146 Perinatal Hypophosphatasia - Prenatal Diagnosis

Abstract

Background: Hypophosphatasia is a rare autosomal recessive disorder characterized by defective bone and teeth mineralization, and deficiency of bone and serum alkaline phosphatase activity (ALP). The clinical expression is highly variable and ranges from stillbirth without mineralized bone to pathologic fractures developing only in late childhood. The responsible gene encoding the tissue non-specific alkaline phosphatase (TNSALP) consists of 12 exons and is localized on chromosome 1p36.1. More than 138 distinct mutations including a great number of compound heterozygous genotypes have been described. Case report: The patient was the first child of unrelated healthy Turkish parents. At 30 weeks of gestation ultrasound examination showed polyhydramnion, short limbs, reduced mineralization of the skull, and short ribs with a hypoplastic chest. Hypophosphatasia was suspected. Analysis of fetal cord blood showed absence of ALP-activity. These findings prompted us to initiate molecular analysis of the TSNALP-gene which revealed compound heterozygous mutations in the TNSALP-gene (G203V and R206Q) (E. Mornet, Versailles, France). The girl was born at 36 weeks gestational age and died of respiratory failure 30 minutes after birth. Clinically, she presented with a large head, soft calotte, muscular hypotonia, short and hyperflexible limbs. X-ray examination proved a severely reduced mineralisation of the bones with marked shortening of the long bones, very short and thin ribs and a hypoplastic chest and lungs. Conclusion: Reduced mineralization especially of the skull and the absence of ALP led to the clinical diagnosis of hypophosphatasia. The mutations found in the fetus predicted a lethal outcome. Prenatal molecular diagnosis is important for the perinatal management.