title: ZC4H2 deletions can cause severe phenotype in female carriers.
abstract: ZC4H2 is involved in human brain development, and, if mutated, can be responsible for a rare X-linked disorder, originally presented in literature as Wieacker-Wolff syndrome and Miles-Carpenter syndrome. In males, severe intellectual disability is associated with variable symptoms of central and peripheral nervous system involvement, such as spasticity, hyperreflexia, muscle weakness, and arthrogryposis. Female carriers are usually described as asymptomatic or only mildly affected. Here, we report on a girl carrying a de novo deletion of ZC4H2 detected by array-CGH analysis. She showed a complex neurodevelopmental disorder resembling the clinical picture commonly observed in male patients. X-inactivation was found to be random. Additionally, she had an unusual appearance of fingers and hand creases, and electromyography showed a peculiar pattern of both neurogenic and myopathic anomalies. The present patient confirms that female carriers can also be severely affected. Systematic clinical investigations of both males and females are needed to define the variety in nature and severity of phenotypes related to ZC4H2 variants.
authors.affiliation: Clinical Genetics Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0001-5691-722X
authors.initials: C
authors.lastname: Zanzottera
authors.affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Milani
authors.affiliation: Developmental Neurology Unit, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Alfei
authors.affiliation: Laboratory of Clinical Pathology and Medical Genetic, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Ambra
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Developmental Neurology Unit, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: D'Arrigo
authors.affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Esposito
authors.affiliation: Developmental Neurology Unit, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pantaleoni
mesh_terms: D000293:Adolescent; D001072:Apraxias / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D055028:Comparative Genomic Hybridization; D003286:Contracture / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D009133:Muscular Atrophy / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins; D009886:Ophthalmoplegia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D017384:Sequence Deletion
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C582075:ZC4H2 protein, human
keywords: X-linked; ZC4H2 deletion; arthrogryposis; electromyography; hand creases; intellectual disability