A rare cause of neurodevelopmental disorder: Luscan–Lumish syndrome associated with de novo SETD2 mutation

Introduction

Luscan–Lumish syndrome (LLS) is a rare neurodevelopmental disorder caused by heterozygous mutations in the SETD2 gene on chromosome 3p21, typically inherited in an autosomal dominant pattern [1] , and characterized by postnatal overgrowth, macrocephaly, developmental delay, intellectual disability, seizures, and associated neuropsychiatric features including autism spectrum disorder, attention-deficit/hyperactivity disorder, behavioral dysregulation often accompanied by dysmorphic features.[2,3]

To acquire a deeper understanding of its clinical presentation and behavioral profile, we present a child with LLS associated with a SETD2 mutation.

Case

A 12.5-year-old boy was first admitted to child psychiatry at 2.5 years of age due to concerns of not responding to his name, persistent crying, and developmental delay compared to peers.

Developmental history showed that he was born at 38 weeks of gestation to non-consanguineous parents, with a birth weight of 4000 g and an uneventful perinatal course. He achieved independent walking at 1.5 years of age. Speech development was markedly delayed, and overall development was below age expectations. His current language is limited to single words without combining words into two-word phrases. Toilet training has not yet been achieved.

At the time of first presentation, clinical evaluation revealed impaired social interaction, language delay, stereotyped repetitive motor behaviors, and echolalia. In addition to these core developmental findings, the patient demonstrated marked behavioral dysregulation characterized by severe hyperactivity, irritability, low frustration tolerance, and aggression toward others.

Based on this clinical presentation, he was diagnosed with autism spectrum disorder and attention-deficit/hyperactivity disorder.

Over the following years, neurological symptoms also emerged, and generalized tonic-clonic seizures began at the age of five.

Physical examination revealed macrocephaly, mild hypertelorism, high-arched palate, and crowded dentition. These morphological findings, together with the coexistence of neurodevelopmental delay, epilepsy, and significant behavioral dysregulation, raised suspicion for an underlying syndromic neurodevelopmental disorder. Metabolic work-up was performed and was unremarkable. Therefore, the patient was referred to clinical genetics for further etiological evaluation, where genetic testing identified a de novo heterozygous pathogenic SETD2 mutation, consistent with a syndromic neurodevelopmental disorder.

From a neurological perspective, seizures were treated with valproate and carbamazepine, resulting in partial seizure control with ongoing breakthrough episodes.

From a psychiatric perspective, multiple pharmacological trials were attempted, including risperidone, aripiprazole, methylphenidate, atomoxetine, olanzapine and haloperidol. Antipsychotic medications provided only partial and transient improvement in behavioral symptoms, while methylphenidate exacerbated irritability and aggression. Overall, behavioral dysregulation remained only partially responsive to treatment.

Conclusion

Luscan–Lumish syndrome should be considered in syndromic neurodevelopmental presentations with macrocephaly, epilepsy, and early developmental delay. SETD2-related neurodevelopmental disorders may present with a broad and complex neuropsychiatric phenotype, often including severe behavioral dysregulation that can be partially or poorly responsive to standard psychopharmacological interventions. These findings highlight that apparent treatment resistance in neurodevelopmental disorders may reflect an underlying genetic etiology rather than primary pharmacologic nonresponse. Early recognition and multidisciplinary management are essential for diagnostic clarification and longitudinal care.

References

1. Asadi S. The role of genetic mutations in SETD2 gene on the Luscan–Lumish syndrome (LLS). Journal of BioMed Research and Reports. 2025;9(1). doi:10.59657/2837-4681.brs.25.218.
2. Clinical and genetic features of Luscan–Lumish syndrome associated with a novel de novo variant of SETD2 gene: case report and literature review. Front Genet. 2023 Jan 27;14:1081391. doi:10.3389/fgene.2023.1081391.
3. Wu Y, Liu F, Wan R, Jiao B. A novel SETD2 variant causing global developmental delay without overgrowth in a Chinese 3-year-old boy. Front Genet. 2023;14:1153284. doi:10.3389/fgene.2023.1153284.