Advertisement

A novel pathogenic NFIX variant in a Malan syndrome patient associated with hindbrain overcrowding

  • Author Footnotes
    1 The authors contributed equally.
    Kenshiro Tabata
    Footnotes
    1 The authors contributed equally.
    Affiliations
    Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Author Footnotes
    1 The authors contributed equally.
    Aritoshi Iida
    Footnotes
    1 The authors contributed equally.
    Affiliations
    Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Eri Takeshita
    Affiliations
    Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Eiji Nakagawa
    Affiliations
    Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Noriko Sato
    Affiliations
    Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Masayuki Sasaki
    Affiliations
    Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Ken Inoue
    Affiliations
    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Yu-ichi Goto
    Correspondence
    Corresponding author at: 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan.
    Affiliations
    Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan

    Medical Genome Center, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan
    Search for articles by this author
  • Author Footnotes
    1 The authors contributed equally.
Published:February 22, 2020DOI:https://doi.org/10.1016/j.jns.2020.116758
      Malan syndrome (MIM# 614753; also known as Sotos syndrome 2) is a disorder characterized by postnatal overgrowth, macrocephaly, advanced bone age, long narrow face, high forehead, and intellectual disability. It results from heterozygous variants or microdeletions of nuclear factor I/X (NFIX; MIM# 164005) on chromosome 19p13.2 [
      • Priolo M.
      • Schanze D.
      • Tatton-Brown K.
      • Mulder P.A.
      • Tenorio J.
      • Kooblall K.
      • Acero I.H.
      • Alkuraya F.S.
      • Arias P.
      • Bernardini L.
      • Bijlsma E.K.
      • Cole T.
      • Coubes C.
      • Dapia I.
      • Davies S.
      • Di Donato N.
      • Elcioglu N.H.
      • Fahrner J.A.
      • Foster A.
      • Gonzalez N.G.
      • Huber I.
      • Iascone M.
      • Kaiser A.S.
      • Kamath A.
      • Liebelt J.
      • Lynch S.A.
      • Maas S.M.
      • Mammi C.
      • Mathijssen I.B.
      • McKee S.
      • Menke L.A.
      • Mirzaa G.M.
      • Montgomery T.
      • Neubauer D.
      • Neumann T.E.
      • Pintomalli L.
      • Pisanti M.A.
      • Plomp A.S.
      • Price S.
      • Salter C.
      • Santos-Simarro F.
      • Sarda P.
      • Segovia M.
      • Shaw-Smith C.
      • Smithson S.
      • Suri M.
      • Valdez R.M.
      • Van Haeringen A.
      • Van Hagen J.M.
      • Zollino M.
      • Lapunzina P.
      • Thakker R.V.
      • Zenker M.
      • Hennekam R.C.
      Further delineation of Malan syndrome.
      ]. Although distinguishing Malan syndrome from two similar overgrowth disorders—Sotos (MIM# 117550) and Weaver syndromes (MIM# 277590)—is possible by clinical evaluation [
      • Priolo M.
      • Schanze D.
      • Tatton-Brown K.
      • Mulder P.A.
      • Tenorio J.
      • Kooblall K.
      • Acero I.H.
      • Alkuraya F.S.
      • Arias P.
      • Bernardini L.
      • Bijlsma E.K.
      • Cole T.
      • Coubes C.
      • Dapia I.
      • Davies S.
      • Di Donato N.
      • Elcioglu N.H.
      • Fahrner J.A.
      • Foster A.
      • Gonzalez N.G.
      • Huber I.
      • Iascone M.
      • Kaiser A.S.
      • Kamath A.
      • Liebelt J.
      • Lynch S.A.
      • Maas S.M.
      • Mammi C.
      • Mathijssen I.B.
      • McKee S.
      • Menke L.A.
      • Mirzaa G.M.
      • Montgomery T.
      • Neubauer D.
      • Neumann T.E.
      • Pintomalli L.
      • Pisanti M.A.
      • Plomp A.S.
      • Price S.
      • Salter C.
      • Santos-Simarro F.
      • Sarda P.
      • Segovia M.
      • Shaw-Smith C.
      • Smithson S.
      • Suri M.
      • Valdez R.M.
      • Van Haeringen A.
      • Van Hagen J.M.
      • Zollino M.
      • Lapunzina P.
      • Thakker R.V.
      • Zenker M.
      • Hennekam R.C.
      Further delineation of Malan syndrome.
