Hypophosphatasia: Causes, Symptoms, Diagnosis, Treatment, and Prevention
The rare genetic disorder hypophosphatasia affects bone and tooth growth and maintenance. Mutations in the gene that encodes alkaline phosphatase (ALP), an enzyme involved in phosphate and calcium metabolism, cause hypophosphatasia. As a result of hypophosphatasia, bone and tooth mineralization and growth are interfered with by low levels of ALP and high levels of phosphate and pyrophosphate in the blood and tissues.
Causes of Hypophosphatasia
Depending on the type and severity of the condition, hyperphosphatasia can be inherited either recessively or dominantly. When a condition is inherited autosomally recessively, both copies of a gene must be altered, whereas when the condition is inherited autosomally dominantly, only one copy of the gene has to be altered. Mutations can be inherited from either parent, or they can occur spontaneously during egg or sperm development.
There are six types of hypophosphatasia, based on the age of onset and the severity of the symptoms:
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Perinatal hypophosphatasia, which is the most severe type and occurs before or shortly after birth. Perinatal hypophosphatasia can cause respiratory failure, skeletal deformities, and death in infancy.
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Infantile hypophosphatasia, which occurs in the first six months of life. Infantile hypophosphatasia can cause failure to thrive, rickets, seizures, and developmental delays.
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Childhood hypophosphatasia, which occurs in later childhood or adolescence. Childhood hypophosphatasia can cause premature loss of teeth, bone fractures, short stature, and osteomalacia.
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Adult hypophosphatasia, which occurs in adulthood. Adult hypophosphatasia can cause osteoporosis, dental problems, joint pain, and fractures.
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Odontohypophosphatasia, which affects only the teeth and occurs at any age. Odontohypophosphatasia can cause dental caries, tooth loss, and periodontal disease.
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Prenatal benign hypophosphatasia, which is a mild type that occurs before birth and resolves spontaneously after birth. Prenatal benign hypophosphatasia can cause softening of the skull bones, but does not cause any other symptoms or complications.
Symptoms of Hypophosphatasia
The symptoms of hypophosphatasia vary depending on the type and severity of the condition, as well as the age and health status of the patient. Some of the common symptoms include:
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Skeletal problems, such as rickets, osteomalacia, osteoporosis, bone fractures, bone pain, bone deformities, short stature, or scoliosis
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Dental problems, such as dental caries, tooth loss, enamel hypoplasia, or periodontal disease
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Neurological problems, such as seizures, craniosynostosis, hydrocephalus, or developmental delays
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Respiratory problems, such as respiratory failure, chest deformities, or pulmonary hypertension
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Muscular problems, such as muscle weakness, hypotonia, or myopathy
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Renal problems, such as nephrocalcinosis, renal stones, or renal failure
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Gastrointestinal problems, such as vomiting, diarrhea, or malabsorption
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Endocrine problems, such as hypothyroidism, hypogonadism, or diabetes
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Hematological problems, such as anemia, thrombocytopenia, or leukopenia
Diagnosis of Hypophosphatasia
As part of the diagnosis of hypophosphatasia, a medical history, physical examination, and laboratory tests are performed. The medical history and physical examination can help to identify the possible causes and symptoms of hypophosphatasia, as well as any family history or other medical conditions that may affect the ALP levels. The laboratory tests can measure the levels of ALP and other related substances in the blood or urine, including:
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Alkaline phosphatase (ALP), which is an enzyme that is involved in the metabolism of phosphate and calcium
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Phosphate, which is a mineral that is important for the formation and maintenance of the bones and teeth
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Pyrophosphate, which is a compound that inhibits the mineralization of the bones and teeth
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Calcium, which is a mineral that is essential for the function of the muscles, nerves, and bones
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Vitamin B6, which is a vitamin that is required for the activity of ALP
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Parathyroid hormone (PTH), which is a hormone that regulates the levels of calcium and phosphate in the blood and bones
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Vitamin D, which is a hormone that helps the body to absorb calcium from the food and supplements
It is possible to tell if hypophosphatasia is present and how severe it is by the levels of these substances. Hypophosphatasia, for instance, is characterized by low levels of ALP and vitamin B6 and high levels of phosphate and pyrophosphate, while pseudohypophosphatasia is characterized by high levels of ALP and vitamin B6 and low levels of phosphate and pyrophosphate.
