Hypophosphatasia

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). The lethal form is characterized by a moth-eaten appearance at the ends of the long bones, severe deficiency of ossification throughout the skeleton, and marked shortening of the long bones. Patients with mild disease can present with bowing of the legs and variable statural shortening. Hypercalcemia is common in the neonatal and infantile forms, and because calcium accumulation by mature chondrocytes does not occur, patients might appear to have rickets.

Figure 696-1 A, Fetus with congenital lethal hypophosphatasia showing thin wavy ribs, platyspondyly, missing cervical vertebrae, ossification, and bent femurs. B, Seven yr old with hypophosphatasia tarda showing osteopenia, bent tibias, and punched-out metaphyseal lesions.

Unusual clinical manifestations include wormian bones in the calvariae; poor calcification of the frontal, parietal, and occipital bones; and premature loss of deciduous or permanent teeth, due to hypoplasia of dental cementum. Because of the hypercalcemia in the infantile form, nephrocalcinosis is also found. In the childhood form, bone pain, frequent fractures, and milder skeletal deformities are evident, as well as premature tooth loss. The metaphyseal defect consists of irregular ossification, punched-out areas, and metaphyseal cupping. There is an adult form, manifesting in middle age, which is characterized by recurrent metaphyseal stress fractures and femoral pseudofractures.

In hypophosphatasia, large quantities of phosphoethanolamine are found in the urine because this compound cannot be degraded in the absence of TNSALP activity. Plasma inorganic pyrophosphate and pyridoxal-5-phosphate (PLP) levels are also elevated for the same reason. PLP levels tend to be lower than normal in most other bone diseases and hence can aid in the differential diagnosis of hypophosphatasia. Seizures in patients with the lethal and infantile forms of the disease may be related to impaired pyridoxine metabolism. Although no satisfactory therapy has been found, infusion of plasma rich in alkaline phosphatase activity has been helpful in healing bone in short-term studies. Bone marrow transplantation has been successful using donors with normal TNSALP values. The clinical course of this condition often improves spontaneously as an affected child matures, although early death due to renal failure or flail chest leading to pneumonia can occur in the severe infantile form of the disorder.

Rare patients presenting with identical clinical and radiographic patterns have normal serum alkaline phosphatase activity. Their disease has been labeled pseudohypophosphatasia and might represent the presence of a mutant alkaline phosphatase isoenzyme that reacts to artificial substrates in an alkaline environment (in a test tube) but not in vivo with natural substrates.

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