title: Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature.
abstract: De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall-Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.
authors.affiliation: 1] Department of Paediatrics, Maastricht University Medical Center, Maastricht, The Netherlands [2] Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands [3] North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Merel
authors.initials: M
authors.lastname: Klaassens
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morrogh
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Rosser
authors.affiliation: MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Fatima
authors.initials: F
authors.lastname: Jaffer
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Vreeburg
authors.affiliation: Department of Paediatrics, Maxima Medical Centre, Belhaven, The Netherlands.
authors.forename: Levinus A
authors.initials: LA
authors.lastname: Bok
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Segboer
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: van Belzen
authors.affiliation: MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Ros M
authors.initials: RM
authors.lastname: Quinlivan
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Ajith
authors.initials: A
authors.lastname: Kumar
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: 1] North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK [2] Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Scott
mesh_terms: D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D003937:Diagnosis, Differential; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D051839:NFI Transcription Factors / Q000235:genetics*; D010641:Phenotype; D017384:Sequence Deletion; D058495:Sotos Syndrome / Q000175:diagnosis / Q000235:genetics; D013577:Syndrome
chemical_list: D051839:NFI Transcription Factors; C000594474:NFIX protein, human