authorisation holder, is the largest observational study of the disease, with more than 1,500 patients; European authorisation requires the holder to maintain a long-term prospective observational registry (ALX-HPP-501) [8, 15, 55].

12. Summary and Final Considerations

Hypophosphatasia is deficiency of tissue-nonspecific alkaline phosphatase encoded by ALPL. PPi accumulation prevents bone and tooth mineralisation; PLP accumulation explains neonatal vitamin B6-dependent seizures; and enzyme function in extraskeletal tissues helps explain adult pain, weakness and fatigue. The spectrum extends from perinatal death to isolated dental disease, and age-at-onset classification is being complemented by the distinction between onset before and after 6 months and the concepts of asymptomatic carrier and subclinical disease.

Diagnosis rests on persistently low ALP for age and sex after exclusion of other causes, and on the 2024 International Working Group major and minor criteria integrating substrates, genetics and clinical manifestations; ALPL testing is standard care but not mandatory, and its limitations — variants of uncertain significance, reduced penetrance in heterozygotes, an undetected second allele — require careful interpretation. Inheritance is recessive in severe forms and recessive or dominant in mild forms, making counselling individualised and dependent on parental investigation.

Asfotase alfa changed survival in perinatal and infantile disease and improves rickets, mobility and quality of life in paediatric-onset forms, with injection-site reactions, lipodystrophy, ectopic calcifications, anaphylaxis and neutralising antibodies as the main problems. Labels differ: the US label allows 9 mg/kg/week in perinatal/infantile-onset disease and the European label limits dosing to 6 mg/kg/week, and neither covers adult-onset disease. Bisphosphonates and denosumab should be avoided, and hypophosphatasia excluded before initiating antiresorptives in adults with low ALP. Fortnightly efzimfotase alfa met the primary efficacy endpoint in previously untreated children (MULBERRY), showed in CHESTNUT, whose primary endpoint was safety, an adverse-event incidence similar to asfotase alfa, and did not meet the primary endpoint in HICKORY in adolescents and adults, according to data still reported solely by the sponsor, and is undergoing regulatory submission in Japan; ilofotase alfa has shown only biomarker effects after a single dose.

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