Hypophosphatasia

Last updated • 13 min readFrom Wikipedia, The Free Encyclopedia
Hypophosphatasia
Other namesPhosphoethanolaminuria; Rathbun's syndrome [1]
1ALK.png
Ribbon diagram of the alkaline phosphatase protein, which is deficient in individuals with hypophosphatasia
Pronunciation
  • /ˌhaɪpoʊˈfɒsfeɪtˌeɪʒə/
Specialty Orthopedics, pediatrics, endocrinology
Symptoms Variable—may include osteopenia, skeletal hypomineralization, respiratory compromise
OnsetBirth
DurationLifelong
TypesInfantile, childhood, adult, and odontohypophosphatasia
Causes Mutation of the ALPL gene [2]
Diagnostic method Comprehensive metabolic panel test for serum alkaline phosphatase level; examination of X-rays; genetic tests of ALPL
Differential diagnosis Osteogenesis imperfecta, congenital dwarfisms, skeletal dysplasias
Treatment Asfotase alfa (Strensiq), an enzyme replacement therapy
Prognosis Severe perinatal forms are lethal without treatment; adult forms may only show moderate symptoms
FrequencyRare (1 in 100,000); [3] more common in some populations [4]

Hypophosphatasia ( /ˌhaɪpoʊˈfɒsfeɪtˌeɪʒə/ ; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, [5] or Rathbun's syndrome; [1] sometimes abbreviated HPP [6] ) is a rare, and sometimes fatal, inherited [7] metabolic bone disease. [8] Clinical symptoms are heterogeneous, ranging from the rapidly fatal, perinatal variant, with profound skeletal hypomineralization, respiratory compromise or vitamin B6 dependent seizures [6] 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. [7] The pathognomonic finding is subnormal serum activity of the TNSALP enzyme, which is caused by one of 388 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 the milder forms.

Contents

The prevalence of hypophosphatasia is not known; one study estimated the live birth incidence of severe forms to be 1:100,000. [3] and some studies report a higher prevalence of milder disease. [9]

Symptoms and signs

There is a remarkable variety of symptoms that depends, largely, on the age of the patient at initial presentation, ranging from death in utero to relatively mild bone problems with or without dentition symptoms [10] in adult life although neurological and extra-skeletal symptoms are also reported. [11] The stages of this disease are generally included in the following categories: perinatal, infantile, childhood, adult, benign prenatal and odontohypophosphatasia. [12] 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.[ citation needed ]

As the presentation of adult disease is highly variable, incorrect or missed diagnosis may occur. [10] In one study, 19% of patients diagnosed with fibromyalgia had laboratory findings suggestive of possible hypophosphatasia. [13]

One case report details a 35-year old female with low serum ALP and mild pains but no history of rickets, fractures or dental problems. Subsequent evaluation showed osteopenia and renal microcalcifications and an elevation of PEA. The genetic mutations found in this case were previously reported in perinatal, infantile and childhood hypophosphatasia, but not adult hypophosphatasia. [10]

Perinatal hypophosphatasia

Perinatal hypophosphatasia is the most lethal form. Profound hypomineralization results in caput membranaceum (a soft calvarium), deformed or shortened limbs during gestation and at birth, and rapid death due to respiratory failure. [14] Stillbirth is not uncommon and long-term survival is rare. Neonates who manage to survive suffer increasing respiratory compromise due to softening of the bones (osteomalacia) and underdeveloped lungs (hypoplastic). Ultimately, this leads to respiratory failure. Epilepsy (seizures) can occur and can prove lethal. [15] Regions of developing, unmineralized bone (osteoid) may expand and encroach on the marrow space, resulting in myelophthisic anemia. [16] [17]

In radiographic examinations, perinatal hypophosphatasia can be distinguished from even the most severe forms of osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked undermineralization and severe osteomalacia. Occasionally, there can be a complete absence of ossification in one or more vertebrae. In the skull, individual bones may calcify only at their centers. Another unusual radiographic feature is bony spurs that protrude laterally from the shafts 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.[ citation needed ]

