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Van der Woude syndrome 1(VWS1)

MedGen UID:
1640616
Concept ID:
C4551864
Disease or Syndrome
Synonym: IRF6-Related Disorders
 
Gene (location): IRF6 (1q32.2)
 
Monarch Initiative: MONDO:0007333
OMIM®: 119300

Disease characteristics

Excerpted from the GeneReview: IRF6-Related Disorders
Most commonly, IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. In rare instances, IRF6 pathogenic variants have also been reported in individuals with nonsyndromic orofacial cleft (18/3,811; 0.47%) and in individuals with spina bifida (2/192). Individuals with VWS show one or more of the following anomalies: Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip. Cleft lip (CL). Cleft palate (CP). Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP). The PPS phenotype includes the following: CL±P. Fistulae of the lower lip. Webbing of the skin extending from the ischial tuberosities to the heels. In males: bifid scrotum and cryptorchidism. In females: hypoplasia of the labia majora. Syndactyly of fingers and/or toes. Anomalies of the skin around the nails. A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic). In some nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum. In VWS, PPS, IRF6-related neural tube defect, and IRF6-related orofacial cleft, growth and intelligence are typical. [from GeneReviews]
Authors:
Brian C Schutte  |  Howard M Saal  |  Steven Goudy, et. al.   view full author information

Additional descriptions

From OMIM
Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, and cleft lip and/or cleft palate (CL/P, CP). It is the most common cleft syndrome. Genetic Heterogeneity of van der Woude Syndrome Also see VWS2 (606713), caused by mutation in the GRHL3 gene (608317) on chromosome 1p36.  http://www.omim.org/entry/119300
From MedlinePlus Genetics
Van der Woude syndrome is a condition that affects the development of the face. Many people with this disorder are born with either a cleft lip or a cleft palate (an opening in the upper lip or roof of the mouth), or both. Affected individuals usually have depressions (pits) near the center of the lower lip, which may appear moist due to the presence of salivary and mucous glands in the pits. Small mounds of tissue on the lower lip may also occur. In some cases, people with van der Woude syndrome have missing teeth.

People with van der Woude syndrome who have cleft lip and/or palate, like other individuals with these facial conditions, have an increased risk of delayed language development, learning disabilities, or other mild cognitive problems. The average IQ of individuals with van der Woude syndrome is not significantly different from that of the general population.  https://medlineplus.gov/genetics/condition/van-der-woude-syndrome

Clinical features

From HPO
Cleft upper lip
MedGen UID:
40327
Concept ID:
C0008924
Congenital Abnormality
A gap in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Partial congenital absence of teeth
MedGen UID:
43794
Concept ID:
C0020608
Congenital Abnormality
Tooth agenesis in some form is a common human anomaly that affects approximately 20% of the population. Although tooth agenesis is associated with numerous syndromes, several case reports describe nonsyndromic forms that are either sporadic or familial in nature, as reviewed by Gorlin et al. (1990). The incidence of familial tooth agenesis varies with each class of teeth. Most commonly affected are third molars (wisdom teeth), followed by either upper lateral incisors or lower second premolars; agenesis involving first and second molars is very rare. Also see 114600 and 302400. Selective tooth agenesis without associated systemic disorders has sometimes been divided into 2 types: oligodontia, defined as agenesis of 6 or more permanent teeth, and hypodontia, defined as agenesis of less than 6 teeth. The number in both cases does not include absence of third molars (wisdom teeth). Faulty use of the terms, however, have confounded their use. The term 'partial anodontia' is obsolete (Salinas, 1978). Genetic Heterogeneity of Selective Tooth Agenesis Other forms of selective tooth agenesis include STHAG2 (602639), mapped to chromosome 16q12; STHAG3 (604625), caused by mutation in the PAX9 gene (167416) on chromosome 14q12; STHAG4 (150400), caused by mutation in the WNT10A gene (606268) on chromosome 2q35; STHAG5 (610926), mapped to chromosome 10q11; STHAG7 (616724), caused by mutation in the LRP6 gene (603507) on chromosome 12p13; STHAG8 (617073), caused by mutation in the WNT10B gene (601906) on chromosome 12q13; STHAG9 (617275), caused by mutation in the GREM2 gene (608832) on chromosome 1q43; STHAG10 (620173), caused by mutation in the TSPEAR gene (612920) on chromosome 21q22; and STHAGX1 (313500), caused by mutation in the EDA gene (300451) on chromosome Xq13. A type of selective tooth agenesis that was formerly designated STHAG6 has been incorporated into the dental anomalies and short stature syndrome (DASS; 601216). Of 34 unrelated patients with nonsyndromic tooth agenesis, van den Boogaard et al. (2012) found that 56% (19 patients) had mutations in the WNT10A gene (STHAG4), whereas only 3% and 9% had mutations in the MSX1 (STHAG1) and PAX9 (STHAG3) genes, respectively. The authors concluded that WNT10A is a major gene in the etiology of isolated hypodontia. Genotype-Phenotype Correlations Yu et al. (2016) observed that the most frequently missing permanent teeth in WNT10B-associated oligodontia were the lateral incisors (83.3%), whereas premolars were missing only 51.4% of the time, which they noted was a pattern 'clearly different' from the oligodontia patterns resulting from WNT10A mutations. They also stated that the selective pattern in WNT10B mutants was different from that associated with mutations in other genes, such as MSX1, in which second premolars are missing, and PAX9, in which there is agenesis of molars.
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
Lower lip pit
MedGen UID:
396160
Concept ID:
C1861544
Finding
Depression located on the vermilion of the lower lip, usually paramedian.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Li S, Zhang X, Chen D, Zhao W, Zhang X, Jiao J, Guo L, Yin L, Song X, Liang C, Sun C
Mol Med Rep 2018 Jan;17(1):1241-1246. Epub 2017 Nov 6 doi: 10.3892/mmr.2017.7978. PMID: 29115498
Leslie EJ, Mancuso JL, Schutte BC, Cooper ME, Durda KM, L'Heureux J, Zucchero TM, Marazita ML, Murray JC
Am J Med Genet A 2013 Oct;161A(10):2535-2544. Epub 2013 Aug 15 doi: 10.1002/ajmg.a.36133. PMID: 23949966Free PMC Article
Rizos M, Spyropoulos MN
Eur J Orthod 2004 Feb;26(1):17-24. doi: 10.1093/ejo/26.1.17. PMID: 14994878

