NORD gratefully acknowledges Michael P. Whyte, MD, Medical-Scientific Director, Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, and Professor of Medicine, Pediatrics, and Genetics, Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, for assistance in the preparation of this report.
Synonyms of Hypophosphatasia
- Rathbun disease
- hypophosphatasia, adult
- hypophosphatasia, childhood
- hypophosphatasia, infantile
- hypophosphatasia, perinatal
- hypophosphatasia, prenatal benign
Hypophosphatasia (HPP) is a rare genetic disorder characterized the abnormal development of bones and teeth. These abnormalities occur due to defective mineralization, the process by which bones and teeth take up minerals such as calcium and phosphorus. These minerals are 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 premature tooth loss. The specific symptoms can vary greatly from one person to another, sometimes even among members of the same family. There are five major clinical forms of HPP that range from an extremely severe form that can cause stillbirth to a form associated with only premature loss of baby (deciduous) teeth, but no bone abnormalities. Hypophosphatasia is caused by mutations in the tissue nonspecific alkaline phosphatase (ALPL) gene. This gene is also known as the TNSALP gene. Such mutations lead to low levels of the tissue nonspecific alkaline phosphatase enzyme. Depending on the specific form, hypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner.
Hypophosphatasia is an extremely variable disorder. Five major clinical forms have been identified based primarily upon the age of onset of symptoms and diagnosis. These are known as perinatal, infantile, childhood, adult, and odontohypophosphatasia. Generally, the severity of these different forms of hypophosphatasia correlates to the residual alkaline phosphate activity in the body, with less enzyme activity causing more severe disease. Because hypophosphatasia is a highly variable disorder, it is important to note that affected individuals may not have all of the symptoms discussed below and that every individual case is unique. Some children will develop 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 overall prognosis.
Perinatal hypophosphatasia is associated with profound inactivity of alkaline phosphatase and markedly impaired mineralization. Consequently, the skeleton fails to form properly in the womb. Specific skeletal malformations may vary, but short, bowed arms and legs and underdeveloped ribs often occur. Some pregnancies end in stillbirth. In other cases, affected newborns survive for several days, but pass away from respiratory failure due to deformities of the chest and underdeveloped lungs.
Prenatal benign hypophosphatasia is associated with bowed limbs at birth. The skeletal malformations can be apparent by ultrasound studies before birth. The skeletal malformations associated with this form improve after birth, eventually resembling the signs and symptoms of individuals who range from infantile hypophosphatasia to odontohypophosphatasia.
Infantile hypophosphatasia may have no noticeable abnormalities at birth, but symptoms may become apparent at any time within the first six months. The initial symptom may be the failure to gain weight and grow at the expected rate for age and gender referred to as "failure to thrive." Some affected babies later exhibit early fusion of the bones of the skull (craniosynostosis), which can result in the head appearing disproportionately wide (brachycephaly). Craniosynostosis may be associated with increased pressure of the fluid that surrounds the brain (cerebrospinal fluid), a condition known as "intracranial hypertension." This complication can cause headaches, swelling of the optic disk (papilledema), and bulging of the eyes (proptosis). Affected infants have softened, weakened bones that lead to the skeletal malformations of rickets. Rickets is a bone disease that occurs during growth with softening of bone and characteristic bowing deformities of the legs from growth plate abnormalities. Enlarged wrist and ankle joints may occur. Affected infants may also have deformities in the chest and ribs and rib fractures, predisposing them to pneumonia. Varying degrees of pulmonary insufficiency and breathing difficulties may develop, potentially progressing to life-threatening respiratory failure. Episodes of fever and bone pain, or tender bones may occur. Some infants exhibit diminished muscle tone (hypotonia) so that a baby appears "floppy" as well as elevated levels of calcium in the blood (hypercalcemia). Hypercalcemia can cause vomiting, constipation, weakness, and poor feeding. In rare cases, vitamin B6-dependent seizures may occur. Increased excretion of calcium may lead to kidney (renal) damage. Sometimes there is spontaneous improvement in mineralization during early childhood, with the exception of craniosynostosis. Short stature and skeletal deformities may persist lifelong.
