Hypophosphatasia (HPP)

Updated: Aug 07, 2019
Author: Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG 



Hypophosphatasia (HPP) is a multisystem disease with deleterious effects that can appear at different ages and progress over time. In adults, the symptoms of HPP are often misdiagnosed and confused with other, more common, bone or rheumatologic diseases, leading to delayed diagnosis and inappropriate treatment, such as high-dose vitamin D supplementation, excessive calcium supplementation, and bisphosphonates that could be ineffective or even worsen the symptoms.[1] Patients presenting with abnormal bone features should undergo alkaline phosphatase and vitamin B6 testing to rule out this diagnosis.

Initially recognized by Rathbun in 1948, HPP is a rare inborn error of metabolism caused by mutations in the ALPL gene located on chromosome 1 (1p36.1) and consists of 12 exons distributed over 50 kb, encoding tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP).[2] TNSALP is an ectoenzyme bound to the outer surface of osteoblasts. TNSALP is a phosphomonoesterase of 507 residues and is anchored at its carboxyl terminus to the plasma membrane by a phosphatidylinositol-glycan moiety. It dephosphorylates several substrates, including inorganic pyrophosphate (PPi), which inhibits bone mineralization produced by osteoblasts and chondrocytes. Accumulation of PPi when TNSALP is deficient impairs calcium/phosphate formation of hydroxyapatite, leading to accumulation of unmineralized osteoid (a feature of rickets and osteomalacia).[3, 4]

The clinical presentation of hypophosphatasia varies from devastating prenatal intrauterine disease to mild manifestations in adulthood. Six clinical forms have been identified: perinatal, prenatal benign (with spontaneous improvement of skeletal defects despite prenatal signs of disease), infantile, juvenile, adult form, and odontohypophosphatasia[5] (no clinical changes in long bones, only biochemical and dental manifestations).

Another condition, pseudohypophosphatasia, is clinically indistinguishable from infantile hypophosphatasia, but serum alkaline phosphatase (ALP) activity is normal. Pseudohypophosphatasia has been suggested as a possible consequence of a mutant TNSALP gene that still has activity in vitro but not in vivo. Conversely, in these patients, phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal-5'-phosphate (PLP) levels are elevated in serum and urine despite normal or elevated alkaline phosphatase activity levels.

Patients may present with varying signs and symptoms, history, and inheritance patterns. The most severe forms of the disease have an autosomal recessive mode of inheritance, but the specific pattern of transmission of mild forms is variable. Analysis of the TNSALP gene aids prenatal diagnosis. Compound heterozygosity and autosomal dominant mutations in the TNSALP gene may cause childhood and adult hypophosphatasia. At least 2 mutations occur in specific populations and are lethal when homozygous: c.1559delT affects Japanese patients and gly317asp is found in a Canadian Mennonite population.


Alkaline phosphatase is present as 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. TNSALP is known to cleave the phosphate-containing substrates PLP, PEA, and PPi, which are all extracellular substrates.

Patients with hypophosphatasia have low alkaline phosphatase activity levels, which leads to increased PPi, an inhibitor of hydroxyapatite crystal formation. The increase in PPi causes defects in calcium and phosphate balance.



United States

The exact prevalence of HPP is unknown and varies by form and region.[6, 7] In the United States, it affects approximately 500-600 individuals per year. In some inbred populations, such as Canadian Mennonites, the frequency is as high as 1 case per 2500 newborns. More than 250 distinct mutations have been described for the gene responsible for HPP, the vast majority (79%) of which are missense mutations.


International incidence is unknown. It appears that the disease is more prevalent in Japan and in a specific Mennonite population in Canada.


The most severe forms of HPP tend to occur before birth and in early infancy. Hypophosphatasia weakens and softens the bones, causing skeletal abnormalities similar to those of another childhood bone disorder called rickets. Affected infants are born with short limbs, an abnormally shaped chest, and soft skull bones. Additional complications in infancy include poor feeding and failure to gain weight, respiratory problems, and high levels of calcium in the blood (hypercalcemia), which can lead to recurrent vomiting and kidney problems. These complications are life-threatening in some cases. The mortality rate in infants with hypophosphatasia is 50% in patients who manifest within 6 months of birth. The most common cause of death in infants with hypophosphatasia is respiratory complications.

