Smith-Magenis Syndrome (SMS) is a rare neurodevelopmental disorder characterized by severe sleep disturbances and an advanced melatonin rhythm. Current treatments, mainly exogenous melatonin and β-blockers, have not been evaluated in children. This study aimed to characterize the clinical, sleep, and chronobiological profiles of children with SMS under treatment, and to assess the effects of melatonin and β-blockers.

In this prospective, single-center study, 20 children with genetically confirmed SMS (aged 5–13 years; 55% female) underwent 15-day home actimetry and 48-hour hospitalization including questionnaires, polysomnography (PSG), and salivary melatonin/cortisol profiling. Melatonin and psychostimulants were discontinued 24 hours before hospitalization.

Ninety-five percent of children received melatonin and 20% β-blockers. Despite treatment, insomnia was reported in 90%, excessive daytime sleepiness in 65% and learning problems in 90%. Melatonin improved mean nocturnal awakening duration (1.4 vs 2.3 min, p = 0.040), wake-up time (06:50 vs 06:11, p = 0.004), and longest continuous sleep episode (398 vs 317 min, p = 0.040), but little effects on total sleep time, efficiency and advanced midsleep times. Very high daytime salivary melatonin persisted despite treatment 48 h washout, suggesting possible iatrogenic accumulation. Melatonin profiling showed a mean peak at 11:57, with no cortisol abnormalities. β-blocker use advanced melatonin peaks but was associated with delayed sleep onset, increased nocturnal awakenings, and reduced total sleep.

Children with SMS show persistent sleep difficulties and an advanced circadian phase despite sleep treatments. Exogenous melatonin provides partial benefit but may lead to daytime accumulation, while β-blockers may have adverse sleep effects despite beneficial effect on melatonin peak secretion, warranting further study.