Successful management of sleep disturbance and attention deficit hyperactivity disorder symptoms with melatonin and methylphenidate in Smith-Magenis syndrome

Introduction

Smith-Magenis syndrome (SMS) is a rare neurodevelopmental disorder caused by an interstitial deletion at 17p11.2 or pathogenic RAI1 gene variants [1]. Core features include intellectual disability, craniofacial dysmorphism, self-injurious behaviour, pain insensitivity, and an inverted circadian melatonin rhythm causing chronic sleep disturbance with frequent nocturnal awakenings [2,5]. Behavioural manifestations such as impulsivity, inattention, irritability, and aggression often overlap with attention deficit hyperactivity disorder (ADHD), creating diagnostic and therapeutic challenges in child and adolescent psychiatry [4]. However, evidence on pharmacological management of ADHD symptoms and sleep problems in SMS remains limited and is based on case reports and small case series [3].

Case Presentation

We report the case of a 9-year-old girl referred to our child and adolescent psychiatry outpatient clinic for hyperactivity, impulsivity, and developmental delay. She also exhibited repetitive skin-picking, onychotillomania, and marked pain insensitivity; she showed no distress after a hammer struck her foot and appeared unaffected after a facial injury with visible bleeding. Physical examination revealed midface hypoplasia, broad nasal bridge, and tented upper lip. Chromosomal microarray confirmed an interstitial deletion at 17p11.2. Developmental history included preterm birth at 7.5 months’ gestation (birth weight 2200 g) without neonatal intensive care admission. First words emerged at 20 months and first sentences at 39 months. Clinical assessment was consistent with mild intellectual disability: she was independent in eating and toileting but required assistance for complex tasks. Sleep disturbance was characterised by difficulty initiating sleep, frequent nocturnal awakenings, and early morning awakening at around 05:00 on most days. The family reported daytime sleepiness, irritability, and occasional naps. DSM-5 diagnoses were mild intellectual disability, ADHD combined presentation, and circadian rhythm sleep-wake disorder. Treatment consisted of long-acting methylphenidate and melatonin 3 mg at bedtime. Methylphenidate was initiated at 10 mg/day for 1 week and increased to 20 mg/day. Follow-up duration was 4 months. Following treatment initiation, nighttime sleep consolidated and daytime somnolence decreased. Impulsive outbursts, including temper tantrums and school-based aggression, were reduced. Temper tantrum frequency declined from 4 episodes per week to 1 episode per week, and overall improvement was rated as CGI-I = 2. No significant adverse effects related to methylphenidate or melatonin were observed during follow-up. Functional improvement was also reported by the family in daily routines and school adaptation. Written informed consent was obtained from the legal guardians.

Conclusions

This case suggests that combined treatment with melatonin and methylphenidate may effectively target two impairing features of SMS: circadian sleep dysregulation and ADHD-like behavioural symptoms. The inverted melatonin rhythm in SMS provides a neurobiological rationale for exogenous melatonin supplementation, while the favourable response to stimulant treatment suggests that ADHD symptoms in SMS may respond to standard pharmacotherapy. In children presenting with developmental delay, behavioural dysregulation, pain insensitivity, and self-injurious behaviours, SMS should be considered in the differential diagnosis. Further studies using standardised outcome measures are needed to guide treatment decisions in this population.

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