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Year : 2010  |  Volume : 28  |  Issue : 2  |  Page : 104-109

The role of 9qh+ in phenotypic and genotypic heterogeneity in a Van der Woude syndrome pedigree

1 Senior Lecturer, Department of Pedodontics and Preventive Dentistry, Panineeya Institute of Dental Sciences and Research Centre, Dilsukhnagar, Hyderabad - 500 060, Andhra Pradesh, India
2 Senior Lecturer, Department of Pedodontics and Preventive Dentistry, BRS Dental College, Panchkula, Haryana, India
3 Professor and Head, Department of Pedodontics and Preventive Dentistry, Christian Dental College, C.M.C, Brown Road, Ludhiana - 141008, Punjab, India
4 Senior Technical Assistant, Centre for Cellular and Molecular Biology, Hyderabad, India
5 Laboratory Assistant, Centre for Cellular and Molecular Biology, Hyderabad, India
6 Scientist, Centre for Cellular and Molecular Biology, Hyderabad, India

Date of Web Publication24-Jul-2010

Correspondence Address:
G A Moghe
Flat no. 202, Gharonda Sargam Apts., 11-1-269, Sitafalmandi, Secunderabad-500 061
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0970-4388.66749

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Van der Woude syndrome (VWS) (OMIM 119300) is a dominantly inherited developmental disorder that is characterized by pits and/or sinuses of the lower lip and cleft lip and/or cleft palate. Mutations in the interferon regulatory factor 6 gene (IRF6) have been recently identified in patients with VWS, with more than 60 mutations reported. We report the phenotypic variants of the syndrome in a family and present the application of the multicolor chromosome banding (mBAND) analysis in the identification of complex intrachromosome rearrangements of chromosome 9 in a child with VWS. The authors conclude that increased heterochromatin on chromosome 9 did not have any effect on the phenotypic expression of the syndrome in the family that was studied.

Keywords: Fluorescent in situ hybridization, interferon regulatory factor mutations, lower lip pits, multicolor chromosome banding, orofacial clefting syndromes

How to cite this article:
Moghe G A, Kaur M S, Thomas A M, Raseswari T, Swapna M, Rao L. The role of 9qh+ in phenotypic and genotypic heterogeneity in a Van der Woude syndrome pedigree. J Indian Soc Pedod Prev Dent 2010;28:104-9

How to cite this URL:
Moghe G A, Kaur M S, Thomas A M, Raseswari T, Swapna M, Rao L. The role of 9qh+ in phenotypic and genotypic heterogeneity in a Van der Woude syndrome pedigree. J Indian Soc Pedod Prev Dent [serial online] 2010 [cited 2023 Feb 1];28:104-9. Available from: http://www.jisppd.com/text.asp?2010/28/2/104/66749

   Introduction Top

Van der Woude syndrome (VWS) is the most common form of syndromic clefting, accounting for 1-2% cases of cleft lip and palate (CLP). With an autosomal dominant mode of inheritance, the prevalence of VWS varies from 1:100,000 to 1:40,000 still born or live births. [1],[2] No significant difference between sexes has been reported with regard to the prevalence of the syndrome. [3]

The syndrome shows a varied phenotypic expression. Lower lip pits, cleft lip (CL) with or without cleft palate (CP), and isolated CP are its cardinal signs. Phenotypic expression of the clefts ranges from incomplete unilateral CL, submucous CP, bifid uvula, to complete bilateral CLP. VWS is also associated with Popliteal pterygium syndrome (PPS) and orofacial-digital syndrome type I (OFD-I). [2]

VWS is of special interest because the phenotype closely resembles nonsyndromic forms of both CL and CP. [4] One of the unusual features of VWS is that different forms of clefts occur in vertical and horizontal directions in the same pedigree; the average penetrance has been reported to be 96.7%. [5] In this article, we report one such family which presented with lower lip pits with variable forms of CLP.

