Last Updated on October 29, 2023
Hypophosphatasia is an inherited disorder of defect in alkaline phosphatase coding gene that affects the development of bones and teeth because mineralization is disrupted.
It was described initially by Rathbun in 1948.
Hypophosphatasia has got varied presentation. The symptoms can appear anywhere from before birth to adulthood
Severe forms of hypophosphatasia affect an estimated 1 in 100,000 newborns. Milder cases, such as those that appear in childhood or adulthood, probably occur more frequently.
Hypophosphatasia has been reported worldwide.
Clinical presentation varies widely, from death in utero to cases in which pathologic fractures first present in adulthood.
At least 6 clinical forms of hypophosphatasia have been reported.
These are perinatal, infantile, childhood, and adult. Two other forms are odontohypophosphatasia ( only dental clinical manifestations) and pseudohypophosphatasia.
Hypophosphatasia occurs in all races and affects both genders equally.
Pathophysiology of Hypophosphatasia
Alkaline phosphatase is has 4 isomers, each with its own gene locus. Three of these isoforms are tissue specific and are known as germ cell, placental, and intestinal alkaline phosphatase. The fourth isoform, TNSALP, is found in the bone, liver, kidney, and other tissues. The enzyme is physiologically active when in its dimeric form. More than 250 distinct mutations have been described for this gene.
Patients with hypophosphatasia have low alkaline phosphatase activity levels, which leads to increased PPi which is an inhibitor of hydroxyapatite crystal formation. This causes defects in calcium and phosphate balance. Hypophosphatasia weakens and softens the bones like rickets in children and osteomalacia in adults.
Additional complications in infancy include poor feeding and a failure to gain weight, respiratory problems, and high levels of calcium in the blood.
Hypophosphatasia in children and adults are less severe than those that appear in infancy.
The mildest form of this condition, called odontohypophosphatasia, only affects the teeth characterized by abnormal tooth development and premature tooth loss. Skeletal deformities are not seen.
Clinical Presentation of Hypophosphatasia
Perinatal hypophosphatasia
Perinatal hypophosphatasia is the most lethal form. Infants with extremely severe hypophosphatasia may be stillborn. Some infants survive a few days but have respiratory complications due to hypoplastic lungs and rachitic deformities of the chest. Apnea, seizures, craniosynostosis, and marked shortening of the long bones may be noted.
Infantile hypophosphatasia
Infantile hypophosphatasia presents in the first 6 months of life. Initially, affected infants may appear healthy until the onset of signs. The child shows poor feeding, inadequate weight gain and often a clinical picture rickets.
Widening of cranial sutures, chest deformities, respiratory compromise, and pneumonia may occur.
Calcium levels are elevated in blood and urine.
Increased excretion of calcium may lead to nephrocalcinosis and renal damage. Infants may also present with severe epileptic encephalopathy that results in death. These seizures respond to vitamin B-6 treatment.
Affected children often have a history of delayed walking and early loss of deciduous teeth. Bone pain is a frequent symptom.
Childhood hypophosphatasia
The presentation in this type varies. Due to poor development of the dental cementum, the deciduous teeth (baby teeth) are often lost
Adult hypophosphatasia
Adults usually present with signs and symptoms during middle age, but the history of symptoms may be present as early as childhood, or in some cases infants. Usually, the diagnosis is made after a low alkaline phosphatase level is detected during routine blood work.
The first symptom may be foot pain, which is due to stress fractures of the metatarsals.
Premature loss of deciduous teeth due to disturbed cementum formation is common. Mineralization of dentin is less likely.
There may be a history of stress fractures often resulting in painful feet. Affected adults may have signs and symptoms of osteomalacia.
Some patients suffer from calcium pyrophosphate dihydrate crystal depositions with occasional attacks of arthritis (pseudogout).
Odontohypophosphatasia
Odontohypophosphatasia presents with a premature loss of adult teeth.
Lab Studies
Laboratory evaluations should include levels of calcium, phosphorus, magnesium, alkaline phosphatase, creatinine, parathyroid hormone (PTH), 25(OH) vitamin D, and 1,25(OH)2 vitamin D.
Alkaline phosphatase levels are consistently low.
Plasma levels of PPi in plasma are low but
Phenylethylamine and pyridoxal 5-Phosphate levels are elevated.
Liver function test results tend to be normal.
Genetic screening of family members is warranted.
Imaging
Perform a radiologic skeletal survey on patients in whom the diagnosis of hypophosphatasia is being considered.
Skeletal manifestations of the severe cases vary widely among patients. Typical radiographic features include marked variability in the degree of bone ossification; unusually dense, round, flattened, and butterfly-shaped vertebral bodies; and generalized smaller ossified bones.
Bones are affected to different degrees in the same patient. Similarly, the bones affected differ among patients.
Variability in femoral shape is also observed.
In lethal cases, there is frequently a near absence of skeletal mineralization. Fractures and rachitic changes are often present
Premature cranial synostosis often occurs despite an open fontanelle. Xrays occasionally show a complete absence of ossification in one or more vertebrae. Bowdler spurs (osteochondral projections) of the midshaft of the fibula and ulna may be present. Prognosis is poor, but affected newborns may briefly survive.
Radiographic features in infants are generally less severe than those seen in perinatal hypophosphatasia.
Abrupt change from a normal appearance in the shaft (diaphysis) to uncalcified regions near the ends (metaphysis
In children rachitic deformities are seen. There is evidence of radiolucent projections from the epiphyseal plate into the metaphysis is present. This feature is not found in other types of rickets.
Dental radiographs can show the enlarged pulp chambers and root canals that are characteristic of rickets.
In adults, pseudofractures are one of the hallmarks of hypophosphatasia. These are often seen in the lateral cortices of the proximal femora. The x-rays also osteopenia, chondrocalcinosis, features of pyrophosphate arthropathy, and calcific periarthritis.
Renal ultrasound may reveal nephrocalcinosis.
Radiography findings are normal for patients with odontohypophosphatasia, except for osteopenic appearance of the maxilla.
Treatment of Hypophosphatasia
Until 2015, there was no effective drug therapy for hypophosphatasia.
Asfotase alfa is a recently approved drug for hypophosphatasia treatment. It is a kind of enzyme replacement that is a soluble glycoprotein composed of 2 identical polypeptide chains. It is given as a subcutaneous injection.
It is indicated for perinatal/infantile- and juvenile-onset hypophosphatasia. Patients with either perinatal or infant onset of the disease who were treated with asfotase alfa showed improvement in overall survival, as well as ventilator-free survival.
No special diet for hypophosphatasia is followed.
Complications of Hypophsphatasia
Skeletal deformities can predispose an infant to respiratory compromise or pneumonia. In the infantile form, craniosynostosis can lead to increased intracranial pressure.
Neonatal seizures may occur
Deformities and gait abnormalities may require surgical correction.
Prognosis
The perinatal form is considered lethal and the cause of death is often respiratory complication. The infantile form is believed to be fatal in approximately 50% of patients.
Lesser data is available for childhood hypophosphatasia. Individuals with less severe disease can reach adulthood, although often with significantly increased morbidity. Children with hypophosphatasia often have rachitic deformities.
Individuals with the adult and odontohypophosphatasic forms are believed to have normal lifespans.
Genetic counseling is important for all families who have affected children.
