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Chapter 696 Hypophosphatasia

Hypophosphatasia is defined by low serum alkaline phosphatase activity and radiographically resembles rickets. This autosomal recessive disorder, affecting mainly the skeleton and teeth, is an inborn error of metabolism in which activity of the tissue-nonspecific (liver, bone, kidney) alkaline phosphatase isoenzyme (TNSALP) is deficient, although activity of the intestinal and placental isoenzymes is normal. Single point mutations of the gene prevent expression of the activity of this enzyme in vitro and indicate its necessity for normal skeletal mineralization. A large proportion of the >100 mutations of the gene identified to date are missense mutations, although splice-site mutations, small deletions, and frame-shift mutations also have been found. The only phenotype associated with these mutations is hypophosphatasia. Some patients have a regulatory defect involving this enzyme rather than a mutation.

There is considerable heterogeneity in the severity of the disease. Some cases appear at birth, and diagnosis has even been made in utero by radiographic examination of a fetus. The disease can appear in a lethal neonatal or perinatal form (congenital lethal hypophosphatasia), a severe infantile form, or a milder form occurring in childhood or late adolescence (hypophosphatasia tarda) (Fig. 696-1

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