Prader-Willy syndrome: heterogenous genetic mechanisms in a wide phenotypic spectrum

Abstract

Prader-Willi syndrome (PWS) is an imprinted neuro-behavioral syndrome, affecting many organ systems, characterized by severe hypothalamic-pituitary dysfunction, severe hypotonia, feeding difficulties in the neonatal period, followed by hyperphagia with gradual development of morbid obesity since early childhood, short stature, hypogonadism, infertility, characteristic facial features, impaired motor and language development, cognitive impairment of varying degrees, delayed speech, increased risk of developing autism spectrum disorders (ASD), impaired social skills, and behavioral problems and / or severe psychiatric problems. Loss of expression of the preferentially paternally expressed of genes from the chromosomal region 15q11-q13 are the basis of pathogenesis of PWS, which occur through several mechanisms: deletion of 5-6 Mb DNA fragment from the 15q11-q13 region of the inherited paternal chromosome (65-75%), maternal uniparental disomy (mUPD) (in 20-30%) and Imprinting center (IC) defects, as microdeletions and epimutations (in 1-4%). In this paper, we present two cases diagnosed with PWS from our experience. The importance of diagnosis and familial recurrence risk will be discussed, as well as genotype-phenotype relationships in PWS. Patients with PWS should benefit from multidisciplinary management very early for greatly improving their quality of life, taking into consideration that obesity is a major factor influencing morbidity and mortality. In addition, a better understanding of the molecular basis of PWS pathogenesis offers hope for the development of new, revolutionary, epigenetic therapies in PWS, as well as in other genetic imprinting diseases.