Hypophosphatasia (HPP) is an extremely rare disease of calcium and phosphate metabolism with systemic involvement and a progressive course, characterized by defective bone mineralization due to reduced activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).1,2 Alkaline phosphatase (ALP) is a key enzyme in bone and tooth mineralization of which there are at least 4 isoenzymes: TNSALP (which accounts for 95% of the total serum ALP activity) and 3 tissue-specific isoenzymes (intestinal, placental and germ cell).1,2 The TNSALP isoenzyme is encoded by the ALPL gene (1p36.12; OMIM 171760), which is mainly expressed in liver, bone, kidney, muscle and sensory areas of the cerebral cortex.3 The presence of variants in ALPL associated with changes in TNSALP function determines the development of HPP, and more than 330 mutations have been described to date.4

The main substrates of TNSALP are inorganic pyrophosphate (PPi), pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA).3 In patients with HPP, low TNSALP activity leads to accumulation of these substrates and the manifestations associated with the disease. The high concentration of PPi in the extracellular osseous matrix prevents the nucleation of calcium and phosphate crystals, interfering with the growth of hydroxyapatite crystals and leading to skeletal abnormalities.3 On the other hand, the dephosphorylation of PLP (an active metabolite of vitamin B6 or pyridoxine) to pyridoxal (PL) by TNSALP is necessary for pyridoxine to cross the cell membrane or the blood-brain barrier. Pyridoxal 5′-phosphate is an essential cofactor of inhibitory neurotransmitters such as gamma-aminobutyric acid. Symptomatic neonatal and infantile forms of HPP characteristically manifest with seizures secondary to a central deficiency of vitamin B6, despite the accumulation of PLP in plasma.1–3 In addition, the frequent presence of inflammatory damage in the joints in patients with HPP suggests that TNSALP plays a role in inflammatory processes activated by the deposition of calcium pyrophosphate dihydrate crystals.

Historically, hypophosphatasia has been classified into a form with exclusive involvement of tooth (odontohypophosphatasia) and 5 subtypes with systemic involvement classified according to age at onset (4 paediatric forms and 1 adult form) (Tables 1–3). At present, it is also important to differentiate between mild and severe forms, at least in the infantile and childhood subtypes.1 Furthermore, there have been descriptions in the literature of another disease with manifestations that are similar to those of HPP but with a normal or even mildly elevated serum TNSALP activity (pseudohypophosphatasia),1 although in these cases, activity in the normal range might be due to intercurrent conditions.1

Generally, forms with earlier onset have a poorer prognosis1,2,5 due to the potentially fatal complications of skeletal abnormalities (severe respiratory difficulties due to chest deformities) or extraskeletal manifestations (presence of seizures).6

The prevalence of severe forms of HPP is estimated at 1 case per 300,000 births in Europe.5 It varies between populations, with severe forms being most frequent in Canadian Mennonites (1:2500)2 and perinatal lethal forms in Japan.7 The prevalence of mild forms with a dominant pattern of inheritance is estimated at 1 case in 6370 births in Europe.8 In contrast, the prevalence of hypophosphatasaemia (low serum ALP activity) is much higher, as this state may be due to multiple causes in the absence of HPP (Table 4).1

The diagnosis of HPP in clinical practice poses challenges due to the low prevalence of the disease and the considerable phenotypic overlap with other diseases that are more common. Furthermore, the little importance that is normally given to low serum ALP activity (compared to the usual assessment that follows detection of hyperphosphatasaemia) is a limiting factor in the diagnosis of HPP. Yet, diagnosis is particularly important given the potential severity of the disease, the considerable impact it has in the quality of life of many of those affected, or the iatrogenic problems that could result from misdiagnosis. Furthermore, a targeted enzyme replacement therapy for HPP has recently become available,9,10 so correct diagnosis is now even more crucial to allow early and appropriate treatment.

The main aim of this article is to provide general recommendations to facilitate the identification of paediatric patients with HPP. We recommend that those seeking detailed information on the genetic basis, pathophysiology and clinical manifestations of the disease consult recently published literature reviews on the subject.1,2,6,10

Fig. 1 shows an algorithm for the diagnosis of HPP in paediatric patients based on current evidence and expert recommendations derived from clinical experience. It aims to provide a logical sequence for diagnosis of potential cases of symptomatic HPP, although there are forms of the disease with minimal to non-existent clinical manifestations in childhood and adolescence. In such cases, persistence of low serum TNSALP activity, even in the absence of skeletal manifestations, may suggest the presence of a mild form of HPP (whose severity may increase in adulthood). A diagnosis of HPP should be considered mainly in patients presenting with certain musculoskeletal or dental signs and symptoms (although in severe perinatal and infantile forms, respiratory and neurologic symptoms are strongly suggestive of HPP). Tables 1–3 list the most frequent clinical features of the paediatric forms of HPP.

