Journal of Pediatric Neurology 2023; 21(04): 292-298
DOI: 10.1055/s-0041-1727270
Review Article

FOXG1 Gene and Its Related Phenotypes

Giulia Pecora
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Vincenzo Sortino
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Viviana Brafa Musicoro
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Giulia Salomone
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Francesco Pizzo
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Giuseppe Costanza
1   Pediatric Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Raffaele Falsaperla
2   Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
3   Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
,
Antonio Zanghì
4   Department of Medical and Surgical Sciences and Advanced Technology “G.F. Ingrassia,” University of Catania, Catania, Italy
,
Andrea D. Praticò
5   Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
› Author Affiliations

Abstract

FOXG1 is an important transcriptional repressor found in cell precursor of the ventricular region and in neurons in the early stage of differentiation during the development of the nervous epithelium in the cerebrum and optical formation. Mutations involving FOXG1 gene have been described first in subjects with congenital Rett syndrome. They can cause seizure, delayed psychomotor development, language disorders, and autism. FOXG1 deletions or intragenic mutations also determinate reduction in head circumference, structural defects in the corpus callosum, abnormal movements, especially choreiform, and intellectual retardation with no speech. Patients with duplications of 14q12 present infantile spasms and have subsequent intellectual disability with autistic features, head circumference in the normal range, and regular aspect of corpus callosum. Clinical characteristics of patients with FOXG1 variants include growth deficit after birth associated with microcephaly, facial dysmorphisms, important delay with no language, deficit in social interaction like autism, sleep disorders, stereotypes, including dyskinesia, and seizures. In these patients, it is not characteristic a history of loss of acquired skills.



