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Hypophosphatasia

, PhD and , MD.

Author Information
, PhD
Laboratoire de Pathologie Cellulaire et Génétique EA 2493
Université de Versailles Saint-Quentin-en-Yvelines
Laboratoire SESEP
Centre Hospitalier de Versailles
Versailles, France
, MD
Division Chief, Medical Genetics
San Diego Medical Center
Kaiser Permanente
San Diego, California

Initial Posting: ; Last Revision: November 10, 2011.

Summary

Disease characteristics. Hypophosphatasia is characterized by defective mineralization of bone and/or teeth in the presence of low activity of serum and bone alkaline phosphatase. Clinical features range from stillbirth without mineralized bone at the severe end to pathologic fractures of the lower extremities in later adulthood at the mild end. At least six clinical forms are currently recognized based on age at diagnosis and severity of features:

  • Perinatal (lethal) hypophosphatasia characterized by respiratory insufficiency and hypercalcemia
  • Perinatal (benign) hypophosphatasia with prenatal skeletal manifestations that slowly resolve into the milder childhood or adult form
  • Infantile hypophosphatasia with onset between birth and age six months of rickets without elevated serum alkaline phosphatase activity
  • Childhood hypophosphatasia that ranges from low bone mineral density for age with unexplained fractures to rickets
  • Adult hypophosphatasia characterized by early loss of adult dentition and stress fractures and pseudofractures of the lower extremities in middle age
  • Odontohypophosphatasia characterized by premature exfoliation of primary teeth and/or severe dental caries as an isolated finding or as part of the above forms of hypophosphatasia

Diagnosis/testing. Although formal diagnostic criteria are not established, all forms of hypophosphatasia (except pseudohypophosphatasia) share in common reduced activity of unfractionated serum alkaline phosphatase (ALP) and presence of either one or two pathologic mutations in ALPL, the gene encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP). ALPL is the only gene known to be associated with hypophosphatasia.

Management. Treatment of manifestations: Perinatal lethal type: expectant management and family support. Infantile types: respiratory support, treatment of hypercalcemia/hypercalciuria; treatment of seizures with vitamin B6; routine treatment of craniosynostosis. All other types: routine dental care starting at age one year; nonsteroidal anti-inflammatory drugs (NSAID) for osteoarthritis, bone pain, and osteomalacia; internal fixation for pseudofractures and stress fractures.

Surveillance: Dental visits twice yearly starting at age one year; monitoring children with infantile type for increased intracranial pressure secondary to craniosynostosis.

Agents/circumstances to avoid: Bisphosphonates, excess vitamin D.

Genetic counseling. Perinatal and infantile hypophosphatasia are inherited in an autosomal recessive manner. The milder forms, especially adult and odontohypophosphatasia, may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect that the ALPL mutation has on TNSALP activity.

In autosomal recessive hypophosphatasia, heterozygotes (carriers) either are asymptomatic (manifesting biochemical but not clinical abnormality) or may manifest milder symptoms, depending on the mutation. Although de novo mutation has been reported, in most instances each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an "asymptomatic" carrier, and a 25% chance of being unaffected and not a carrier.

In autosomal dominant hypophosphatasia, most probands have an affected parent; de novo mutation has not been reported. Each child of an individual with the autosomal dominant form of hypophosphatasia has a 50% chance of inheriting the pathogenic allele. For both modes of inheritance, prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) of an affected family member are known. Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination.

Diagnosis

Clinical Diagnosis

Hypophosphatasia is characterized by defective mineralization of bone and/or teeth in the context of low activity of serum and bone alkaline phosphatase.

Although formal diagnostic criteria are not established, all forms of hypophosphatasia share in common:

  • Reduced serum alkaline phosphatase (ALP) activity (except pseudohypophosphatasia, in which serum alkaline phosphatase activity is normal);
  • Presence of either one or two pathogenic variants in ALPL, the gene encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP).

At least six clinical forms are currently recognized based on age at diagnosis and severity of features (see Table 1). Clinical features include the following:

  • Prenatal long-bone bowing with osteochondral spurs and pretibial dimpling
  • Infantile rickets without elevated serum alkaline phosphatase activity. These features can include growth failure, craniotabes, craniosynostosis, blue sclerae, costochondral enlargement ("rachitic rosary"), scoliosis, thickening of wrists and ankles, bowing of long bones, lax ligaments, and hypotonia.
  • Hypercalcemia and hypercalciuria during the first year of life
  • Pathologic fractures and bone pain. Growing children may have a predilection to metaphyseal fractures; however, epiphyseal and diaphyseal fractures are also seen. In adults, metatarsal fractures and femoral pseudofractures prevail.
  • Premature loss of deciduous teeth beginning with the incisors. Dental caries and early loss or extraction of adult teeth is also seen.
  • Family history of any of the forms of hypophosphatasia consistent with autosomal recessive inheritance or autosomal dominant inheritance with variable expressivity

The radiographic signs of hypophosphatasia vary with age and type, and may be quite distinctive. Perinatal lethal hypophosphatasia is radiographically distinct. In milder cases, the combination of clinical, laboratory, and radiographic findings are required for diagnosis because the radiographic signs are not pathognomonic.

