Hypophosphatasia

Hypophosphatasia (HPP) is a rare genetic disorder characterized by impaired mineralization (“calcification”) of bones and teeth. Problems occur because mineralization is the process by which bones and teeth take up calcium and phosphorus required for proper hardness and strength.

Defective mineralization results in bones that are soft and prone to fracture and deformity. Defective mineralization of teeth can lead to tooth loss. The specific symptoms of HPP are broad-ranging in severity, and can vary greatly from one person to another, sometimes even among affected members of the same family. There are six major clinical forms of HPP that range from an extremely severe “perinatal” (at birth) form that can cause stillbirth to a more common (“odonto”) form associated with only early loss of baby (deciduous) teeth, but no bone abnormalities. HPP is caused by changes (mutations) in the ALPL gene that produces an enzyme called tissue nonspecific alkaline phosphatase (TNSALP). Such mutations lead to low activity of this enzyme that should be breaking down a chemical called inorganic pyrophosphate that blocks mineralization. Depending on the specific form, HPP can be inherited in an autosomal recessive (among brothers and sisters) or autosomal dominant (multiple generations) manner.

Signs & Symptoms
HPP has remarkably wide-ranging severity. The six major clinical forms are separated based primarily upon the age when symptoms occur and the diagnosis is made. By decreasing severity, these forms are called perinatal, infantile, childhood (severe or mild), adult, and odontohypophosphatasia.

Generally, HPP severity correlates with how much alkaline phosphatase activity remains in the body, with less enzyme activity causing more severe disease. Because HPP has broad-ranging severity, it is important to note that affected individuals rarely have all of the symptoms discussed below, and that every affected individual is essentially unique. Some children have severe complications early in life; others have mild disease that may improve during young adult life. Parents should talk to their child’s physician and medical team about the specific symptoms and what the future might hold.

Perinatal HPP has very low alkaline phosphatase markedly blocking skeletal mineralization, including in the womb. Short, bowed arms and legs, underdeveloped ribs, and chest deformity are typical. Some pregnancies end in stillbirth. Some affected newborns survive for several days, but if untreated die from respiratory failure due to deformities and weakness of the chest.

Prenatal benign HPP at birth is much less severe than perinatal HPP and features bowed limbs. Skeletal deformity can be identified by ultrasound studies during the pregnancy. In this form, the skeletal malformations improve gradually after birth, eventually with the signs and symptoms ranging from infantile HPP to odontohypophosphatasia.

Infantile HPP may have no noticeable abnormalities at birth, but complications become apparent within the first six months of life. The initial problem may be the baby’s failure to gain weight and grow as expected, referred to as “failure to thrive.” Sometimes the skull bones fuse, called craniosynostosis, which can lead to a deformed head (brachycephaly). Craniosynostosis may also increase the pressure of the fluid (cerebrospinal fluid) that surrounds the brain, a condition known as “intracranial hypertension.” This can cause headaches and bulging of the eyes (proptosis), and be detected at the back of the eye by swelling of the optic disk (papilledema). Affected infants have softened, weakened and deformed bones consistent with rickets. Rickets is a general term for the complications due to defective skeletal mineralization during growth with softening of bone and characteristic bowing deformities. Widened bones at the wrists and ankles may occur. Affected infants often have chest and rib deformities and fractures, predisposing them to pneumonia. Varying degrees of pulmonary insufficiency and breathing difficulties may develop, sometimes progressing to life-threatening respiratory failure. Episodes of fever and painful and tender bones may occur. Diminished muscle tone (hypotonia) is characteristic, so that the baby appears “floppy”, sometimes caused by elevated levels of calcium in the blood (hypercalcemia) that may also cause vomiting, constipation, weakness, poor feeding, and kidney (renal) damage. Vitamin B6-dependent seizures may occur. Sometimes skeletal mineralization improves spontaneously during early childhood, but if untreated short stature and skeletal deformities may persist lifelong.

Childhood HPP is highly variable, and severe and mild forms should be considered. Affected children sometimes develop craniosynostosis with intracranial hypertension. Skeletal malformations may become apparent at 2 to 3 years of age. Bone and joint pain may occur. Typically, one or more baby teeth fall out earlier than the fifth birthday. Some patients are weak with delayed walking, and then with a distinct, waddling gait. Sometimes spontaneous improvements occur in young adult life, but complications can recur during middle-age or late adult life.

Adult HPP too has wide-ranging signs and symptoms. Affected men and women have “adult rickets” called “osteomalacia”, a softening of the bones in adults. Bone pain is common. Affected adults may experience loss of teeth. Some have a history of rickets during childhood, or baby teeth lost early.

Fractures can occur, especially “stress fractures” in the feet early on, or subsequently “pseudofractures” in the thigh. Repeated fracturing can cause chronic pain and weakness. Spine fractures are less common. Joint inflammation and pain near or around certain joints due to the accumulation of calcium phosphate crystals (calcific periarthritis), or a condition called chondrocalcinosis within cartilage sometimes damages joints. Some affected individuals have sudden, severe arthritis called pseudogout.

Odontohypophosphatasia features early loss of “baby” teeth in infancy or early childhood, or unexpected loss of teeth sometime in adulthood. Here, the dental problems are an isolated finding without the characteristic bone problems of other forms of HPP.

Individuals with an extremely rare form of HPP called pseudohypophosphatasia have normal rather than low blood levels of alkaline phosphatase in the routine clinical laboratory.

Causes
HPP is caused by mutations in the ALPL gene. This is the only gene that causes HPP. Genes provide instructions for making proteins that have an important function in the body. When a mutation occurs, the protein may be faulty, inefficient, or absent, as in HPP. Depending upon the protein’s function, one or more organ systems of the body can be compromised.

The ALPL gene creates (encodes) a type of protein called an enzyme named TNSALP. Enzymes are specialized proteins that break down specific chemicals in the body. TNSALP is essential for the proper development and health of bones and teeth, and is abundant in the skeleton, liver, and kidneys. Mutations in the ALPL gene lower the activity of TNSALP, in turn leading to accumulation of phosphoethanolamine (PEA), pyridoxal 5’-phosphate (PLP), and inorganic pyrophosphate (PPi). Inorganic pyrophosphate is an inhibitor of mineralization that controls mineral entry into the skeleton. Elevated PPi levels can block calcium and phosphorus from entering bone, and thereby cause elevated levels of calcium in the blood and urine. Generally, the reduction of TNSALP enzyme activity correlates with HPP severity (less enzyme activity causes more severe disease).

HPP can be inherited in an autosomal recessive (affecting siblings) or autosomal dominant (affecting multiple generations) manner. The perinatal and infantile forms of HPP are autosomal recessive. The childhood form can be either autosomal recessive or autosomal dominant. The adult form and odontohypophosphatasia typically are autosomal dominant disorders, but rarely autosomal recessive.

Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.