Publication History

Received: 21 September 2020

Accepted: 23 February 2021

Article published online:
21 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Bourguignon C, Li J, Papalopulu N. XBF-1, a winged helix transcription factor with dual activity, has a role in positioning neurogenesis in Xenopus competent ectoderm. Development 1998; 125 (24) 4889-4900
  • 2 Tao W, Lai E. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron 1992; 8 (05) 957-966
  • 3 Xuan S, Baptista CA, Balas G, Tao W, Soares VC, Lai E. Winged helix transcription factor BF-1 is essential for the development of the cerebral hemispheres. Neuron 1995; 14 (06) 1141-1152
  • 4 Dou CL, Li S, Lai E. Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres. Cereb Cortex 1999; 9 (06) 543-550
  • 5 Hanashima C, Li SC, Shen L, Lai E, Fishell G. Foxg1 suppresses early cortical cell fate. Science 2004; 303 (5654): 56-59
  • 6 Muzio L, Mallamaci A. Foxg1 confines Cajal-Retzius neuronogenesis and hippocampal morphogenesis to the dorsomedial pallium. J Neurosci 2005; 25 (17) 4435-4441
  • 7 Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia 2012; 53 (12) 2067-2078
  • 8 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Early history of the different forms of neurofibromatosis from ancient Egypt to the British Empire and beyond: First descriptions, medical curiosities, misconceptions, landmarks, and the persons behind the syndromes. Am J Med Genet A 2018; 176 (03) 515-550
  • 9 Pavone P, Nigro F, Falsaperla R. et al. Hemihydranencephaly: living with half brain dysfunction. Ital J Pediatr 2013; 39: 3
  • 10 Pavone P, Praticò AD, Rizzo R. et al. A clinical review on megalencephaly: a large brain as a possible sign of cerebral impairment. Medicine (Baltimore) 2017; 96 (26) e6814
  • 11 Ruggieri M, Praticò AD, Serra A. et al. Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms. Childs Nerv Syst 2017; 33 (04) 549-560
  • 12 Ruggieri M, Praticò AD, Caltabiano R, Polizzi A. Rediagnosing one of Smith's patients (John McCann) with “neuromas tumours” (1849). Neurol Sci 2017; 38 (03) 493-499
  • 13 Ruggieri M, Praticò AD, Scuderi A, Sorge G, Polizzi A. The multiple faces of artwork diagnoses. Lancet Neurol 2017; 16 (06) 417-418
  • 14 Kortüm F, Das S, Flindt M. et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J Med Genet 2011; 48 (06) 396-406
  • 15 Jacob FD, Ramaswamy V, Andersen J, Bolduc FV. Atypical Rett syndrome with selective FOXG1 deletion detected by comparative genomic hybridization: case report and review of literature. Eur J Hum Genet 2009; 17 (12) 1577-1581
  • 16 Hou PS, hAilín DÓ, Vogel T, Hanashima C. Transcription and beyond: delineating FOXG1 function in cortical development and disorders. Front Cell Neurosci 2020; 14: 35
  • 17 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
  • 18 Pavone P, Praticò AD, Gentile G. et al. A neurocutaneous phenotype with paired hypo- and hyperpigmented macules, microcephaly and stunted growth as prominent features. Eur J Med Genet 2016; 59 (05) 283-289
  • 19 Pavone P, Praticò AD, Falsaperla R. et al. Congenital generalized hypertrichosis: the skin as a clue to complex malformation syndromes. Ital J Pediatr 2015; 41: 55
  • 20 Seltzer LE, Ma M, Ahmed S. et al. Epilepsy and outcome in FOXG1-related disorders. Epilepsia 2014; 55 (08) 1292-1300
  • 21 Pavone P, Praticò AD, Ruggieri M, Falsaperla R. Hypomelanosis of Ito: a round on the frequency and type of epileptic complications. Neurol Sci 2015; 36 (07) 1173-1180
  • 22 Pavone V, Signorelli SS, Praticò AD. et al. Total hemi-overgrowth in pigmentary mosaicism of the (hypomelanosis of) Ito type: eight case reports. Medicine (Baltimore) 2016; 95 (10) e2705
  • 23 Weigel D, Jäckle H. The fork head domain: a novel DNA binding motif of eukaryotic transcription factors?. Cell 1990; 63 (03) 455-456
  • 24 Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 1993; 364 (6436): 412-420
  • 25 Miller LM, Gallegos ME, Morisseau BA, Kim SK. lin-31, a Caenorhabditis elegans HNF-3/fork head transcription factor homolog, specifies three alternative cell fates in vulval development. Genes Dev 1993; 7 (06) 933-947
  • 26 Weigel D, Jäckle H. Novel homeotic genes in Drosophila melanogaster. Biochem Cell Biol 1989; 67 (08) 393-396
  • 27 Strähle U, Blader P, Henrique D, Ingham PW. Axial, a zebrafish gene expressed along the developing body axis, shows altered expression in cyclops mutant embryos. Genes Dev 1993; 7 (7B): 1436-1446