Infantile hypophosphatasia

Infantile hypophosphatasia presents in the first 6 months of life, with the onset of poor feeding and inadequate weight gain. Clinical manifestations of rickets often appear at this time. Although cranial sutures appear to be wide, this reflects hypomineralization of the skull, and there is often "functional" craniosynostosis. If the patient survives infancy, these sutures can permanently fuse. Defects in the chest, such as flail chest resulting from rib fractures, lead to respiratory compromise and pneumonia. Elevated calcium in the blood (hypercalcemia) and urine (hypercalciuria) are also common, and may explain the renal problems and recurrent vomiting seen in this disease. [18]

Radiographic features in infants are generally less severe than those seen in perinatal hypophosphatasia. In the long bones, there is an abrupt change from a normal appearance in the shaft (diaphysis) to uncalcified regions near the ends (metaphysis), which suggests the occurrence of an abrupt metabolic change. In addition, serial radiography studies suggest that defects in skeletal mineralization (i.e. rickets) persist and become more generalized. Mortality is estimated to be 50% in the first year of life. [19]

Childhood hypophosphatasia

Hypophosphatasia in childhood has variable clinical expression. As a result of defects in the development of the dental cementum, the deciduous teeth (baby teeth) are often lost before the age of 5. Frequently, the incisors are lost first; occasionally all of the teeth are lost prematurely. Dental radiographs can show the enlarged pulp chambers and root canals that are characteristic of rickets. [20]

Patients may experience delayed walking, a characteristic waddling gait, stiffness and pain, and muscle weakness (especially in the thighs) consistent with nonprogressive myopathy. Typically, radiographs show defects in calcification and characteristic bony defects near the ends of major long bones. Growth retardation, frequent fractures, and low bone density (osteopenia) are common. In severely-affected infants and young children, cranial bones can fuse prematurely, despite the appearance of open fontanels on radiographic studies. The illusion of open fontanels results from hypomineralization of large areas of the calvarium. Premature bony fusion of the cranial sutures may elevate intracranial pressure. [21]

Adult hypophosphatasia

Adult hypophosphatasia can be associated with rickets, premature loss of deciduous teeth, or early loss of adult dentation followed by relatively good health. Osteomalacia results in painful feet due to poor healing of metatarsal stress fractures. Discomfort in the thighs or hips due to femoral pseudofractures can be distinguished from other types of osteomalacia by their location in the lateral cortices of the femora. [22] The symptoms of this disease usually begin during middle age of an adult patient and can include bone pain, and hypomineralization. [23] [12]

Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional 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 reveal pseudofractures in the lateral cortices of the proximal femora and stress fractures, and patients may experience osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis. [22]

Odontohypophosphatasia

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.[ citation needed ]

Causes

Hypophosphatasia is associated with a molecular defect in the gene encoding tissue non-specific alkaline phosphatase (TNSALP). TNSALP is an enzyme that is tethered to the outer surface of osteoblasts and chondrocytes. TNSALP hydrolyzes several substances, including mineralization-inhibiting inorganic pyrophosphate (PPi) and pyridoxal 5’-phosphate (PLP), a major form of vitamin B. A relationship describing physiologic regulation of mineralization has been termed the Stenciling Principle of mineralization, whereby enzyme-substrate pairs imprint mineralization patterns locally into the extracellular matrix (most notably described for bone) by degrading mineralization inhibitors (e.g. TNAP/TNSALP/ALPL enzyme degrading the pyrophosphate inhibition of mineralization, and PHEX enzyme degrading the osteopontin inhibition of mineralization). [24] [25] The Stenciling Principle for mineralization is particularly relevant to the osteomalacia and odontomalacia observed in hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH). [25] 6.

When TSNALP enzymatic activity is low, inorganic pyrophosphate (PPi) accumulates outside of cells in the extracellular matrix of bones and teeth, and inhibits formation of hydroxyapatite mineral, the main hardening component of bone, causing rickets in infants and children and osteomalacia (soft bones) and odontomalacia (soft teeth) in children and adults. PLP is the principal form of vitamin B6 and must be dephosphorylated by TNSALP before it can cross the cell membrane. Vitamin B6 deficiency in the brain impairs synthesis of neurotransmitters, which can cause seizures. In some cases, a build-up of calcium pyrophosphate dihydrate (CPPD) crystals in the joint can cause pseudogout. [26]

Genetics

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. [27]

Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. [3] The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed. The highest incidence of hypophosphatasia 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 exhibits severe disease. [4] Hypophosphatasia is considered particularly rare in people of African ancestry in the U.S. [28]

Diagnosis

Dental findings

Hypophosphatasia is often discovered because of an early loss of deciduous (baby or primary) teeth with the root intact. Researchers have recently documented a positive correlation between dental abnormalities and clinical phenotype. Poor dentition is also noted in adults. [29]

Laboratory testing

The symptom that best characterizes hypophosphatasia is low serum activity of alkaline phosphatase enzyme (ALP). In general, lower levels of enzyme activity correlate with more severe symptoms. The decrease in ALP activity leads to an increase in pyridoxal 5’-phosphate (PLP), which is the major form of Vitamin B6, in the blood, although tissue levels of Vitamin B6 may be unremarkable [30] and correlates with disease severity. [31] Urinary inorganic pyrophosphate (PPi) levels are elevated in most hypophosphatasia patients and, although it remains only a research technique, this increase has been reported to accurately detect carriers of the disease. In addition, most patients have an increased level of urinary phosphoethanolamine (PEA) although some may not. [6] PLP screening is preferred over PEA due to cost and sensitivity. [32]

Tests for serum tissue-non-specific ALP (sometimes referred to as TNSALP) levels are part of the standard comprehensive metabolic panel (CMP) that is used in routine exams, although bone-specific ALP testing may be indicative of disease severity. [33]

Radiography

Despite patient-to-patient variability and the diversity of radiographic findings, the X-ray is diagnostic in infantile hypophosphatasia. [34] Skeletal defects are found in nearly all patients and include hypomineralization, rachitic changes, incomplete vertebrate ossification and, occasionally, lateral bony spurs on the ulnae and fibulae.[ citation needed ]

In newborns, X-rays readily distinguish hypophosphatasia from osteogenesis imperfecta and congenital dwarfism. Some stillborn skeletons show almost no mineralization; others have marked 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, making it appear that areas of the unossified calvarium have cranial sutures that are widely separated when, in fact, they are functionally closed. Small protrusions (or "tongues") of radiolucency often extend from the metaphyses into the bone shaft.

In infants, radiographic features of hypophosphatasia are striking, though generally less severe than those found in perinatal hypophosphatasia. In some newly diagnosed patients, there is an abrupt transition from relatively normal-appearing diaphyses to uncalcified metaphases, suggesting an abrupt metabolic change has occurred. Serial radiography studies can 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, but they may not heal until they break completely or the patient receives intramedullary fixation. These patients may also experience recurrent metatarsal fractures. DXA may show abnormal bone mineral density which may correlate with disease severity, although bone mineral density in HPP patients may not be systemically reduced. [35]

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 388 distinct mutations have been described in the TNSALP gene. [2] "The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database". Archived from the original on 2016-03-04. Retrieved 2009-08-14. About 80% of the mutations are missense mutations. The number and diversity of mutations results in highly variable phenotypic expression, and there appears to be a correlation between genotype and phenotype in hypophosphatasia. [36] Mutation analysis is possible and available in 3 laboratories. [37]

Treatment

As of October 2015, asfotase alfa (Strensiq) has been approved by the FDA for the treatment of hypophosphatasia.

Some evidence exists to support the use of teriparatide in adult-HPP. [38] [39] [40] [41]

Current management consists of palliating symptoms, maintaining calcium balance and applying physical, occupational, dental and orthopedic interventions, as necessary. [8]

History

It was discovered initially in 1936 but was fully named and documented by a Canadian pediatrician, John Campbell Rathbun (1915-1972), while examining and treating a baby boy with very low levels of alkaline phosphatase in 1948. The genetic basis of the disease was mapped out only some 40 years later. Hypophosphatasia is sometimes called Rathbun's syndrome after its principal documenter. [55] [1]

See also

Related Research Articles

<span class="mw-page-title-main">Rickets</span> Childhood bone disorder

Rickets, scientific nomenclature: rachitis, is a condition that results in weak or soft bones in children and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone deformities, bone pseudofractures and fractures, muscle spasms, or an abnormally curved spine. The analogous condition in adults is osteomalacia.