Recent clinical studies

Etiology

Kousa YA, Schutte BC
Dev Dyn 2016 Mar;245(3):220-32. Epub 2015 Sep 17 doi: 10.1002/dvdy.24341. PMID: 26332872Free PMC Article
Heliövaara A, Karhulahti R, Rautio J
J Plast Surg Hand Surg 2015;49(4):209-13. Epub 2014 Dec 17 doi: 10.3109/2000656X.2014.992904. PMID: 25516228
Lam AK, David DJ, Townsend GC, Anderson PJ
Aust Dent J 2010 Mar;55(1):51-8. doi: 10.1111/j.1834-7819.2009.01178.x. PMID: 20415912
Nawa H, Oberoi S, Vargervik K
Angle Orthod 2008 Sep;78(5):832-7. doi: 10.2319/081707-384.1. PMID: 18298211
Huang JJ, Hou JW, Tan YC, Chen KT, Lo LJ, Chen YR
Cleft Palate Craniofac J 2007 Nov;44(6):649-52. doi: 10.1597/06-094.1. PMID: 18177185

Diagnosis

Allam KA, Haredy MM
Ann Plast Surg 2021 Aug 1;87(2):165-168. doi: 10.1097/SAP.0000000000002605. PMID: 33346530
Alade AA, Buxo-Martinez CJ, Mossey PA, Gowans LJJ, Eshete MA, Adeyemo WL, Naicker T, Awotoye WA, Adeleke C, Busch T, Toraño AM, Bello CA, Soto M, Soto M, Ledesma R, Marquez M, Cordero JF, Lopez-Del Valle LM, Salcedo MI, Debs N, Li M, Petrin A, Olotu J, Aldous C, Olutayo J, Ogunlewe MO, Abate F, Hailu T, Muhammed I, Gravem P, Deribew M, Gesses M, Hassan M, Pape J, Adeniyan OA, Obiri-Yeboah S, Arthur FKN, Oti AA, Olatosi O, Miller SE, Donkor P, Dunnwald MM, Marazita ML, Adeyemo AA, Murray JC, Butali A
Mol Genet Genomic Med 2020 Aug;8(8):e1355. Epub 2020 Jun 17 doi: 10.1002/mgg3.1355. PMID: 32558391Free PMC Article
James O, Adeyemo WL, Emeka CI, Ogunlewe MO, Ladeinde AL, Butali A
Afr J Paediatr Surg 2014 Jan-Mar;11(1):52-5. doi: 10.4103/0189-6725.129235. PMID: 24647295Free PMC Article
Lam AK, David DJ, Townsend GC, Anderson PJ
Aust Dent J 2010 Mar;55(1):51-8. doi: 10.1111/j.1834-7819.2009.01178.x. PMID: 20415912
Rizos M, Spyropoulos MN
Eur J Orthod 2004 Feb;26(1):17-24. doi: 10.1093/ejo/26.1.17. PMID: 14994878

