Hypophosphatasia

Hypophosphatasia is a rare, and in its most severe forms life-threatening, inherited metabolic bone disease caused by a deficiency of the enzyme alkaline phosphatase, resulting from mutations in the ALPL gene. More than three hundred distinct mutations have been identified, roughly eighty percent of which are missense mutations, and the disease can be inherited in an autosomal recessive pattern for the more severe perinatal and infantile forms or in either an autosomal dominant or recessive pattern for milder forms that appear later in life. Reduced alkaline phosphatase activity impairs bone mineralization, producing a range of effects that can include osteopenia, skeletal hypomineralization, respiratory compromise in severe infantile cases, and rickets or osteomalacia depending on the age of onset and severity. It is coded E83.3 in the ICD-10, and severe forms are estimated to occur in about one in one hundred thousand births. The disease was first observed in 1936, but was formally named and characterized in 1948 by the Canadian pediatrician John Campbell Rathbun, who studied an infant with very low alkaline phosphatase levels; it is sometimes called Rathbun's syndrome in his honor.