<span class="mw-page-title-main">Osteopetrosis</span> Rare disease of the bones

Osteopetrosis, literally 'stone bone', also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.

<span class="mw-page-title-main">Osteomalacia</span> Softening of bones due to impaired bone metabolism

Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization.

<span class="mw-page-title-main">Hyperparathyroidism</span> Increase in parathyroid hormone levels in the blood

Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands or as response to external stimuli. Symptoms of hyperparathyroidism are caused by inappropriately normal or elevated blood calcium excreted from the bones and flowing into the blood stream in response to increased production of parathyroid hormone. In healthy people, when blood calcium levels are high, parathyroid hormone levels should be low. With long-standing hyperparathyroidism, the most common symptom is kidney stones. Other symptoms may include bone pain, weakness, depression, confusion, and increased urination. Both primary and secondary may result in osteoporosis.

<span class="mw-page-title-main">Osteogenesis imperfecta</span> Group of genetic disorders resulting in fragile bones

Osteogenesis imperfecta, colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth. Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (dissection) of the major arteries, such as the aorta; pulmonary valve insufficiency secondary to distortion of the ribcage; and basilar invagination.

<span class="mw-page-title-main">Calcitriol</span> Active form of vitamin D

Calcitriol is a hormone and the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the expression of many genes. Calcitriol increases blood calcium mainly by increasing the uptake of calcium from the intestines.

Renal osteodystrophy is currently defined as an alteration of bone morphology in patients with chronic kidney disease (CKD). It is one measure of the skeletal component of the systemic disorder of chronic kidney disease-mineral and bone disorder (CKD-MBD). The term "renal osteodystrophy" was coined in 1943, 60 years after an association was identified between bone disease and kidney failure.

<span class="mw-page-title-main">Renal tubular acidosis</span> Higher blood acidity due to failure of the kidneys to fully acidify urine

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

An osteochondrodysplasia, or skeletal dysplasia, is a disorder of the development of bone and cartilage. Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. These disorders lead to disproportionate short stature and bone abnormalities, particularly in the arms, legs, and spine. Skeletal dysplasia can result in marked functional limitation and even mortality.

<span class="mw-page-title-main">X-linked hypophosphatemia</span> X-linked dominant disorder that causes rickets

X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, and local elevations of the mineralization/calcification-inhibiting protein osteopontin in the extracellular matrix of bones and teeth. An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia.

<span class="mw-page-title-main">PHEX</span> Protein-coding gene in the species Homo sapiens

Phosphate-regulating endopeptidase homolog X-linked also known as phosphate-regulating gene with homologies to endopeptidases on the X chromosome or metalloendopeptidase homolog PEX is an enzyme that in humans is encoded by the PHEX gene. This gene contains 18 exons and is located on the X chromosome.

Bone disease refers to the medical conditions which affect the bone.

<span class="mw-page-title-main">ALPL</span> Protein-coding gene in the species Homo sapiens

Alkaline phosphatase, tissue-nonspecific isozyme (TNAP) is an enzyme that in humans is encoded by the ALPL gene.

<span class="mw-page-title-main">Pathologic fracture</span> Bone breakage due to structural weakness of the bone

A pathologic fracture is a bone fracture caused by weakness of the bone structure that leads to decrease mechanical resistance to normal mechanical loads. This process is most commonly due to osteoporosis, but may also be due to other pathologies such as cancer, infection, inherited bone disorders, or a bone cyst. Only a small number of conditions are commonly responsible for pathological fractures, including osteoporosis, osteomalacia, Paget's disease, Osteitis, osteogenesis imperfecta, benign bone tumours and cysts, secondary malignant bone tumours and primary malignant bone tumours.

Oncogenic osteomalacia, also known as tumor-induced osteomalacia or oncogenic hypophosphatemic osteomalacia, is an uncommon disorder resulting in increased renal phosphate excretion, hypophosphatemia and osteomalacia. It may be caused by a phosphaturic mesenchymal tumor. Symptoms typically include crushing fatigue, severe muscle weakness and brain fog due to the low circulating levels of serum phosphate.

