Clinical Information

Hypophosphatasia (HPP) is a metabolic bone disorder caused by disease-causing variants in the ALPL gene. This gene encodes the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, which plays an essential role in mineralization of the skeleton and teeth. As a result, HPP is characterized by defective mineralization of bones and teeth in the presence of low activity of serum and bone alkaline phosphatase (ALP).

Inheritance of HPP can be autosomal dominant or recessive. Clinical variability is common in both dominant and recessive forms, with the most severe cases resulting from autosomal recessive inheritance. HPP is most severe when is presents perinatally or in infancy and may be lethal, while heterozygous individuals are more likely to manifest moderate, mild, or even asymptomatic disease. Regardless of the number of ALPL disease-causing variants, many affected individuals suffer from pain, disability, and reduced quality of life because of decreased bone mineralization.

The disease spectrum of HPP is a continuum; however, there are seven clinically recognized forms of HPP determined by age of onset and severity of symptoms. These include perinatal severe, perinatal benign, infantile, severe childhood, mild childhood, adult, and odontohypophosphatasia. The wide range of clinical features and age of onset make timely diagnosis of HPP challenging, especially with later onset or milder forms of the disease. Common clinical findings include rickets, premature loss of deciduous teeth, vitamin B6 responsive seizures, and bone pain.

Hypophosphatasia can be diagnosed by decreased activity of serum ALP and increased excretion of the TNSALP substrate phosphoethanolamine (PEA) in urine. Molecular analysis of ALPL is also recommended to confirm a diagnosis of HPP (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify gene list ID: RENAL-D5DR9D). There is strong genotype-phenotype correlation with some variants. Monitoring urinary PEA is useful for assessing response to enzyme replacement therapy, which was approved by the US Food and Drug Administration in 2015 and is a first-line therapy for several forms of HPP.