   Case Report Top

The proband, a 6-year-old male child, the first-born of a non-consanguineous marriage, was a case of repaired bilateral CLP, with remaining esthetic defects leading to columella deformity and alar base depression, in addition to lip pits [Figure 1]. He was referred to our department for restoration of carious teeth. Intraoral examination revealed clinically missing maxillary deciduous lateral incisors and carious lesions with respect to deciduous maxillary right central incisor and second molar, and deciduous maxillary left first molar. Bilateral lip pits, circular to oval, were noted on the lower lip at the junction of the wet and dry vermilion, and were paramedian in location and asymptomatic. Complete physical examination did not reveal any other systemic abnormality.

The mother's antenatal history was insignificant. There was no history of any major cardiac illnesses, diabetes, tuberculosis, epilepsy or any teratogenic drug exposure. The birth of the child was by normal vaginal delivery at full term.

Further, family history revealed that the patient's younger sibling, a 2.5-year-old female child, also suffered from congenital lip pits and had undergone corrective surgery for bilateral CLP [Figure 2]. The third pregnancy ended in a miscarriage, details of which could not be elucidated.

No clefts were known to have existed in previous generations or in distant relatives. The children's mother was examined and it was noticed that she had a bifid uvula [Figure 3] and bilaterally symmetrical lower labial fistulae. The patient's father was phenotypically normal. None of the mother's or father's siblings, as reported by them, was affected [Figure 7], but the parents were concerned about the trait being passed on to subsequent generations.

After written, informed consent for further investigations the and institutional review board approval were obtained, radiographs of the proband were taken to investigate the depth and extent of the labial fistulae. A radiograph of the lower lip revealed that the gutta percha points traversed a depth of 6 mm in the right fistula and 5 mm in the left fistula.

Peripheral venous blood samples were collected in vacutainers precoated with heparin and Ethylene Diamine Tetraacetic Acid, and transported to the laboratory within 24 hours for further processing and testing.

All the samples were subjected to Giemsa banding. Additionally, fluorescent in situ hybridization (FISH) and multicolor chromosome banding analysis (mBAND) were performed using the proband's blood sample .

   Results Top

In this family, karyotyping of the samples done using the Giemsa banding technique. Interestingly, an increase in heterochromatin in the long arm of chromosome 9 of father [Figure 4], the younger sibling [Figure 5], and the proband [Figure 6] was noted, heterozygous in all cases. Since many authors have confirmed the occurrence of microdeletions on chromosome 1 in VWS, no further attempt was made to characterize these deletions. Rather, special emphasis was laid on chromosome 9 which may have acted as a modifier locus leading to complete phenotypic expression of the syndrome in the children. The mBAND confirmed an increase in heterochromatin in the long arm of chromosome 9, read as 9qh+.[Figure 6]

Nonparametric linkage analysis (NPL) was done using a Unix-based version of GENEHUNTER and a NPL Logarithm of the odds (LOD) score of 0.48 was obtained. Chi-square value obtained was 2.20, which was not statistically significant.

   Discussion Top

Congenital lip pits can be a sole developmental abnormality or may be syndromic. The pits are usually found at the junction of the wet and dry vermilion, at a distance of 5-25 mm from each other, [6] and they traverse the orbicularis oris. The lip pits form canals lined by labial mucosa, and are between 1 and 25 mm long. The canals have blind ends in/near minor salivary glands. Lip pits are usually asymptomatic; the only symptom might be the intermittent drainage of salivary/watery secretions. [7] Taylor and Lane have suggested that a peristaltic projection of the mucous secretion may occur upon contraction of the orbicularis oris fibers. [8]

The genetic basis of VWS can be traced back to the study of Bocian et al.[9] who reported a patient with lip pits and a deletion in 1q32-q41, and subsequently to a study of Murray et al.[10] who found linkage between VWS and markers from the same region.

