Normal Mid-Gestation Fetal Ultrasonography Cannot Reliably Exclude Severe Perinatal Hypophosphatasia

Hypophosphatasia is a systemic bone disease characterized by inhibition of bone mineralization due to mutations in the ALPL gene that results in a deficiency of tissue nonspecific alkaline phosphatase. The perinatal form is the most severe. In the past, this form was lethal, although human recombinant enzyme replacement therapy has now been developed and licensed, which improves survival. Perinatal hypophosphatasia is usually suggested on antenatal ultrasonography with undermineralization of the long bones, skull, and thoracic cavity. In the UK, antenatal ultrasonography for fetal anomalies is conducted at mid-gestation (i.e., 18-21 weeks gestational age), and if normal, no further routine scans are performed. Usually, this would identify abnormalities in bone mineralization suggestive of perinatal hypophosphatasia.

We describe 2 cases of perinatal hypophosphatasia where mid-gestation ultrasonography was normal. In the first case, where a previous pregnancy had been terminated for perinatal hypophosphatasia, third trimester ultrasonography revealed skeletal features of hypophosphatasia. In the second case, the diagnosis of perinatal hypophosphatasia was made only immediately after birth.

We conclude that serial antenatal ultrasonography or antenatal genetic testing should be considered in all pregnancies with a positive family history of hypophosphatasia, as mid-gestation ultrasonography cannot reliably exclude perinatal hypophosphatasia. This is especially important given that effective enzyme replacement therapy is now available.