SlideShare a Scribd company logo
1 of 6
Download to read offline
Clinics of Oncology
Review Article ISSN: 2640-1037 Volume 6
The Role of Mutations on Gene IRF6 in IRF6 Related Syndrome
Asadi S*
and Fayyazian E
Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, USA
*
Corresponding author:
Shahin Asadi,
Medical Genetics-Harvard University, Division
of Medical Genetics and Molecular Optogenetic
Research, Harvard University, Boston Children’s
Hospital, USA, Tel: +1-857-600-7921;
E-mail: shahin.asadi1985@gmail.com
Received: 25 Mar 2022
Accepted: 14 Apr 2022
Published: 20 Apr 2022
J Short Name: COO
Copyright:
©2022 Asadi S. This is an open access article distribut-
ed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and
build upon your work non-commercially.
Citation:
Asadi S, The Role of Mutations on Gene IRF6 in IRF6
Related Syndrome. Clin Onco. 2022; 6(4): 1-6
Keywords:
IRF6 Related Syndrome; IRF6 gene; Genetic
Mutation; Autosomal Dominant
clinicsofoncology.com 1
1. Abstract
IRF6-related syndrome is a group of cleft lip and palate disorders
including Van der Wood Syndrome (VWS) and Popliteal Pteryg-
ium Syndrome (PPS). People with VWS are at the lowest end of
the spectrum. They can have cleft lip or palate or cleft palate or a
combination of these abnormalities. People with PPS usually have
cleft lip, cleft lip, or cleft palate, with additional skin and limb
abnormalities, including dark skin on the back of both feet (papil-
lary) and between the legs (between the veins), deformity, or ab-
normalities of the device. Mutations in the interferon-6 regulatory
factor (IRF6) gene, located on the long arm of chromosome 1 at
1q32.2, have been linked to IRF6 syndrome.
2. Generalities of IRF6 Related Syndrome
IRF6-related syndrome is a group of cleft lip and palate disorders
including Van der Wood Syndrome (VWS) and Popliteal Pterygi-
um Syndrome (PPS). People with VWS are at the lowest end of the
spectrum. They can have cleft lip or palate or cleft palate or a com-
bination of these abnormalities. People with PPS usually have cleft
lip, cleft lip, or cleft palate, with additional skin and limb abnor-
malities, including dark skin on the back of both feet (papillary)
and between the legs (between the veins), deformity, or abnormal-
ities of the device. Genital warts are swollen or swollen fingers or
toes (syndactyly), maxillary and mandibular adhesions (intraoral
adhesions), and upper and lower eyelids (ankylobulpharon). The
conical crease of the skin on the thumb nail is one of the definite
findings in PPS [1, 2] Figure 1.
Figure 1: Images of patients with IRF6-related syndrome.
clinicsofoncology.com 2
Volume 6 Issue 4 -2022 Review Article
3. Clinical Signs and Symptoms of IRF6 Related Syn-
drome
The symptoms of IRF6 syndrome vary greatly from person to per-
son. Some people with the disease may have mild clinical symp-
toms, while others may have a more severe form of the disease
(variable expression) [1, 3].
People with VWS can have lip sores, cleft lip or cleft palate alone,
or a combination of these abnormalities. Lip sores are usually
formed as a pair of dimples on the lower lip. In less common cases
in VWS, a person may develop lip cone, lip pit, partial missing
teeth, incomplete cleft palate, and limited tongue movement (an-
gioglossia) [1, 3].
People with PPS typically have a thick network of skin on the back
of both feet that extends from the hip (isial tuberosity) to the heel.
In some patients, this abnormal thick skin network may be present
on one foot (unilateral). Because full leg stretching may be limited
or the legs may rotate abnormally (in or out), this may make it
difficult to walk [1, 3].
In most patients, dark skin may also be present between the legs
in the upper thigh area (intermittent fingernail). Some joints may
become permanently bent (joint contraction), especially the knees.
Babies with PPS may also have swelling or swelling of one or
more toes and / or toes (syndactyly), and some children may have
a triangular (pyramidal) crease in the toenails, especially the big
toe. To cover. There may also be dimples on the skin of the elbows
and knees [1, 4].
PPS may also be associated with facial abnormalities, including
incomplete closure of the roof of the mouth (cleft palate) or upper
lip (cleft lip) in most infants. Children with cleft palate may also
be prone to recurrent middle ear infections (otitis media). Children
with PPS may have abnormal bands of fibrous tissue on the gums
(gums) or between the upper (maxillary) and lower (mandible)
bones of the jaws (syngenatia), which can cause problems with
opening the mouth. In addition, some people with the disease may
have abnormal fibrous tissue that connects the edges of the eye-
lids (filiform ankylosing spondylitis) and may show limited tongue
movement (angioglossia). Many of these facial abnormalities, es-
pecially cleft palate, can contribute to eating problems, breathing
problems, or speech disorders. [1, 4] Figure 2.
People with PPS may also have genital abnormalities. In some
women, two long folds of skin on either side of the vaginal open-
ing (large lips) or uterus may not have grown (hypoplastic). In
some patients, the clitoris may not grow enough. In some men with
this disorder, the scrotum may split abnormally (bifid). In rare cas-
es, the scrotum may be small (hypoplastic) or absent, leaving the
testicles in the abdomen (undescended testicles). In approximately
40% of men with testicular disorder, the testicles may also not be
able to descend from the abdomen to the scrotum (cryptorchidism)
[1, 5].
In severe cases of PPS, abnormalities of the hands and feet (limbs)
may be present, including the absence (agenesis) or insufficient
growth (hypoplasia) of the fingers or toes, abnormal bending of
the outside (valgus), or Bending inside (varus) of the foot, or de-
formity (dysplasia) of the nails. It is worth noting that growth and
intelligence are usually normal in IRF6 syndrome [1, 5].
Figure 2: Images of disorders associated with IRF6-related syndrome.
clinicsofoncology.com 3
Volume 6 Issue 4 -2022 Review Article
4. Etiology of IRF6-Related Syndrome
Mutations in the interferon-6 regulatory factor (IRF6) gene, locat-
ed on the long arm of chromosome 1 at 1q32.2, have been linked
to IRF6 syndrome [1, 6].
IRF6-related syndrome follows an autosomal dominant inheri-
tance pattern. Therefore, a copy of the IRF6 mutant gene (either
parent) is required to cause the syndrome, and the chance of hav-
ing a child with the autosomal dominant syndrome is 50% for each
possible pregnancy [1, 6] Figure 3.
Figure 3: Schematic of chromosome 1 where the IRF6 gene is located in the long arm of this chromosome as 1q32.2.
5. Frequency of IRF6-Related Syndrome
VWS is the most common cause of a single cleft lip and palate
gene. The prevalence of this syndrome in Europe and Asia is es-
timated at 1 in 35,000 to 1 in 100,000. The prevalence of PPS is
approximately 1 in 300,000 [1, 7].
6. IRF6-Related Syndrome Disorders
The symptoms of the following disorders may be similar to those
of IRF6 syndrome. A comparison may be useful for the differential
diagnosis of this syndrome:
Van der Woude 2 Syndrome (VWS2) is an autosomal dominant
cleft palate disorder that is almost identical to VWS. They differ in
two ways. First, the phenotypic spectrum of VWS2 is the same as
VWS. Therefore, it is impossible to distinguish an individual case
of VWS from VWS2 based on clinical criteria alone. However,
people with VWS2 are more prone to cleft palate and less likely
to develop cleft lip and palate. Second, VWS2 is a GRHL3-related
disorder because it is caused by a mutation in the gene encoding
the GRHL3 transcription factor. While 70% of VWS cases are due
to mutations in IRF6, 5% of VWS cases are due to mutations in
GRHL3 [1, 8] Figure 4.
Kabuki Syndrome, also known as Nikawa-Kuruki Syndrome, is
a rare genetic disorder characterized by mental retardation, short
stature, unusual facial features (reminiscent of Kabuki makeup in
Japanese theater), skeletal abnormalities, and prominent skin pat-
terns on the fingers. Hands, toes, and palms are marked. Disorders
of the palms of the hands and soles of the feet, cleft lip and palate
are relatively common findings in Kabuki syndrome. In addition,
cases of Kabuki syndrome, cleft palate, and cleft lip have been
reported, as seen in IRF6 syndrome [1, 8].
Hirschsprung's Disease (HSCR) is characterized by aganglonic
megacolon. However, it has been reported that the cases include
cleft palate and in one case, cleft palate and lip cavity [1, 9].
Oro-Facio-Digital syndrome (OFD) is a predominantly X-related
disorder that is fatal in men. Affected women have a highly vari-
able phenotype characterized by abnormalities of the mouth, face,
and fingers, and can include kidney and brain abnormalities. Oral
abnormalities include an arched palate or cleft palate or cleft lip.
In one reported case, an infected person had an internal pit in the
lower lip [1, 9].
Branchio-Oculo-Facial Syndrome (BOFS) is a very rare genetic
disease that is evident from birth (congenital). This disorder may
be characterized by low birth weight. An abnormal pit, seen as
a cleft lip, or a tumor-like skin abnormality (hemangiomatous or
atrophic skin lesion) occur behind both ears (postauricular area) in
this syndrome. Specific abnormalities in the head and face (skull
and face); Eye abnormalities; Premature graying of the scalp
during adolescence or other abnormalities also occur in this syn-
drome. Some people with BOFS have cleft lip or cleft palate, while
others may have unusually wide, prominent upper lip protrusion
(filtrum) that resembles surgery-repaired cleft lip. Additional skull
and facial abnormalities may include a large, dysplastic nose and
defective ears. In people with this disorder, characteristic eye ab-
normalities may include abnormally small eyes (microphthalmia).
Blurring of the lenses of the eyes (cataracts); Congenital ocular
stenosis (congenital strabismus); Wide distance of eyes from each
other (hyperthermia); Or the absence of tissue (coloboma) from
the colored part of the eye (iris), gives the iris an appearance like
a "keyhole". BOFS is inherited as an autosomal dominant genetic
trait [1, 10].
Bartsocas-Papas syndrome is a disorder that can include cleft lip
or palate and dark skin similar to that seen in PPS. This is a more
severe phenotype and in some cases, but not all, is fatal. This is an
autosomal recessive inherited pattern and has been shown to have
mutations in the RIPK4 gene, at least in some cases. In addition,
a recent molecular study showed that RIPK4 activates IRF6 func-
tion [1, 11].
Isolated cleft lip and palate (iCLP), also called non-syndrom-
ic cleft lip and palate, is a disorder that involves only the cleft
lip and palate and has no other abnormal features of a syndrome.
Isolated CLP is special because it is related to IRF6 syndrome in
two phenotypic and genotypic ways. This is phenotypically relat-
ed because up to 15% of people with VWS do not have dimples.
Because these people with VWS only have an oral-facial cleft,
their phenotype is the same as that of people with iCLP. In most
cases, they were diagnosed with VWS because another affected
family member had a lip sore with a cleft lip. Therefore, physi-
cians can diagnose these two disorders only by careful analysis
of the family tree. Isolated CLP is genotypically related to IRF6
syndrome because common types of DNA in IRF6, although not
clinicsofoncology.com 4
Volume 6 Issue 4 -2022 Review Article
causing IRF6-related syndrome, can increase the risk of cleft lip
and palate. The role of IRF6 mutations in iCLP is less clear due
to the phenotypic overlap between iCLP and IRF6-related syn-
drome. Data from 2472 families identified rare IRF6 mutations in
0.24-0.44% of apparently iCLP families. The ability to distinguish
between autosomal dominant disorders associated with IRF6 and
iCLP is significant because the risk of recurrence for an individual
with iCLP (3%) while much higher than the general population
risk (0.1%) is much lower than the risk of recurrence [1, 12].
Figure 4: Schematic of the dominant autosomal inherited pattern that
IRF6-related syndrome follows.
7. Diagnosis of IRF6-Related Syndrome
The diagnosis of IRF6 syndrome is based on physical characteris-
tics confirmed by molecular genetic testing. If a baby is born with
cleft lip or palate, a diagnosis of VWS should be considered, even
if there are no cleft lip and palate. However, the current method
does not include the IRF6 sequence for such individuals because
the cost is very high and the performance is very low (<0.5). Mo-
lecular genetic testing can be used to confirm a diagnosis based
on physical characteristics. Traditionally, molecular genetic test-
ing of the Sanger method has been used to sequence each of the
9 IRF6 exons. For VWS, more mutations were detected in exons
3, 4, 7 and 9, suggesting a two-tier method for optimal screen-
ing. For PPS, almost all mutations were detected in exons 3, 4,
and 9, and a rationale for a two-tier screening method is provided.
In addition, mutations in MCS9.7 were observed in a family with
VWS. MCS9.7 is a 600 bp sequence that is 9.7 KB upstream of
the IRF6 gene. Studies have shown that MCS9.7 is an amplifying
element, a DNA sequence that acts as a regulatory key to the pro-
duction of IRF6 gene products. Mutations detected in this VWS
family reduce MCS9.7 enhancer activity, suggesting that it may
be the cause of the phenotype in infected individuals. Thus, recent
molecular genetic testing protocols include the MCS9.7 region.
To date, approximately 70% of people with VWS have detectable
mutations in the IRF6 gene. Approximately 97% of people with
PPS have detectable mutations in the IRF6 gene [1, 13].
If the suspected diagnosis of IRF6-related disorder is not molecu-
larly confirmed, there are at least two hypotheses for the inability
to detect all mutations. First, traditional methods for molecular
genetic testing do not screen the entire IRF6 and surrounding re-
gion for mutations in potential regulatory sequences. In support
of this hypothesis, a highly penetrating mutation in the MCS9.7
amplifier of IRF6 was detected in a family with VWS. Second,
mutations in other genes may be IRF6-related phenotypes in some
families. This includes 5% of VWS families that have mutations in
the VWS2 locus in GRHL3 and 2-3% of PPS cases with mutations
in RIPK4 or other genes associated with this syndrome (e.g., SFN
and IKKA). Over time, molecular genetic plates are becoming
next-generation sequencing platforms that allow the sequencing
of whole organisms (all exons in the genome) and whole genomes.
These platforms provide a more complete evaluation of the IRF6
gene and regulatory elements in order to detect any mutations in
the IRF6 syndrome [1, 14].
If the diagnosis of IRF6 syndrome is confirmed, the affected per-
son should have a thorough physical examination to determine if
they have any symptoms of the disorder. For example, the pres-
ence of an abnormality in the lower lip or the presence of a pyra-
midal skin fold on the toenail [1, 15].
If an IRF6 gene mutation is detected, prenatal diagnosis and pre-
implantation genetic diagnosis are available for IRF6 syndrome.
Molecular genetic testing for IRF6 gene mutations can be per-
formed on amniocentesis-induced embryonic cells at 18-16 weeks
of gestation or placental aberrations at 12-12 weeks of gestation.
Pre-implantation genetic diagnosis involves in vitro fertilization
and testing for gene mutations in blastocyst-derived cells. Only
embryos that do not have mutations are implanted [1, 16].
8. Treatment Routes for IRF6-Related Syndrome
Genetic counseling is an important intervention for sufferers and
their families. The risk of recurrence for IRF6-related disorders is
up to 50%, as expected for autosomal dominant inheritance with
high permeability. In addition, a specific set of mutations in the
IRF6 gene (unpleasant mutations that alter amino acids predicted
to interact directly with DNA) are associated with PPS, but are
not identified. In other words, people with VWS who have one
of these PPS-related mutations are potentially at risk of having a
child with a more severe PPS phenotype. Conversely, people with
PPS can have a child with a low-intensity VWS phenotype. At this
time, the factors that modify the phenotype in both directions are
clinicsofoncology.com 5
Volume 6 Issue 4 -2022 Review Article
unknown. Thus, while the risk of having a child with IRF6 syn-
drome is predictable, the severity of the phenotype for children at
risk is unpredictable [1, 17].
Cleft lip and palate are treated with surgery and orthodontics. Peo-
ple with cleft palate usually need speech therapy and hearing tests.
Lip pits can be surgically cut for cosmetic or lip function reasons
[1, 17].
Treatment for PPS is specific to the symptoms that are specific to
each individual. Treatment may require the coordinated efforts of
a team of specialists, including pediatricians; Plastic, orthopedic