Figure 1.

Algorithm for diagnosis of hypophosphatasia in paediatric patients. ALPL tissue nonspecific alkaline phosphatase gene; TNSALP, tissue non-specific alkaline phosphatase; HPP, hypophosphatasia; PEA, phosphoethanolamine; PLP, pyridoxal 5′-phosphate. *In≥2 measurements, with no history of normal ALP activity levels and in the absence of acute disease. **PEA has a low specificity and is not always elevated in HPP. Patients with HPP often have a total TNSALP activity level at the limit of detection, while in less severe forms of disease the level may be at the lower limit of normal or mildly decreased. A decrease in TNSALP activity results in accumulation of TNSALP substrates. ***A diagnosis of HPP should not be ruled out in patients in whom other causes that may account for the clinical manifestations could not be identified, regardless of the levels of TNSALP substrates.

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In the lethal perinatal form, the radiologic features are highly indicative of HPP: absence of mineralization in some bones (for which the main differential diagnosis would be osteogenesis imperfecta), caput membranaceum and osteochondral spurs in forearms and legs (a pathognomonic finding) (Fig. 2).2 While hypocalcaemia and hypophosphataemia are associated with different types of rickets, HPP may manifest with hypercalcemia and hyperphosphataemia (prevalence up to 50%), and low serum levels of calcium and phosphate are rare in this disease.11 The cause of hypercalcemia is unknown, although it could be due to impaired calcium uptake in bone. Hyperphosphataemia results from increased tubular reabsorption of inorganic phosphate.1

Figure 2.

Characteristic findings of imaging tests in cases of perinatal lethal hypophosphatasia (a) and infantile hypophosphatasia (b). (a) Ultrasound at 18 weeks’ gestation: bone spurs in right knew and right elbow (3D). (b) Radiologic evaluation in patient aged 17 months: marked changes in long bone methaphyses (proximal metaphyses of both humeri, distal metaphyses of both radii and ulnae, and proximal metaphyses of both femora, tibiae and fibulae), with metaphyseal flaring, reduced bone density, thickened trabeculae and radiolucent projections that extend from physis to metaphysis. Linear periosteal reaction in the left radius. Images reproduced with the authorization of Zankl A, Mornet E, Wong S. Specific ultrasonography features of perinatal lethal hypophosphatasia. Am J Med Gen Part A. 2008;146A:1200–1204, and Caballero Mora FJ, Martos Moreno GA, García Esparza E, Argente J. Hipofosfatasia infantil. An Pediatr. 2012;76:368–369.

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In the benign perinatal form, prenatal ultrasound examination reveals signs of reduced mineralization in the long bones, but patients start improving spontaneously in the third trimester and may have a normal development.

The most characteristic findings of infantile HPP are bone and muscle pain (with or without fractures), skeletal deformities similar to those observed in patients with rickets, impaired weight gain hypotonia/muscle weakness and delays in achievement of psychomotor development milestones.6 The most frequent skeletal abnormalities are rachitic chest deformity, bowing of the long bones, genu varum (after achieving independent standing), bone fractures and craniosynostosis. This corresponds to detection of metaphyseal widening, fraying and radiolucencies in the long bones in imaging tests5,11,12 (Fig. 2b).

There is often a significant overlap between the presentation of the most severe forms of infantile HPP and the presentation of the perinatal lethal form. Respiratory difficulties resulting from chest deformities predispose infants to pneumonia and respiratory failure and are the leading cause of death in these patients.1,2 Craniosynostosis may cause raised intracranial pressure, which may be associated with Arnold Chiari type I malformation, hydrocephalus and hydrosyringomyelia, among other central nervous system abnormalities.1,2,5,6 Raised intracranial pressure and calcification of the basal ganglia may play a role, along with changes in PLP metabolism, in the development of the seizures characteristic of perinatal and infantile HPP, which are associated with a poor prognosis and a high mortality.5,11,13