Therapy

Alade AA, Buxo-Martinez CJ, Mossey PA, Gowans LJJ, Eshete MA, Adeyemo WL, Naicker T, Awotoye WA, Adeleke C, Busch T, Toraño AM, Bello CA, Soto M, Soto M, Ledesma R, Marquez M, Cordero JF, Lopez-Del Valle LM, Salcedo MI, Debs N, Li M, Petrin A, Olotu J, Aldous C, Olutayo J, Ogunlewe MO, Abate F, Hailu T, Muhammed I, Gravem P, Deribew M, Gesses M, Hassan M, Pape J, Adeniyan OA, Obiri-Yeboah S, Arthur FKN, Oti AA, Olatosi O, Miller SE, Donkor P, Dunnwald MM, Marazita ML, Adeyemo AA, Murray JC, Butali A
Mol Genet Genomic Med 2020 Aug;8(8):e1355. Epub 2020 Jun 17 doi: 10.1002/mgg3.1355. PMID: 32558391Free PMC Article
Hills SE, Maddalozzo J
Otolaryngol Clin North Am 2015 Feb;48(1):209-23. doi: 10.1016/j.otc.2014.09.014. PMID: 25439555
Melo C, Gama-de-Sousa S, Almeida F, Rendeiro P, Tavares P, Cardoso H, Carvalho S
Gene 2013 Oct 15;529(1):186-9. Epub 2013 Aug 6 doi: 10.1016/j.gene.2013.07.031. PMID: 23928108

Prognosis

Eshete MA, Liu H, Li M, Adeyemo WL, Gowans LJJ, Mossey PA, Busch T, Deressa W, Donkor P, Olaitan PB, Aregbesola BS, Braimah RO, Oseni GO, Oginni F, Audu R, Onwuamah C, James O, Augustine-Akpan E, Rahman LA, Ogunlewe MO, Arthur FKN, Bello SA, Agbenorku P, Twumasi P, Abate F, Hailu T, Demissie Y, Hailu A, Plange-Rhule G, Obiri-Yeboah S, Dunnwald MM, Gravem PE, Marazita ML, Adeyemo AA, Murray JC, Cornell RA, Butali A
J Dent Res 2018 Jan;97(1):41-48. Epub 2017 Sep 8 doi: 10.1177/0022034517729819. PMID: 28886269Free PMC Article
Hills SE, Maddalozzo J
Otolaryngol Clin North Am 2015 Feb;48(1):209-23. doi: 10.1016/j.otc.2014.09.014. PMID: 25439555
James O, Adeyemo WL, Emeka CI, Ogunlewe MO, Ladeinde AL, Butali A
Afr J Paediatr Surg 2014 Jan-Mar;11(1):52-5. doi: 10.4103/0189-6725.129235. PMID: 24647295Free PMC Article
Chen CH, Liao HT, Shyu VB, Chen PK
Int J Oral Maxillofac Surg 2013 Feb;42(2):198-203. Epub 2013 Jan 3 doi: 10.1016/j.ijom.2012.11.018. PMID: 23290085
Matsuzawa N, Yoshiura K, Machida J, Nakamura T, Niimi T, Furukawa H, Toyoda T, Natsume N, Shimozato K, Niikawa N
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004 Oct;98(4):414-7. doi: 10.1016/j.tripleo.2003.12.034. PMID: 15472655

Clinical prediction guides

Alade AA, Buxo-Martinez CJ, Mossey PA, Gowans LJJ, Eshete MA, Adeyemo WL, Naicker T, Awotoye WA, Adeleke C, Busch T, Toraño AM, Bello CA, Soto M, Soto M, Ledesma R, Marquez M, Cordero JF, Lopez-Del Valle LM, Salcedo MI, Debs N, Li M, Petrin A, Olotu J, Aldous C, Olutayo J, Ogunlewe MO, Abate F, Hailu T, Muhammed I, Gravem P, Deribew M, Gesses M, Hassan M, Pape J, Adeniyan OA, Obiri-Yeboah S, Arthur FKN, Oti AA, Olatosi O, Miller SE, Donkor P, Dunnwald MM, Marazita ML, Adeyemo AA, Murray JC, Butali A
Mol Genet Genomic Med 2020 Aug;8(8):e1355. Epub 2020 Jun 17 doi: 10.1002/mgg3.1355. PMID: 32558391Free PMC Article
Eshete MA, Liu H, Li M, Adeyemo WL, Gowans LJJ, Mossey PA, Busch T, Deressa W, Donkor P, Olaitan PB, Aregbesola BS, Braimah RO, Oseni GO, Oginni F, Audu R, Onwuamah C, James O, Augustine-Akpan E, Rahman LA, Ogunlewe MO, Arthur FKN, Bello SA, Agbenorku P, Twumasi P, Abate F, Hailu T, Demissie Y, Hailu A, Plange-Rhule G, Obiri-Yeboah S, Dunnwald MM, Gravem PE, Marazita ML, Adeyemo AA, Murray JC, Cornell RA, Butali A
J Dent Res 2018 Jan;97(1):41-48. Epub 2017 Sep 8 doi: 10.1177/0022034517729819. PMID: 28886269Free PMC Article
Rizos M, Spyropoulos MN
Eur J Orthod 2004 Feb;26(1):17-24. doi: 10.1093/ejo/26.1.17. PMID: 14994878
Wong FK, Karsten A, Larson O, Huggare J, Hagberg C, Larsson C, Teh BT, Linder-Aronson S
Acta Odontol Scand 1999 Apr;57(2):72-6. doi: 10.1080/000163599428931. PMID: 10445358
Burdick AB, Bixler D, Puckett CL
J Craniofac Genet Dev Biol 1985;5(2):181-208. PMID: 4019732

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