Down syndrome: comments and reflections on the 50th anniversary of Lejeune's discovery

Over the past some 160 years, the study of Down syndrome (DS) went from early efforts of differentiating it from cretinism (Séguin) to its establishment as a specific nosologic category of mental deficiency (Down) and subsequent attempts to infer its cause. DS was known to be an overwhelmingly sporadic disorder, concordant in MZ and discordant in DZ twins and associated with increased maternal reproductive age (Penrose). Beginning in the 1920s and based in part on phenotype analysis and early cytogenetic insights in Drosophilia, several clinicians (Halbertsma, Waardenburg, Bleyer, Fanconi) and the geneticist C.B. Davenport postulated that DS might be due to a chromosome abnormality; only Davenport, with T.S. Painter, made an actual attempt to perform a clinical/cytological study (with inconclusive results). It was only with the application of the methods of Belling (colchicine, squash preparations) and of T.C. Hsu (hypotonic solution) to PHA-treated cell cultures in the mid-late 1950s, that it became possible to study, accurately, the human karyotype and its aberrations, allowing Lejeune et al. and Jacobs et al. in 1959 to discover the cause of DS. Nowadays, aided with powerful molecular methods, it has become possible to attain insights into the pathogenesis of DS based on the study of many duplications/deficiencies of HSA21 in humans and ingeniously constructed cytogenetic rearrangements of MMA16 in the mouse. These suggest a complex epigenetic interaction between genes on HSA21 and many (?most) other genes in the human genome, akin to an attempt at speciation as suggested early during the last century by Blakesly in his work on Datura. Many important ongoing efforts are underway in several countries to understand the developmental biology of DS, offering hope of ultimate amelioration for those averse to pregnancy termination.