The forms of hypophosphatasia that appear in childhood or adulthood are typically less severe than those that appear in infancy. Early loss of primary (baby) teeth is one of the first signs of HPP in children. Affected children may have short stature with bowed legs or knock knees, enlarged wrist and ankle joints, and an abnormal skull shape. Adult forms of hypophosphatasia are characterized by a softening of the bones, known as osteomalacia. In adults, recurrent fractures of the feet and thigh bones can lead to chronic pain. Affected adults may lose their secondary (adult) teeth prematurely and are at increased risk of joint pain and inflammation. Patients may also present with nephrocalcinosis, neurological damage secondary to vitamin B6 respondent seizures, increased intracranial pressure secondary to craniosynostosis, and joint problems secondary to calcium deposits. Adults may present with severe mobility impairment (about 23% require the use of a wheelchair; about 25% require the use of a walking device). On the other side of the spectrum, adults may be diagnosed incidentally after a low alkaline phosphatase level is detected.

The mildest form of HPP, called odontohypophosphatasia, affects only the teeth. People with this disorder typically experience abnormal tooth development and premature tooth loss but do not have the skeletal abnormalities seen in other forms of hypophosphatasia.[8]


Hypophosphatasia occurs in all races.


Males and females are equally affected.


Hypophosphatasia affects all age groups; however, the severity of the disease in general varies with age, from a lethal disorder in neonates to a less severe condition in some adults. Most cases are diagnosed during childhood and adolescence.


The most severe form is perinatal HPP, which is considered lethal in most cases. The infantile form is fatal in approximately 30% of patients. Longevity studies have not been conducted for the infantile and childhood forms. Individuals with the adult and odontohypophosphatasic forms have normal lifespans.

Patient Education

Genetic counseling is important for all families with affected individuals. A pedigree is essential, especially for the childhood, adult, or odontohypophosphatasic forms, which can have either autosomal dominant or recessive forms. Options for future pregnancies, such as prenatal testing for the perinatal form, should be discussed with parents.




The most severe form of hypophosphatasia is universally lethal and occurs in the perinatal stage. Review of pregnancy history may reveal polyhydramnios. Skeletal manifestations of the severe cases vary widely among patients. Typical radiographic features include lack of ossification in some bones; marked variability in the degree of bone ossification; unusually dense, round, flattened, and butterfly-shaped vertebral bodies; and generalized smaller ossified bones. Bones are affected to different degrees in the same patient; the bones affected differ among patients. Variability in femoral shape is also observed, and osteochondral projections (Bowdler spurs) of the midshaft of the fibula and ulna may be present. Prognosis is poor, but affected newborns may briefly survive. The cause of death is usually severe respiratory compromise, which may occur with fever of unknown origin, anemia, irritability, seizures, and dehydration.

Initially, affected infants may appear healthy until the onset of signs, which occurs when they are younger than 6 months. These infants have a history of poor feeding and failure to thrive, developmental delays, and muscle weakness. Hypotonia has also been reported.

Affected children often have a history of delayed walking and early loss of deciduous teeth. Bone pain is a frequent symptom. Both infants and children may present with nephrocalcinosis.

Adults usually present with signs and symptoms during the third and fourth decades of life, although careful interrogation often reveals signs during childhood or even infancy. They present with early loss of primary or secondary teeth, osteoporosis, bone pain, chondrocalcinosis, chronic muscle pain, reduced muscular strength, and fractures. Joint pain and restricted range of motion (ROM) may be associated because of chondrocalcinosis.[1] Adults may also have a history of foot pain due to unhealed stress fractures. Affected adults may manifest osteomalacia, with slowly healing or nonunion stress fractures (commonly metatarsal) and proximal femur pseudofractures.

Asymptomatic HPP in adults is uncommon: in these cases, the diagnosis is made based on laboratory findings including elevated vitamin B6 and its metabolite in the urine and low alkaline phosphatase (ALP).[1]

Odontohypophosphatasia presents with a premature loss of adult teeth.


Infants with extremely severe hypophosphatasia may be stillborn. Some infants survive a few days but have respiratory complications due to hypoplastic lungs and rachitic deformities of the chest. Other findings include apnea, seizures, craniosynostosis, and marked shortening of the long bones.

