Hypophosphatasia is an inherited bone disease whose clinical symptoms are highly variable, ranging from a profound lack of mineralization of bone with death occurring prior to delivery up to early loss of teeth in adulthood as the only sign. Still other affected individuals may have the characteristic biochemical abnormality but no outward clinical signs of the disorder. Hypophosphatasia is due to consistently low levels of an important enzyme in the body, alkaline phosphatase.
The term hypophosphatasia was first coined in 1948 by a Canadian pediatrician, Dr. J.C. Rathbun. He used it to describe a male infant who developed and then died from severe rickets, weight loss, and seizures. Levels of the enzyme alkaline phosphatase were below normal in samples of blood and bone from this child.
Rickets is a condition resulting from a deficiency of vitamin D in children, causing inadequate strengthening of developing cartilage and newly formed bone. While this disorder shares many clinical characteristics with hypophosphatasia, the two conditions are separate and distinct. A major difference is that rickets are typically not lethal.
In 1953, the clinical features of hypophosphatasia were expanded to include not only abnormal mineralization of bone but also premature loss of the permanent teeth in adulthood. Since then, hypophosphatasia has been further divided into six different clinical forms. Each form is defined by the severity of the disease and the age at which symptoms first appear.
Alkaline phosphatase (ALP) is present in nearly all plants and animals. There are at least four different genes known to encode different forms of ALP in humans. Hypophosphatasia is due to a deficiency of the form of ALP that is particularly abundant in the liver, bones, and kidneys. This is often referred to as the tissue non-specific form of ALP, or TNSALP. This form of alkaline phosphatase is important in the mineralization, or hardening, of the bones of the skeleton as well as the teeth. Thus, abnormalities in either the production or function of this enzyme have a direct effect on the formation and strength of these parts of the body. In general, the more severe forms of hypophosphatasia are associated with lower serum TNSALP activity for that individual's age.
The first report of siblings affected with hypophosphatasia was published in 1950, providing supportive evidence that it is an inherited abnormality as opposed to one that is acquired. This is an important distinction, particularly since rickets alone is often due to a lack of vitamin D in a person's diet. Good sources of vitamin D include fortified milk and sunlight. Rickets can therefore be an acquired medical problem.
Nearly all forms of hypophosphatasia are inherited as an autosomal recessive condition. In order to be affected, an individual must inherit two copies of a hypophosphatasia gene , or one copy from each carrier parent. Carriers have one normal gene and one hypophosphatasia gene and are typically asymptomatic. In some families, hypophosphatasia carriers have been found to have low to low-normal levels of TNSALP in their blood. As a general rule, however, it is difficult to detect carriers with biochemical tests due to the wide range of enzyme levels found among both carriers and non-carriers.
Two hypophosphatasia carriers face a risk of 25%, or a one in four chance, of both passing on the disease gene and having an affected child. On the other hand, there is a 75% chance that they will have an unaffected, normal child. These risks apply to each pregnancy.
In contrast, evidence suggests that some of the more mild adult forms of hypophosphatasia may be inherited as an autosomal dominant trait. In this mode of inheritance , a single copy of a hypophosphatasia gene can cause clinical abnormalities. An affected individual would consequently have a 50% risk of passing on the abnormal gene to each of his or her children.
The gene for TNSALP is located near the tip of the short arm of chromosome 1 at band 1p36.1-p34. Mutations in this gene are responsible for both the autosomal recessive and autosomal dominant forms of hypophosphatasia. Although it is not yet entirely clear how mutations in this gene cause impaired mineralization of bone, more recent work has shown that the type of mutation and its location within the gene each have an effect on the severity of disease. A wide range of mutations have been described to date. A common mutation for any form of hypophosphatasia has not yet been identified in most populations. Consequently, genetic analysis of TNSALP in most families requires extensive study of the entire gene.
Hypophosphatasia has been described worldwide and is believed to occur in all races. The most severe form of the disease is estimated to occur in approximately one in every 100,000 liveborns. This corresponds to a carrier frequency of roughly one in every 200–300 individuals. The milder childhood and adult forms of hypophosphatasia are probably more common than the severe perinatal form.
Of note, hypophosphatasia is especially common among Mennonite families from Manitoba, Canada, where mating between blood relatives is not unusual. The frequency of severe disease in this population is approximately one in every 2,500 newborns with a corresponding carrier frequency of one in every 25. The number of mutations identified in this group is smaller than the general population.