<span class="mw-page-title-main">Vitamin D deficiency</span> Human disorder

Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D; disorders that limit vitamin D absorption; and disorders that impair the conversion of vitamin D to active metabolites, including certain liver, kidney, and hereditary disorders. Deficiency impairs bone mineralization, leading to bone-softening diseases, such as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, increasing the risk of bone fractures. Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of falls and bone fractures in adults. Vitamin D deficiency is associated with the development of schizophrenia.

<span class="mw-page-title-main">Elevated alkaline phosphatase</span> Medical condition

Elevated alkaline phosphatase occurs when levels of alkaline phosphatase (ALP) exceed the reference range. This group of enzymes has a low substrate specificity and catalyzes the hydrolysis of phosphate esters in a basic environment. The major function of alkaline phosphatase is transporting chemicals across cell membranes. Alkaline phosphatases are present in many human tissues, including bone, intestine, kidney, liver, placenta and white blood cells. Damage to these tissues causes the release of ALP into the bloodstream. Elevated levels can be detected through a blood test. Elevated alkaline phosphate is associated with certain medical conditions or syndromes. It serves as a significant indicator for certain medical conditions, diseases and syndromes.

Asfotase alfa, sold under the brand name Strensiq, is a medication used in the treatment of people with perinatal/infantile- and juvenile-onset hypophosphatasia.

<span class="mw-page-title-main">Phosphate diabetes</span> Medical condition

Phosphate diabetes is a rare, congenital, hereditary disorder associated with inadequate tubular reabsorption that affects the way the body processes and absorbs phosphate. Also named as X-linked dominant hypophosphatemic rickets (XLH), this disease is caused by a mutation in the X-linked PHEX gene, which encodes for a protein that regulates phosphate levels in the human body. phosphate is an essential mineral which plays a significant role in the formation and maintenance of bones and teeth, energy production and other important cellular processes. phosphate diabetes is a condition that falls under the category of tubulopathies, which refers to the pathologies of the renal tubules. The mutated PHEX gene causes pathological elevations in fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis by decreasing the reabsorption of phosphate in the kidneys.

Michael A. Levine is an American physician, scientist, academic, and author. He is an emeritus Professor of Pediatrics and Medicine in the Perelman School of Medicine at the University of Pennsylvania.

