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Hypophosphatasia is a rare, and sometimes fatal metabolic bone disease. Clinical symptoms are heterogeneous ranging from the rapidly fatal perinatal variant, with profound skeletal hypomineralization and respiratory compromise to a milder, progressive osteomalacia later in life. Tissue non-specific alkaline phosphatase (TNSALP) deficiency in osteoblasts and chondrocytes impairs bone mineralization, leading to rickets or osteomalacia. The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 200 genetic mutations identified to date in the gene encoding TNSALP. Genetic inheritance is autosomal recessive for the perinatal and infantile forms but either autosomal recessive or autosomal dominant in milder forms. The prevalence of hypophosphatasia is not known. One study estimated the live birth incidence of severe forms to be 1:100,000.
There is a remarkable heterogeneity in symptom presentation depending largely on age at initial presentation, ranging from death in utero to relatively simple problems with dentition in adult life. Although several clinical sub-types of the disease have been characterized based on the age at which skeletal lesions are discovered, the disease is best understood as a single continuous spectrum of severity.
Perinatal hypophosphatasia is the most pernicious form of hypophosphatasia. In utero, profound hypomineralization results in caput membraneceum, deformed or shortened limbs during gestation and at birth and rapid death due to respiratory failure. Stillbirth is not uncommon and long-term survival is rare. Neonates who manage to survive several days or weeks suffer increasing respiratory compromise due to rachitic chest disease and hypoplastic lungs, and ultimately, respiratory failure. Epilepsy (seizures) can occur and prove lethal (vide infra). Excessive osteoid may encroach on the marrow space and result in myelophthisic anemia. In radiographic examinations, perinatal hypophosphatasia is readily distinguished from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, giving areas of the unossified calvaruim the illusion that cranial sutures are widely separated when they are in fact functionally closed. Another unusual radiographic feature is bony spurs that protrude laterally from the midshafts of the ulnae and fibulae. Despite the considerable patient-to-patient variability and the diversity of radiographic findings, the X-ray can be considered diagnostic.
Infantile hypophosphatasia presents in the first 6 months of life. Postnatal development often appears normal until the onset of poor feeding and inadequate weight gain, and clinical manifestations of rickets are recognized. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often “functional” craniosynostosis; and if the patient survives infancy, these sutures can permanently fuse. Often, a flail chest from rib fractures, rachitic deformity, etc. leads to respiratory compromise and pneumonia. Hypercalcemia and hypercalcenuria are also common and may explain the nephrocalcinosis, renal compromise, and episodes of recurrent vomiting. Radiographic features are striking though generally less severe than those found in perinatal hypophosphatasia. In some newly diagnosed patients an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears, which suggests the occurrence of abrupt metabolic change. In addition, serial radiography studies may demonstrate the persistence of impaired skeletal mineralization (i.e. rickets) and reveal gradual generalized demineralization. Mortality is estimated to be 50% in the first year of life.
Hypophosphatasia in childhood has variable clinical expression. As a result of aplasia, hypoplasia, or dysplasia of dental cementum, premature loss of deciduous teeth (i.e. before the age of 5) occurs. Frequently, incisors are shed first; occasionally almost the entire primary dentition is exfoliated prematurely. Dental radiographs sometimes show the enlarged pulp chambers and root canals characteristic of the “shell teeth” of rickets. Patients may also experience delayed walking, a characteristic waddling gait, complain of stiffness and pain, and have an appendicular muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show rachitic deformities and characteristic bony defects near the ends of major long bones (i.e. “tongues” of radiolucency projecting from the rachitic growth plate into the metaphsysis). Growth retardation, frequent fractures and osteopenia are common. In severely affected infants and young children it is not uncommon, despite the appearance of widely “open” fontanels on radiographic studies, for functional synostosis of cranial sutures to occur. The illusion of “open” fontanels results from large areas of hypomineralized calvarium. Subsequently true premature bony fusion of cranial sutures may elevate intracranial pressure.
Adult hypophosphatasia can be associated with rickets, premature loss of deciduous teeth, or early loss of adult dentition followed by relatively good health. Osteomalacia manifests in painful feet resulting from recurrent poorly healing metatarsal stress fractures, and discomfort in the thighs or hips due to femoral pseudofractures which, when they appear in radiographic study, are distinguished from most other types of osteomalacia (which occur medially) by their location in the lateral cortices of the proximal femora. Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional overt attacks of arthritis (pseudogout), which appears to be the result of elevated endogenous inorganic pyrophosphate (PPi) levels. These patients may also suffer articular cartilage degeneration and pyrophosphate arthropathy. Radiographs may reveal pseudofractures in the lateral cortices of the proximal femora, stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis.