  • 28 Knöchel S, Lef J, Clement J. et al. Activin A induced expression of a fork head related gene in posterior chordamesoderm (notochord) of Xenopus laevis embryos. Mech Dev 1992; 38 (02) 157-165
  • 29 Sasaki H, Hogan BL. Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development 1993; 118 (01) 47-59
  • 30 Hromas R, Moore J, Johnston T, Socha C, Klemsz M. Drosophila forkhead homologues are expressed in a lineage-restricted manner in human hematopoietic cells. Blood 1993; 81 (11) 2854-2859
  • 31 Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development 2016; 143 (24) 4558-4570
  • 32 Ranieri C, Di Tommaso S, Loconte DC. et al. In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS). Neurogenetics 2018; 19 (02) 77-91
  • 33 Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet 2009; 10 (04) 233-240
  • 34 Caltabiano R, Magro G, Polizzi A. et al. A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. Childs Nerv Syst 2017; 33 (06) 933-940
  • 35 Kumamoto T, Hanashima C. Evolutionary conservation and conversion of Foxg1 function in brain development. Dev Growth Differ 2017; 59 (04) 258-269
  • 36 Li J, Chang HW, Lai E, Parker EJ, Vogt PK. The oncogene qin codes for a transcriptional repressor. Cancer Res 1995; 55 (23) 5540-5544
  • 37 Pauley S, Lai E, Fritzsch B. Foxg1 is required for morphogenesis and histogenesis of the mammalian inner ear. Dev Dyn 2006; 235 (09) 2470-2482
  • 38 Murphy DB, Wiese S, Burfeind P. et al. Human brain factor 1, a new member of the fork head gene family. Genomics 1994; 21 (03) 551-557
  • 39 Wong LC, Singh S, Wang HP, Hsu CJ, Hu SC, Lee WT. FOXG1-related syndrome: from clinical to molecular genetics and pathogenic mechanisms. Int J Mol Sci 2019; 20 (17) 4176
  • 40 Siegenthaler JA, Tremper-Wells BA, Miller MW. Foxg1 haploinsufficiency reduces the population of cortical intermediate progenitor cells: effect of increased p21 expression. Cereb Cortex 2008; 18 (08) 1865-1875
  • 41 Bredenkamp N, Seoighe C, Illing N. Comparative evolutionary analysis of the FoxG1 transcription factor from diverse vertebrates identifies conserved recognition sites for microRNA regulation. Dev Genes Evol 2007; 217 (03) 227-233
  • 42 Wiese S, Murphy DB, Schlung A. et al. The genes for human brain factor 1 and 2, members of the fork head gene family, are clustered on chromosome 14q. Biochim Biophys Acta 1995; 1262 (2-3): 105-112
  • 43 Brunetti-Pierri N, Paciorkowski AR, Ciccone R. et al. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur J Hum Genet 2011; 19 (01) 102-107
  • 44 Cellini E, Vignoli A, Pisano T. et al; FOXG1 Syndrome Study Group. The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy. Dev Med Child Neurol 2016; 58 (01) 93-97
  • 45 Philippe C, Amsallem D, Francannet C. et al. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet 2010; 47 (01) 59-65
  • 46 Ariani F, Hayek G, Rondinella D. et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 2008; 83 (01) 89-93
  • 47 Neul JL, Kaufmann WE, Glaze DG. et al; RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 2010; 68 (06) 944-950
  • 48 Rett A. [On a unusual brain atrophy syndrome in hyperammonemia in childhood]. Wien Med Wochenschr 1966; 116 (37) 723-726
  • 49 Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol 1983; 14 (04) 471-479
  • 50 Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999; 23 (02) 185-188
  • 51 Rolando S. Rett syndrome: report of eight cases. Brain Dev 1985; 7 (03) 290-296
  • 52 Shoichet SA, Kunde SA, Viertel P. et al. Haploinsufficiency of novel FOXG1B variants in a patient with severe mental retardation, brain malformations and microcephaly. Hum Genet 2005; 117 (06) 536-544
  • 53 Bisgaard AM, Kirchhoff M, Tümer Z. et al. Additional chromosomal abnormalities in patients with a previously detected abnormal karyotype, mental retardation, and dysmorphic features. Am J Med Genet A 2006; 140 (20) 2180-2187
  • 54 Papa FT, Mencarelli MA, Caselli R. et al. A 3 Mb deletion in 14q12 causes severe mental retardation, mild facial dysmorphisms and Rett-like features. Am J Med Genet A 2008; 146A (15) 1994-1998
  • 55 Operto FF, Mazza R, Pastorino GMG, Verrotti A, Coppola G. Epilepsy and genetic in Rett syndrome: a review. Brain Behav 2019; 9 (05) e01250
  • 56 Mencarelli MA, Kleefstra T, Katzaki E. et al. 14q12 Microdeletion syndrome and congenital variant of Rett syndrome. Eur J Med Genet 2009; 52 (2-3): 148-152
