Background: Hypophosphatasia (HPP) is a rare, inherited metabolic disease caused by loss-of-function mutations in the gene encoding tissue nonspecific alkaline phosphatase (TNSALP), resulting in hypomineralisation of bone. HPP presenting <6 months of age is often lethal due to respiratory insufficiency, with survival of 42% at 1 year. Asfotase alfa, a human recombinant TNSALP replacement, promotes bone mineralisation, with survival of 95% at 1 year in infants with HPP.
Objective: We characterised tracheobronchomalacia (TBM) occurring in infants with HPP treated with asfotase alfa.
Methods: Patients with perinatal- or infantile-onset HPP who received asfotase alfa in a clinical study or a compassionate-use programme were identified as having severe TBM. Clinical data analysed included: presenting features; predetermined manifestations of interest including TBM; and management of TBM.
Results: Four patients (two female, two male) with TBM were identified; three enrolled in Study ENB-010-10 (NCT01176266); one received asfotase alfa in a compassionate-use programme. All patients received ongoing treatment with asfotase alfa starting at ≤2 months of age (dose 615 mg/kg per week). All four patients required ventilation at birth and experienced frequent respiratory distress, two experienced respiratory arrests. Management included tracheostomy and continuous positive pressure ventilation with positive end-expiratory pressure (upto 12 cm H2O). At the time of this report, the TBM had resolved in two patients (15 and 24 months old; off ventilatory support), partially resolved in one (27 months old, ventilatory support) and remained significant in one patient (23 months old, tracheostomy in situ).
Conclusion: This is the first report of TBM in infants with HPP. We recommend screening infants with HPP who require intermittent positive pressure ventilation for TBM with flexible bronchoscopy. Further data are needed to determine the role that asfotase alfa may have played in the improvements, beyond enabling prolonged survival and subsequent maturation of the airways.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology