Hypophosphatasia is a rare, inherited metabolic disorder that affects the bones and teeth. The condition leads to impaired mineralization, a process where calcium and phosphorus are usually taken up by the bones and teeth to strengthen and harden them. When this process is faulty, the bones become soft, weak and susceptible to fracture and tooth loss may occur prematurely.
The specific symptoms vary widely between affected individuals. The different types of hypophosphatasia range from an extremely severe form of the condition that can lead to stillbirth due to the skeleton failing to form properly in the womb, through to a milder form where only the teeth are affected (odontohypophosphatasia).
Hypophosphatasia arises due to mutation of a gene called ALPL, which codes for the enzyme alkaline phosphatase (ALP). This enzyme plays an important role in mineralization of the bones and teeth. Mutation of the ALPL gene leads to the production of abnormal ALP that cannot contribute effectively to this mineralization process. Substrates that would normally be metabolized by ALP accumulate to abnormal levels in the body. The build-up of one of these substrates, namely inorganic pyrophosphate leads to defective mineralization in people with hypophosphatasia.
Depending on the particular form of hypophosphatasia, this condition may be inherited in an autosomal recessive or autosomal dominant pattern. Estimates show that the prevalence of severe hypophosphatasia is around 1 in 100,000 live births, while the milder forms that develop during childhood or adulthood are more common.
There are six known forms of hypophosphatasia and these are described in more detail below.
Perinatal lethal hypophosphatasia
This is one of the most severe forms of hypophosphatasia and pregnancies may end in still birth. Both livebirth and stillbirth infants are born with an abnormally small thoracic cavity and bowed limbs. These infants also tend to have a very soft skullcap and short limb dwarfism. Further symptoms and signs that patients may present with include:
- Prominent transverse bone spurs in the middle of the lower legs and forearms
- Blue sclera
- Inconsistent bone ossification
- Lack of ossification in vertebrae, neural arches of the spine and hands
- Clefted vertebral bodies
The main complication of perinatal lethal hypophosphatasia is pulmonary hypoplasia, which refers to deficient development in parts of the lung. The most likely prognosis is death. Neonates who manage to survive several days or weeks suffer increasing respiratory compromise and ultimately, respiratory failure. Mothers of affected individuals are at a 25% risk that future pregnancies will also be affected.
Prenatal benign hypophosphatasia
Prenatal benign hypophosphatasia is characterized by skeletal manifestations including bowed and shortened limbs. Some prenatal ultrasound examinations have shown that mineralization and skeletal deformities improve during the third trimester of pregnancy. After birth, the skeletal abnormalities gradually resolve until the patient can be classified as having a milder childhood or adult form of the condition.
This form of hypophosphatasia usually presents with initial symptoms at some point between birth and six months of age. Rachitic chest deformities lead to respiratory complications and hypercalcemia may cause poor appetite, anorexia, vomiting, hypotonia, polyuria, polydipsia, constipation and dehydration. This excess of calcium may also lead to renal damage and kidney failure. Infants who survive initial symptoms tend to experience remission and the long term prognosis is then positive.
This form of the condition presents with various different signs and symptoms. There may be premature loss of primary (baby) teeth, short stature, difficulty walking and skeletal deformities such as enlarged joints and a dolichocephalic skull. Other signs include intracranial hypertension, a history of bone pain and fracture, failure to thrive and defects near the ends of major long bones. Symptoms may begin to resolve, with children often being symptom-free for periods. However, symptoms also often return during adulthood.
Adult hypophosphatasia usually develops during middle age and is characterized by stress fractures and pseudofractures of the lower limbs. Other features of the condition include premature loss of secondary (adult) teeth and thigh, hip and foot pain. This condition is sometimes associated with a history of rickets in childhood and premature loss of primary teeth.
Among patients with this condition, only the teeth are affected and there are no skeletal abnormalities. Odontohypophosphatasia may also be seen as part of the symptom profile in the forms of hypophosphatasia listed above. Signs of this condition include absence of teeth and premature loss of teeth due to their poor stability.