Hypophosphatasia (HPP) is an inherited systemic metabolic bone disease occurring due to mutations in the ALPL gene which encodes for tissue-nonspecific alkaline phosphatase (TNSALP), resulting in defective bone mineralisation due to accumulation of inorganic pyrophosphate (PPi). The perinatal form of this condition lays at the most severe end of the spectrum. Enzyme replacement therapy with asfotase alfa, a recombinant fusion protein that includes the catalytic domain of TNSALP and a peptide that targets the enzyme to bone, is now licensed for management of the childhood form of HPP. We report a baby recently born with an antenatal diagnosis of HPP. Parents were healthy and non-consanguineous. A previous pregnancy had been terminated because of deformities in the foetal skeleton, with genetic testing confirming HPP in the foetus and parents being carriers. Antenatally, foetal scans were normal at 16- and 20-weeks. However, scans at 30 weeks gestation showed features of HPP poor mineralisation of skull bones and shortening of limb bones. Genetic confirmation of HPP was obtained from chorionic villus biopsy sample. She was born by normal vaginal delivery. Intubation was required upon delivery. Asfotase alfa, obtained on compassionate use, was initiated within 12 hours of birth. A skeletal survey showed gross under-mineralisation throughout the skeleton, with the ribs, distal limb bones and skull most severely affected. In view of rib under-mineralisation and likely need for long-term ventilation, a tracheostomy was performed on day 3, along with central venous access. Currently she remains on stable ventilation settings and fully enterally fed with expressed breast milk. Serial antenatal scans and neonatal radiographs demonstrate that there has been progressive worsening of skeletal mineralisation, presumably secondary to accumulation of PPi. We therefore recommend that, in the presence of a family history of HPP, antenatal scans are continued to be performed into later pregnancy for diagnosis and monitoring of severity of HPP. We believe this is the earliest asfotase alfa has been administered to a neonate with perinatal HPP. To what extent this improves outcomes and prevents complications remains to be seen, with close monitoring for craniosynostosis, seizures, tracheomalacia, respiratory deterioration and calcium abnormalities ongoing.
23 - 25 Nov 2016
British Society for Paediatric Endocrinology and Diabetes