and maxillofacial surgeons, speech pathologists; And specialists
who treat the ear, nose and throat (ENT specialists) may need reg-
ular and comprehensive planning to diagnose and treat the affected
child [1, 18].
Dark skin on the back of the legs (papillary) may be removed sur-
gically. Corrective surgery should be performed as soon as possi-
ble because the skin networks may limit the injured person's ability
to stretch their legs and inhibit normal gait. In many cases, how-
ever, surgery can be complicated because it can block nerves (for
example, the sciatic nerve and its branches) and blood vessels that
run down through the legs (vascular bundles). Is located in the skin
tissue. In these cases, surgeons must remove the nerves and blood
vessels from the extra skin and try to place them in their natural
place inside the legs [1, 19].
The extra skin network between the legs may also be surgically re-
moved, as it may limit a person's ability to open and close the legs
and move the legs independently, interfering with normal walking.
Swelling or fusion of one or more fingers or toes (syndactyly) may
also be corrected with surgery [1, 19].
Abnormal fibrous fibers of the mouth (oral syncytia), such as those
that connect the jaws (syngathia) or the gums (synechiae gums)
and abnormal fibrous tissue that connects the edges of the eyelids
(ankyloblepharon phylliform) It may also be corrected with sur-
gery [1, 20].
Surgery may also be performed to correct genital abnormalities
that may be associated with PPS but lead to infertility. In women,
plastic surgery may help regenerate the vagina and related struc-
tures (big lip, clitoris). In men, surgery can be performed to trans-
fer the undescended testicles to the scrotum and attach them to
prevent them from contracting (archipexia). Plastic surgery may
also be performed to correct the abnormal division of the scrotum.
Treatment with an endocrinologist may be necessary to remove
any small penis (micropenis) that may be present [1, 21].
Movement support (dynamic splint) or surgery may be used to
treat joint contractions. Physiotherapy is also useful for children
with joint contractions [1, 22].
A team approach for infants with the disorder may be helpful and
may include special social support, speech therapy, physiotherapy
and other medical services. Other treatments are symptomatic and
supportive. All babies born with cleft lip and palate are best moni-
tored by a cleft or skull and face medical team [1, 22].
9. Discussion and Conclusion
People with VWS are at the lowest end of the spectrum. They can
have cleft lip or palate or cleft palate or a combination of these
abnormalities. People with PPS usually have cleft lip, cleft lip, or
cleft palate, with additional skin and limb abnormalities, includ-
ing dark skin on the back of both feet (papillary) and between the
legs (between the veins), deformity, or abnormalities of the device.
Genital warts are swollen or swollen fingers or toes (syndactyly),
maxillary and mandibular adhesions (intraoral adhesions), and up-
per and lower eyelids (ankylobulpharon). Van der Woude 2 Syn-
drome (VWS2) is an autosomal dominant cleft palate disorder that
is almost identical to VWS. They differ in two ways. First, the phe-
notypic spectrum of VWS2 is the same as VWS. Therefore, it is
impossible to distinguish an individual case of VWS from VWS2
based on clinical criteria alone. However, people with VWS2 are
more prone to cleft palate and less likely to develop cleft lip and
palate. Genetic counseling is an important intervention for suf-
ferers and their families. The risk of recurrence for IRF6-related
disorders is up to 50%, as expected for autosomal dominant inher-
itance with high permeability. Treatment may require the coordi-
nated efforts of a team of specialists, including pediatricians; Plas-
tic, orthopedic and maxillofacial surgeons, speech pathologists;
And specialists who treat the ear, nose and throat (ENT specialists)
may need regular and comprehensive planning to diagnose and
treat the affected child. Surgery may also be performed to correct
genital abnormalities that may be associated with PPS but lead to
infertility. In women, plastic surgery may help regenerate the vagi-