  • 57 Eagleson KL, Schlueter McFadyen-Ketchum LJ, Ahrens ET. et al. Disruption of Foxg1 expression by knock-in of cre recombinase: effects on the development of the mouse telencephalon. Neuroscience 2007; 148 (02) 385-399
  • 58 Niu Y, Cao L, Zhao P, Cai C. A case of congenital Rett variant in a Chinese patient caused by a FOXG1 mutation. Ann Saudi Med 2020; 40 (04) 347-353
  • 59 Bahi-Buisson N, Nectoux J, Girard B. et al. Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics 2010; 11 (02) 241-249
  • 60 Pavone P, Praticò AD, Pavone V. et al. Ataxia in children: early recognition and clinical evaluation. Ital J Pediatr 2017; 43 (01) 6
  • 61 Pratico AD, Ruggieri M, Falsaperla R, Pavone P. A probable topiramate-induced limbs paraesthesia and rigid fingers flexion. Curr Drug Saf 2018; 13 (02) 131-136
  • 62 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
  • 63 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
  • 64 Falsaperla R, Perciavalle V, Pavone P. et al. Unilateral eye blinking arising from the ictal ipsilateral occipital area. Clin EEG Neurosci 2016; 47 (03) 243-246
  • 65 Barbagallo M, Ruggieri M, Incorpora G. et al. Infantile spasms in the setting of Sturge-Weber syndrome. Childs Nerv Syst 2009; 25 (01) 111-118
  • 66 Pavone P, Rizzo R, Conti I. et al. Primary headaches in children: clinical findings on the association with other conditions. Int J Immunopathol Pharmacol 2012; 25 (04) 1083-1091
  • 67 Falsaperla R, Praticò AD, Ruggieri M. et al. Congenital muscular dystrophy: from muscle to brain. Ital J Pediatr 2016; 42 (01) 78
  • 68 Pavone P, Praticò AD, Ruggieri M. et al. Acquired peripheral neuropathy: a report on 20 children. Int J Immunopathol Pharmacol 2012; 25 (02) 513-517
  • 69 Salafia S, Praticò AD, Pizzo E, Greco F, Di Bella D. Hemiconvulsion-hemiplegia-epilepsy syndrome. Magnetic resonance findings in a 3-year-old boy. Neurol Neurochir Pol 2013; 47 (06) 584-589
  • 70 Mencarelli MA, Spanhol-Rosseto A, Artuso R. et al. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet 2010; 47 (01) 49-53
  • 71 Bertossi C, Cassina M, De Palma L. et al. 14q12 duplication including FOXG1: is there a common age-dependent epileptic phenotype?. Brain Dev 2014; 36 (05) 402-407
  • 72 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. Short syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
  • 73 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
  • 74 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
  • 75 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
  • 76 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
  • 77 Polizzi A, Coghill S, McShane MA, Squier W. Acute ataxia complicating Langherans cell histiocytosis. Arch Dis Child 2002; 86 (02) 130-131
  • 78 Adesina AM, Nguyen Y, Guanaratne P. et al. FOXG1 is overexpressed in hepatoblastoma. Hum Pathol 2007; 38 (03) 400-409
  • 79 Adesina AM, Nguyen Y, Mehta V. et al. FOXG1 dysregulation is a frequent event in medulloblastoma. J Neurooncol 2007; 85 (02) 111-122
  • 80 Chen J, Wu X, Xing Z. et al. FOXG1 expression is elevated in glioma and inhibits glioma cell apoptosis. J Cancer 2018; 9 (05) 778-783
  • 81 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
  • 82 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
  • 83 Martínez-Cerdeño V. Dendrite and spine modifications in autism and related neurodevelopmental disorders in patients and animal models. Dev Neurobiol 2017; 77 (04) 393-404
  • 84 Chiola S, Do MD, Centrone L, Mallamaci A. Foxg1 overexpression in neocortical pyramids stimulates dendrite elongation via Hes1 and pCreb1 upregulation. Cereb Cortex 2019; 29 (03) 1006-1019
  • 85 Praticò AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
  • 86 Pavone P, Falsaperla R, Ruggieri M. et al. Clinical course of N-Methyl-D-aspartate receptor encephalitis and the effectiveness of cyclophosphamide treatment. J Pediatr Neurol 2017; 15: 84-89
  • 87 Praticò AD, Pavone P, Scuderi MG. et al. Symptomatic hypocalcemia in an epileptic child treated with valproic acid plus lamotrigine: a case report. Cases J 2009; 2: 7394
  • 88 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
  • 89 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; 112: 107361
  • 90 Incorpora G, Pavone P, Castellano-Chiodo D, Praticò AD, Ruggieri M, Pavone L. Gelastic seizures due to hypothalamic hamartoma: rapid resolution after endoscopic tumor disconnection. Neurocase 2013; 19 (05) 458-461