  • Osteopenia, osteoporosis, or low bone mineral content for age detected by dual-energy x-ray absorptiometry (DEXA). Bone mineral content increases with age, and there may be improvement during adolescence with recurrence in middle age.
  • Infantile rickets. Findings include undermineralized bones, widened-appearing sutures, brachycephaly, rachitic costochondral rib changes, poorly ossified epiphyses, flared metaphyses (resulting in enlarged wrists, knees, and ankles), and bowed legs.
  • Alveolar bone loss resulting in premature loss of deciduous teeth. This most typically involves the anterior mandible, with the central incisors lost first. However, any teeth may be affected (see Figure 1A).
  • Focal bony defects of the metaphyses resembling radiolucent "tongues" (see Figure 1B). This feature is fairly specific for childhood hypophosphatasia.
  • Metatarsal stress fractures in childhood and adult hypophosphatasia
  • Osteomalacia with lateral pseudofractures (Looser zones) in adult hypophosphatsia (see Figure 1C)
Figure 1

Figure

Figure 1. Radiographic signs of hypophosphatasia

A. Alveolar bone loss surrounding molars in childhood hypophosphatasia
B. Hypolucent "tongue" mid-metaphysis in childhood hypophosphatasia
C. Looser zone (pseudofracture) (more...)

Table 1. Clinical Features of Hypophosphatasia by Type

TypeInheritance 1 Cardinal FeaturesDental FeaturesClinical Diagnosis
Perinatal (lethal)ARHypomineralization, osteochondral spursN/ARadiographs, prenatal ultrasound examination
Perinatal (benign)AR or ADLong-bone bowing, benign postnatal course±Prenatal ultrasound examination, clinical course
Infantile 2 ARCraniosynostosis, Hypomineralization, rachitic ribs, hypercalciuriaPremature loss, deciduous teethClinical course, radiographs, laboratory findings
ChildhoodAR or ADShort stature, skeletal deformity, bone pain/fracturesPremature loss, deciduous teeth (incisors)Clinical course, radiographs, laboratory findings
Adult 3 AR or ADStress fractures: metatarsal, tibia; chondrocalcinosis±Clinical course, radiographs, laboratory findings
OdontohypophosphatasiaAR or ADAlveolar bone lossExfoliation (incisors), dental cariesClinical course, dental panorex, laboratory findings

1. AR = autosomal recessive; AD = autosomal dominant

2. Rare reported cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity (in vitro) have been designated "pseudohypophosphatasia." The biochemical and molecular basis of pseudohypophosphasia remains unclear.

3. Persons with adult hypophosphatasia may give a history of features typically reported in childhood, infantile, and even prenatal hypophosphatasia.

Testing

Total serum alkaline phosphatase (ALP) activity: low. In all the types of hypophosphatasia, serum ALP activity is low.

  • Laboratories both within and across countries use different methods and thus have very different reference ranges; the gender- and age-specific reference range determined by each reference laboratory should be used. See Table 2 for the lowest normal reference values for a major North American reference laboratory.

    Note: The values in Table 2 are not relevant for other laboratories.
  • TNSALP activity requires Zn++ and Mg++, so EDTA tubes should not be used.
  • Transient increases in serum ALP activity in affected individuals invariably occur during pregnancy. Small increases in serum ALP activity may be seen with liver disease and acute fracture or surgery. Thus, serial measurement of serum ALP activity may be necessary when the diagnosis is suspected in toddlers with unexplained fractures.
  • Quantitation of the activity of the bone isoform of ALP in serum is generally unnecessary; however, in the setting of liver disease, the serum activity of ALP may be "falsely" normal. The bone isoform is heat labile; the liver isoform heat stable.

Table 2. Typical Lowest Normal Reference Values for Serum Alkaline Phosphatase Activity in North America

AgeLowest Normal Total Serum or Plasma Alkaline Phosphatase Activity (U/L)
MaleFemale
0-30 days60 60
1-11 months7070
1-3 years125125
4-11 years150150
12-13 years160110
14-15 years13055
16-19 years6040
>20 years4040

Adapted from ARUP laboratories

Note: (1) Full reference values depend on the method used and population sampled. The low normal total serum or plasma alkaline phosphatase activity is specific to the laboratory from which measurement of alkaline phosphatase activity is ordered and differs among laboratories. (2) Empiric historical references for the laboratory employed should be preferentially used.

