Hypophosphatasia

At a glance

Hypophosphatasia (HPP) is a rare genetic disorder characterized by the abnormal development of bones (similar to vitamin D-resistant rickets) and teeth. Other features in this inherited inborn error of metabolism include failure to thrive, movement disorders, and low plasma levels of alkaline phosphatase. HPP is an extremely variable disorder. Six major clinical forms have been identified based primarily upon the age of onset of symptoms and diagnosis.

Synonym

Rathbun Disease.

Classification

• Hypophosphatasia Perinatal Type: Known as the neonatal hypophosphatasia

• Hypophosphatasia Infantile Type: Phosphoethanolaminuria

• Hypophosphatasia Childhood Type

• Hypophosphatasia Adult Type: Mild hypophosphatasia

• Odontohypophosphatasia

• Pseudohypophosphatasia

History

Inborn error of metabolism initially identified by Rathbun in 1948.

Incidence

Estimated at 1:100,000 live births (and 1 carrier per 200 individuals in the United States). Some ethnic or religious groups have a higher incidence of the disease (1:2,500 among Canadian Mennonites). HPP affects males and females in equal numbers. In Canada, the severe forms of HPP are estimated in 1:100,000 live births. The overall incidence and prevalence of all forms of HPP is unknown. Milder cases can go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of HPP in the general population. HPP occurs with greatest frequency in the Mennonite population in Canada, is relatively prevalent in Japan, and is relatively rare in black individuals.

Genetic inheritance

Autosomal recessive. However, mild adult hypophosphatasia and odontohypophosphatasia cases seem to be inherited as an autosomal dominant trait. Prenatal diagnosis is possible by measuring alkaline phosphatase activity in chorionic villus samples from amniocentesis, and the perinatal (severe) form of the disease can be detected by ultrasonography. The defective gene, called ALPL, is located at 1p36.1-34.

Pathophysiology

Deficient activity of tissue-nonspecific alkaline phosphatase, one of the four isomers of alkaline phosphatase (each of which has its own gene locus). This results in accumulation of several metabolites including phosphoethanolamine, pyridoxal-5′-phosphate (a form of vitamin B₆), and inorganic pyrophosphate, which are found in large amounts in the blood and urine. The characteristic defective calcification of bones in children (rickets) and adults (osteomalacia) is caused by the accumulation of inorganic pyrophosphate.

Diagnosis

Clinical features. Radiologic appearance: epiphyseal and metaphyseal abnormalities of long bones, vertebrae, and ribs. Elevated plasma and urine levels of phosphoethanolamine are usually characteristic in the laboratory reports. Elevated plasma inorganic pyrophosphate and pyridoxal-5′-phosphate are associated with this medical condition.

Clinical aspects

Hypophosphatasia varies widely in clinical presentation. It has been subdivided into six categories: perinatal, infantile, childhood, adult, odontohypophosphatasia, and pseudohypophosphatasia. The earlier the symptoms occur, the more severe the disease.

• Perinatal Form: Presents with a ...