na and related structures (big lip, clitoris). In men, surgery can be
performed to transfer the undescended testicles to the scrotum and
attach them to prevent them from contracting (archipexia) [1-22].
References
1.	 Asadi S. Pathology in Medical Genetics Book, Vol 18, Amidi Publi-
cations Iran 2021.
2.	 Rincic M, Rados M, Krsnik Z, et al. Complex intrachromosomal re-
arrangement in 1q leading to 1q32.2 microdeletion: a potential role
of SRGAP2 in the gyrification of cerebral cortex. Mol Cytogenet.
2016; 9: 19.
3.	 Mangold E, Bohmer AC, Ishorst N, et al. Sequencing the GRHL3
Coding Region Reveals Rare Truncating Mutations and a Common
Susceptibility Variant for Nonsyndromic Cleft. Am J Hum Genet.
2016; 98: 755-62.
4.	 Ikwa MQ, Huynh J, Reynolds EC, Hamilton JA, Scholz GM. Dis-
ease-associated mutations in IRF6 and RIPK4 dysregulate their sig-
nalling functions. Cell Signal. 2015; 27(7): 1509-16.
5.	 Leslie EJ1, O’Sullivan J, Cunningham ML, Singh A, Goudy SL,
Ababneh F, et al. Expanding the genetic and phenotypic spectrum of
popliteal pterygium disorders. Am J Med Genet A. 2015; 167A(4):
545-52.
clinicsofoncology.com 6
Volume 6 Issue 4 -2022 Review Article
6.	 Fakhouri, W, Rahimov F, Attanasio C, et al. An etiologic regulatory
mutation in IRF6 with loss- and gain-of-function effects. Hum Mol
Genet. 2014; 23: 2711-20.
7.	 Peyrard-Janvid, M, Leslie EJ, Kousa YA, et al. Dominant mutations
in GRHL3 cause Van der Woude syndrome and disrupt periderm de-
velopment. Am J Hum Genet. 2014; 94: 23-32.
8.	 Leslie EJ, Mancuso JL, Schutte BC, et al. Search for genetic mod-
ifiers of IRF6 and genotype-phenotype correlations in Van der
Woude and popliteal pterygium syndromes. Am J Med Genet. 2013;
161A(10): 2535-44.
9.	 Tan E-C, Lim ECP, Lee S-T. De novo 2.3 Mb microdeletion of
1q32.2 involving the Van der Woude Syndrome locus. Mol Cytoge-
net. 2013; 6: 31-36.
10.	 Mitchell K, O’Sullivan J, Missero C, et al. Exome sequence identifies
RIPK4 as the Bartsocas-Papas syndrome locus. Am J Hum Genet.
2012; 90(1): 69-75.
11.	 Kalay E, Sezgin O, Chellappa V, dt al. Mutations in RIPK4 cause
the autosomal-recessive form of popliteal pterygium syndrome. Am
J Hum Genet. 2012; 90(1): 76-85.
12.	 Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA. De novo
interstitial deletion of 1q32.2-q32.3 including the entire IRF6 gene
in a patient with oral cleft and other dysmorphic features. Cyogenet
Genome Res. 2011; 134(2): 83-87.
13.	 Desmyter L, Ghassibe M, Revencu N, et al. IRF6 Screening of Syn-
dromic and a priori Non-Syndromic Cleft Lip and Palate Patients:
Identification of a New Type of Minor VWS Sign. Mol Syndromol.
2010; 1(2): 67-74.
14.	 Jones JLP, Canady JW, Brookes JT, et al. Wound Complications after
cleft repair in children with Van der Woude syndrome. J Craniofac
Surg. 2010; 21: 1350-3.
15.	 de Lima RL, Hoper SA, Ghassibe M, et al. Prevalence and nonran-
dom distribution of exonic mutations in interferon regulatory factor
6 in 307 families with Van der Woude syndrome and 37 families with
popliteal pterygium syndrome. Genet Med. 2009; 11(4): 241-7.
16.	 Houweling AC, Gille JJP, Baart JA, van Hagen JM, Lachmeijer AM.
Variable phenotypic manifestation of IRF6 mutations in the Van der
Woude syndrome and popliteal pterygium syndrome: implications
for genetic counseling. Clin Dysmorphol. 2009; 18: 225-7.
17.	 Yeetong P, Mahatumarat C, Siriwan P, Rojvachiranonda N, Suphap-
eetiporn K, Shotelersuk V. Three novel mutations of the IRF6 gene
with one associated with an unusual feature in Van der Woude syn-
drome. Am J Med Genet A. 2009; 149A: 2489-92.
18.	 Rahimov F, Visel A, Pennacchio LA, et al. Disruption of a transcrip-
tion factor AP-2a binding site in an IRF6 enhancer is commonly as-
sociated with nonsyndromic cleft lip and palate. Nat Genet. 2008;
40: 1341-7.
19.	 Schutte BC, Saal HM, Goudy S, et al. IRF6-Related Disorders. 2003.
20.	 Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins
University. Van Der Woude Syndrome 1; VWS1. Entry No: 119300.
Last Update 2015.
21.	 Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins
University. Popliteal Pterygium Syndrome; PPS. Entry No: 119500.
22.	 Online Mendelian Inheritance in Man (OMIM). The Johns Hop-
kins University. Interferon Regulatory Factor 6; IRF6 . Entry No:
607199.

