World Hypophosphatasia Day - October 30
Today is World Hypophosphatasia Day, which raises awareness and gives support to people living with this rare bone disease.
What is HPP?
Hypophosphatasia (hī-pō-ˌfäs-fə-ˈtā-zh(ē-)ə) or HPP is an inherited (genetic) metabolic disorder. People with this condition have low levels of the enzyme alkaline phosphatase (ALP), which often affects the development of bones and teeth. However, signs and symptoms vary widely, with mild cases causing only dental abnormalities while more severe types may have life-threatening consequences. Without adequate ALP, bones may become weak or soft, causing skeletal deformities, fractures, premature tooth loss, and pain, among other symptoms.
Typically, the earlier HPP symptoms become apparent, the more severe the condition. It is estimated that severe forms of HPP occur in approximately one of every 100,000 live births. While exact numbers are unknown, it is estimated that one out of every 200 Americans may be a carrier for HPP.
Diagnosis is generally made through x-rays and blood tests and the disease is classified based on the age at which symptoms first appear. The five main types of HPP are Odonto, Perinatal, Infantile, Childhood, and Adult. Researchers understand HPP is a genetic condition of the TNSALP gene, which is part of a patient’s genetic makeup, regardless of when it is diagnosed. However, a genetic diagnosis is currently not an adequate predictor of the severity of the disease. More research is underway and funded by Soft Bones to gain a better understanding of the genotype/phenotype relationship.
However, most physicians are unaware of HPP, often leading to a frustrating experience for patients and their families before a correct diagnosis is made.
Signs and 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 diseases 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. The skeletal deformity can be identified by ultrasound studies during 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 pain 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 the 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.
Affected Populations
HPP affects males and females in equal numbers. In Canada, severe HPP is estimated to occur in approximately 1 in 100,000 live births. The overall incidence and prevalence of the various forms of HPP are poorly understood or unknown. Milder cases can go undiagnosed or misdiagnosed. HPP occurs with the greatest frequency in the Mennonite population in Canada, is relatively prevalent in Japan, and seems to be rare in individuals with Black ancestry.
Related Disorders
Other disorders can resemble HPP. Osteogenesis imperfecta (OI), also called “brittle bone disease”, is a group of rare disorders that together are more common than HPP. OI features bones that fracture easily from osteoporosis rather than rickets. OI may be mild or severe. As for HPP, the signs and symptoms and physical findings of OI vary greatly from affected person to person, even among individuals in the same family. Four main types of OI have been identified. OI type I is the most common and the mildest form. OI type II is the most severe. Most forms of OI are inherited as an autosomal dominant trait (For more information on this disorder, choose “osteogenesis imperfecta” as your search term in the Rare Disease Database.)
Vitamin-D deficiency rickets, a disorder that often becomes apparent during infancy or early childhood, results from poor nutrition, a lack of exposure to sunshine, or malabsorption syndromes in which the intestines do not adequately absorb nutrients including vitamin D added to some foods. Vitamin D is needed for calcium and phosphorus uptake from the gut to then be deposited into the skeleton. Thus, adequate vitamin D is essential for proper bone development and growth. Vitamin D deficiency rickets features bone softening, slow growth, and muscle weakness. This disorder is more common than HPP in the United States and much more common in certain underprivileged areas worldwide (For more information on this disorder, choose “vitamin D deficiency rickets” as your search term in the Rare Disease Database.)
Hypophosphatemia spelling looks like hypophosphatasia, but refers to low blood phosphate levels. X-linked hypophosphatemia (XLH) is the most common inherited form of rickets/osteomalacia, and is characterized by the inability of the kidneys to activate vitamin D and to keep phosphate out of the urine and in the bloodstream. Also, phosphate in food may not be absorbed well from the intestines. Low blood phosphate (hypophosphatemia) leads to rickets or osteomalacia. In early childhood, bowing deformities of the legs reflect softened bones. Growth is impaired, frequently resulting in short stature. In adults, there is osteomalacia. XLH is caused by mutations in the PHEX gene located on the X-chromosome (incidence approx. 1/25,000 births). However, rarer autosomal dominant and recessive forms of hypophosphatemia occur as well (For more information on this disorder, choose “familial hypophosphatemia” as your search term in the Rare Disease Database.)
A wide variety of metabolic bone disorders and skeletal dysplasias have some symptoms similar to HPP (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
Sources:
https://softbones.org/wp-content/uploads/2020/10/Introduction-to-HPP-A-Clinical-Overview.pdf