Childhood hypophosphatasia is highly variable, but is less severe than the infantile form. Affected children may sometimes have craniosynostosis and exhibit signs of intracranial hypertension. Skeletal malformations that resemble rickets may become apparent at 2 to 3 years of age. Bone and joint pain and fractures may occur. Baby teeth may fall out earlier than normal. Some children are weak and experience delays in walking, and when they do learn to walk may have a distinct, waddling gait. Spontaneous remission of bone symptoms has been reported in young adult life, but such symptoms can recur during middle-age or late adulthood.
Adult hypophosphatasia is characterized by a wide variety of symptoms. Affected individuals have osteomalacia, a softening of the bones in adults. Some individuals have a history of rickets during childhood, or have experienced premature loss of their baby teeth. Individuals with adult hypophosphatasia can experience fractures, especially stress fractures in the feet or pseudofractures of the thigh. Repeated fractures can result in chronic pain and debility. Fractures of the spine seem less common, but also occur. Bone pain is a common complication. Some affected adults develop joint inflammation and pain near or around certain joints due to the accumulation of calcium crystals (calcific periarthritis) or a condition called chondrocalcinosis, characterized by the accumulation of calcium crystals within the cartilage of joints, sometimes damaging the joint. Others have sudden, severe pain in the joint (pseudogout). Affected adults may experience loss of adult teeth.
Odontohypophosphatasia is characterized by the premature loss of teeth in childhood, or loss of teeth in adulthood. It is an isolated finding that does not occur along with the characteristic bone symptoms of other forms of hypophosphatasia.
Hypophosphatasia is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene, also called the ALPL gene. This is the only gene established to be involved in hypophosphatasia. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, one or more organ systems of the body can be affected.
Investigators have determined that the ALPL gene is located on the short arm (p) of chromosome 1 (1p36.12). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q".
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits an abnormal copy of a disease gene from each parent. If an individual receives one normal gene and one gene for the disease, he or she will be a "carrier" for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective 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 normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
For hypophosphatasia, mutations in the ALPL gene can be inherited in an autosomal recessive or autosomal dominant manner. The perinatal and infantile forms of HPP are inherited in an autosomal recessive manner. The childhood form can be autosomal recessive or autosomal dominant. The adult form and odontohypophosphatasia typically are autosomal dominant disorders, but in rare cases can be inherited as an autosomal recessive trait.
The ALPL gene creates (encodes) an enzyme known as tissue nonspecific alkaline phosphatase or TNSALP. Enzymes are specialized proteins that break down other chemicals in the body. TNSALP is essential for the proper development and health of bones and teeth and is expressed in the liver and kidneys as well as bone. Mutations in the ALPL gene result in insufficient levels of functional TNSALP, which, in turn, leads to the accumulation of certain chemicals in the body including phosphoethanolamine, pyridoxal 5’-phosphate, and inorganic pyrophosphate. Inorganic pyrophosphate helps to regulate mineralization. Elevated levels of inorganic pyrophosphate can indirectly lead to elevated levels of calcium in the body and insufficient calcification of bone. Generally, TNSALP enzyme activity correlates with disease severity, typically with less residual enzyme activity when there is more severe disease expression.
Individuals with an extremely rare form of HPP called pseudohypophosphatasia have normal blood levels alkaline phosphatase as detected with routine clinical laboratory testing.
Hypophosphatasia affects males and females in equal numbers. In Canada, the severe forms of hypophosphatasia are estimated to affect approximately 1 in 100,000 live births. The overall incidence and prevalence of all forms of hypophosphatasia is unknown. Milder cases can go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of hypophosphatasia in the general population. Hypophosphatasia occurs with greatest frequency in the Mennonite population in Canada, and is relatively prevalent in Japan.
Signs and symptoms of the following disorders can be similar to those of hypophosphatasia. Comparisons may be useful for a differential diagnosis.
Osteogenesis imperfecta (OI) is a group of rare disorders affecting connective tissues and characterized by fragile bones that fracture easily (brittle bones). Like for hypophosphatasia, the specific symptoms and physical findings vary greatly from case to case. The severity of OI can also vary greatly among individuals of the same family. OI may be mild or severe. 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 autosomal dominant traits. (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 childhood, results from insufficient vitamin D caused by poor nutrition, a lack of exposure to the sun, or malabsorption syndromes in which the intestines do not adequately absorb nutrients including vitamin D added to foods. Vitamin D is needed for calcium and phosphorus absorption from food into the body, which, in turn affects how calcium is deposited in the bones. Thus, adequate vitamin D is essential for proper bone development and growth. Major symptoms of vitamin D deficiency rickets include bone softening and slow growth. This disorder is more common than HPP in the United States, and is quite common in certain areas of the world. (For more information on this disorder, choose "vitamin-D deficiency rickets" as your search term in the Rare Disease Database.)
