[en] Cohen syndrome (CS) is a rare autosomal recessive condition caused by mutations and/or large rearrangements in the VPS13B gene. CS clinical features, including developmental delay, the typical facial gestalt, chorioretinal dystrophy (CRD) and neutropenia, are well described. CS diagnosis is generally raised after school age, when visual disturbances lead to CRD diagnosis and to VPS13B gene testing. This relatively late diagnosis precludes accurate genetic counselling. The aim of this study was to analyse the evolution of CS facial features in the early period of life, particularly before school age (6 years), to find clues for an earlier diagnosis. Photographs of 17 patients with molecularly confirmed CS were analysed, from birth to preschool age. By comparing their facial phenotype when growing, we show that there are no special facial characteristics before 1 year. However, between 2 and 6 years, CS children already share common facial features such as a short neck, a square face with micrognathia and full cheeks, a hypotonic facial appearance, epicanthic folds, long ears with an everted upper part of the auricle and/or a prominent lobe, a relatively short philtrum, a small and open mouth with downturned corners, a thick lower lip and abnormal eye shapes. These early transient facial features evolve to typical CS facial features with aging. These observations emphasize the importance of ophthalmological tests and neutrophil count in children in preschool age presenting with developmental delay, hypotonia and the facial features we described here, for an earlier CS diagnosis.
Disciplines :
Genetics & genetic processes
Author, co-author :
El Chehadeh-Djebbar, Salima
Blair, Edward
Holder-Espinasse, Muriel
Moncla, Anne
Frances, Anne-Marie
Rio, Marlene
Debray, François-Guillaume ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Maladies métaboliques d'origine génétique
Kolehmainen J, Black GCM, Saarinen A et al: Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet 2003; 72: 1359-1369.
Balikova I, Lehesjoki AE, de Ravel TJ et al: Deletions in the VPS13B (COH1) Gene as a Cause of Cohen Syndrome. Hum Mutat 2009; 30: E845-E854.
Rivera-Brugués N, Albrecht B, Wieczorek D et al: Cohen syndrome diagnosis using whole genome arrays. J Med Genet 2011; 48: 136-140.
Parri V, Katzaki E, Uliana V et al: High frequency of COH1 intragenic deletions and duplications detected by MLPA in patients with Cohen syndrome. Eur J Hum Genet 2010; 18: 1133-1140.
El Chehadeh-Djebbar S, Faivre L, Moncla A et al: The power of high-resolution non-targeted array-CGH in identifying intragenic rearrangements responsible for Cohen syndrome. J Med Genet 2011; 48: e1.
Cohen Jr MM, Hall BD, Smith DW et al: A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular and limb anomalies. J Pediatr 1973; 83: 280-284.
Kivitie-Kallio S, Norio R: Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet 2001; 102: 125-135.
Chandler KE, Kidd A, Al-Gazali L et al: Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. J Med Genet 2003; 40: 233-241.
Kolehmainen J, Wilkinson R, Lehesjoki AE et al: Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet 2004; 75: 122-127.
Hurmerinta K, Pirinen S, Kovero O, Kivitie-Kallio S: Craniofacial features in Cohen syndrome: an anthropometric and cephalometric analysis of 14 patients. Clin Genet 2002; 62: 157-164.
García-Ballesta C, Pérez-Lajarín L, Lillo OC, Bravo-González LA: New oral findings in cohen syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95: 681-687.
Falk MJ, Feiler HS, Neilson DE et al: Cohen syndrome in the Ohio Amish. Am J Med Genet Part A 2004; 128A: 23-28.
Hennies HC, Rauch A, Seifert W et al: Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am J Hum Genet 2004; 75: 138-145.
Kondo I, Shimizu A, Asakawa S et al: COH1 analysis and linkage study in two Japanese families with Cohen syndrome. Clin Genet 2004; 67: 270-272.
Mochida GH, Rajab A, Eyaid W et al: Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet 2004; 41: e87.
Seifert W, Holder-Espinasse M, Spranger S et al: Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J Med Genet 2006; 43: e22.
Fryns JP, Legius E, Devriendt K et al: Cohen syndrome: the clinical symptoms and stigmata at a young age. Clin Genet 1996; 49: 237-241.
El Chehadeh S, Aral B, Gigot N et al: Search for the best indicators for the presence of a VPS13B gene mutation and confirmation of diagnostic criteria in a series of 34 patients genotyped for suspected Cohen syndrome. J Med Genet 2010; 47: 549-553.
Kivitie-Kallio S, Larsen A, Kajasto K, Norio R: Neurological and psychological findings in patients with Cohen syndrome: a study of 18 patients aged 11 months to 57 years. Neuropediatrics 1999; 30: 181-189.
Horn D, Krebsová A, Kunze J, Reis A: Homozygosity mapping in a family with microcephaly, mental retardation, and short stature to a Cohen syndrome region on 8q21.3-8q22.1: redefining a clinical entity. Am J Med Genet 2000; 92: 285-292.
Chandler KE, Biswas S, Lloyd IC et al: The ophthalmic findings in Cohen syndrome. Br J Ophthalmol 2002; 86: 1395-1398.
Katzaki E, Pescucci C, Uliana V et al: Clinical and molecular characterization of Italian patients affected by Cohen syndrome. J Hum Genet 2007; 52: 1011-1017.
Seifert W, Holder-Espinasse M, Kühnisch J et al: Expanded mutational spectrum in Cohen syndrome, tissue expression, and transcript variants of COH1. Hum Mutat 2009; 30: E404-E420.