More Related Content

Similar to IMG_46767.pdf

Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
Abu-Hussein Muhamad
 

Similar to IMG_46767.pdf (20)

IOSR Journal of Pharmacy (IOSRPHR)
IOSR Journal of Pharmacy (IOSRPHR)IOSR Journal of Pharmacy (IOSRPHR)
IOSR Journal of Pharmacy (IOSRPHR)
 
D/D of white lesions- journal club
D/D of white lesions- journal clubD/D of white lesions- journal club
D/D of white lesions- journal club
 
Cleft lip and palate/prosthodontic courses
Cleft lip and palate/prosthodontic coursesCleft lip and palate/prosthodontic courses
Cleft lip and palate/prosthodontic courses
 
aniridia.pdf
aniridia.pdfaniridia.pdf
aniridia.pdf
 
Phenotypic analysis of a case of “3MC syndrome” with review of literature
Phenotypic analysis of a case of “3MC syndrome” with review of literaturePhenotypic analysis of a case of “3MC syndrome” with review of literature
Phenotypic analysis of a case of “3MC syndrome” with review of literature
 
Cleft lip and palate
Cleft lip and palateCleft lip and palate
Cleft lip and palate
 
Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
Prevalence of Tooth Agenesis in Orthodontic Patients at Arab Population in Is...
 
Cleft lip and palate/ dental crown & bridge courses
Cleft lip and palate/ dental crown & bridge coursesCleft lip and palate/ dental crown & bridge courses
Cleft lip and palate/ dental crown & bridge courses
 
Role of Pediatric Dentist - Orthodontic In Cleft Lip and Cleft Palate Patients
Role of Pediatric Dentist - Orthodontic In Cleft Lip and Cleft Palate PatientsRole of Pediatric Dentist - Orthodontic In Cleft Lip and Cleft Palate Patients
Role of Pediatric Dentist - Orthodontic In Cleft Lip and Cleft Palate Patients
 
Fordyce Spots
Fordyce SpotsFordyce Spots
Fordyce Spots
 
CLEFT LIP & PALATE
CLEFT LIP & PALATECLEFT LIP & PALATE
CLEFT LIP & PALATE
 
Cleft lip
Cleft lipCleft lip
Cleft lip
 
cleft lip and palate
cleft lip and palatecleft lip and palate
cleft lip and palate
 
