Hypophosphatasia

Hypophosphatasia is a rare inherited metabolic disorder characterized by defective mineralization of bones and teeth, caused by a deficiency in the activity of the enzyme alkaline phosphatase (ALP) in blood and bone. This enzyme deficiency leads to the accumulation of substrates such as inorganic pyrophosphate, which inhibits bone mineralization. As a result, bones become soft and prone to fractures, and teeth may fall out prematurely. The severity of hypophosphatasia varies widely, from life-threatening forms evident in utero or infancy to milder forms that appear only in adulthood.

Hypophosphatasia is classified into six clinical types based on the age of onset and severity:

• Perinatal (lethal): Severe hypomineralization is evident in utero, and affected infants often die within days after birth.
• Prenatal benign: Prenatal skeletal abnormalities may be present, but symptoms improve spontaneously after birth.
• Infantile: Symptoms appear within the first 6 months of life and may include chest deformities, craniosynostosis, and hypercalcemia.
• Childhood: Affected children may have short stature, gait disturbances, bone pain, fractures, and premature loss of primary teeth.
• Adult: Symptoms may first appear in middle age and include stress fractures, joint pain, and osteomalacia.
• Odontohypophosphatasia: Only dental symptoms are present, such as early loss of primary teeth and severe dental caries.

Symptoms vary depending on the patient’s age and the form of the disease. Severe forms may result in perinatal death due to profound hypomineralization, which can lead to chest wall deformities and respiratory failure. Milder cases may be diagnosed in adulthood due to unexplained fractures or dental problems. Other common symptoms include premature loss of teeth, skeletal deformities, short stature, muscle weakness, delayed motor development and craniosynostosis.

Hypophosphatasia is caused by mutations in the ALPL gene, which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Mutations in this gene lead to reduced enzyme activity and accumulation of pyrophosphate and other substrates that inhibit bone mineralization. The disorder can be inherited in either an autosomal recessive or autosomal dominant manner, and the wide range of mutations accounts for the variability in clinical presentations.