X-linked hypophosphatemia (XLH) is a rare inherited disorder characterized by impaired transport of phosphate and altered vitamin-D activation in the kidneys. In addition, phosphate may not be well-absorbed from the intestines. The low blood phosphate level (hypophosphatemia) resulting from these impairments can lead to rickets or osteomalacia. In childhood bone disease, bowing deformities of the legs from progressive softening of the bone occurs. In adults, the growth plate is no longer open so that osteomalacia is the bone problem. In children, growth rates may be slower than normal, frequently resulting in short stature. X-linked hypophosphatemia is caused by mutations in the PHEX gene located on the X chromosome. It is the most common heritable form of hypophosphatemia. However, 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 disorders may have some symptoms that are similar to those seen in individuals with hypophosphatasia, depending of the age and specific form of hypophosphatasia that is present. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
A diagnosis of hypophosphatasia is based upon identification of characteristic signs and symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of laboratory tests including x-ray studies. Proper diagnosis of hypophosphatasia is easy for physicians who are familiar or experienced with this disorder. However, most physicians have little or no knowledge of hypophosphatasia. Consequently, affected individuals and families may face a frustrating delay in diagnosis.
Clinical Testing and Workup
The diagnosis is rarely first suspected from a routine panel of biochemical tests that includes measuring the activity of alkaline phosphatase in blood. Instead signs and symptoms have led to this routine test where the low levels of alkaline phosphatase must be recognized. Individuals with hypophosphatasia have reduced serum alkaline phosphatase activity for their age, except for the extremely rare individual with pseudohypophosphatasia who has normal activity levels. Identification of deficient alkaline phosphatase activity is consistent with hypophosphatasia, but not conclusive since other conditions can result in this finding. Additionally, some individuals who are genetic carriers of HPP, but who do not develop any symptoms of the disorder, may also have low blood ALP levels.
The range of serum ALP activity also varies by age. Healthy children normally have higher ALP levels than healthy adults. If the laboratory doing the testing only gives the normal range of ALP activity in adults in its report, a diagnosis of HPP in a child can be missed because the child’s ALP activity will mistakenly be believed to be normal.
In the U.S., a suspected diagnosis of HPP can be further supported by measuring the serum level of vitamin B6. This test is performed by several commercial laboratories. Individuals with HPP have elevated levels of pyridoxal 5’-phosphate (PLP: the active form of vitamin B6) in the blood because PLP is normally broken down by TNSALP. PLP is elevated even in individuals with mild hypophosphatasia. However, some genetic carriers of HPP who do not develop any symptoms can have an elevated PLP level as well. Examination of a blood or urine sample can reveal increased amounts of phosphoethanolamine (PEA), another chemical normally broken down by TNSALP. However, this finding is not specific to hypophosphatasia and can occur because of other metabolic bone diseases. Additionally, some individuals with hypophosphatasia have normal PEA levels. Screening for elevated PLP is preferred over screening for PEA because it is more sensitive, more precise, and less expensive.
In the most severe cases of hypophosphatasia, specifically the perinatal and infantile forms, x-ray studies can reveal characteristic changes within the bones. However, these changes may not be recognized as being associated with hypophosphatasia, except by radiologists familiar with the disorder.
Molecular genetic testing can support a diagnosis of hypophosphatasia. Molecular genetic testing can detect mutations in the ALPL gene known to cause the disorder, but it is only available as a diagnostic service at specialized laboratories. The test is often expensive and often not necessary to confirm a diagnosis of HPP.
There are no medications or treatments approved by the Food and Drug Administration (FDA) for the treatment of hypophosphatasia. However, several therapies are under investigation and there are various treatment options aimed at managing the symptoms and complications of hypophosphatasia to help affected individuals remain active and healthy and maintain their quality of life.
Current treatment of hypophosphatasia is directed toward the specific symptoms and complications that may differ from individual to individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, dental specialists (e.g. pediatric dentist), pain management specialist, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling may be of benefit for affected individuals and their families. With children with hypophosphatasia, psychosocial support for the entire family is essential as well.
