A case report of unsuccessful enzyme replacement therapy in perinatal hypophosphatasia: impact of comorbid tetralogy of Fallot, prematurity, and novel variants

Abstract Hypophosphatasia (HPP) is a rare inborn error of metabolism characterized by defective bone mineralization due to alkaline phosphatase (ALP) deficiency encoded by the gene ALPL (Orphanet J Rare Dis 2:40, 2007), (Am J Med 22:730-746, 1957). The current treatment for HPP is enzyme replacement therapy (ERT) to improve bone mineralization (J Clin Endocrinol Metab 101:334-342, 2016), (N Engl J Med 366:904-913, 2012). However, severe perinatal forms of HPP is lethal in non-responders. We report a male infant with tetralogy of Fallot (TOF) and perinatal HPP who exhibited progressive skeletal demineralization despite ERT. Initial chest X-ray findings were unremarkable; however, subsequent skeletal surveys demonstrated diffuse demineralization, metaphyseal fraying, and absent thoracic mineralization, correlating with poor clinical outcomes. Genetic analysis confirmed HPP diagnosis with one heterozygous variant of c.891C > G (p.Tyr297Ter) and one heterozygous partial ALPL deletion. Our patient was started on ERT and maintained on the highest dose throughout his lifetime of 7 months without clinical and radiographic improvement. This case presents a lethal form of perinatal HPP resulting from compound heterozygosity, including a novel pathogenic ALPL variant, contributing new insights into genetic counseling and diagnostic evaluation. It also underscores the importance of recognizing multifactorial determinants of ERT failure, such as the complex interplay of comorbidities, including extreme prematurity, bronchopulmonary dysplasia, and congenital heart disease (tetralogy of Fallot), and the need for early multidisciplinary evaluation and individualized prognostication in neonates with perinatal HPP and complex comorbidities.