Prenatal genetic diagnosis of severe perinatal (lethal) hypophosphatasia

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency in tissue-nonspecific alkaline phosphatase (TNSALP) activity. This disorder is caused by various mutations of the TNSALP gene. We report here the prenatal diagnosis of the perinatal (lethal) type of hypophosphatasia in a sibling of an affected infant. The infant had been found to have hypophosphatasia on the basis of both clinical and radiologic manifestations and the finding of a homozygous single T nucleotide deletion at 1559 (1559delT) of the TNSALP gene on molecular analysis. Both parents were carriers with a heterozygous mutation in the same position, although they were not consanguineous. After their next child had been conceived, fetal genomic DNA was extracted from cultured cells of amniotic fluid at 15 weeks' gestation. The fetus had a homozygous 1559delT mutation. An ultrasonography examination at 19 weeks' gestation showed marked hypomineralization of all bony structures. A prenatal genetic diagnosis for hypophosphatasia in combination with ultrasonography is thus considered to be useful for confirming the diagnosis of hypophosphatasia, which presents with a wide variety of phenotypes. As a result, prenatal genetic counseling for hypophosphatasia with collaboration between obstetricians and clinical genetics teams.