OVERVIEW

What is hypophosphatasia?

Hypophosphatasia (HPP), also known as hereditary hypophosphatasia, is a rare inherited systemic disorder characterized by defective development of bones and dental hard tissues, along with low serum alkaline phosphatase (ALP) activity.

Currently, its etiology and pathogenesis remain unclear, and there is no definitive cure.

Is hypophosphatasia common?

HPP patients can be found across all ethnic groups worldwide, but prevalence rates vary significantly by region. Canada has the highest reported prevalence, with severe HPP occurring in approximately 1:100,000 individuals.

Due to varying clinical manifestations and a large number of undiagnosed cases, accurately estimating the prevalence of milder forms of HPP remains challenging.

SYMPTOMS

What are the types of hypophosphatasia?

• Perinatal lethal form: This is fatal, usually manifesting in the fetal stage, with significant poor bone mineralization and skin-covered bone spurs protruding from the forearms or legs. Infants often die during the perinatal period, though some may survive for a few days after birth but suffer severe respiratory complications due to pulmonary hypoplasia and rickets-induced chest deformities.
• Perinatal benign form: Presents with fetal manifestations, but ultrasound may reveal spontaneous improvement in skeletal defects. Infants have short and curved limbs with depressed long bones.
• Infantile form: Appears normal at birth, with symptoms emerging within 6 months after birth, including respiratory complications due to rickets-related chest deformities. Increased intracranial pressure often occurs due to premature cranial suture closure. Infants may have hypercalcemia, elevated urinary calcium, and nephrocalcinosis. Symptoms in young children include irritability, poor appetite, vomiting, polyuria, constipation, and hypotonia. Excessive calcium excretion can cause kidney damage. Surviving infants may show improved mineralization and symptom relief.
• Childhood form: Symptoms appear after 6 months of age, making it the most complex type. Typical symptoms include intracranial hypertension, growth retardation, skeletal deformities, enlarged joints, short stature, and an unsteady gait. Fractures and bone pain are common, with localized bone defects at the ends of long bones. Premature tooth loss, often starting with incisors, may occur. Bone defects may improve spontaneously but skeletal symptoms can recur in adulthood.
• Adult form: Symptoms typically appear in middle age, often discovered due to foot or leg pain caused by metatarsal or femoral fractures. Chondrocalcinosis and osteoarthropathy are also common. Many patients have a history of premature primary tooth loss. Some may also develop kidney stones, renal dysfunction, and psychiatric symptoms such as insomnia, anxiety, and depression.
• Odontohypophosphatasia: Can occur in both children and adults, with typical symptoms being premature primary tooth loss and severe dental caries, usually without systemic skeletal abnormalities. X-rays may show insufficient alveolar bone mass and enlarged pulp chambers and root canals.

CAUSES

Why does hypophosphatasia cause skeletal defects?

The ALPL gene on chromosome 1p36.1 encodes tissue-nonspecific alkaline phosphatase, which is biologically active in dimer form. This enzyme hydrolyzes phosphometabolites in the extracellular matrix, releasing inorganic phosphorus to promote mineralization. Gene mutations reduce enzyme activity, leading to skeletal/dental developmental defects and abnormal mineralization.

Is hypophosphatasia contagious?

Hypophosphatasia is a genetic disorder and is not contagious.

Is hypophosphatasia hereditary?

This rare disease follows autosomal inheritance patterns, which may be either dominant or recessive.

DIAGNOSIS

How is hypophosphatasia diagnosed?

The diagnosis of HPP is primarily based on clinical manifestations, physical examinations, laboratory tests, and X-ray examinations. Genotype analysis and detection of ALPL gene mutations are of definitive value for suspected cases.

What tests are needed for hypophosphatasia?

• Blood biochemical tests: Decreased serum ALP activity should raise strong suspicion of HPP, but the severity of HPP may not correlate with the degree of ALP reduction across different ages. Note that low ALP activity may also occur in other conditions such as early pregnancy, hypothyroidism, celiac disease, malnutrition, or anemia.
• Genetic testing: ALPL gene analysis is a key diagnostic method for HPP, particularly when clinical manifestations and laboratory results are inconclusive, such as in pregnant women with a history of giving birth to HPP-affected infants. Mutation screening is a more reliable indicator than serum ALP activity testing, though novel mutation types should also be considered.
• X-ray: X-ray examinations assess the severity of impaired bone mineralization and rickets. Abnormalities such as bone spurs or shortened bones in the legs may be detected.
• Bone density testing: There is little evidence that bone density aids in HPP diagnosis.
• Histopathological examination: Except for odontohypophosphatasia, nearly all patients show insufficient mineralization and altered trabecular microstructure in bone histology. Osteoblasts and chondrocytes producing TNSALP are present, but TNSALP activity remains significantly reduced or entirely absent.

Which diseases are easily confused with hypophosphatasia?

Hypophosphatasia is often associated with oral manifestations, including periodontitis and dental caries. Any patient with a history of spontaneous tooth loss or abnormal tooth mobility during oral examination should be evaluated for this condition.

TREATMENT

Which department should be consulted for hypophosphatasia?

This is a genetic disease. When it occurs in children or infants, pediatric treatment is required.

What are the treatment options for hypophosphatasia?

Currently, there is no cure for hypophosphatasia, and most treatments focus on symptom management.

• General treatment:

  • Dental care includes extracting excessively loose teeth, maintaining oral hygiene, and performing periodontal surgery in certain areas.

  • Growth hormone replacement therapy can promote bone growth and increase alkaline phosphatase activity.

  • Long-term supplementation with vitamin D and calcium may be beneficial.

  • Limiting phosphate in the diet.

  • Nonsteroidal anti-inflammatory drugs can be used for pain, and bone marrow and mesenchymal stem cell transplantation may improve bone mineralization.

• Bone marrow transplantation: Some infantile HPP patients have shown significant benefits after bone marrow transplantation.

• Additionally, enzyme replacement therapy with TNAP recombinant protein is still in the research stage.

DIET & LIFESTYLE

Can hypophosphatasia be cured?

The prognosis varies greatly depending on the subtype. Perinatal patients usually die within days or weeks after birth, with 50% of infant patients dying from severe respiratory complications. The childhood type shows significant variability, while the adult and odontohypophosphatasia types do not affect lifespan.

Will there be sequelae after hypophosphatasia is treated?

Hypophosphatasia can lead to tooth decay and loosening, as well as frequent fractures of the metatarsal or femoral bones, causing foot or leg pain.

How long does hypophosphatasia need to be treated?

Hypophosphatasia is a genetic disorder, and there is currently no complete cure. Most treatments are symptomatic and lifelong.

PREVENTION

Can Hypophosphatasia Be Prevented?

Genetic analysis of hypophosphatasia is challenging, as it may follow autosomal dominant or recessive inheritance patterns, with heterozygous patients exhibiting diverse clinical manifestations. Due to genetic polymorphisms, mutations or variations in other genes can influence the phenotype. Family pedigree investigations are crucial. However, there is currently no clear evidence indicating that prenatal diagnosis aids in the screening or prevention of HPP.