hypophosphatasia validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients hypophosphatasia hpp is caused by lossoffunction mutations within the gene tnsalp that encodes the tissuenonspecific isoenzyme of alkaline phosphatase tnsalp in hpp inorganic pyrophosphate an inhibitor of mineralization and substrate for tnsalp accumulates extracellularly often leading to rickets or osteomalacia and tooth loss and sometimes to craniosynostosis and calcium crystal arthropathies hpps remarkably broadranging expressivity spans stillbirth from profound skeletal hypomineralization to adultonset dental problems or arthropathies without bone disease which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred usually missense tnsalp mutations for clinical purposes this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis pediatric patients are reported principally with odonto childhood infantile or perinatal hpp however this nosology has not been tested using a cohort of patients and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups to evaluate the extant nosology for hpp in children we assessed our 25 years experience with 173 pediatric hpp patients data were exclusively from inpatient studies the childhood form of hpp was further designated mild or severe here we focused on demographic clinical and dualenergy xray absorptiometry parameters compared to data from healthy american children the 173patient cohort comprised 64 individuals with odonto hpp 38 with mild childhood hpp 58 with severe childhood hpp and 13 with infantile hpp none was a survivor of perinatal hpp tnsalp analysis revealed a mutations in all 105 probands tested thirteen mutations were unique most patients represented autosomal dominant inheritance of hpp mutant allele dosage generally indicated the disorders severity gender discordance was found for severe childhood hpp 42 boys versus 16 girls p0006 perhaps reflecting parental concern about stature and strength key disease parameters eg height weight numbers of teeth lost prematurely grip strength spine and hip bone mineral density were increasingly compromised as hpp was designated more severe although data overlapped successively between the four patient groups body size height and weight differed significantly thus our expanded nosology for hpp in children organizes the disorders broadranging expressivity and should improve understanding of hpp presentation natural history complications and prognosis