Perinatal form hypophosphatasia caused by a novel large duplication of ALPL gene and one year follow-up under enzyme replacement therapy; a case report

Hypophosphatasia is a rare disease caused by mutations in the gene encoding tissue-nonspecific isoenzyme of alkaline phosphatase. Duplications of the gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa treatment mineralizes the skeleton and improves respiratory function and survival in severe forms of hypophosphatasia. The newborn was evaluated for respira¬tory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high levels of substrates of tissue-nonspecific isoenzyme of alkaline phosphatase and radiologic findings. On day 21 after birth, enzyme replacement therapy using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. We were able to discharge our patient when he was 7 months old. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. No mutation was detected in the gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction. As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with enzyme replacement therapy is life-saving in the severe form of hypophosphatasia. Quantitative polymerase chain reaction can detect duplications if a mutation cannot be detected by sequence analysis in patients with hypophosphatasia.