The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

Abstract Multiple sclerosis (MS) is increasingly recognized in the paediatric age. In a smaller, but well-established, proportion of paediatric MS patients [20% of total paediatric MS cases: 0.2% to 0.7% of the total MS patients] the onset of disease is before 10 years of age [pre-pubescent (childhood) MS]; in the majority [80%] of paediatric MS patients, however [1.7% to 5.6% of the total MS population], the onset of disease is between 10 and 18 years [post-pubertal (juvenile) MS]. Notably, while pre-pubertal MS occurs almost equally in both genders (female/male ratio = 0.9:1; reverting to 0.4–0.6/1 in pre-school MS children) the female/male ratio rises to 2.2/3:1 in the post-pubertal age. Interestingly, precocious puberty has been associated to: (a) a higher risk of developing MS; and (b) a more severe disease course. In addition to that, males are more susceptible to MS (and manifest more neurodegeneration) than females the latter being however more inflammatory than males; pregnancy however reduces MS relapses. All the above findings led to the suggestion of an underlying female sex hormonal involvement in the pathophysiology of MS vs. a protective role of male sex hormones. Epigenetic perspectives indicate that the interplay between genetic background, environmental triggers and neuroendocrine changes, typically occurring around the time of adolescence, could all play a combined role in initiating and/or promoting MS with onset in the paediatric age including many of the most frequent disease-associated risk factors (e.g., overweight/obesity, low vitamin D levels, reduced sunlight exposure, Epstein-Barr virus infection). According to this proposed complex multifactorial model, susceptibility to MS may be thus acquired during pre-pubertal age and children have probably to wait until the adolescence to manifest their first clinical signs/symptoms