Futher studies [11] narrowed the region to a 1.6-cM region between the flanking markers D1S491 and D1S205. In this region, there are at least 15 confirmed genes, 9 putative genes and 3 pseudogenes. [12]

The identification of deletion mutations in three independent cases of VWS [4],[10],[13] suggests that VWS is caused by haploinsufficiency of a gene at the VWS locus. A second locus (VWS2) has been mapped to 1p34. [12] Kondo, [14] Matsuzawa [15] and Gatta [16] have reported missense mutations in the IRF6 gene. IRF6 is a member of a gene family of transcription factors characterized by the presence of an highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain termed Smad-interferon regulatory factor binding domain (SMIR), required to form homo and heterodimers. [16]

For those with VWS, the risk of transmitting a cleft is between 11 and 22%. [2],[3] The relative risk of transmitting lower lip pits only, or being nonpenetrant, is from 24.7 to 42.7%. [2],[3] Study of the reported family reveals a combination of cleft of soft palate and lip pits in the mother. Both the siblings, however, presented with a complete bilateral cleft of the lip and palate along with lip pits. Thus, the expressivity was calculated to be 100% [Figure 7].

Explanations for the difference in expressivity in this family may be (1) the development of clefts in persons carrying a "lip pit" major gene may be influenced by modifying genes at other loci; (2) a mutant allele may produce lip pits with only occasional clefts; (3) a different mutant allele (at the same or a different locus) may frequently lead to clefts in addition to lip pits.

On the simple assumption that everybody with the disease carries a mutant allele at the affected locus/loci, if the disease is dominant,one may conclude they will share at least one parental haplotype.

Because sib-pair analysis is model free, it can be performed without making any assumption about the genetics of the disease. By convention, an LOD score greater than 3.0 is considered as an evidence for linkage. But NPL analysis revealed an LOD score of 0.48 which clearly indicated that increased heterochromatin on chromosome 9 did not have any effect on the phenotypic expression of the syndrome in the proband. This is in agreement with several literature reports which state that 9qh+ is a normal variant among populations.

Among Asiatic population groups, the frequency of 9qh+ varies from total absence among both the sexes of newborns of Delhi city (Bhasin et al.) [17] to 8.30% among Indian normal individuals. [18]

Holbek et al.[19] observed a high frequency of 9qh+ in parents of chromosomally abnormal abortions, whereas Hemming and Burns [20] did not encounter a significant difference in the 9qh+ regions between aborting and nonaborting couples. Kunze and Mau [21] reported high frequency of 9qh+ heteromorphism in patients with multiple congenital malformations. Nielsen and Sillesen [22] observed 9qh+ heteromorphism in 8% of the members of children with de novo major chromosomal aberrations, whereas the incidence of 9qh+ was 0.04% among newborns. 9qh+ mutations have also been reported in patients with schizophrenia, fragile X syndrome, and Elllis van Creveld syndrome. Contrary to this, Madan and Bobrow did not observe any adverse effect of 9qh+ in their study. [23]

Further linkage analysis studies need to be performed to narrow the critical region responsible in this family.

   Conclusions Top

A case of VWS with familial occurrence has been presented. However, it should also be noted that congenital lip pits could also be a part of other syndromes of great heterogeneity. Careful physical examination of family members should be done, in all sporadic cases, to confirm the diagnosis in those presenting only minor manifestations and to identify less severely affected relatives of those with full expression. VWS patients may rarely show clefts without pits; these cases represent a small group of cleft patients with a high recurrence risk and underline the need for specific questions and examination for lip pits, including microforms, in relatives of cleft patients. The importance of genetic counseling should be emphasized at all times along with multidisciplinary treatment. Further research should be done to detect the genetic basis of the developmental abnormality, since VWS is the most common form of syndromic clefting. Any other modifier locus whose alteration may lead to a variable phenotypic expression still needs to be established.

   Acknowledgments Top

The authors gratefully acknowledge the contribution of Dr. Vijay Obed , Dr. Deepak J. Bhatti (Department of Plastic and Microvascular Surgery, CMC, Ludhiana, India), and Dr. Viraj S. Tambwekar (Plastic Surgeon, Seven Hills Hospital, Mumbai, India) for their support. We also thank Dr. Lalji Singh, Ex-Director, Centre for Cellular and Molecular Biology, Hyderabad, India, for allowing us to use the laboratory facilities at the institute.

