Mania in genetically confirmed Wieacker–Wolff syndrome with congenital vertical talus: expanding the neuropsychiatric spectrum of ZC4H2-associated disorder

Abstract Background Wieacker–Wolff syndrome (WWS), also termed ZC4H2 -associated rare disorder (ZARD), is a rare X-linked neurodevelopmental disorder caused by pathogenic variants in ZC4H2 at chromosome Xq11.2. Core manifestations include developmental delay, hypotonia, intellectual disability, distal muscle weakness and congenital contractures. Psychiatric presentations, particularly affective syndromes, remain insufficiently characterised. Case presentation A 31-year-old unmarried woman with lifelong developmental delay, articulation disorder and surgically corrected congenital vertical talus presented with a one-week history of irritability, decreased need for sleep, excessive talkativeness, aggression, overfamiliarity and psychomotor agitation. Mental status examination revealed pressured speech, irritable affect, distractibility, impaired judgment and partial insight without psychotic symptoms. Whole exome sequencing identified a heterozygous ZC4H2 variant c.599 C > T (p.Ala200Val) [Exon 5; NM_018684.4; variant allele fraction 43.52%], classified as likely pathogenic under ACMG/AMP criteria, confirming Wieacker–Wolff syndrome. Sodium valproate, risperidone, clonazepam and propranolol were initiated; risperidone was subsequently replaced with aripiprazole owing to hyperprolactinaemia, with gradual improvement in irritability, sleep, aggression and psychomotor agitation. To our knowledge, this is the first report of a frank manic episode in genetically confirmed WWS. Congenital vertical talus, previously reported once in a hemizygous male infant, is described here for the first time in an adult female with this disorder. Conclusions Underlying genetic syndromes should be considered when mood symptoms arise against a background of developmental delay and congenital musculoskeletal abnormality. Genomic testing can provide diagnostic clarity in such complex neuropsychiatric presentations and incrementally expands the recognised neuropsychiatric spectrum of ZC4H2 -associated disorders.