Hypophosphatasia (HPP) Clinical Presentation

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  more...
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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.