Urine concentration of phosphoethanolamine (PEA): elevated

  • This is the most commonly obtained secondary screen for hypophosphatasia. It may be obtained as part of a urine amino acid chromatogram.
  • An elevated urine concentration of PEA supports the diagnosis of hypophosphatasia; however, the concentration in urine may be elevated with other metabolic bone disease and may be normal in affected individuals.

    Note: Finding an elevated urine concentration of proline adds specificity in interpretation of test results.
  • Asymptomatic heterozygotes may have reduced serum ALP activity and increased urine PEA concentration.

Serum concentration of pyridoxal 5'-phosphate (PLP): elevated

  • This biologically active metabolite of vitamin B6 may be the most sensitive indicator of hypophosphatasia [Cole et al 1986].
  • Use of vitamin supplements within a week of assaying serum concentration of PLP may lead to false positive results.

Serum concentration of calcium, ionized calcium, and inorganic phosphate: normal

  • Normal levels distinguish hypophosphatasia from other forms of rickets.
  • Hypercalciuria may be present with or without elevated serum concentration of calcium.
  • Although inorganic phosphate concentration in serum or urine is most typically normal, it may be elevated and thus is too variable to be used in diagnosis.

Serum concentration of vitamin D (25-hydroxy and 1,25-dihydroxy) and parathyroid hormone (nPTH): normal

Urine inorganic pyrophosphate (PPi): elevated

  • This is a sensitive marker in affected individuals and asymptomatic heterozygotes.

Molecular Genetic Testing

Gene. ALPL, encoding alkaline phosphatase, tissue-nonspecific isozyme (TNSALP), is the only gene in which mutation is known to cause hypophosphatasia.

Clinical testing

Table 3. Summary of Molecular Genetic Testing Used in Hypophosphatasia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
ALPLTargeted mutation analysis Mennonite mutation: c.1001G>A or other mutant alleles in specific populations (see Targeted mutation analysis4 c.571G>A: ~30% of those of European ancestry with mild disease 5
Sequence analysis 6Nonsense mutations, missense mutations, splice-site mutations, small deletions and insertions of ALPL Perinatal: ~95% 7, 8
Infantile: ~95% 7, 8
Childhood: <95% 8, 9
Adult: <95% 8, 9
Odonto: <95% 8, 9
Deletion/duplication analysis 10Exonic, multiexonic, and whole-gene deletionsUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Targeted mutations may vary by laboratory.

5. Mild disease corresponds to childhood, adult, and odontohypophosphatasia.

6. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. In individuals with severe (perinatal and infantile) hypophosphatasia, two ALPL mutations are identified in approximately 95% of cases of European ancestry.

8. Japanese overall mutation detection frequency is the same as European, but c.1559delT accounts for 40.9% of alleles, c.979T>C 13.6% of alleles.

9. In more moderate forms in which one mutant allele is believed sufficient to cause disease, mutation detection rate is more difficult to estimate. Overall, ~50% have two ALPL mutations (compound heterozygote or homozygote); about 40%-45% only one identified mutation. The milder the disease, the higher the proportion in which only one ALPL mutation is detected in both European and Japanese populations.

10. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Clinical suspicion based on history, physical examination, and radiographs
  • Routine laboratory testing to screen for hypophosphatasia: unfractionated serum alkaline phosphatase activity

    Note: Serial measurements may be necessary in the presence of conditions that result in elevated serum alkaline phosphatase activity, including acute fracture.
  • Confirmation of the diagnosis of hypophosphatasia by one of the following:
    • Specialized evaluation of TNSALP substrates (serum PLP concentration and/or urine PEA concentration)

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Description

Natural History

The clinical features of hypophosphatasia represent a spectrum ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood [Whyte 1994].

The clinical classification reflects a continuous spectrum of severity, with pseudohypophosphatasia distinguished by infantile phenotype and normal alkaline phosphatase activity.

Perinatal (lethal) hypophosphatasia is typically identified by prenatal ultrasound examination. Pregnancies may end in stillbirth. Small thoracic cavity and short, bowed limbs are seen in both liveborn and stillborn infants. A flail chest may be present. Infants with perinatal hypophosphatasia may experience pulmonary insufficiency; it is the most frequent cause of death. Hypercalcemia is common and may be associated with apnea or seizures.

Perinatal (benign) hypophosphatasia is typically identified by prenatal ultrasound examination. Postnatally, skeletal manifestations slowly resolve with an eventual childhood or adult hypophosphatasia phenotype. All reported cases have been born to mothers who have at least biochemical, if not clinical, evidence of hypophosphatasia [Pauli et al 1999].

Infantile hypophosphatasia cases may be normal at birth. Clinical signs may be recognized between birth and age six months. Clinical features resemble rickets. Clinical severity depends on the degree of pulmonary insufficiency and the complications of hypercalcemia, including irritability, poor feeding, failure to thrive, hypotonia, and more rarely vitamin B6-dependent seizures (see Management). Older children may have renal damage.

