|Year : 2022 | Volume
| Issue : 1 | Page : 85-87
Van der Woude syndrome: Presentation of child with duodenal atresia with an interferon regulatory factor 6 variant
Helen Livesey1, Uchechika Iroegbu2, Meena Balasubramanian3
1 Department of Clinical Genetics, Leeds Teaching Hospitals NHS Trust, Leeds, UK
2 Department of Infection and Travel Medicine, Leeds Teaching Hospitals NHS Trust, Leeds, UK
3 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
|Date of Submission||23-Sep-2021|
|Date of Acceptance||11-Oct-2021|
|Date of Web Publication||01-Jan-2022|
Dr. Meena Balasubramanian
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield
Source of Support: None, Conflict of Interest: None
Orofacial clefts are common birth defects and Van der Woude syndrome (VWS) is the most common form of orofacial cleft syndrome, accounting for approximately 2% of patients with a cleft., The cardinal features of VWS are lower lip pits associated with cleft lip and/or palate.,, Lip pits are reported to occur in over 80% of individuals with VWS. Most reported cases of VWS have been linked to chromosome 1q32-q41.,, The interferon regulatory factor 6 (IRF6) gene, which is located at 1q32-p41 region, has been implicated in several studies., There are over 300 IRF6 variants that have been identified in patients with VWS, with approximately 50% of these being missense variants. This paper describes a 7.5-year-old male patient that is heterozygous for a missense variant in C.101A >C p.(Lys34Thr) which is likely to be pathogenic. This patient has the cardinal features for VWS but also has duodenal atresia. Neither the truncating variant identified in this patient nor other variants associated with VWS have been previously linked to duodenal atresia.
Keywords: Duodenal atresia, interferon regulatory factor 6 gene, orofacial cleft syndrome, Van der Woude syndrome
|How to cite this article:|
Livesey H, Iroegbu U, Balasubramanian M. Van der Woude syndrome: Presentation of child with duodenal atresia with an interferon regulatory factor 6 variant. J Cleft Lip Palate Craniofac Anomal 2022;9:85-7
|How to cite this URL:|
Livesey H, Iroegbu U, Balasubramanian M. Van der Woude syndrome: Presentation of child with duodenal atresia with an interferon regulatory factor 6 variant. J Cleft Lip Palate Craniofac Anomal [serial online] 2022 [cited 2022 Jan 25];9:85-7. Available from: https://www.jclpca.org/text.asp?2022/9/1/85/333649
| Introduction|| |
Orofacial clefts are common birth defects and Van der Woude syndrome (VWS) is the most common form of orofacial cleft syndrome, accounting for approximately 2% of patients with a cleft., The syndrome has an autosomal dominant pattern of inheritance, but mutations arise de novo in approximately 30%–50% of cases. VWS has a variable expressivity, and penetrance has been reported to be between 80% and 100%, with equal gender distribution.,
The cardinal features of VWS are lower lip pits associated with cleft lip and/or palate.,, Lip pits are reported to occur in over 80% of individuals with VWS and are usually asymptomatic. However, they can exhibit drainage of a salivary secretion, particularly on mastication. Lip pits form during an early stage of embryological development, either by the fixation of tissues at the base of the notch or as a result of failure of complete union of embryonic lateral sulci of the lip. Rather unusually, the cleft can either be of the lip or of the palate within the same pedigree.
Most reported cases of VWS have been linked to chromosome 1q32-q41.,, However, a second VWS locus has been mapped to 1p36-p32.,, The interferon regulatory factor 6 (IRF6) gene, which is located at 1q32-p41 region, has been implicated in several studies., Up to 25% of families with a diagnosis of VWS do not have a variant in the IRF6, and a second gene, grainyhead-like 3, has also been identified in patients with VWS.
IRF6 belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA binding domain and a less conserved protein-binding domain called SMIR., IRF6 is responsible for regulating the proliferation and differentiation of epithelial tissues. The variant distribution in patients with VWS appears not to be randomly distributed, but mutations are overly represented in the highly conserved DNA-binding domain on exon 4. There are over 300 IRF6 variants that have been identified in patients with VWS, with approximately 50% of these being missense variants. Our patient is heterozygous for a missense variant in C.101A>C p.(Lys34Thr), and a study by Li et al. suggests that this truncating variant is likely to be pathogenic.
| Case Report|| |
A 5-month-old boy was referred to the Clinical Genetics Department by the Paediatric Surgical team following a surgical correction of duodenal atresia on day 1 of life. The pregnancy was a natural conception with nonconsanguineous parents. Family history included cleft palate in the father along with lip pits in the father and several other members on the paternal side of the family. There was nothing else of significance in the rest of the family history.
The diagnosis of duodenal atresia was made during the 20-week anomaly scan, and the pregnancy was investigated for other syndromic features. An amniocentesis confirmed normal male karyotype. The male infant was delivered at 37 + 3 weeks due to maternal cholestasis. He was born in good clinical condition through a normal delivery with a birth weight of 3.51 kg. At birth, he was noted to have a cleft palate, and a patent ductus arteriosus (PDA) was identified during newborn screening. His PDA had resolved without intervention at the time of his review in the Genetics Clinic and his development at this stage was normal. An abdominal X-ray at birth showed a double bubble and nasogastric tube in the stomach. He was transferred to the neonatal surgical unit for correction with a duodenoduodenostomy performed on D1 of life.
Father who was said to also have lip pits, cleft palate, and bowel problems was unfortunately not available for examination. Clinically, the findings were suggestive of VWS. Given duodenal atresia is not known to be associated with this syndrome, genetic testing was organized.
On review at age 4, clinical features showed cleft palate repair. He was under the care of the speech and language therapists due to moderate hearing difficulties. His parents reported that he was walking by the age of 17 months, he spoke his first words at age 20 months, and he demonstrated a pincer grip in clinic. His older siblings were also reviewed at this time and were noted to have lip pits, but none of the other features seen in the patient [Figure 1].
Genetic testing results
The patient had a microarray which demonstrated a male profile with no clinically significant imbalance detected. He underwent FISH for 22q11.2 using the cytocell TBX1 probe, which excluded any deletion or duplication. Next-generation sequencing of IRF6 identified a pathogenic variant c.101A>C p.(Lys34Thr). This was a missense change occurring in the DNA binding domain of the IRF6 protein. This variant has previously been identified in a patient with VWS and occurred in the DNA binding domain of the IRF6 protein, which is known to be crucial for protein function. Pathogenic missense variants in this exon are widely reported in patients with VWS in the literature.
| Discussion|| |
A rare case of VWS with an associated duodenal atresia has been presented, which has not previously been reported in the literature. VWS is an autosomal dominant inherited syndrome, which has previously been known to present with features of cleft lip/palate and lip pits. Advances in genetic sequencing techniques have enabled the identification of several variants that are associated with VWS, with multiple variants located in IRF6.
IRF6 protein function has been identified as being involved in signaling pathways related to craniofacial development., Li et al. identified two families with the same c.101A>C variant seen in our family and demonstrated that the injection of this mRNA variant into maternal-null irf6-/-zebrafish embryos did not rescue the maternal-null irf6-/-rupture phenotype thereby suggesting its pathogenicity.
The wide range of cleft phenotypes exhibited in VWS demonstrates the highly variable phenotypic expression. Interestingly, family members with the same pathogenic variants have been shown to exhibit different clinical phenotypes. In some patients with VWS, the only phenotypic feature is lower lip pits, meaning that careful physical examination is required to ensure patients and family members are phenotyped correctly.,
To summarize, we describe duodenal atresia as an additional clinical feature in VWS.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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