Abstract / Summary
Abstract Hypophosphatasia (HPP) is a rare inborn error of metabolism caused by pathogenic variants in the ALPL . Reduced alkaline phosphatase (ALP) activity impairs hydroxyapatite formation and thereby reduces skeletal mineralization. Six clinical forms have been identified: perinatal lethal, benign prenatal, infantile, childhood, adult form, and odontohypophosphatasia. This study included twelve patients from nine unrelated Egyptian families diagnosed with HPP based on medical history, physical and radiological examinations, and laboratory investigations. Targeted sequencing of the whole coding region and exon-intron boundaries of ALPL was carried out for all patients which revealed homozygous or compound heterozygous variants in all 9 families. Nine different variants were identified including two novel ones, a missense (c.1405 C > T, p.His469Tyr) and a frameshift (c.70_74del, p.Lys24ProfsTer27). We report the largest Egyptian cohort of autosomal recessive HPP patients, delineating the severity patterns of the disorder and the associated interfamilial and intrafamilial variability. The results of this study expand the spectrum of ALPL variants associated with HPP. Clinical and genetic analysis is important for proper genetic counseling to curb this rare disorder in the families and provide treatment. Premature tooth loss may be an important clinical clue prompting evaluation for HPP. The shortage of reported cases in Egypt addresses the problems of misdiagnosis.