Pseudohypophosphatasia is characterized by clinical, biochemical, and radiographic findings reminiscent of infantile hypophosphatasia, with the exception that clinical laboratory assays of serum alkaline phosphatase activity are in the normal range.

Childhood hypophosphatasia displays wide variability in clinical presentation, ranging from low bone mineral density for age with unexplained fractures to rickets. Children may have premature loss of deciduous teeth (age <5 years), usually beginning with incisors. More severely affected toddlers have short stature and delay in walking, and develop a waddling myopathic gait. Bone and joint pain are typical. Diaphyseal and metaphyseal fractures may occur.

The radiographic appearance of open fontanels and wide sutures is deceptive because the hypomineralized bone causing this appearance is prone to premature fusion. Thus, craniosynostosis and intracranial hypertension are potential complications.

Adult hypophosphatasia is sometimes associated with a history of transient rickets in childhood and/or premature loss of deciduous teeth. Early loss of adult dentition is common. Other dental problems in adolescents and adults with hypophosphatasia are more poorly characterized, although enamel hypoplasia and tooth mobility have been described. Adult hypophosphatasia is usually recognized in middle age, the cardinal features being stress fractures and pseudofractures of the lower extremities. Foot pain is common; slow-to-heal stress fractures of the metatarsals are common. Thigh and hip pain may reflect pseudofractures, or "Looser zones," in the lateral cortex of the femoral diaphysis (Figure 1C). Chondrocalcinosis and osteoarthropathy may develop with age. Osteomalacia distinguishes adult hypophosphatasia from odontohypophosphatasia.

Odontohypophosphatasia can be seen as an isolated finding without additional abnormalities of the skeletal system or can be variably seen in the above forms of hypophosphatasia. Premature exfoliation of primary teeth and/or severe dental caries may be seen, with the incisors most frequently lost.

Histologic evaluation. Bone histology reveals rachitic abnormalities of the growth plate. Histochemical testing of osteoclasts reveals lack of membrane-associated ALP activity. Osteoclasts and osteoblasts otherwise appear normal.

Tooth histology reveals a decrease in cementum, which varies with the severity of the disease.

Genotype-Phenotype Correlations

Most affected individuals have unique mutant alleles, making the prediction of the phenotype difficult. However, there is a good correlation between the severity of the phenotype and the residual enzymatic activity produced in vitro by the enzyme [Zurutuza et al 1999, Orimo et al 2001].

Genotype-phenotype correlations have been studied by the use of site-directed mutagenesis and 3D modeling of the enzyme [Fukushi et al 1998, Shibata et al 1998, Zurutuza et al 1999, Mornet et al 2001, Watanabe et al 2002, Nasu et al 2006, Brun-Heath et al 2007]. According to 3D modeling studies, more than 70% of the mutations affect functional domains of the protein, namely the active site, the calcium binding site, the crown domain, and the homodimer interface. Mutations with a dominant negative effect are preferentially located in functional domains, particularly the active site.

Nomenclature

Hypophosphatasia takes its name from low activity of the enzyme alkaline phosphatase, rather than reflecting serum concentration of phosphorus.

In classifications of genetic conditions, hypophosphatasia may be considered a metabolic bone disease, a skeletal dysplasia, a metaphyseal dysplasia, a dental disorder, or a disorder of membrane-bound ectoenzyme activity in the extracellular matrix.

Prevalence

Based on pediatric hospital records in Ontario, Canada, the birth prevalence of (autosomal recessive) perinatal and infantile hypophosphatasia was estimated at 1:100,000 [Fraser 1957].

Applying the Hardy-Weinberg equation to this estimate, the frequency of heterozygotes for deleterious ALPL mutations in Ontario, Canada is about 1:150.

In the Canadian Mennonite population, the prevalence of the perinatal lethal form is 1:2500, for a carrier frequency of 1:25.

In Africa, no cases have been reported outside of North Africa; however, clinical ascertainment bias is likely significant. African American cases are rare; it is assumed that mutations in this population represent European admixture.

On the basis of the frequency of heterozygotes, and of the proportion of mutations exhibiting a dominant negative effect [Muller et al 2000, Lia-Baldini et al 2001, Fauvert et al 2009], it is expected that mild forms of hypophosphatasia (childhood, adult, and odontohypophosphatasia) are more common than severe forms. However, because of incomplete penetrance in these forms, an estimate of the prevalence is difficult to establish.

Differential Diagnosis

The differential diagnosis of hypophosphatasia depends on the age at which the diagnosis is considered. Clinical features that help differentiate hypophosphatasia from other conditions include bone hypomineralization prenatally and immediately postnatally; elevated serum concentrations of calcium and phosphorus postnatally; and of course, persistently low serum alkaline phosphatase enzyme activity.