   References Top

1.Rintala AE, Ranta R. Lower lip sinuses 1. Epidemiology, microforms and transverse sulci. Br J Plast Surg 1981;34:26-30.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Cervenka J, Gorlin RJ, Anderson VE. The syndromes of pits of the lower lip and cleft lip and/or palate. Genetic considerations. Am J Hum Genet 1967;19:416-32.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Janku P, Robinow M, Kelly T, Bralley R, Baynes A, Edgerton MT. The van der Woude syndrome in a large kindred: variability, penetrance and genetic risks. Am J Med Genet 1980;5:117-23.  Back to cited text no. 3  [PUBMED]    
4.Schutte BC, Basart AM, Watanabe Y, Laffin JJ, Coppage K, Bjork BC, et al. Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome. Am J Med Genet 1999;84:145-50.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Gatta V, Scarciolla O, Cupaioli M, Palka C, Chiesa PL, Stuppia L. A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome. Mutat Res 2004;547:49-53.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
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7.Nagore E, Sαnchez-Motilla JM, Febrer MI, Serrano G, Bonillo J, Aliaga A. Congenital lower lip pits (Van der Woude syndrome): presentation of 10 cases. Pediatr Dermatol 1998;15:442-5.  Back to cited text no. 7      
8.Taylor WB, Lane DK. Congenital fistulas of the lower lip. Associations with cleft lip-palate and anomalies of the extremities. Arch Dermatol 1966;94:421-4.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Bocian M, Walker AP. Lip pits and deletion 1q32-41. Am J Med Genet 1987;26:437-43.  Back to cited text no. 9  [PUBMED]    
10.Murray JC, Nishimura DY, Buetow KH, Ardinger HH, Spence MA, Sparkes RS, et al. Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome 1q. Am J Hum Genet 1990;46:486-91.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Schutte BC, Bjork BC, Coppage KB, Malik MI, Gregory SG, Scott DJ, et al. A preliminary gene map for the Van der Woude syndrome critical region derived from 900 kb of genomic sequence at 1q32-q41. Genome Res 2000;10:81-94.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Koillinen H, Wong FK, Rautio J, Ollikainen V, Karsten A, Larson O, et al. Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34. Eur J Hum Genet 2001;9:747-52.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Sander A, Schmelzle R, Murray J. Evidence for microdeletion in 1q32-41 involving the gene responsible for Van der Woude syndrome. Hum Mol Genet 1994;3:575-8.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y, et al. Mutations in IRF6 cause Van de Woude and popliteal pterygium syndromes. Nat Genet 2002;32:285-9.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]  
15.Matsuzawa N, Yoshiura K, Machida J, Nakamura T, Niimi T, Furukawa H, et al. Two missense mutations in the IRF6 gene in two Japanese families with Van der Woude syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;98:414-7.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Gatta V, Scarciolla O, Cupaioli M, Palka C, Chiesa PL, Stuppia L. A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome. Mutat Res 2004;547:49-53.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Bhasin MK, Singh IP, Gupta S, Rao PV, Kenue R, Murty VV. Cytogenetics of newborns of delhi with special references to chromosomal abnormalities. Report for Department of Science of Technology and Indian Council of Medical Research, Government of India, New Delhi: 1981.  Back to cited text no. 17      
18.Ghosh PK, Singh IP. Morphologic variability of human chromosome: polymorphism of constitutive heterochromatin. Hum Genet 1976;32:149-54.  Back to cited text no. 18  [PUBMED]    
19.Holbek S, Friedrich U, Brostrom K, Petersen GB. Monosomy for the centromeric and juxtacentromeric region of chromosome 21. Humangenetik 1974;24:191-5.   Back to cited text no. 19  [PUBMED]    
20.Hemming L, Burns C. Heterochromatic polymorphism in spontaneous abortion. J Med Genet 1979;16:358-62.  Back to cited text no. 20  [PUBMED]  [FULLTEXT]  
21.Kunze J, Mau G. A1 and C9 marker chromosomes in children with combined minor and major malformations. Lancet 1975;1:273.   Back to cited text no. 21  [PUBMED]    
22.Nielsen J, Sillesen I. Incidence of chromosomal aberrations among 11148 newborn children. Humangenetik 1975;30:1-12.  Back to cited text no. 22  [PUBMED]    
23.Madan K, Bobrow M. Structural variation in chromosome No. 9. Ann Genet 1974;17:81-6.  Back to cited text no. 23  [PUBMED]    


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

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