References

  1. 1 2 3 Rogers K, Chauhan Y (2013-09-30). "Hypophosphatasia". Encyclopedia Britannica. Retrieved 2021-08-23.
  2. 1 2 Choida V, Bubbear JS (2019-01-01). "Update on the management of hypophosphatasia". Therapeutic Advances in Musculoskeletal Disease. 11: 1759720X19863997. doi:10.1177/1759720X19863997. PMC   6676257 . PMID   31413732.
  3. 1 2 3 Fraser D (May 1957). "Hypophosphatasia". The American Journal of Medicine. 22 (5): 730–746. doi:10.1016/0002-9343(57)90124-9. PMID   13410963.
  4. 1 2 Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN (July 1993). "A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites". Genomics. 17 (1): 215–217. doi:10.1006/geno.1993.1305. PMID   8406453.
  5. ↑ "Hypophosphatasia". Genetics Home Reference.
  6. 1 2 3 "Hypophosphatasia". NORD (National Organization for Rare Disorders). Retrieved 2020-12-24.
  7. 1 2 Orimo H (2016-05-17). "Pathophysiology of hypophosphatasia and the potential role of asfotase alfa". Therapeutics and Clinical Risk Management. 12: 777–786. doi: 10.2147/TCRM.S87956 . PMC   4876073 . PMID   27274262.
  8. 1 2 Whyte MP (2001). "Hypophosphatasia". In Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds.). The Metabolic & Molecular Bases of Inherited Disease. Vol. 4 (8th ed.). New York: McGraw-Hill. pp. 5313–29. ISBN   978-0-07-913035-8.
  9. ↑ García-Fontana C, Villa-Suárez JM, Andújar-Vera F, González-Salvatierra S, Martínez-Navajas G, Real PJ, et al. (July 2019). "Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene". Scientific Reports. 9 (1): 9569. Bibcode:2019NatSR...9.9569G. doi:10.1038/s41598-019-46004-2. PMC   6606844 . PMID   31267001.
  10. 1 2 3 Fukushima K, Kawai-Kowase K, Yonemoto Y, Fujiwara M, Sato H, Sato M, et al. (April 2019). "Adult hypophosphatasia with compound heterozygous p.Phe327Leu missense and c.1559delT frameshift mutations in tissue-nonspecific alkaline phosphatase gene: a case report". Journal of Medical Case Reports. 13 (1): 101. doi: 10.1186/s13256-019-2045-4 . PMC   6480864 . PMID   31014398.
  11. ↑ Colazo JM, Hu JR, Dahir KM, Simmons JH (February 2019). "Neurological symptoms in Hypophosphatasia". Osteoporosis International. 30 (2): 469–480. doi:10.1007/s00198-018-4691-6. PMID   30215116. S2CID   52273027.
  12. 1 2 Magdaleno AL, Singh S, Venkataraman S, Perilli GA, Lee YY (November 2019). "Adult-Onset Hypophosphatasia: Before and After Treatment with Asfotase ALFA". AACE Clinical Case Reports. 5 (6): e344 –e348. doi:10.4158/ACCR-2019-0143. PMC   6873847 . PMID   31967067.
  13. ↑ "Hypophosphatasia May Be Misdiagnosed as Fibromyalgia: A Single Center Experience". ACR Meeting Abstracts. Retrieved 2021-01-05.
  14. ↑ Jaruratanasirikul S, Chanvitan P (December 1999). "Hypophosphatasia: the importance of alkaline phosphatase in bone mineralization". Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 82 (12): 1268–1272. PMID   10659574.
  15. 1 2 Baumgartner-Sigl S, Haberlandt E, Mumm S, Scholl-Bürgi S, Sergi C, Ryan L, et al. (June 2007). "Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene". Bone. 40 (6): 1655–1661. doi:10.1016/j.bone.2007.01.020. PMID   17395561.
  16. ↑ Millán JL, Plotkin H (September 2012). "Hypophosphatasia - pathophysiology and treatment". Actualizaciones en Osteologia. 8 (3): 164–182. PMC   4171060 . PMID   25254037.
  17. ↑ Villa-Suárez JM, García-Fontana C, Andújar-Vera F, González-Salvatierra S, de Haro-Muñoz T, Contreras-Bolívar V, et al. (April 2021). "Hypophosphatasia: A Unique Disorder of Bone Mineralization". International Journal of Molecular Sciences. 22 (9): 4303. doi: 10.3390/ijms22094303 . PMC   8122659 . PMID   33919113.
  18. ↑ "Hypophosphatasia Signs and Symptoms". Hypophosphatasia.com. Archived from the original on 15 October 2014. Retrieved 10 September 2014.
  19. ↑ Shohat, M.; Rimoin, D. L.; Gruber, H. E.; Lachman, R. S. (1991). "Perinatal lethal hypophosphatasia; Clinical, radiologic and morphologic findings". Pediatric Radiology. 21 (6). Springer Science and Business Media LLC: 421–427. doi:10.1007/bf02026677. ISSN   0301-0449. PMID   1749675. S2CID   1088742.