Signs and symptoms
Each individual who has hypophosphatasia has clinical features derived from generalized impairment of skeletal mineralization. Six different clinical forms have been recognized. The prognosis associated with each form is dependent upon the severity of the disease and the age at which the condition is first recognized. Although affected individuals within a family tend to have similar abnormalities, it is possible to see clinical variability even between relatives.
Perinatal (lethal) hypophosphatasia
This is the most severe form of hypophosphatasia. Affected fetuses are often diagnosed during pregnancy with profound undermineralization of their bones. The limbs are typically shortened and abnormal. Bone fractures may be present. An excessive amount of amniotic fluid (polyhydramnios) during pregnancy is common. Many affected infants die prior to delivery, or are stillborn. Those who survive delivery are often irritable, have a high-pitched cry, and fail to gain weight. Respiratory failure is a common cause of death. This is usually due to deformities of the chest and associated underdevelopment of the lungs.
Many infants with this form of the disease appear normal at birth and initially begin to develop normally. However, difficulties such as poor feeding and poor weight gain along with early clinical signs of rickets often begin before six months of age. Bony abnormalities of the chest as well as an increased susceptibility to fractures make affected infants more prone to developing pneumonia. Over 50% of affected children die during infancy, usually from severe respiratory failure. Those infants who do survive often suffer from episodes of recurrent vomiting and from abnormal kidney function due to excess loss of calcium from bone. Additionally, they may develop a misshapen head due to early closure of specific bones of the skull. Spontaneous overall improvement in health has, however, also been reported.
The most common clinical feature in this form of hypophosphatasia is loss of the primary (deciduous) teeth before the age of five. This premature loss is directly related to abnormal dental cementum. It is this structure that normally establishes the appropriate connection of the teeth to the jaw. In hypophosphatasia, it is frequently completely missing or present but either underdeveloped or abnormally developed.
Rickets is another feature commonly seen in this later onset form. Rickets frequently leads to delayed walking as a toddler, short stature, and a characteristic waddling gait. Other rachitic deformities may also be present such as bowed legs or enlargement of the wrists, knees, and ankles.
Most affected individuals are formally diagnosed in adulthood. However, a careful review of an individual's health often reveals a childhood history of rickets and early loss of the primary teeth. This is typically followed by relatively good health during adolescence and young adulthood.
Dental and skeletal abnormalities, however, gradually recur. The age at their onset as well as their severity varies between individuals. Early loss or even extraction of the permanent teeth is common. Other skeletal abnormalities, however, are of greater concern. Osteomalacia is a common complaint. Osteomalacia is the adult form of rickets. It is characterized by increasing softness of the bones. This, in turn, leads to increased flexibility and fragility and causes deformities. Clinically, osteomalacia is typified by chronic pain in the feet due to recurrent, poorly healing stress fractures. Affected adults may also experience discomfort in their thighs and hips from painful thin zones of decalcification (pseudofractures) in the bones of the thigh.
The only clinical abnormality associated with this form of hypophosphatasia is dental disease. It may occur in children or adults. Neither rickets nor osteomalacia has been found to occur.
Pseudo-, or false, hypophosphatasia
This is an especially rare clinical form documented in only a few infants. The physical features all resemble those seen in the infantile form of the disease. However, in contrast to all of the other forms of hypophosphatasia, the total alkaline phosphatase activity has been consistently normal or even increased in blood samples from the affected children. It is unclear what the exact biochemical or molecular abnormality is in these children.
After birth, a diagnosis of hypophosphatasia is based on a combination of physical examination, x ray, and biochemical studies. X ray can be particularly helpful in differentiating between the more severe forms of hypophosphatasia (perinatal, infantile) and other inherited bone diseases. In the perinatal form, the skeleton generally appears completely undermineralized, occasionally absent. Bone fractures may be observed. The xray findings in the infantile form are similar to those seen in the perinatal form, but are usually much less severe.
Biochemical analysis may be performed on a routine blood sample. The serum may be used to determine the level of alkaline phosphatase activity. This usually represents TNSALP, and, in affected individuals, is generally low. However, it is important that the sample be obtained and handled correctly in the laboratory so as not to interfere with the enzyme activity and raise the likelihood of an incorrect result. Also, the values from each individual should be interpreted carefully as variation normally occurs based on a person's sex and his or her age.