Surviving infants may appear healthy at birth; however, the clinical signs of hypophosphatasia appear during the first 6 months of life. These patients also have respiratory complications due to rachitic deformities of the chest. Despite the presence of an open fontanelle, premature craniosynostosis is a common finding that may result in increased intracranial pressure. Hypercalcemia is also present, and increased excretion of calcium may lead to nephrocalcinosis and renal damage. Infants may also present with severe epileptic encephalopathy that results in death. These seizures respond to vitamin B-6 treatment.[9]

Skeletal deformities (eg, dolichocephalic skull and enlarged joints), a delay in walking, short stature, and waddling gait accompany the childhood form. A history of fractures and bone pain is usually noted.[10] Premature loss of dentition is common; the incisor teeth are often the first affected.

HPP in adults is often diagnosed in the third and fourth decades of life. The condition can be completely asymptomatic and is suspected after an elevated vitamin B6 level or low alkaline phosphatase activity level is found during routine laboratory studies, although careful interrogation often reveals signs and symptoms that started early in life. The first symptom may be foot pain, which is due to unhealed stress fractures of the metatarsals. Thigh pain due to pseudofractures of the femur may also be a presenting symptom. Upon obtaining an in-depth history, many of these patients reveal that they have experienced premature loss of their deciduous teeth Elevated vitamin B6 levels in these individuals may be associated with neuropathy.

The only physical finding in odontohypophosphatasia is the premature loss of teeth.

Chronic bone edema in the adult form and chronic hyperprostaglandinism in the childhood form suggest that, in some patients, bone inflammation is present in conjunction with the metabolic defect. Sterile multifocal osteomyelitis has been reported but is uncommon.[11]


HPP is caused by a mutation in the ALPL gene on chromosome 1(1p36.1-34), encoding TNSALP. TNSALP is an ectoenzyme bound to the outer surface of osteoblasts. It dephosphorylates several substrates, including inorganic pyrophosphate (PPi), which inhibits bone mineralization produced by osteoblasts and chondrocytes. Accumulation of PPi when TNSALP is deficient impairs calcium/phosphate formation of hydroxyapatite, leading to accumulation of unmineralized osteoid (a feature of rickets and osteomalacia).[3, 4]

More than 250 mutations have been described to date. Perinatal and infantile hypophosphatasia have an autosomal recessive mode of inheritance. Both autosomal recessive and autosomal dominant patterns of inheritance have been demonstrated for the childhood, adult, and odontohypophosphatasia forms. Frequently, patients are compound heterozygous. The penetrance of the mutation is unknown.


Complications of the more severe forms of hypophosphatasia usually involve the respiratory system. Skeletal deformities can predispose an infant to respiratory compromise or pneumonia. In the infantile form, craniosynostosis can lead to increased intracranial pressure.

HPP has a significantly negative effect on quality of life. Almost all adult patients reported chronic pain (of the bones, joints, and muscles), and a significant majority required daily use of analgesics; this finding was confirmed in other studies.[12] Therefore, pain management is a mainstay of therapy. A physiotherapist, occupational therapist, and chronic-pain management team are most effective.[13] Nephrocalcinosis has also been reported as a complication.



Differential Diagnoses



Laboratory Studies

Assess the alkaline phosphatase and vitamin B6 levels. The former is consistently low and the latter consistently elevated. Do not use ethylenediaminetetraacetic acid (EDTA) tubes because these cause erroneous test results. The reference range should be appropriate for the age group undergoing testing, and results vary among laboratories.

Laboratory testing must be performed on fasting individuals for phosphate analysis (alkaline phosphatase activity levels can be measured in nonfasting patients). Laboratory evaluations should include levels of calcium, phosphorus, magnesium, alkaline phosphatase, creatinine, parathyroid hormone (PTH), 25(OH) vitamin D, and 1,25(OH)2 vitamin D. Levels of PLP, PPi in plasma, and PEA in urine determine the diagnosis. Measurement of ALP in amniotic fluid yields variable results, which are of relative value in the prenatal diagnosis of this entity. ALP in cultured amniotic cells may be quantified, but interpretation of the results is difficult. Monoclonal antibodies against TNSALP may serve to reveal a deficiency in chorionic villous tissue. The test for PPi is typically performed only in research laboratories.

