2. Academic Validation
  3. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

  • Eur J Hum Genet. 2015 Mar;23(3):292-301. doi: 10.1038/ejhg.2014.95.
Alain Verloes 1,  Nataliya Di Donato 2,  Julien Masliah-Planchon 3,  Marjolijn Jongmans 4,  Omar A Abdul-Raman 5,  Beate Albrecht 6,  Judith Allanson 7,  Han Brunner 4,  Debora Bertola 8,  Nicolas Chassaing 9,  Albert David 10,  Koen Devriendt 11,  Pirayeh Eftekhari 12,  Valérie Drouin-Garraud 13,  Francesca Faravelli 14,  Laurence Faivre 15,  Fabienne Giuliano 16,  Leina Guion Almeida 17,  Jorge Juncos 18,  Marlies Kempers 4,  Hatice Koçak Eker 19,  Didier Lacombe 20,  Angela Lin 21,  Grazia Mancini 22,  Daniela Melis 23,  Charles Marques Lourenço 24,  Victoria Mok Siu 25,  Gilles Morin 26,  Marjan Nezarati 27,  Malgorzata J M Nowaczyk 28,  Jeanette C Ramer 29,  Sara Osimani 3,  Nicole Philip 30,  Mary Ella Pierpont 31,  Vincent Procaccio 32,  Zeichi-Seide Roseli 17,  Massimiliano Rossi 33,  Cristina Rusu 34,  Yves Sznajer 35,  Ludivine Templin 30,  Vera Uliana 14,  Mirjam Klaus 36,  Bregje Van Bon 4,  Conny Van Ravenswaaij 37,  Bruce Wainer 38,  Andrew E Fry 39,  Andreas Rump 2,  Alexander Hoischen 4,  Séverine Drunat 3,  Jean-Baptiste Rivière 40,  William B Dobyns 41,  Daniela T Pilz 39
Affiliations

Affiliations

  • 1 1] Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France [2] INSERM UMR 1141, Hôspital Robert DEBRE, Paris, France.
  • 2 Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden, Germany.
  • 3 Department of Genetics, APHP-Robert DEBRE University Hospital, and Paris-Diderot University, Paris, France.
  • 4 Radboud University Medical Centre, Nijmegen, The Netherlands.
  • 5 Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA.
  • 6 Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
  • 7 Children's Hospital of Eastern Ontario, Ottawa, Canada.
  • 8 Hospital das Clínicas da Faculdade de Medicina da Universidade and Instituto de Biociênicas da Universidade, São Paulo, Brazil.
  • 9 Service de Génétique Médicale, Purpan University Hospital, Toulouse, France.
  • 10 Service de Génétique Médicale, University Hospital, Nantes, France.
  • 11 Department of Genetics, University Hospital Gasthuisberg, Leuven, Belgium.
  • 12 Department of Hematology, APHP Lariboisière Hospital, Paris, France.
  • 13 Service de Génétique Médicale, University Hospital, Rouen, France.
  • 14 Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy.
  • 15 Service de Génétique Médicale, University Hospital, Dijon, France.
  • 16 Service de Génétique Médicale, University Hospital, Nice, France.
  • 17 Department of Clinical Genetics, Hospital of Rehabilitation of Craniofacial Anomalies (HRAC), University of São Paulo, Bauru, Brazil.
  • 18 Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
  • 19 Department of Medical Genetics, Dr Faruk Sükan Maternity and Children's Hospital, Konya, Turkey.
  • 20 Service de Génétique Médicale, University Hospital, Bordeaux, France.
  • 21 Medical Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • 22 Erasmus Medical Center, Rotterdam, The Netherlands.
  • 23 Dipartimento di Pediatria, Università Federico II, Naples, Italy.
  • 24 Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
  • 25 Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
  • 26 Service de Génétique Médicale, University Hospital, Amiens, France.
  • 27 North York General Hospital, Toronto, Ontario, Canada.
  • 28 McMaster University, Hamilton, Ontario, Canada.
  • 29 Department of Pediatrics, Pennsylvania State University, Hershey, PA, USA.
  • 30 Service de Génétique Médicale, La Timone University Hospital, Marseille, France.
  • 31 Department of Pediatrics and Ophthalmology, University of Minnesota Medical Center, Minneapolis, MN, USA.
  • 32 Genetic Department, University Hospital, Angers, France.
  • 33 Service de Génétique Médicale, University Hospital, Lyon, France.
  • 34 Department of Genetics, University Hospital, Iasi, Romania.
  • 35 Service de Génétique Médicale, St Luc University Hospital, Brussels, Belgium.
  • 36 Mitteldeutscher Praxisverbund Humangenetik, Dresden, Germany.
  • 37 Department of Genetics, University Hospital, Groningen, The Netherlands.
  • 38 Office of the Chief Medical Examiner, City and County of San Francisco, CA, USA.
  • 39 Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK.
  • 40 1] Dipartimento di Genetica Medica, Ospedale Galliera, Genova, Italy [2] Seattle Children's Hospital, Seattle, WA, USA.
  • 41 Seattle Children's Hospital, Seattle, WA, USA.
PMID: 25052316 DOI: 10.1038/ejhg.2014.95
Abstract

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.

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