Other tests that may be done to confirm or rule out the diagnosis of hypophosphatasia include:
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X-rays, which are tests that use radiation to create images of the bones and can detect any signs of rickets, osteomalacia, osteoporosis, or fractures
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Ultrasound, which is a test that uses sound waves to create images of the kidneys and can detect any signs of nephrocalcinosis or renal stones
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Genetic tests, which are tests that analyze the DNA and can detect any mutations or abnormalities that may cause hypophosphatasia
Treatment of Hypophosphatasia
The treatment of hypophosphatasia depends on the type and severity of the condition, as well as the age and health status of the patient. Treatment aims to increase the levels and functions of ALP and to prevent or treat any complications that can result from hypophosphatasia. The main types of treatment include:
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An enzyme replacement therapy (ERT) involves the use of synthetic or natural ALP to supplement or replace the body's deficient or absent enzymes. A number of forms of ERT are available, including injections and infusions. By reducing phosphate and pyrophosphate levels and improving bone and tooth mineralization, ERT can be beneficial. As well as helping patients with hypophosphatasia relieve their symptoms and improve quality of life, ERT can also prevent or treat respiratory failure, seizures, and other life-threatening conditions. There are, however, some risks and side effects associated with ERT, including allergic reactions, injection site reactions, and antibody formation. ERT should be used with caution under the supervision of a doctor who can monitor the ALP levels and adjust the dosage and frequency as necessary.
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An oral or intravenous injection of vitamin B6 is used to increase ALP activity. As well as reducing phosphate and pyrophosphate levels, vitamin B6 therapy can improve the mineralization and growth of bones and teeth. Patients with hypophosphatasia can also benefit from vitamin B6 therapy, especially those with a specific mutation that responds to vitamin B6, as it can relieve their symptoms and improve their quality of life. There are, however, some risks and side effects associated with vitamin B6 therapy, including nerve damage, skin lesions, or nausea. Vitamin B6 therapy should therefore be used with caution and under the supervision of a doctor, who will be able to monitor the levels of vitamin B6 and adjust the dosage and frequency of the therapy accordingly.
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Supportive care, which is the use of medications or procedures to prevent or treat any complications that may result from hypophosphatasia. Supportive care can include:
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Calcium and vitamin D supplements, which can help to maintain the levels of calcium and vitamin D in the body and to prevent or treat osteoporosis and other bone problems
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Phosphate binders, which can help to reduce the absorption of phosphate from the food and to lower the levels of phosphate and pyrophosphate in the blood and tissues
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Pain relievers, which can help to reduce the pain and inflammation caused by bone fractures or joint problems
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Anticonvulsants, which can help to prevent or control the seizures caused by low calcium levels
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Antibiotics, which can help to prevent or treat the infections that may occur due to the compromised immune system
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Respiratory support, which can help to provide oxygen or mechanical ventilation to the patients who have respiratory failure or difficulty breathing
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Dental care, which can help to prevent or treat the dental problems that may occur due to the poor development and mineralization of the teeth and gums
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Physical therapy, which can help to improve the mobility and function of the muscles and joints
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Occupational therapy, which can help to improve the skills and abilities of the patients to perform daily activities
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Psychological counseling, which can help to cope with the emotional and social challenges that may arise from living with hypophosphatasia
Prevention of Hypophosphatasia
The prevention of hypophosphatasia is not always possible, especially if the condition is caused by genetic factors. However, some of the possible ways to prevent or reduce the risk of hypophosphatasia include:
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Genetic counseling and testing, which can help to identify the carriers or affected individuals of hypophosphatasia and to provide information and guidance on the inheritance, diagnosis, treatment, and prognosis of the condition
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Prenatal diagnosis and treatment, which can help to detect and treat the condition in the fetus or newborn and to prevent or reduce the severity of the symptoms and complications
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Newborn screening, which can help to identify and treat the condition in the newborn and to prevent or reduce the delay or damage to the development and growth of the bones and teeth
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Regular monitoring and follow-up, which can help to check the levels of ALP and other substances in the blood and urine and to adjust the treatment and dosage of the supplements or medications as needed
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Avoiding or limiting the exposure to factors that may worsen the condition or increase the risk of complications, such as infections, injuries, or certain drugs
A rare genetic disorder known as hypophosphatasia affects the well-being and health of affected individuals on a physical, dental, and mental level. However, with proper diagnosis and treatment, hypophosphatasia can be managed and the quality of life can be improved.
