Robust response to methylphenidate in a child with Weiss–Kruszka syndrome: the importance of genetic screening in attention-deficit/hyperactivity disorder with dysmorphism

Introduction

Weiss-Kruszka syndrome (WSKA; OMIM #618619) is a rare, autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in the ZNF462 gene or deletions of the 9q31.2 chromosomal region encompassing ZNF462 [1,2]. Phenotypically, WSKA is characterized by ptosis, nonspecific craniofacial dysmorphism, developmental delay, and corpus callosum abnormalities [1,2]. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder may occur within the WSKA phenotype, yet psychopharmacological data remain scarce [3]. Evidence from children with intellectual disability and complex neurodevelopmental presentations suggests that methylphenidate response may be less robust and more variable than in typically developing children with ADHD [4,5].

Case Presentation

A 7-year-old girl was referred to our child and adolescent psychiatry outpatient clinic due to severe hyperactivity, impulsivity, oppositional behavior toward caregivers and poor academic performance. Her developmental history revealed delayed language milestones, with her first sentences emerging at 4 years of age. Physical examination revealed distinctive syndromic facial features, including ptosis, downslanting palpebral fissures, epicanthal folds, irregular dentition, low-set ears, and prominent prognathia. Psychometric evaluation (Leiter International Performance Scale) indicated an IQ of 66, consistent with mild intellectual disability. DSM-5 diagnoses were attention-deficit/hyperactivity disorder (combined presentation), mild intellectual disability (intellectual developmental disorder), and language disorder. Due to the coexistence of ADHD symptoms and these dysmorphic facial features, a referral to the medical genetics department was initiated. Chromosomal microarray analysis (CMA) revealed a ~1.224 Mb heterozygous deletion at the 9q31.2 region: arr[GRCh38]9q31.2(106,950,624_108,174,851)x1. This deletion encompasses ZNF462, confirming the diagnosis of WSKA. In this case, it was the clinician’s recognition of syndromic facial features during psychiatric evaluation that triggered the genetic referral, ultimately leading to the underlying diagnosis. Baseline severity was rated using the Clinical Global Impression–Severity scale (CGI-S = 6, severely ill). She was started on methylphenidate, titrated to an osmotic-release oral system (OROS) formulation at 27 mg/day. Written informed consent was obtained from the legal guardians.

Following the titration of OROS methylphenidate to 27 mg/day, the patient exhibited a dramatic clinical improvement. In contrast to the typically limited responses observed in many genetic syndromes, this patient demonstrated a robust, objectively measurable response. Post-treatment evaluations revealed a CGI-Improvement (CGI-I) score of 2 (much improved). The CGI-Efficacy Index rating indicated marked therapeutic effect with no side effects. Impulsivity, oppositional behaviors, and motor restlessness resolved; attention and classroom adaptation improved markedly. Treatment gains persisted without dose escalation or adverse events at the 6-month follow-up with stable blood pressure, heart rate and growth parameters.

Conclusions

This case highlights two clinical messages. First, in children with ADHD, accompanying dysmorphic features should prompt referral to clinical genetics, as undiagnosed conditions such as a 9q31.2 microdeletion underlying WSKA may be revealed. Second, standard ADHD pharmacotherapy should not be withheld in genetic syndromes. In our case methylphenidate proved effective and well-tolerated, showing that a trial of first-line treatment is warranted even in syndromic presentations.

References

1. Weiss, K., Wigby, K., Fannemel, M., Henderson, L.B., Beck, N., Ghali, N., et al., 2017. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay. Eur. J. Hum. Genet. 25 (8), 946-951.
2. Kruszka, P., Hu, T., Hong, S., Signer, R., Cogné, B., Isidor, B., et al., 2019. Phenotype delineation of ZNF462 related syndrome. Am. J. Med. Genet. A 179A, 2075-2082.
3. Hau, A., Baxter, A., Chandler, K., Fennell, A., Hsieh, T.-C., Krawitz, P.M., et al., 2025. Seven novel variants of Weiss-Kruszka syndrome and phenotype expansion. Am. J. Med. Genet. A 197, e63856.
4. Tarrant, N., Roy, M., Deb, S., Odedra, S., Retzer, A., Roy, A., 2018. The effectiveness of methylphenidate in the management of Attention Deficit Hyperactivity Disorder (ADHD) in people with intellectual disabilities: a systematic review. Res. Dev. Disabil. 83, 217-232.
5. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, 2005. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch. Gen. Psychiatry 62, 1266-1274.