  20. ↑ Foster BL, Nociti FH, Somerman MJ (February 2014). "The rachitic tooth". Endocrine Reviews. 35 (1): 1–34. doi:10.1210/er.2013-1009. PMC   3895863 . PMID   23939820.
  21. ↑ Vogt M, Girschick H, Schweitzer T, Benoit C, Holl-Wieden A, Seefried L, et al. (August 2020). "Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children". Orphanet Journal of Rare Diseases. 15 (1): 212. doi: 10.1186/s13023-020-01500-x . PMC   7436954 . PMID   32811521.
  22. 1 2 Marini F, Brandi ML (2017). "Atypical femur fractures: a distinctive tract of adult hypophosphatasia". Clinical Cases in Mineral and Bone Metabolism. 14 (3): 324–328. doi:10.11138/ccmbm/2017.14.3.324. PMC   5762223 . PMID   29354161.
  23. ↑ Whyte MP (September 2017). "Hypophosphatasia: An overview For 2017". Bone. Rare Bone Diseases. 102: 15–25. doi:10.1016/j.bone.2017.02.011. PMID   28238808.
  24. ↑ Reznikov N, Hoac B, Buss DJ, Addison WN, Barros NM, McKee MD (September 2020). "Biological stenciling of mineralization in the skeleton: Local enzymatic removal of inhibitors in the extracellular matrix". Bone. 138: 115447. doi:10.1016/j.bone.2020.115447. PMID   32454257. S2CID   218909350.
  25. 1 2 McKee MD, Buss DJ, Reznikov N (March 2022). "Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization". Journal of Structural Biology. 214 (1): 107823. doi:10.1016/j.jsb.2021.107823. PMID   34915130. S2CID   245187449.
  26. ↑ "T3DB: Pyrophosphate". T3DB. October 2, 2014. Retrieved October 19, 2023.
  27. ↑ Simon-Bouy B, Taillandier A, Fauvert D, Brun-Heath I, Serre JL, Armengod CG, et al. (November 2008). "Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling". Prenatal Diagnosis. 28 (11): 993–998. doi: 10.1002/pd.2088 . PMID   18925618. S2CID   33682973.
  28. ↑ Whyte MP, Essmyer K, Geimer M, Mumm S (June 2006). "Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry". The Journal of Pediatrics. 148 (6): 753–758. doi:10.1016/j.jpeds.2006.01.031. PMID   16769381.
  29. 1 2 Reibel A, Manière MC, Clauss F, Droz D, Alembik Y, Mornet E, Bloch-Zupan A (February 2009). "Orodental phenotype and genotype findings in all subtypes of hypophosphatasia". Orphanet Journal of Rare Diseases. 4: 6. doi: 10.1186/1750-1172-4-6 . PMC   2654544 . PMID   19232125.
  30. ↑ Whyte MP, Mahuren JD, Fedde KN, Cole FS, McCabe ER, Coburn SP (April 1988). "Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase". The Journal of Clinical Investigation. 81 (4): 1234–1239. doi: 10.1172/JCI113440 . PMC   329654 . PMID   3350970.
  31. ↑ Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Rüther W, et al. (September 2017). "Clinical, radiographic and biochemical characteristics of adult hypophosphatasia". Osteoporosis International. 28 (9): 2653–2662. doi:10.1007/s00198-017-4087-z. PMID   28547134. S2CID   25864719.
  32. ↑ "Hypophosphatasia". NORD (National Organization for Rare Disorders). Retrieved 2021-09-28.
  33. ↑ Whyte MP, Walkenhorst DA, Fedde KN, Henthorn PS, Hill CS (June 1996). "Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity". The Journal of Clinical Endocrinology and Metabolism. 81 (6): 2142–2148. doi: 10.1210/jcem.81.6.8964842 . PMID   8964842.
  34. ↑ Shohat M, Rimoin DL, Gruber HE, Lachman RS (1991). "Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings". Pediatric Radiology. 21 (6): 421–427. doi:10.1007/BF02026677. PMID   1749675. S2CID   1088742.
  35. ↑ Genest F, Claußen L, Rak D, Seefried L (February 2021). "Bone mineral density and fracture risk in adult patients with hypophosphatasia". Osteoporosis International. 32 (2): 377–385. doi: 10.1007/s00198-020-05612-9 . PMC   7838076 . PMID   32879991.
  36. ↑ Zurutuza L, Muller F, Gibrat JF, Taillandier A, Simon-Bouy B, Serre JL, Mornet E (June 1999). "Correlations of genotype and phenotype in hypophosphatasia". Human Molecular Genetics. 8 (6): 1039–1046. doi: 10.1093/hmg/8.6.1039 . PMID   10332035.
  37. ↑ "geneteset.org homepage". Archived from the original on 2020-11-06. Retrieved 2016-05-19.
