Hypophosphatasia is an inherited metabolic disorder that affects the bones and teeth. The condition disrupts a process called mineralization, where calcium and phosphorus are deposited into the bones and teeth to harden and strengthen them. When this process is defective, bones become weak and prone to fracture and there is an increased likelihood of premature tooth loss.
Hypophosphatasia is caused by mutations in a gene called ALPL, which codes for the enzyme alkaline phophatase (ALP). This enzyme plays an important role in mineralization and ALPL mutation leads to the production of ALP that no longer contributes effectively to this process. In healthy individuals, ALP metabolizes several substrates, but low ALP activity as a result of ALPL mutation enables these substrates to accumulate to abnormal levels in the body. The accumulation of one of these compounds, inorganic pyrophosphate, causes the defective mineralization of bones and teeth seen in hypophosphatasia. Generally, ALPL mutations that completely eliminate ALP result in the most severe forms of the condition, while those that reduce rather than eliminate ALP activity lead to milder forms.
There are six main forms of hypophosphatasia and these include the following:
Perinatal lethal hypophosphatasia
This is one of the most severe forms of hypophosphatasia and pregnancies may end in stillbirth due to the baby’s skeleton failing to form properly in the womb. Whether stillborn or liveborn, infants are born with a small thoracic cavity and bowed, short limbs. The main complication of this condition is pulmonary hypoplasia, which refers to incomplete development of the lungs. This can lead to respiratory failure and death.
Prenatal benign hypophosphatasia
Here, the developing fetus has shortened and bowed limbs along with other bone deformities, but these skeletal defects and impaired mineralization may improve during the third trimester of pregnancy. Once an infant is born, the abnormal skeletal manifestations may resolve over time until the child can be classified as having a milder childhood or adult form of the condition.
Symptoms usually present at some point between birth and six months. Chest deformities lead to respiratory complications and hypercalcemia may lead to poor feeding and nutrition, hypotonia, polydipsia, vomiting, polyuria, dehydration and constipation. Excess calcium excretion may also cause kidney damage and renal failure.
Generally, the first clinical manifestations of childhood hypophosphatasia is premature loss of primary (baby) teeth, short stature and skeletal deformities that may result in a waddling gait or difficulty walking.
This condition is usually diagnosed in middle age, with the main features being bones that are susceptible to fracture, premature loss of secondary (adult) teeth and pain in the feet, thighs and hips.
In patients with odontophosphatasia, only the teeth are affected and there are no signs of osteomalacia such as fractures, rickets or abnormal bone length. In these patients, some teeth may be absent or premature tooth loss may occur.
The ALPL gene is located on the short arm of chromosome 1. The nucleus of each human cell contains pairs of chromosomes numbered from 1 to 22, as well as an additional pair of sex chromosome (X and Y in males, X and X in females). Each human cell therefore usually consists of 46 chromosomes, which carry all of the genetic material required for each individual.
The inheritance of genetic disorders depends on the combination of genes for a certain trait that is present on the chromosomes passed onto a child by the mother and father. In the case of genetic diseases that have an autosomal dominant inheritance pattern, only one copy of an abnormal gene needs to be present for symptoms of the disorder to manifest. That abnormal gene copy may be inherited from either parent or may occur as a new mutation in an affected person. For each pregnancy, the risk of the abnormal gene being passed from an affected parent to their child is 50%.
In the case of recessive disorders, a child needs to inherit two abnormal copies of the gene, one from each parent. If only one abnormal copy is passed on, the offspring will be a “carrier” of the disorder, but will not usually develop any symptoms. For each pregnancy, the risk of two carrier parents both passing on their defective gene and therefore having a child who develops the disorder is 25%, while the risk of the child inheriting one copy and becoming a “carrier” is 50%. The likelihood of the child receiving two normal copies of the gene and therefore being neither affected or a carrier is 25%.
In the case of hypophosphatasia, an ALPL gene mutation may be inherited in either an autosomal recessive or autosomal dominant pattern. The more severe perinatal and infantile forms of the condition have an autosomal recessive inheritance pattern. Childhood forms of hypophosphatasia may be inherited in either an autosomal recessive or autosomal dominant manner, while adult hypophosphatasia and odontohypophosphatasia are usually autosomal dominant conditions, although they may be autosomal recessive in rare cases.
The severe forms of hypophosphatasia are estimated to affect around 1 in 100,000 live births, while less severe forms, which develop during childhood, adolescence or adulthood are thought to occur more frequently. Hypophosphatasia affects individuals from various different ethnicities, but is more common in white populations. The condition is most prevalent in the Mennonite population of Canada, where it affects about 1 in 2,500 newborns.