PEA levels can be obtained from urine to help support the diagnosis. Elevated levels of PEA may also characterize other forms of bone disease.

An elevation of PLP is also present. This test must be done carefully, as the patient's intake of vitamins or energy drinks (particularly those containing vitamin B6) may affect results.

Low alkaline phosphatase levels can result from severe or long-term vitamin and/or mineral deficiencies or chronic conditions that can cause malnutrition, such as untreated celiac disease.  

Liver function test results tend to be normal.

Whenever possible, measure alkaline phosphatase activity and vitamin B6 levels in all members of the direct family. Genetic screening of family members is warranted if vitamin B6 levels are high or alkaline phosphatase levels low.

Imaging Studies

Perform a radiologic skeletal survey on patients in whom the diagnosis of hypophosphatasia is being considered.

In lethal cases, there is frequently a near absence of skeletal mineralization. Fractures and rachitic changes are often present. Skin-covered spurs that extend from the medial and lateral aspects of the knee and elbow joints may also be present. Deficient skeletal mineralization is also evident in surviving infants, although it tends to be less severe than in the lethal perinatal cases. Premature cranial synostosis often occurs despite an open fontanelle.

Rachitic deformities characterize the disease in children. Upon radiologic examination of the metaphysis, evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This is not found in other types of rickets.

Pseudofractures are one of the hallmarks of hypophosphatasia in adults, often occurring in the lateral aspect of the proximal femur. An increased incidence of poorly healing stress fractures, especially of the metatarsals, also occurs.

Chondrocalcinosis may be visible on radiographic imaging.

Renal ultrasonography may reveal nephrocalcinosis and, in some cases, kidney stones.

Radiography findings are normal for patients with odontohypophosphatasia, except for osteopenic appearance of the maxilla.


Bone biopsy is not the standard of care. It is usually performed for research purposes (see Histologic findings).

Histologic Findings

Bone biopsy findings include structural parameters (bone volume per tissue volume, trabecular number, trabecular thickness) that are close to the age-specific average of the reference range findings. Osteoid indices (osteoid thickness, osteoid surface per bone surface, osteoid volume per bone volume) are markedly elevated. Among dynamic parameters of bone formation (ie, those that require tetracycline labels to be measurable), mineralizing surface is below the age-specific average of the reference range, whether related to bone surface or osteoid surface. Bone formation rate per bone surface is below average. Mineralization lag time is markedly elevated. The accumulation of osteoid is not distributed evenly, as is seen in osteomalacia, but is patchy. These patches typically consist of a mixture of calcified cartilage.[14]

Both osteoclasts and osteoblasts appear morphologically normal, but the latter lack membrane-associated ALP activity on histochemical testing. This disrupts incorporation of calcium into the matrix.

Histologic examination of the teeth reveals a decrease in cementum, which varies with the severity of the disease. The pulp chamber also appears to be enlarged. The incisors tend to be the most affected.

Other Tests

Genetic testing of the ALPL gene is recommended when biochemical and clinical evaluation findings suggest a high probability of HPP.



Medical Care

Enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase, or asfotase alfa (Strensiq), was approved by the FDA in 2015 and is used as first-line therapy in infants, children, and some adults with HPP. The drug may be used in addition to supportive care to decrease the morbidity associated with the disease.[13]

Approval of asfotase alfa was based on four prospective, open-label studies involving 99 patients who developed hypophosphatasia in utero, as an infant, or as a juvenile. They received the drug for up to 6.5 years. Patients with either perinatal or infant onset of the disease who were treated with asfotase alfa showed improvement in overall survival, as well as ventilator-free survival. Ninety-seven percent of patients receiving the drug were alive at age 1 year compared with 42% of control patients selected from a natural history study group. The ventilator-free survival rates for both groups followed much the same pattern. Patients with juvenile-onset hypophosphatasia also experienced improved growth and bone health compared with patients in a natural history database.[15, 16] One patient was reported with improved bone mineralization after starting enzyme replacement with recombinant asfotase alfa (ALP) from 1 day after birth.[17]

A long-term study of asfotase alfa demonstrated improved bone mineralization, respiratory function, and survival rate in 73 patients with perinatal and infantile HPP compared with 48 historical controls. Suggested indications for asfotase alfa treatment in adults include a history of childhood involvement (before age 18 years) and one or more of the following:

