A novel ZC4H2 variant in a female with severe respiratory complications



      An X-linked ZC4H2 variant is associated with a variety of phenotypes that have abnormalities related to external malformation and neurodevelopment. There have been no reports on severe respiratory dysfunction resulting in surgical treatments not being possible due to the deformity resulting from in this disease. Here we report a female with arthrogryposis multiplex congenita with a severe respiratory complication.


      A two-year-old girl had arthrogryposis multiplex congenita at delivery and subsequently had hypotonia and feeding difficulty. A novel ZC4H2 frameshift variant was identified by whole-exome sequencing in her genome. At eight months, she had recurrent aspiration pneumonia. A tracheostomy and gastrostomy were required; however, surgical intervention was not possible because of her short neck and complicated airway.


      We compared this case with previous reports. The truncation group had more described phenotypes than the non-truncation group. The patient had the most severe respiratory dysfunction in truncating variant.


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        • Frints S.G.M.
        • Hennig F.
        • Colombo R.
        • Jacquemont S.
        • Terhal P.
        • Zimmerman H.H.
        • et al.
        Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.
        Hum Mutat. 2019; 40: 2270-2285
        • Hirata H.
        • Nanda I.
        • van Riesen A.
        • McMichael G.
        • Hu H.
        • Hambrock M.
        • et al.
        ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity.
        Am J Hum Genet. 2013; 92: 681-695
        • May M.
        • Hwang K.S.
        • Miles J.
        • Williams C.
        • Niranjan T.
        • Kahler S.G.
        • et al.
        ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons.
        Hum Mol Genet. 2015; 24: 4848-4861
        • Okubo Y.
        • Endo W.
        • Inui T.
        • Suzuki-Muromoto S.
        • Miyabayashi T.
        • Togashi N.
        • et al.
        A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation.
        Brain Dev. 2018; 40: 334-338
        • Zanzottera C.
        • Milani D.
        • Alfei E.
        • Rizzo A.
        • D'Arrigo S.
        • Esposito S.
        • et al.
        ZC4H2 deletions can cause severe phenotype in female carriers.
        Am J Med Genet A. 2017; 173: 1358-1363
        • Laureano A.N.
        • Rybak L.P.
        Severe otolaryngologic manifestations of arthrogryposis multiplex congenita.
        Ann Otol Rhinol Laryngol. 1990; 99: 94-97
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Godfrey N.D.
        • Dowlatshahi S.
        • Martin M.M.
        • Rothkopf D.M.
        Wieacker-Wolff syndrome with associated cleft palate in a female case.
        Am J Med Genet A. 2018; 176: 167-170
        • Kondo D.
        • Noguchi A.
        • Takahashi I.
        • Kubota H.
        • Yano T.
        • Sato Y.
        • et al.
        A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings.
        Brain Dev. 2018; 40: 760-767
        • Nagara S.
        • Fukaya S.
        • Muramatsu Y.
        • Kaname T.
        • Tanaka T.
        A case report of rare ZC4H2-associated disorders associated with three large hernias.
        Pediatr Int. 2020; 62: 985-986
        • Wang D.
        • Hu D.
        • Guo Z.
        • Hu R.
        • Wang Q.
        • Liu Y.
        • et al.
        A novel de novo nonsense mutation in ZC4H2 causes Wieacker-Wolff Syndrome.
        Mol Genet Genomic Med. 2020; 8e1100
        • Raimondi N.
        • Vial M.R.
        • Calleja J.
        • Quintero A.
        • Cortés A.
        • Celis E.
        • et al.
        Evidence-based guidelines for the use of tracheostomy in critically ill patients.
        J Crit Care. 2017; 38: 304-318