2026 ECNP Congress

PS02-2151

Severe autism phenotype and functional impairment in Tonne–Kalscheuer syndrome

Başak Günal Sivri — M.C. Tarakçıoğlu · Istanbul University Cerrahpasa-Cerrahpasa School of Medicine, Child and Adoloscent Psychiatry, Istanbul, Türkiye

2026 ECNP Congress

Introduction

Tonne-Kalscheuer syndrome (TOKAS) is a rare X-linked neurodevelopmental disorder caused by variants in the RLIM gene. Prior research has reported that affected males exhibit developmental delay, intellectual disability, limited speech, and autistic features, often accompanied by behavioural abnormalities and generally normal neuroimaging findings [1–3]. However, comprehensive psychiatric phenotyping in these cases remains limited. This report seeks to advance the psychiatric characterisation of TOKAS through a detailed and structured assessment of autism severity and functional impairment.

Case Presentation

A 4.5-year-old boy with TOKAS, resulting from a hemizygous nonsense variant in RLIM inherited from his carrier mother, was identified through whole exome sequencing at 3 years of age. He was born at 37 weeks of gestation and required a 7-day stay in the neonatal intensive care unit due to amniotic fluid aspiration. Early developmental milestones were delayed. The patient experienced febrile seizures at 9, 15, and 16 months of age, which led to a diagnosis of epilepsy and subsequent treatment with levetiracetam until 3.5 years of age. Neurological investigations, including EEG, MRI, and hearing evaluation, yielded unremarkable results. Initial genetic investigations, including conventional karyotyping, chromosomal microarray analysis, and subsequent SCN1A sequencing, were unremarkable.

The patient received a diagnosis of autism spectrum disorder (DSM-5; Level 3, ‘requiring very substantial support’, with accompanying intellectual and language impairment, associated with a known genetic condition) at 2.5 years of age due to social communication deficits and restricted, repetitive behaviours. At 4.5 years, psychiatric evaluation identified severe and pervasive impairments in social communication, characterised by absence of verbal language, lack of pointing, markedly limited joint attention, minimal eye contact, absence of peer relationships, social withdrawal, resistance to change, hand stereotypies, and toe walking. Functional impairment was substantial, with feeding and toileting entirely dependent on maternal assistance.

The Childhood Autism Rating Scale (CARS) showed a total score of 39.5, which points to severe autism [4]. The analysis found consistent difficulties across several areas, such as social relatedness (3), imitation (3.5), body use (3), object use (3), adaptation to change (3), visual response (3), sensory responses (3), verbal communication (4), nonverbal communication (3), consistency of intellectual response (3), and general impressions (3). Lower scores were seen in listening response (1.5) and activity level (1.5), and fear or anxiety was less noticeable (2).

Functional impairment assessed using the Weiss Functional Impairment Rating Scale (WFIRS) parent form indicated clinically meaningful impairment in domains with mean scores ≥1.5, specifically school/learning (1.75) and life skills (1.5), consistent with marked impairment in adaptive functioning [5]. At the time of current evaluation, the patient was not receiving any pharmacological treatment and was being followed with structured special education programmes and occupational therapy interventions.

Conclusions

This case highlights a severe autism phenotype with marked functional impairment in TOKAS. Domain-specific assessment with standardised tools such as the CARS and WFIRS provides clinically relevant insight into the psychiatric profiles of rare genetic neurodevelopmental disorders, for which systematic phenotypic characterisation remains limited.

References

  1. Tønne, E., Holdhus, R., Stansberg, C., Stray-Pedersen, A., Petersen, K., Brunner, H.G., Gilissen, C., Hoischen, A., Prescott, T., Steen, V.M., Fiskerstrand, T., 2015. Syndromic X-linked intellectual disability segregating with a missense variant in RLIM. Eur. J. Hum. Genet. 23 (12), 1652–1656.
  2. Hu, H., Haas, S.A., Chelly, J., Van Esch, H., Raynaud, M., De Brouwer, A.P.M., Weinert, S., Froyen, G., Frints, S.G.M., Laumonnier, F., Zemojtel, T., Love, M.I., Richard, H., Emde, A.K., Bienek, M., Jensen, C., Hambrock, M., Fischer, U., Langnick, C., Kalscheuer, V.M., 2016. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol. Psychiatry 21 (1), 133–148.
  3. Frints, S.G.M., Ozanturk, A., Rodríguez Criado, G., Grasshoff, U., de Hoon, B., Field, M., Manouvrier-Hanu, S., Hickey, S.E., Kammoun, M., Gripp, K.W., Bauer, C., Schroeder, C., Toutain, A., Mihalic Mosher, T., Kelly, B.J., White, P., Dufke, A., Rentmeester, E., Moon, S., Kalscheuer, V.M., 2019. Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder. Mol. Psychiatry 24 (11), 1748–1768.
  4. Schopler, E., Reichler, R.J., DeVellis, R.F., Daly, K., 1980. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J. Autism Dev. Disord. 10 (1), 91–103.
  5. Weiss, M.D., McBride, N.M., Craig, S., Jensen, P., 2018. Conceptual review of measuring functional impairment: findings from the Weiss Functional Impairment Rating Scale. Evid. Based Ment. Health 21 (4), 155.