TY - JOUR
T1 - Natural History of Perinatal and Infantile Hypophosphatasia
T2 - A Retrospective Study
AU - Study 011-10 Investigators
AU - Whyte, Michael P.
AU - Leung, Edward
AU - Wilcox, William R.
AU - Liese, Johannes
AU - Argente, Jesús
AU - Martos-Moreno, Gabriel
AU - Reeves, Amy
AU - Fujita, Kenji P.
AU - Moseley, Scott
AU - Hofmann, Christine
AU - Beck, Michael
AU - DiMeglio, Linda
AU - Wuh-Liang Hwu, Paul
AU - Simm, Peter
AU - Simmons, Jill
AU - Steelman, Joel
AU - Steiner, Robert D.
AU - Superti-Furga, Andrea
N1 - Funding Information:
This study was sponsored by Alexion Pharmaceuticals, Inc, Boston, MA, which was involved in all stages of the study and manuscript development. Medical writing and editorial support were provided by Bina J. Patel, PharmD, CMPP, of Peloton Advantage, LLC (Parsippany, NJ), an OPEN Health company, and was funded by Alexion. M.P.W. was the principal study investigator and received honoraria, travel support, and institutional research funding and/or grant support from Alexion Pharmaceuticals, Inc. C.H. was a clinical study investigator and received consulting fees and institutional research funding and/or grant support from Alexion Pharmaceuticals, Inc. W.W., E.L., G.M.-M., J.A., and J.L. were clinical study investigators and received institutional research funding and/or grant support from Alexion Pharmaceuticals, Inc. S.M. and K.F. are employees of and may own stock/options in Alexion Pharmaceuticals, Inc, which sponsored the study. A.R. declares no conflicts of interest. We acknowledge the International Skeletal Dysplasia Registry (http://ortho.ucla.edu/isdr), from which a number of cases were identified.
Funding Information:
This study was sponsored by Alexion Pharmaceuticals , Inc, Boston, MA, which was involved in all stages of the study and manuscript development. Medical writing and editorial support were provided by Bina J. Patel, PharmD, CMPP, of Peloton Advantage, LLC (Parsippany, NJ), an OPEN Health company, and was funded by Alexion . M.W. was the principal study investigator and received honoraria, travel support, and institutional research funding and/or grant support from Alexion Pharmaceuticals , Inc. C.H. was a clinical study investigator and received consulting fees and institutional research funding and/or grant support from Alexion Pharmaceuticals , Inc. W.W., E.L., G.M.-M., J.A., and J.L. were clinical study investigators and received institutional research funding and/or grant support from Alexion Pharmaceuticals , Inc. S.M. and K.F. are employees of and may own stock/options in Alexion Pharmaceuticals, Inc, which sponsored the study. A.R. declares no conflicts of interest.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/6
Y1 - 2019/6
N2 - Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. Results: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P <.05)with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4]U/L)was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. Conclusions: Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. Trial registration: ClinicalTrials.gov: NCT01419028.
AB - Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. Results: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P <.05)with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4]U/L)was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. Conclusions: Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. Trial registration: ClinicalTrials.gov: NCT01419028.
KW - alkaline phosphatase
KW - craniosynostosis
KW - invasive ventilation
KW - metabolic bone disease
KW - rickets
KW - survival
UR - http://www.scopus.com/inward/record.url?scp=85064000226&partnerID=8YFLogxK
U2 - 10.1016/j.jpeds.2019.01.049
DO - 10.1016/j.jpeds.2019.01.049
M3 - Article
C2 - 30979546
AN - SCOPUS:85064000226
VL - 209
SP - 116-124.e4
JO - Journal of Pediatrics
JF - Journal of Pediatrics
SN - 0022-3476
ER -