In utero. Early prenatal ultrasound examination may lead to a consideration of osteogenesis imperfecta (OI) type II, campomelic dysplasia, and chondrodysplasias with defects in bone mineralization, as well as hypophosphatasia. Experienced sonographers usually have little difficulty in distinguishing among these disorders. Fetal x-rays are sometimes helpful in recognizing the undermineralization of bone that is more typical of perinatal hypophosphatasia than the other disorders considered in the differential diagnosis.

At birth. Outwardly difficult to distinguish, osteogenesis imperfecta (OI type II), thanatophoric dysplasia, campomelic dysplasia, and chondrodysplasias with bone mineralization defects are readily distinguished from hypophosphatasia by radiograph. In cases in which the diagnosis is in doubt, serum alkaline phosphatase activity and specialized biochemical testing (serum concentration of PLP, urine concentration of PEA) can suggest the diagnosis pending confirmation with molecular genetic testing.

Infancy and childhood. Irritability, poor feeding, failure to thrive, hypotonia, and seizures place the infantile type in a broad differential diagnosis that includes inborn errors of energy metabolism, organic acidemia, primary and secondary rickets, neglect, and non-accidental trauma. Providing appropriate pediatric normative reference values are used, infantile hypophosphatasia is suspected with low serum alkaline phosphatase enzyme activity, making the argument for routine screening of serum alkaline phosphatase enzyme activity in cases of failure to thrive and suspected non-accidental skeletal injury.

  • Rickets defines the physical and radiographic features of early hypophosphatasia. However, whether caused by nutritional and/or vitamin D deficiency, vitamin D resistance, or renal osteodystrophy, rickets is readily distinguished from hypophosphatasia by laboratory findings. In rickets, the following are characteristic:
    • Elevated serum alkaline phosphatase activity
    • Low serum concentrations of calcium and phosphorus
    • Low serum concentrations of vitamin D
    • Elevated serum concentration of parathyroid hormone
  • Osteogenesis imperfecta (OI) with deformation (typically type III in infancy or type IV later on) may resemble hypophosphatasia clinically.
  • Dentinogenesis imperfecta (DI), whether part of OI or an isolated finding, is distinguishable from the dental presentation of hypophosphatasia.
  • Cleidocranial dysostosis is characterized by late closure of fontanels and cranial sutures, aplastic clavicles, delayed mineralization of the pubic rami, and delayed eruption of deciduous and permanent teeth. The skeletal dysplasia is distinguishable from hypophosphatasia on clinical examination and skeletal survey. The dental dysplasia does not result in early tooth loss, and the enamel hypoplasia is readily distinguishable from odontohypophosphatasia.
  • Cole-Carpenter syndrome (OMIM 112240) is characterized by bone deformities, multiple fractures, proptosis, shallow orbits, orbital craniosynostosis, frontal bossing, and hydrocephalus.
  • Hadju-Cheney syndrome (OMIM 102500) is characterized by failure to thrive, dysmorphic facial features, early tooth loss, genitourinary anomalies, osteopenia, pathologic fractures, Wormian bones, failure of suture ossification, basilar impression, vertebral abnormalities, joint laxity, bowed fibulae, short distal digits, acroosteolysis, and hirsutism.
  • Idiopathic juvenile osteoporosis (IJO) typically presents in preadolescents with fractures and osteoporosis. The fracture susceptibility and osteoporosis usually resolve spontaneously with puberty. The etiology remains unknown.
  • Renal osteodystrophy may be confused with late presentation of the childhood type associated with renal damage; however, characteristic biochemical findings distinguish the two disorders.
  • Non-accidental trauma (child abuse). Like osteogenesis imperfecta, patient history, family history, physical examination, routine laboratories, radiographic imaging, and the clinical course all contribute to distinguishing hypophosphatasia from child abuse. Multiple fractures are less typical of hypophosphatasia. The family history may be particularly instructive in that the perinatal lethal type is an autosomal recessive disorder, and the childhood, adult, and odontohypophosphatasia types are autosomal dominant disorders; all have been reported in a single family ascertained by unexplained fracture in a child [Lia-Baldini et al 2001]. Serial measurement of serum alkaline phosphatase activity is usually sufficient to identify hypophosphatasia in this circumstance.

Adult and odontohypophosphatasia

  • Osteoarthritis and pseudogout (secondary to calcium pyrophosphate dehydrate deposition) are presentations of adult hypophosphatasia, distinguished from the more common disorders by clinical history and laboratory findings.
  • Osteopenia/osteoporosis needs to be distinguished from adult hypophosphatasia, in that bisphosphonates may be contraindicated (see Management, Agents/Circumstances to Avoid).
  • Periodontal disease may be difficult to distinguish from hypophosphatasia, in that alveolar bone loss can be seen with severe gingivitis. However, gingival inflammation is unusual with odontohypophosphatasia. Familial periodontal disease can be inherited in an autosomal dominant manner (OMIM 170650) as part of a connective tissue disorder (e.g., Ehlers-Danlos syndrome, vascular type or Ehlers-Danlos syndrome, periodontal type) or associated with neutropenia (e.g., ELANE-related neutropenia).

    Rarer autosomal recessive disorders associated with premature tooth loss and periodontal disease include Papillon-Lefevre syndrome and Haim-Munk syndrome (HMS), caused by mutations in CTSC, the gene encoding cathepsin C. The periodontal disease is usually of earlier onset and more severe than that seen with odontohypophosphatasia. Both Papillon-Lefevre syndrome and HMS are usually associated with palmar keratosis, further distinguishing them from odontohypophosphatasia. Measurement of serum alkaline phosphatase enzyme activity is reasonable when either disorder is considered.
  • Dentinogenesis imperfecta (DI). Whether associated with osteogenesis imperfecta or as an isolated condition resulting from DSPP mutation [Rajpar et al 2002], DI is readily distinguishable from odontohypophosphatasia on biochemical findings.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with hypophosphatasia, the following evaluations are recommended:

  • Blood urea nitrogen and serum creatinine concentration to assess renal function
  • Serum concentration of calcium, phosphorus, magnesium
  • Serum concentration of 25(OH) and 1,25(OH)2 vitamin D, nPTH (parathyroid hormone, N-terminal part) to assess rickets
  • Assessment of pulmonary function in infants with the perinatal type to assist in prognosis and distinguishing between the perinatal lethal type and the perinatal benign type
  • X-rays of the skull to assess for craniosynostosis in young children with the infantile form of hypophosphatasia

Treatment of Manifestations

Management at all ages focuses on supportive therapy to minimize disease-related complications.

Perinatal types. In the perinatal period, if multidisciplinary assessment identifies the perinatal lethal type, expectant management and family support are appropriate. Molecular genetic testing should be used to confirm the diagnosis, establish recurrence risk for family members, and provide for potential prenatal diagnosis.

Infantile type. Infantile cases have high mortality, with 50% succumbing to respiratory failure caused by undermineralization of the ribs.

Management can further be complicated by recalcitrant hypercalcemia/hypercalciuria.

When present, seizures may respond to treatment with vitamin B6 (pyridoxine). Pyridoxal phosphate (PLP), one of the natural substrates of alkaline phosphatase, is the active compound by which pyridoxine mediates essential enzyme activity; PLP deficiency in the central nervous system may reduce seizure threshold by reducing neurotransmitter (GABA) synthesis.

Craniosynostosis in infantile cases is variable. When identified, involvement of a neurosurgeon to monitor for complications is prudent. Increased intracranial pressure secondary to craniosynostosis is an indication for surgical release.

Dental care, beginning at age one year (the new universal recommendation for all children, regardless of whether they have an underlying medical condition), is important to preserve primary dentition (to support nutrition) and to preserve or replace secondary dentition.

Osteoarthritis may respond to NSAIDs.

Bone pain and osteomalacia are managed supportively: NSAIDs appear beneficial [Girschick et al 2006]. Hypophosphatasia is a relative contraindication to treatment with bisphosphonates (see Agents/Circumstances to Avoid).

Pseudofractures and stress fractures are difficult to manage; internal fixation has been suggested as the optimal orthopedic management. Foot orthotics may help in management of tarsal fractures and pseudofractures in adults.

Prevention of Primary Manifestations

Low impact physical activity and exercise may improve general bone health. Supervision by a physician specialist familiar with hypophosphatasia is suggested.

Prevention of Secondary Complications

Calcium supplementation and vitamin D therapy may prevent secondary hyperparathyroidism in adults. This should only be pursued with close monitoring by a physician specialist familiar with hypophosphatasia.

Surveillance

Children with hypophosphatasia should be seen by a pediatric dentist twice yearly, beginning at age one year.

Children with the infantile type of hypophosphatasia are at elevated risk for increased intracranial pressure secondary to craniosynostosis, and should be monitored for this complication.

Agents/Circumstances to Avoid

Biphosphonates are relatively contraindicated in hypophosphatasia. Although adverse outcomes have not been identified in children with the severe infantile type [Deeb et al 2000] theoretical concern has long been raised based on the structure of bisphosphonates. The phosphate motifs in bisphosphonates have a similar conformation to inorganic pyrophosphate (PPi), the natural substrate of TNSALP; thus, treatment with bisphosphonates is thought to be analogous to "adding fuel to the fire." In adults with hypophosphatasia and osteomalacia treated with bisphosphonates, lateral subtrochanteric femoral pseudofractures have been described [Whyte 2009]. As the prevalence of adult hypophosphatasia is not known and many undiagnosed adult patients undoubtedly are treated with bisphosphonates, the frequency of this unusual complication is not known.

Excess vitamin D can exacerbate hypercalcemia/hypercalciuria in children with infantile hypophosphatasia who have hypercalcemia.

