Perinatal hypophosphatasia: diagnosis and detection of heterozygote carriers within the family

We report on two families in which one or two children had a severe disorde r of skeletal development detected by prenatal ultrasonography. The childre n died postnatally and showed typical radiological and biochemical findings of perinatal hypophosphatasia. Biochemical analysis revealed a low activit y of alkaline phosphatase (AP) and a high value of pyridoxal-5-phosphate (P LP), one of its natural substrates. The screening for mutations of the tiss ue nonspecific alkaline phosphatase (TNSALP) gene showed homozygosity for a point mutation (G 317 --> D) in the two affected children of the first fam ily. The affected child of the second family was homozygous for a nonsense mutation (R 411 --> X). Family screening revealed that the determination of AP and PLP is helpful for detection of heterozygotes. However, heterozygot e children had values of AP in the lower normal range during phases of rapi d growth. The determination of PLP proved to be more sensitive in these cas es. It should be kept in mind that during the last trimester of gestation t here is an increase in maternal AP activity and a normalization of PLP due to placental AP, which is not affected. Therefore, in the course of a prena tal diagnosis in an index case, paternal blood should be analyzed in parall el. For detailed genetic counseling and early prenatal diagnosis in followi ng pregnancies, the possibility of mutation analysis should be used.