Low parathyroid hormone levels are common in infantile HPP. The reduced secretion of this hormone could be due to hypercalcemia and in turn lead to the development of hyperphosphataemia. In addition, hypercalcemia and hypercalciuria could lead to development of nephrocalcinosis, so performance of kidney ultrasound examinations at regular intervals is recommended as part of the follow-up.14

Despite the poor prognosis of this form of HPP, some patients experience a spontaneous improvement in bone mineralization with the corresponding clinical improvement. Patients with infantile HPP may develop neurologic complications associated with craniosynostosis, have a short stature and loose teeth prematurely, but have a more favourable prognosis compared to patients with perinatal HPP.5,11

Childhood HPP follows in the continuum of disease after infantile HPP, with onset usually occurring after age 1 year.1,2 The main radiologic feature is the presence of characteristic projections of non-ossified tissue in the epiphyseal plates (“tongues” of radiolucency), which differentiate HPP from various forms of rickets and metaphyseal dysplasia.12 Presentation with mild hypercalcemia and hypercalciuria is less frequent in the childhood form, and serum levels of parathyroid hormone and vitamin D are usually normal (or slightly reduced in patients with renal compromise).11

Clinicians should take into account the risk of craniosynostosis in every paediatric form of HPP, and patients should undergo neurologic evaluations at regular intervals, including ophthalmoscopy, until they reach adolescence. It is also important to monitor patients that only have dental manifestations, as they may eventually develop other abnormalities. There is evidence that the severity of HPP is associated with the number of teeth lost and inversely correlated to the age at loss of the first tooth.6

The first step in diagnosis when HPP is suspected is measurement of the total TNSALP activity. Reference values in children vary based on age, sex and the assay used (Table 5). It is important to take into account that mild forms of HPP may manifest with levels of TNSALP activity that are only slightly reduced or even at the lower limit of normal.1 Furthermore, there are multiple conditions that may manifest with a low total serum TNSALP activity (Table 4), so it is also important to assess the potential elevation of certain TNSALP substrates.1 In children with HPP, the degree of PLP accumulation in plasma is associated with the severity of disease, and this is the most sensitive and specific marker for diagnosis of HPP.1 Based on the current international literature, the positive and negative predictive values of PLP for diagnosis in children are very high, although absence of elevation of serum levels of PLP or other substrates of TNSALP (PEA, PPi) is not enough to rule out HPP. Measurement of bone mineral density by dual-energy X-ray absorptiometry may reveal low bone density, although this feature is not required for diagnosis.

In patients presenting with clinical manifestations suggestive of HPP and low levels of total serum TNSALP activity (in the absence of another identifiable cause), with or without elevation of TNSALP substrates, other diseases that are more prevalent and whose manifestations overlap with those of HPP need to be ruled out before making the diagnosis (Table 6).

Detection of mutations in the ALPL gene through molecular analysis can help establish the diagnosis in uncertain cases or serve as confirmation of HPP.15,16 However, some authors consider that in cases with a presentation that is clearly indicative of HPP (clinical manifestations+radiologic features+biochemical profile), mutation analysis is not required for diagnosis.1

Mutation analysis of samples obtained by amniocentesis may be performed in pregnant women in whom fetal abnormalities compatible with HPP have been detected or who have previous children with the disease, although its use is controversial, as it is not possible to differentiate reliably between the lethal and benign perinatal forms until late in the pregnancy.1,2

The management of HPP should be multidisciplinary and tailored to each patient according to the presentation and severity of the disease. Patients should be followed up in medical centres with specialists in metabolic bone diseases. At present, while there is no cure for HPP, patients can receive enzyme replacement therapy.9,17

Due to the symptoms it produces and its poor prognosis, severe perinatal HPP is managed differently, so we have devoted a separate section to this particular form (the remaining sections refer to the management of all paediatric forms of HPP).

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  Hypophosphatasia is a rare hereditary disease of bone and mineral metabolism characterized by deficient serum TNSALP activity that leads to skeletal and dental hypomineralization and extraskeletal manifestations.

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  The phenotypic spectrum ranges from potentially lethal early-onset forms to forms with a later onset with fewer and less specific manifestations.

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  Diagnosis in patients in whom there is a strong suspicion of HPP due to clinical manifestations should be based on the detection of low serum TNSALP activity and radiographic abnormalities, the potential accumulation of TNSALP substrates and the findings of molecular testing, among others.

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  The recent authorization of asfotase alfa for enzyme replacement therapy in patients with childhood-onset HPP has changed the approach to the management of this disease.

The authors have no conflicts of interest to declare.