The genetic abnormality that causes hypophosphatasia leads to an inactive form of TNSALP in most cases. As a result, the chemicals on which the enzyme would normally act begin to accumulate, or increase, in the blood and urine. This accumulation is what hastens the defective calcification of bone. In theory, these substances could be measured to establish a diagnosis of hypophosphatasia. Although none have yet been proven to alone be reliable in all situations, a few appear more promising than others. These include pyridoxal-5-phosphate (PLP), phosphoethanolamine, or inorganic pyrophosphate. Abnormal (high) results lend further support to a diagnosis of hypophosphatasia when other clinical signs have also been recognized.
Prenatal diagnosis of hypophosphatasia has been successfully reported, although prior to the advent of molecular testing, it wasn't always completely reliable. Prenatal testing has been most widely used for the detection of the perinatal lethal form of hypophosphatasia. In some cases, the severe bone abnormalities of this type have been missed with a standard mid-pregnancy ultrasound but subsequently identified at an ultrasound performed much later. While this may be due, in part, to inexperience of the person performing the ultrasound, the highly variable clinical nature of hypophosphatasia is also to blame. A fetal x ray may be performed as a follow-up to any suspicious prenatal ultrasound evaluation.
Both chorionic villus sampling (CVS) and amniocentesis have been performed but have also on occasion been complicated by technical factors. For example, cultured cells from either a villus or amniotic fluid sample may be used to determine ALP activity. Because there are four forms of ALP in humans, the TNSALP form, which is abnormal in hypophosphatasia, may not be directly analyzed. An accurate interpretation of test results may therefore not be possible.
Direct analysis of the TNSALP gene thus holds the greatest promise for accurate prenatal diagnosis. Many different TNSALP mutations have been identified; many have been found in individual families only. It is also not unusual for two carrier parents to each have a different mutation. Direct analysis is therefore only currently possible for those families who have had at least one affected child and whose mutations have already been determined. Either CVS or amniocentesis may be used in these families for mutation studies. Rapid prenatal diagnosis of hypophosphatasia in the context of a negative family history is difficult.
Treatment and management
For those families in whom the underlying mutations are unknown, the most reliable method of prenatal diagnosis for perinatal lethal hypophosphatasia includes a combination of either CVS or amniocentesis for biochemical studies as well as serial ultrasound evaluations during pregnancy. If a diagnosis is made with certainty relatively early in pregnancy, the expectant parents should be offered the option of pregnancy termination.
As of 2001, there is no established, effective medical therapy for any form of hypophosphatasia. Care is mainly directed toward the prevention or correction of disease-related complications. Expert dental care is highly recommended for those individuals with dental abnormalities. Physical therapy and orthopedic management are important in the care and treatment of bone complications such as fractures. Young children with the infantile form should also be monitored carefully for increasing pressure within the head from early fusion of the bones of the skull. Traditional treatments for rickets or osteomalacia, such as vitamin D or other mineral supplements, should be avoided as these bone symptoms represent only one component of an inherited, rather than acquired, complex medical problem.
The prognosis associated with hypophosphatasia is directly related to the severity of the disease. In general, those individuals with the most severe skeletal abnormalities tend to do much worse than those with only mild clinical symptoms. Hence, infants who are diagnosed either during pregnancy or who have significant bone deformities at birth generally die within the first few days or weeks of life. These infants may also be stillborn. The prognosis associated with the infantile form of hypophosphatasia is variable: while over half of affected infants die during their first year due to serious breathing abnormalities, others spontaneously improve and may do well. Childhood disease is associated with skeletal deformities in some cases. Symptoms may improve, however, during adolescence only to occasionally reappear in adulthood. Finally, adult-onset hypophosphatasia is associated with ongoing, orthopedic problems once skeletal symptoms begin. Women, in particular, may notice increased bone loss and fractures after menopause.
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Deeb, A. A., S. N. Bruce, A. A. M. Morris, and T. D. Cheetham. "Infantile hypophosphatasia: disappointing results of treatment." Acta Pediatrica 89, no. 6 (June 2000):730-33.
Gehring, B., E. Mornet, H. Plath, M. Hansmann, P. Bartmann, and R. E. Brenner. "Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family." Clinical Genetics 56, no. 4 (October 1999): 313-17.
MAGIC Foundation for Children's Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 362-4423. Fax: (708) 383-0899. [email protected] <http://www.magicfoundation.org/ghd.html>.
National Institutes of Health, Osteoporosis and Related Bone Diseases. National Resource Center, 1232 22nd Street NW, Washington, DC 20037-1292. Fax: (202) 223-0344. <http://www.osteo.org/hypoph.html>.
OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/omim>.
Terri A. Knutel, MS, CGC