About hypophosphatasia (hhrh)
What is hypophosphatasia (hhrh)?
Hypophosphatasia is a inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Unlike other forms of rickets, Hypophosphatasia does not respond to treatment with vitamin D.
What are the symptoms for hypophosphatasia (hhrh)?
Chest diformity symptom was found in the hypophosphatasia (hhrh) condition
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.
What are the causes for hypophosphatasia (hhrh)?
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.
What are the treatments for hypophosphatasia (hhrh)?
In 2015, the U.S. Food and Drug Administration (FDA) approved asfotase alfa (Strensiq) as the first medical treatment for perinatal, infantile and juvenile-onset HPP. In the US, patients of any age with pediatric-onset HPP are eligible for this bone-targeted TNSALP replacement therapy given by subcutaneous injection.
Supportive treatments for HPP are directed toward specific symptoms and complications. Treatment may require a team of specialists. Pediatricians, orthopedic surgeons, pedodontists, pain management specialists and other healthcare professionals may be needed for comprehensive treatment.
Non-steroidal anti-inflammatory drugs (NSAIDs) may help bone and joint pain. NSAIDs require caution and monitoring for side effects (e.g. they can hurt the stomach and kidneys), especially in excess and if used too long. If craniosynostosis causes intracranial pressure, shunting or skull surgery may be necessary.
Vitamin B6 can help to control specific seizures in severely affected babies. Those with elevated levels of calcium in the blood (hypercalcemia) may need dietary calcium restriction, hydration, certain diuretics, and perhaps injections of calcitonin.
Regular dental care beginning early on is recommended. Physical and occupational therapy may be helpful.
Adults with recurring long bone fractures may need orthopedic “rodding” where a metal rod is inserted within the center cavity of a long bone to increase stability and strength. Special medical devices (foot orthotics) may help foot (metatarsal) fractures.
Patients should avoid bisphosphonates, a class of drugs used to treat other bone disorders such as osteoporosis. Bisphosphonates may worsen HPP or cause problems in individuals with undiagnosed HPP. Examples of bisphosphonate drugs are alendronate, ibandronate, pamidronate, risedronate and zolendronate.
Genetic counseling may be helpful for affected individuals and their families. For children with HPP, psychosocial support for the entire family may be beneficial.
What are the risk factors for hypophosphatasia (hhrh)?
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 is poorly understood or unknown. Milder cases can go undiagnosed or misdiagnosed. HPP occurs with greatest frequency in the Mennonite population in Canada, is relatively prevalent in Japan, and seems to be rare in individuals with Black ancestry.