      ], these are symptomatically similar and share several clinical features. Shimojima et al. [
      • Shimojima K.
      • Okamoto N.
      • Tamasaki A.
      • Sangu N.
      • Shimada S.
      • Yamamoto T.
      An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation.
      ] identified three patients with Malan syndrome due to 19p13.2 microdeletion as having Chiari malformation type I (CMI), including two of their own patients and one reported by Dolan et al. [
      • Dolan M.
      • Mendelsohn N.J.
      • Pierpont M.E.
      • Schimmenti L.A.
      • Berry S.A.
      • Hirsch B.
      A novel microdeletion/microduplication syndrome of 19p13.13.
      ] and stated that the incidence of CMI in patients with 19p13.2 deletions involving NFIX is 15.8% [
      • Shimojima K.
      • Okamoto N.
      • Tamasaki A.
      • Sangu N.
      • Shimada S.
      • Yamamoto T.
      An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation.
      ]. The authors speculated that NFIX or its neighboring genes may be associated with CMI and suggested that the presence of CMI may help differentiate 19p13.2 deletion syndrome from the NSD1-related Sotos syndrome. Following this study, a large cohort of Malan syndrome patients with NFIX mutations was reported and three of 44 cases showed Chiari malformation by imaging studies [
      • Priolo M.
      • Schanze D.
      • Tatton-Brown K.
      • Mulder P.A.
      • Tenorio J.
      • Kooblall K.
      • Acero I.H.
      • Alkuraya F.S.
      • Arias P.
      • Bernardini L.
      • Bijlsma E.K.
      • Cole T.
      • Coubes C.
      • Dapia I.
      • Davies S.
      • Di Donato N.
      • Elcioglu N.H.
      • Fahrner J.A.
      • Foster A.
      • Gonzalez N.G.
      • Huber I.
      • Iascone M.
      • Kaiser A.S.
      • Kamath A.
      • Liebelt J.
      • Lynch S.A.
      • Maas S.M.
      • Mammi C.
      • Mathijssen I.B.
      • McKee S.
      • Menke L.A.
      • Mirzaa G.M.
      • Montgomery T.
      • Neubauer D.
      • Neumann T.E.
      • Pintomalli L.
      • Pisanti M.A.
      • Plomp A.S.
      • Price S.
      • Salter C.
      • Santos-Simarro F.
      • Sarda P.
      • Segovia M.
      • Shaw-Smith C.
      • Smithson S.
      • Suri M.
      • Valdez R.M.
      • Van Haeringen A.
      • Van Hagen J.M.
      • Zollino M.
      • Lapunzina P.
      • Thakker R.V.
      • Zenker M.
      • Hennekam R.C.
      Further delineation of Malan syndrome.
      ]. However, the underlying mechanism by which CMI develops in Malan syndrome patients remains uncertain. Here we report a novel NFIX variant in a subject with Malan syndrome accompanying hindbrain overcrowding reminiscent of CMI.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Priolo M.
        • Schanze D.
        • Tatton-Brown K.
        • Mulder P.A.
        • Tenorio J.
        • Kooblall K.
        • Acero I.H.
        • Alkuraya F.S.
        • Arias P.
        • Bernardini L.
        • Bijlsma E.K.
        • Cole T.
        • Coubes C.
        • Dapia I.
        • Davies S.
        • Di Donato N.
        • Elcioglu N.H.
        • Fahrner J.A.
        • Foster A.
        • Gonzalez N.G.
        • Huber I.
        • Iascone M.
        • Kaiser A.S.
        • Kamath A.
        • Liebelt J.
        • Lynch S.A.
        • Maas S.M.
        • Mammi C.
        • Mathijssen I.B.
        • McKee S.
        • Menke L.A.
        • Mirzaa G.M.
        • Montgomery T.
        • Neubauer D.
        • Neumann T.E.
        • Pintomalli L.
        • Pisanti M.A.
        • Plomp A.S.
        • Price S.
        • Salter C.
        • Santos-Simarro F.
        • Sarda P.
        • Segovia M.
        • Shaw-Smith C.
        • Smithson S.
        • Suri M.
        • Valdez R.M.
        • Van Haeringen A.
        • Van Hagen J.M.
        • Zollino M.
        • Lapunzina P.
        • Thakker R.V.
        • Zenker M.
        • Hennekam R.C.
        Further delineation of Malan syndrome.
        Hum. Mutat. 2018; 39: 1226-1237https://doi.org/10.1002/humu.23563
        • Shimojima K.
