Abstract
Background
Orofacial clefts are common congenital malformations usually characterized by a multifactorial etiology. These heterogeneous defects comprise cleft lip (CL), CL with cleft palate (CL/P), and cleft palate, sometimes observed in recognizable syndromes, with mendelian, chromosomal, or environmental pathogenesis. The Van der Woude syndrome is a mendelian CL/P, accounting for about 2% of all cases and caused by mutations in the interferon regulatory factor 6 (IRF6) gene, located on 1q32.2 chromosome.
Objective
Here, we describe a familial case with a novel IRF6 mutation segregating in the maternal line, displaying a highly intrafamilial variable clinical expression.
Conclusion
This report emphasizes the role of the clinician in recognizing the clinical variability and the genetic heterogeneity of CL/P.
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References
Badovinac RL, Werler MM, Williams PL, Kelsey KT, Hayes C (2007) Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol 79:8–15
Cobourne MT (2004) The complex genetics of cleft lip and palate. Eur J Orthod 26:7–16
Fraser FC (1970) The genetics of cleft lip and cleft palate. Am J Hum Genet 22:336–352
Gorlin RJ, Cohen MMJ, Levin LS (2001) Syndromes of the head and neck. Oxford University Press, Oxford
Gundlach KK, Maus C (2006) Epidemiological studies on the frequency of clefts in Europe and world-wide. J Craniomaxillofac Surg 34(Suppl 2):1–2
Ingraham CR, Kinoshita A, Kondo S, Yang B, Sajan S, Trout KJ, Malik MI, Dunnwald M, Goudy SL, Lovett M, Murray JC, Schutte BC (2006) Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). Nat Genet 38:1335–40
Jugessur A, Rahimov F, Lie RT, Wilcox AJ, Gjessing HK, Nilsen RM, Nguyen TT, Murray JC (2008) Genetic variants in IRF6 and the risk of facial clefts: single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway. Genet Epidemiol 32:413–24
Knight AS, Schutte BC, Jiang R, Dixon MJ (2006) Developmental expression analysis of the mouse and chick orthologues of IRF6: the gene mutated in Van der Woude syndrome. Dev Dyn 235:1441–7
Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, Howard E, de Lima RL, Daack-Hirsch S, Sander A, McDonald-McGinn DM, Zackai EH, Lammer EJ, Aylsworth AS, Ardinger HH, Lidral AC, Pober BR, Moreno L, Arcos-Burgos M, Valencia C, Houdayer C, Bahuau M, Moretti-Ferreira D, Richieri-Costa A, Dixon MJ, Murray JC (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndrome. Nat Genet 32:285–289
Mitchell LE, Beaty TH, Lidral AC, Munger RG, Murray JC, Saal HM, Wyszynski DF (2002) Guidelines for the design and analysis of studies on nonsyndromic cleft lip and cleft palate in humans: summary report from a Workshop of the International Consortium for Oral Clefts Genetics. Cleft Palate Craniofac J 39:93–100
Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, Shore P, Whitmarsh A, Dixon MJ (2006) Irf6 is a key determinant of the keratinocyte proliferation–differentiation switch. Nat Genet 38:1329–34
Rintala AE, Ranta R (1981) Lower lip sinuses: epidemiology, microforms and transverse sulci. Br J Plast Surg 34:26–30
Rizos M, Spyropoulos MN (2004) Van der Woude syndrome: a review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counselling and treatment. Eur J Orthod 26:17–24
Robert E, Kallen B, Harris J (1996) The epidemiology of orofacial clefts. Some general epidemiological characteristics. J Craniofac Genet Dev Biol 16:234–241
Romitti PA, Lidral AC, Munger RG, Daack-Hirsch S, Burns TL, Murray JC (1999) Candidate genes for non-syndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype–environment interactions from a population-based case-control study of orofacial clefts. Teratology 59:39–50
Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, Carinci F (2005) Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate in an Italian population. Am J Hum Genet 76:180–183
Stanier P, Moore GE (2004) Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet 13(Spec No1):R73–81
Wyszynski DF, Duffy DL, Beaty TH (1997) Maternal cigarette smoking and oral clefts: a meta-analysis. Cleft Palate Craniofac J 34:206–210
Wyszynski DF, Sárközi A, Czeizel AE (2006) Oral clefts with associated anomalies: methodological issues. Cleft Palate Craniofac J 43:1–6
Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura K, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu YE, Ray A, Goldstein TH, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC (2004) Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 351:769–80
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We acknowledge the Regione Piemonte Ricerca Finalizzata Program for financial support.
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Ferrero, G.B., Baldassarre, G., Panza, E. et al. A heritable cause of cleft lip and palate—Van der Woude syndrome caused by a novel IRF6 mutation. Review of the literature and of the differential diagnosis. Eur J Pediatr 169, 223–228 (2010). https://doi.org/10.1007/s00431-009-1011-3
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DOI: https://doi.org/10.1007/s00431-009-1011-3