Odontohypophosphatasia is present when dental disease is the only clinical abnormality and radiographic and/or histologic studies reveal no evidence of rickets or osteomalacia. Although hereditary leukocyte abnormalities and other disorders usually account for this condition, odontohypophosphatasia may explain some “early-onset periodontitis” cases.
The metabolic basis of hypophosphatasia stems from a molecular defect in the gene encoding tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an ectoenzyme tethered to the outer surface of osteoblast and chondrocyte cell membranes. TNSALP normally hydrolyzes several substances, including inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP) a major form of vitamin B6.
When TSNALP is low, inorganic pyrophosphate (PPi) accumulates extracellularly and potently inhibits formation of hydroxyapatite (mineralization) causing rickets in infants and children and osteomalacia (soft bones) in adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP for PL to cross over the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, deposition of calcium pyrophosphate dehydrate (CPPD) crystals in the joint can cause pseudogout.
Dental Findings Often, one of the first symptoms of hypophosphatasia is early loss of deciduous (baby or primary teeth) with root intact. Researchers have recently documented a positive correlation of dental abnormalities to clinical phenotype. Poor dentition is noted in adults.
Laboratory Testing The pathognomonic symptom is subnormal serum activity of alkaline phosphatase (ALP). In general, clinical severity mirrors the degree of enzyme deficiency. The most sensitive substrate marker for hypophosphatasia is an increased pyridoxal 5’-phosphate (PLP) plasma level, which often correlates with disease severity. And, although it remains only a research technique, quantification of urinary inorganic pyrophosphate (PPi) levels, which are elevated in most hypophosphatasia patients, has been reported to accurately detect carriers. In addition, increased urinary levels of phosphoethanolamine (PEA) are observed in most patients. Availability of the age-adjusted serum ALP test is widespread and included on many CHEM20 panels.
Radiography Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia, and can reveal the characteristic abnormalities found in other forms. Radiologic evidence of skeletal defects is found in nearly all patients and includes hypomineralization, rachitic changes, incomplete vertebrate ossification and occasionally, lateral bony spurs on the ulnae and fibulae. Availability of XRAYs are widespread.
In newborns X-rays readily distinguish perinatal HPP from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked bony undermineralization and severe rachitic changes; and occasionally, there can be peculiar complete or partial absence of ossification in one or more vertebrae. In the skull, individual membranous bones may calcify only at their centers, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated, when in fact they are functionally closed. Tongues of radiolucency often protrude from the metaphyses into the bone shaft.
In infants, radiographic features of infantile HPP are striking though generally less severe than those found in perinatal HPP. In some newly diagnosed patients, an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphyses appears suggesting an abrupt metabolic change has occurred. Serial radiography studies may reveal the persistence of impaired skeletal mineralization (i.e. rickets), instances of sclerosis and gradual generalized demineralization.
In adults, x-rays may reveal bilateral femoral pseudofractures in the lateral subtrochanteric diaphysis. These pseudofractures may remain for years or worsen, but they may not heal until they break completely or the patient receives intramedullary fixation. These patients may also experience recurrent metatarsal fractures.
Genetic Analysis All clinical sub-types of hypophosphatasia have been traced to genetic mutations in the gene encoding TNSALP, which is localized on chromosome 1p36.1-34 in humans (ALPL; OMIM#171760). Approximately 204 distinct mutations have been described in the TNSALP gene. An up-to-date list of mutations is available online at http://www.sesep.uvsq.fr/database_hypo/Mutation.html. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression. There appears to be a correlation between genotype and phenotype in hypophosphatasia”. Mutation analysis is possible and available in 3 laboratories (as reported on www.genetest.org).
Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.
HPP is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo Saxon origin. The frequency of mild HPP is more challenging to assess because the symptoms may escape notice, or be misdiagnosed. The highest incidence of HPP has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns manifests severe disease. HPP is considered particularly rare in people of African ancestry in the U.S.
There are no approved therapies for HPP today. Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions as necessary.