        • Okamoto N.
        • Tamasaki A.
        • Sangu N.
        • Shimada S.
        • Yamamoto T.
        An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation.
        Am. J. Med. Genet. A. 2015; 167: 724-730https://doi.org/10.1002/ajmg.a.36959
        • Dolan M.
        • Mendelsohn N.J.
        • Pierpont M.E.
        • Schimmenti L.A.
        • Berry S.A.
        • Hirsch B.
        A novel microdeletion/microduplication syndrome of 19p13.13.
        Genet. Med. 2010; 12: 503-511https://doi.org/10.1097/GIM.0b013e3181e59291
        • Saletti V.
        • Vigano I.
        • Melloni G.
        • Pantaleoni C.
        • Vetrano I.G.
        • Valentini L.G.
        Chiari I malformation in defined genetic syndromes in children: are there common pathways?.
        Childs Nerv. Syst. 2019; 35: 1727-1739https://doi.org/10.1007/s00381-019-04319-5
        • Sekula Jr., R.F.
        • Jannetta P.J.
        • Casey K.F.
        • Marchan E.M.
        • Sekula L.K.
        • McCrady C.S.
        Dimensions of the posterior fossa in patients symptomatic for Chiari I malformation but without cerebellar tonsillar descent.
        Cerebrospinal Fluid Res. 2005; 2: 11https://doi.org/10.1186/1743-8454-2-11
        • James Barkovich A.
        Charles Raybaud, Pediatric Neuroimaging.
        sixth ed. Wolters Kluwer, Philadelphia2019
        • Oishi S.
        • Harkins D.
        • Kurniawan N.D.
        • Kasherman M.
        • Harris L.
        • Zalucki O.
        • Gronostajski R.M.
        • Burne T.H.J.
        • Piper M.
        Heterozygosity for nuclear factor one X in mice models features of Malan syndrome.
        EBioMedicine. 2019; 39: 388-400https://doi.org/10.1016/j.ebiom.2018.11.044
        • Malan V.
        • Rajan D.
        • Thomas S.
        • Shaw A.C.
        • Picard H. Louis Dit
        • Layet V.
        • Till M.
        • van Haeringen A.
        • Mortier G.
        • Nampoothiri S.
        • Puseljić S.
        • Legeai-Mallet L.
        • Carter N.P.
        • Vekemans M.
        • Munnich A.
        • Hennekam R.C.
        • Colleaux L.
        • Cormier-Daire V.
        Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome.
        Am. J. Hum. Genet. 2010; 87: 189-198https://doi.org/10.1016/j.ajhg.2010.07.001
        • Yoneda Y.
        • Saitsu H.
        • Touyama M.
        • Makita Y.
        • Miyamoto A.
        • Hamada K.
        • Kurotaki N.
        • Tomita H.
        • Nishiyama K.
        • Tsurusaki Y.
        • Doi H.
        • Miyake N.
        • Ogata K.
        • Naritomi K.
        • Matsumoto N.
        Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features.
        J. Hum. Genet. 2012; 57: 207-211https://doi.org/10.1038/jhg.2012.7
        • Schaefer G.B.
        • Bodensteiner J.B.
        • Buehler B.A.
        • Lin A.
        • Cole T.R.
        The neuroimaging findings in Sotos syndrome.
        Am. J. Med. Genet. 1997; 68: 462-465https://doi.org/10.1002/(sici)1096-8628(19970211)68:4<462::aid-ajmg18>3.0.co;2-q
        • Tatton-Brown K.
        • Murray A.
        • Hanks S.
        • Douglas J.
        • Armstrong R.
        • Banka S.
        • Bird L.M.
        • Clericuzio C.L.
        • Cormier-Daire V.
        • Cushing T.
        • Flinter F.
        • Jacquemont M.L.
        • Joss S.
        • Kinning E.
        • Lynch S.A.
        • Magee A.
        • McConnell V.
        • Medeira A.
        • Ozono K.
        • Patton M.
        • Rankin J.
        • Shears D.
        • Simon M.
        • Splitt M.
        • Strenger V.
        • Stuurman K.
        • Taylor C.
        • Titheradge H.
        • Van Maldergem L.
        • Temple I.K.
        • Cole T.
        • Seal S.
        • Rahman N.
        Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype.
        Am. J. Med. Genet. Part A. 2013; 161a: 2972-2980https://doi.org/10.1002/ajmg.a.36229