  38. ↑ Lawrence JE, Saeed D, Bartlett J, Carrothers AD (2017). "Adult-onset hypophosphatasia diagnosed following bilateral atypical femoral fractures in a 55-year-old woman". Clinical Cases in Mineral and Bone Metabolism. 14 (3): 347–353. doi:10.11138/ccmbm/2017.14.3.347. PMC   5762228 . PMID   29354166.
  39. ↑ Whyte MP (April 2016). "Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment". Nature Reviews. Endocrinology. 12 (4): 233–246. doi:10.1038/nrendo.2016.14. PMID   26893260. S2CID   20805434.
  40. ↑ Camacho PM, Mazhari AM, Wilczynski C, Kadanoff R, Mumm S, Whyte MP (August 2016). "Adult Hypophosphatasia Treated with Teriparatide: Report of 2 Patients and Review of the Literature". Endocrine Practice. 22 (8): 941–950. doi:10.4158/EP15890.OR. PMID   27042741.
  41. ↑ Whyte MP, Mumm S, Deal C (April 2007). "Adult hypophosphatasia treated with teriparatide". The Journal of Clinical Endocrinology and Metabolism. 92 (4): 1203–1208. doi: 10.1210/jc.2006-1902 . PMID   17213282.
  42. ↑ Barcia JP, Strife CF, Langman CB (May 1997). "Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization". The Journal of Pediatrics. 130 (5): 825–828. doi:10.1016/S0022-3476(97)80029-7. PMID   9152296.
  43. ↑ Opshaug O, Maurseth K, Howlid H, Aksnes L, Aarskog D (May 1982). "Vitamin D metabolism in hypophosphatasia". Acta Paediatrica Scandinavica. 71 (3): 517–521. doi:10.1111/j.1651-2227.1982.tb09466.x. PMID   6291316. S2CID   25957674.
  44. ↑ Collmann H, Mornet E, Gattenlöhner S, Beck C, Girschick H (February 2009). "Neurosurgical aspects of childhood hypophosphatasia". Child's Nervous System. 25 (2): 217–223. doi:10.1007/s00381-008-0708-3. PMID   18769927. S2CID   9470770.
  45. ↑ Coe JD, Murphy WA, Whyte MP (September 1986). "Management of femoral fractures and pseudofractures in adult hypophosphatasia". The Journal of Bone and Joint Surgery. American Volume. 68 (7): 981–990. doi:10.2106/00004623-198668070-00004. PMID   3745261.
  46. ↑ Girschick HJ, Seyberth HW, Huppertz HI (November 1999). "Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs". Bone. 25 (5): 603–607. doi:10.1016/S8756-3282(99)00203-3. PMID   10574582.
  47. ↑ Deeb AA, Bruce SN, Morris AA, Cheetham TD (June 2000). "Infantile hypophosphatasia: disappointing results of treatment". Acta Paediatrica. 89 (6): 730–733. doi:10.1080/080352500750044106. PMID   10914973.
  48. ↑ Whyte MP, Kurtzberg J, McAlister WH, Mumm S, Podgornik MN, Coburn SP, et al. (April 2003). "Marrow cell transplantation for infantile hypophosphatasia". Journal of Bone and Mineral Research. 18 (4): 624–636. doi: 10.1359/jbmr.2003.18.4.624 . PMID   12674323.
  49. ↑ Cahill RA, Wenkert D, Perlman SA, Steele A, Coburn SP, McAlister WH, et al. (August 2007). "Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts". The Journal of Clinical Endocrinology and Metabolism. 92 (8): 2923–2930. doi: 10.1210/jc.2006-2131 . PMID   17519318.
  50. ↑ Whyte MP, Valdes R, Ryan LM, McAlister WH (September 1982). "Infantile hypophosphatasia: enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease". The Journal of Pediatrics. 101 (3): 379–386. doi:10.1016/S0022-3476(82)80061-9. PMID   7108657.
  51. ↑ Whyte MP, McAlister WH, Patton LS, Magill HL, Fallon MD, Lorentz WB, Herrod HG (December 1984). "Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients". The Journal of Pediatrics. 105 (6): 926–933. doi:10.1016/S0022-3476(84)80079-7. PMID   6502342.
  52. ↑ "Clinical Trials website". U.S. National Institutes of Health.
  53. ↑ "enobia.com". www.enobia.com.
  54. ↑ Güzel Nur B, Çelmeli G, Manguoğlu E, Soyucen E, Bircan İ, Mıhçı E (September 2016). "Pyridoxine-Responsive Seizures in Infantile Hypophosphatasia and a Novel Homozygous Mutation in ALPL Gene". Journal of Clinical Research in Pediatric Endocrinology. 8 (3): 360–364. doi:10.4274/jcrpe.2798. PMC   5096504 . PMID   27086862.
  55. ↑ Taillefer D. "Our Mission". Soft Bones Canada Inc.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.