Hypophosphatasia (HPP) is a rare inborn error of metabolism characterized by defective bone and tooth mineralization and deficiency of alkaline phosphatase activity in serum and bone. The clinical presentation is a continuum that ranges from a lethal prenatal form with absent skeletal mineralization to a mild form that begins in late adulthood and lacks pathognomonic symptoms. The classification into six types, based primarily on age at initial diagnosis, is as follows:
- perinatal lethal
- prenatal benign
- infantile juvenile
The prevalence of severe forms is low (approximately 1:300,000 in Europe, 1:100,000 in North America), while less severe forms are observed more frequently (approximately 1:6,000 in Europe).The disease is caused by loss-of-function variants in the ALPL gene. ALPL codes for Tissue Nonspecific Alkaline Phosphatase (TNSALP), a key regulator of mineralization.
Severe forms (perinatal and infantile) are inherited in an autosomal recessive manner, while moderate forms can be inherited in an autosomal recessive or dominant manner. The more severe the clinical picture, the more likely it is to be the autosomal recessive form. Diagnosis is based on consistently low serum alkaline phosphatase (AP) activity coupled with the detection of pathogenic variants in the ALPL gene. To date, >400 variants causative for the remarkable clinical heterogeneity have been identified. A clear, yet incomplete, genotype-phenotype correlation has been observed, suggesting that other genetic or environmental factors may modulate the phenotype. Enzyme replacement therapy is now available for HPP; other approaches such as gene therapy are under investigation.