Non-steroidal anti-inflammatory drugs (NSAIDs) may be given to treat bone and joint pain. NSAIDs require caution and monitoring when used because they can cause side effects (e.g. they can hurt the stomach and kidneys), especially when given in excess doses and for prolonged amounts of time. If craniosynostosis causes intracranial pressure, surgery may be necessary to relieve pressure.
Vitamin B6 can help to control specific seizures in severely affected babies. Severely affected infants that develop elevated levels of calcium (hypercalcemia) in the blood may be treated with dietary calcium restriction, hydration, certain diuretics, and perhaps calcitonin, but hypercalcemia is often difficult to manage as it occurs in severely affected patients.
Regular dental care beginning early on is recommended. Physical and occupational therapy may be recommended in some cases.
Adults with repeated long bone fractures may be treated by an orthopedic internal fixation, which is also known as "rodding." During this procedure, an orthopedic surgeon places a metal rod through the center opening of a bone to make it more stable and stronger. Special medical devices designed for the feet (foot orthotics) may be used by adults to help manage foot (tarsal) fractures.
Affected individuals should avoid bisphosphonates, a class of drugs used to treat other bone disorders such as osteoporosis. These medications may worsen HPP or cause symptoms in individuals with undiagnosed HPP. Examples of bisphosphonate drugs include alendronate, ibandronate, pamidronate, risedronate, and zolendronate.
Bone marrow transplantation, specifically hematopoietic stem cell transplantation, was used to treat two unrelated infant girls with life-threatening hypophosphatasia. They improved. One was also treated with bone fragments and cultured osteoblasts, which are bone-forming cells. ‘Cultured cells’ refers to cells that are grown under specific conditions outside of their natural environment (the body) and instead within a laboratory. According to the medical literature, both of these patients demonstrated significant sustained, but incomplete improvement, although no more formal studies have been conducted on these procedures.
The drug teriparatide (parathyroid hormone 1-34) has been given "off-label" to several adults with hypophosphatasia with metatarsal stress fractures or femoral pseudofractures, resulting in healing of the fractures. The drug is not permitted for use in children. More research is necessary to determine the long-term safety and effectiveness of teriparatide in the treatment of hypophosphatasia.
Researchers have been studying enzyme replacement therapy for the treatment of hypophosphatasia. This involves giving the deficient enzyme to affected individuals. Synthetic versions of missing enzymes have been developed and successfully used to treat individuals with other metabolic disorders. A biological agent called asfotase alfa, previously known as ENB-0040, is being studied as a type of bone-targeted TNSALP replacement therapy in clinical trials sponsored by Alexion Pharmaceuticals, Inc., Chesire, CT. Initial results include improvements in skeletal mineralization leading to increased survival, respiratory function, strength, endurance and mobility as well as reduced pain. Research is ongoing to determine the long-term safety and effectiveness of this potential therapy for hypophosphatasia.
Preliminary short-term results have also been reported from the use for HPP of an anti-sclerostin antibody. Sclerostin is a protein found in the star-shaped bone cells known as osteocytes. Sclerostin helps to reduce or suppress (downregulate) bone-forming cells called osteoblasts. Antibodies that act against sclerostin have been shown to increase bone mass.
For additional information regarding HPP, contact:
Michael P. Whyte, MD
Center for Metabolic Bone Disease and Molecular Research,
Shriners Hospital for Children;
2001 South Lindbergh Boulevard
St. Louis, MO 63131
The Center for Metabolic Bone Disease and Molecular Research at Shriners Hospital for Children in St. Louis, Missouri, is a unique research center that diagnoses, treats, and investigates more than 100 rare bone diseases. The Center is known worldwide for its expertise in several rare diseases including hypophosphatasia. The research team has led clinical trials on a new treatment for hypophosphatasia and they follow more pediatric and adult patients with hypophosphatasia than other institute or physicians worldwide. The Center serves as a global resource for patients and physicians seeking information about rare, genetic bone diseases such as hypophosphatasia. For more information, contact:
Center for Metabolic Bone Disease and Molecular Research
Shriners Hospital for Children;
2001 South Lindbergh Boulevard
St. Louis, MO 63131
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