  • Musculoskeletal pain requiring prescription pain medications
  • Disabling polyarthropathy or chondrocalcinosis
  • Major low-trauma fracture attributable to HPP (spine, hip, humerus)
  • Delayed or incomplete fracture healing or fracture nonunion
  • Repeated orthopedic surgeries to treat complications of HPP
  • Disabling functional impairment that affects mobility, gait, and activities of daily living (ADL)
  • Low bone marrow density on dual X-ray absorptiometry (DXA)
  • Radiological evidence of nephrocalcinosis

Currently, there are no guidelines for selecting adult patients with HPP for treatment, evaluating results of treatment, or determining optimal duration of treatment.[13, 18, 19]

In a study of 10 adult patients with HPP, teriparatide was administered to increase osteoblast production of ALP. Effects of treatment on bone marrow density (BMD) varied, although the study reported improved pain, mobility, and fracture repair in some cases.[20] Another study involving six postmenopausal women with HPP showed that teriparatide treatment decreased pain, but no response was seen in one premenopausal woman.[21]

A study involving eight adult patients with HPP treated with monoclonal anti-sclerostin antibody found that treatment for 29 weeks increased bone formation markers and transiently decreased C-telopeptide levels. Lumbar spine BMD showed a mean increase of 3.9% at the end of the study.[22]

Antiresorptive agents such as bisphosphonates are contraindicated, as they may further lower ALP and are harmful in patients with HPP.                                                                                                                                    

Adult pseudofractures may require orthopedic care to heal properly. A dentist should closely monitor all individuals with hypophosphatasia.

Although HPP is a physical disease, several studies have found that mental health can also be affected.[1, 23]

Various other treatments have been attempted, including zinc, magnesium, cortisone, and plasma. The results have not been encouraging with these older therapies.

Donor bone fragments and marrow may provide precursor cells for distribution and engraftment in the skeletal microenvironment to form TNSALP-replete osteoblasts, which may improve mineralization.[24] The effects of bone marrow transplant in hypophosphatasia appear to be transient, as bone lesions may recur approximately 6 months after the transplantation. Nonsteroidal anti-inflammatory drugs have been used in patients with childhood hypophosphatasia with some clinical improvement, although more experience is warranted before this therapy can be recommended.

Enzyme replacement therapy with partially purified plasma enzyme was attempted, but with little clinical improvement.

Some success has been achieved in delivering functional TNSALP enzyme to bone.

Vitamin B-6 may be indicated to treat neonatal seizures.[25]

Surgical Care

Orthopedic surgical involvement may be necessary in patients with hypophosphatasia. Rachitic deformities and gait abnormalities require orthopedic evaluation. For them to heal completely, fractures, pseudofractures, and bone deformities may require rod placement. Patients may need neurosurgery for craniosynostosis.


The skeletal involvement of hypophosphatasia requires consultation with an orthopedist. Patients with the infantile and childhood form should have regular follow-up appointments with their orthopedist. Evaluate adults for pseudofractures of the femur or stress fractures of the metatarsals. Refer all patients with any form of hypophosphatasia to a dental specialist. Construction of dentures may be necessary if the permanent teeth cannot be preserved. Patients should see a metabolic bone diseases specialist.


No special diet for hypophosphatasia is followed. Avoid vitamin and mineral supplements for rickets. The traditional defects of vitamin D metabolism are not present in hypophosphatasia, and excessive vitamin D can cause hypercalcemia and other side effects. Patients should also avoid energy drinks.


Gait difficulties may hamper activity in children. Although no distinct guidelines have been established, avoidance of contact sports and adequate protection of the teeth are advisable.



Medication Summary

Until 2015, no effective drug therapy had been approved for hypophosphatasia. The FDA approved asfotase alfa as the first-ever therapy for hypophosphatasia caused by a rare hereditary mutation in alkaline phosphatase gene.[15, 16]

Enzymes, Metabolic

Class Summary

Enzyme replacement therapy helps to prevent bone demineralization.

Asfotase alfa (Strensiq)

Enzyme replacement that is a soluble glycoprotein composed of 2 identical polypeptide chains; each chain consists of the catalytic domain of human tissue–nonspecific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartate peptide used as a bone-targeting domain. It is indicated for perinatal/infantile- and juvenile-onset hypophosphatasia.