Teriparatide (recombinant human parathyroid hormone fragment, amino acids 1-34) at high doses induces osteosarcoma in rats, and may increase the risk of radiation-induced osteosarcoma (a pediatric growth plate tumor) in humans. It is contraindicated in children with childhood hypophosphatasia.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Autosomal recessive hypophosphatasia is an extremely rare and severe condition; thus, clinical therapies are compassionate and anecdotal. Bone marrow transplantation (i.e., hematopoietic stem cell transplantation) was used to treat an eight-month-old girl with severe hypophosphatasia with prolonged, significant clinical and radiologic improvement [Whyte et al 2003]. Seven years after transplantation, the patient was reported to be active and growing, and to have the clinical phenotype of the more mild childhood form of hypophosphatasia [Cahill et al 2007].

Restoration of a normal bone phenotype is seen in Alpl (Akp2) knockout mice in which an Alpl antagonist gene, Pc-1 (Enpp1), is inactivated. PC-1 (ENPP1) suppression, therefore, may be a potential pharmacologic option in treating human hypophosphatasia [Hessle et al 2002].

Enzyme replacement therapy (ERT) has been developed and successively tested in mice [Millán et al 2008]. Clinical trials recently started and ERT should be available soon for persons with hypophosphatasia. Note: Confirmation of the diagnosis of hypophosphatasia by molecular genetic testing will be indispensable before starting the treatment, and perhaps for milder forms, the characterization of the mutation(s) will orient and personalize the treatment.

Although autosomal dominant (AD) hypophosphatasia is more common than autosomal recessive hypophosphatasia, it is less likely to be recognized. For this reason and because affected individuals are often older at the time of diagnosis of AD hypophosphatasia, no large scale or long term clinical trials have been performed for AD hypophosphatasia. In case reports of teriparatide treatment, which is felt to upregulate wildtype ALPL expression, reduced bone pain, increased alkaline phosphatase activity, and improved biochemical markers of bone turnover were observed in three postmenopausal women with adult hypophosphatasia [Whyte et al 2007, Camacho et al 2008]. It is not clear whether the response is transient, and to what extent genotype and molecular/biochemical phenotype modulate the effect [Gagnon et al 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Treatment with calcitonin, chlorthiazide, and bisphosphonates has shown little or no efficacy [Deeb et al 2000].

Treatment with cortisone, vitamin B6, zinc, magnesium, and parathyroid hormone makes no significant clinical difference.

Calcium supplementation or treatment with vitamin D does not offer major benefit in childhood hypophosphatasia as these parameters are usually normal.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Perinatal and infantile hypophosphatasia are inherited in an autosomal recessive manner. The milder forms, especially adult and odontohypophosphatasia may be inherited in an autosomal recessive or autosomal dominant manner depending on the effect the ALPL mutation has on TNSALP activity.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore typically carry one mutant allele.
  • Taillandier et al [2005] reported one case of de novo mutation in the second ALPL allele in an individual with autosomal recessive hypophosphatasia; thus, parents of an affected individual are not always carriers.
  • Heterozygotes (carriers) either are asymptomatic, manifesting biochemical but not clinical abnormality, or may manifest milder symptoms depending on the mutation.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an "asymptomatic" carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) either are asymptomatic, manifesting biochemical but not clinical abnormality, or they may manifest milder symptoms depending on the mutation. Determining the mode of inheritance in such families is difficult as mildly affected parents may lead to consideration of autosomal dominant inheritance.

Offspring of a proband. The offspring of an individual with hypophosphatasia are obligate heterozygotes (carriers) for a pathogenic variant in ALPL.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the mutations have been identified in the family.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with the autosomal dominant form of hypophosphatasia have inherited the pathogenic variant from a parent who may or may not have symptoms. A proband with the autosomal dominant form of hypophosphatasia could have the disorder as the result of new gene mutation. However, de novo mutation in the autosomal dominant form of hypophosphatasia has never been reported, indicating that the proportion of cases caused by de novo mutation is very low.
  • If the pathogenic variant found in the proband cannot be detected in DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include careful review of clinical history and laboratory evaluations for signs of hypophosphatasia. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with the autosomal dominant form of hypophosphatasia have inherited the pathogenic variant from a parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with the autosomal dominant form of hypophosphatasia has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Determining the mode of inheritance can be difficult in some families as dominance is sometimes difficult to demonstrate by using familial analysis. Expression of the disease may be highly variable, with parents of even markedly affected children showing no or extremely mild symptoms of the disease.

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that mutation occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Pregnancy with high a priori risk (pregnancy known to be at increased risk based on family history)

  • Molecular genetic testing. If the pathogenic variant(s) have been identified or linkage established in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

    Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
  • Fetal ultrasonography. Recurrence of perinatal and infantile hypophosphatasia may reliably be identified by prenatal ultrasound examination. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. Long bone bowing has been reported prenatally in affected sibs and in children of individuals with childhood or adult hypophosphatasia, but the finding is not diagnostic of hypophosphatasia.
  • Biochemical testing. Concentration of alkaline phosphatase in amniotic fluid, amniocytes, and chorionic villous samples is prone to misinterpretation (particularly in distinguishing unaffected heterozygotes); molecular genetic testing is the preferred method in confirming prenatal diagnosis [Mornet et al 1999].

Pregnancy with low a priori risk (pregnancy not known to be at risk)

  • Fetal ultrasonography. Although perinatal and infantile hypophosphatasia may be distinguished from other skeletal dysplasias by prenatal ultrasonography, care must be taken in the interpretation of bowed long bones. Undermineralization, small thoracic cavity, shortened long bones, and bowing are typical features of autosomal recessive and severe hypophosphatasia. However, prognosis is difficult to predict based on ultrasound findings alone. Bowed and shortened long bones have been observed on prenatal ultrasound in individuals who ultimately were shown to have benign perinatal, childhood, and adult hypophosphatasia. The bowing resolves postnatally. In such cases when ALPL molecular testing has been performed, a single mutation in ALPL has been identified.

Preimplantation genetic diagnosis (PGD) may be available for families in which the pathogenic variant(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hypophosphatasie Europe
    16 rue Barbanègre
    Huningue 68330
    France
    Email: contact@hypophosphatasie.com
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423; 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hypophosphatasia: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hypophosphatasia (View All in OMIM)

146300HYPOPHOSPHATASIA, ADULT
171760ALKALINE PHOSPHATASE, LIVER; ALPL
241500HYPOPHOSPHATASIA, INFANTILE
241510HYPOPHOSPHATASIA, CHILDHOOD

Gene structure. The gene consists of 12 exons: 11 coding exons and one untranslated exon. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Three benign variants are c.455G>A, c.787T>C, and c.876A>G. A number of exonic and intronic sequence variations have been reported as polymorphisms in the ALPL mutation database.

Pathogenic allelic variants. To date, more than 218 distinct pathogenic variants have been described in ALPL in persons from North America, Japan, and Europe. A continually updated list of mutations is available online; see www.sesep.uvsq.fr. (See also Table A.)

The mutations are distributed throughout the 12 exons of the gene. Missense mutations account for 78.7% of mutations; the remainder comprise microdeletions/insertions (11.7%), splicing mutations (4.8%), nonsense mutations (2.7%), gross deletions (1.1%), and a nucleotide substitution affecting the major transcription initiation site. This variety of mutations results in highly variable clinical expression and in a great number of compound heterozygous genotypes.

Table 4. Selected ALPL Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.455G>Ap.Arg152His
(Arg135His)
NM_000478​.3
NP_000469​.3
c.787T>Cp.Tyr263His
(Tyr246His)
c.1565T>Cp.Val522Ala
(Val505Ala)
Pathogenicc.979T>C p.Phe327Leu
(Phe310Leu)
c.571G>A p.Glu191Lys
(Glu174Lys)
c.1001G>A p.Gly334Asp
(Gly317Asp)
c.1133A>T p.Asp378Val
(Asp361Val)
c.1559delTLonger sized protein

The amino acid residues are numbered from the beginning of the signal peptide sequence.

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions. In this instance, the alias is the amino acid residue of the mature peptide.

Normal gene product. ALPL encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP), the isozyme present in liver, kidney, and bone. Alkaline phosphatase comprises 524 amino acids, with a signal peptide of 17 amino acids and a mature peptide of 507.

The enzyme acts as a (lipid) membrane-bound ectophosphatase with PLP and PEA as natural substrates.

Abnormal gene product. The catalytic activity of mutated proteins is affected and/or the mutated protein is sequestered in cell compartments and consequently unable to reach the cell membrane, its final destination for physiologic activity [Cai et al 1998, Fukushi et al 1998, Shibata et al 1998, Watanabe et al 2002, Brun-Heath et al 2007].

References

Literature Cited

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  2. Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, Mumm S, Whyte MP. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. 2007;92:2923–30. [PubMed: 17519318]
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  13. Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN. A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics. 1993;17:215–7. [PubMed: 8406453]
  14. Hérasse M, Spentchian M, Taillandier A, Mornet E. Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. Eur J Hum Genet. 2002;10:666–8. [PubMed: 12357339]
  15. Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R, Millan JL. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A. 2002;99:9445–9. [PMC free article: PMC123160] [PubMed: 12082181]
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Suggested Reading

  1. Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 207. Available online. Accessed 3-07-14.

Chapter Notes

Revision History

  • 10 November 2011 (cd) Revision: deletion/duplication analysis of ALPL available clinically
  • 5 August 2010 (me) Comprehensive update posted live
  • 20 November 2007 (me) Review posted to live Web site
  • 18 December 2006 (men) Original submission
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