I0141134143
I0141134143I0141134143
I0141134143
 
Role of pediatric dentist orthodontic in cleft lip and cleft palate patients
Role of pediatric dentist   orthodontic in cleft lip and cleft palate patients Role of pediatric dentist   orthodontic in cleft lip and cleft palate patients
Role of pediatric dentist orthodontic in cleft lip and cleft palate patients
 
Aarskog syndrome
Aarskog syndromeAarskog syndrome
Aarskog syndrome
 
Management of cleft lip and palate 1. /certified fixed orthodontic courses ...
Management of cleft lip and palate 1.   /certified fixed orthodontic courses ...Management of cleft lip and palate 1.   /certified fixed orthodontic courses ...
Management of cleft lip and palate 1. /certified fixed orthodontic courses ...
 
2 CLEFT LIP AND PALATE.pptx
2 CLEFT LIP AND PALATE.pptx2 CLEFT LIP AND PALATE.pptx
2 CLEFT LIP AND PALATE.pptx
 
Syndromes /certified fixed orthodontic courses by Indian dental academy
Syndromes /certified fixed orthodontic courses by Indian dental academy Syndromes /certified fixed orthodontic courses by Indian dental academy
Syndromes /certified fixed orthodontic courses by Indian dental academy
 
management of impacted teeth
management of impacted teethmanagement of impacted teeth
management of impacted teeth
 

More from EditorSara

More from EditorSara (20)

Pancreatic Adenocarcinoma with Isolated Venous Involvement: Is Neoadjuvant Tr...
Pancreatic Adenocarcinoma with Isolated Venous Involvement: Is Neoadjuvant Tr...Pancreatic Adenocarcinoma with Isolated Venous Involvement: Is Neoadjuvant Tr...
Pancreatic Adenocarcinoma with Isolated Venous Involvement: Is Neoadjuvant Tr...
 
Racial Differences in Accepting Pegfilgrastim Onpro Kit (On-Body Injector) Us...
Racial Differences in Accepting Pegfilgrastim Onpro Kit (On-Body Injector) Us...Racial Differences in Accepting Pegfilgrastim Onpro Kit (On-Body Injector) Us...
Racial Differences in Accepting Pegfilgrastim Onpro Kit (On-Body Injector) Us...
 
APL:Retinoic Acid and Retinoid Pharmacology, a Breakthrough Today
APL:Retinoic Acid and Retinoid Pharmacology, a Breakthrough TodayAPL:Retinoic Acid and Retinoid Pharmacology, a Breakthrough Today
APL:Retinoic Acid and Retinoid Pharmacology, a Breakthrough Today
 
Novel Therapies in Hairy Cell Leukemia
Novel Therapies in Hairy Cell LeukemiaNovel Therapies in Hairy Cell Leukemia
Novel Therapies in Hairy Cell Leukemia
 
STAT-6 In Hodgkin Lymphoma Pathobiology and Treatment-Review of the Literature
STAT-6 In Hodgkin Lymphoma Pathobiology and Treatment-Review of the LiteratureSTAT-6 In Hodgkin Lymphoma Pathobiology and Treatment-Review of the Literature
STAT-6 In Hodgkin Lymphoma Pathobiology and Treatment-Review of the Literature
 
Lipocalin 2 as a Potential Diagnostic and/or Prognostic Biomarker in Prostate...
Lipocalin 2 as a Potential Diagnostic and/or Prognostic Biomarker in Prostate...Lipocalin 2 as a Potential Diagnostic and/or Prognostic Biomarker in Prostate...
Lipocalin 2 as a Potential Diagnostic and/or Prognostic Biomarker in Prostate...
 
Breast Cancer Awareness
Breast Cancer AwarenessBreast Cancer Awareness
Breast Cancer Awareness
 
Peripheral T-Cell Lymphomas: Progress in Treatment
Peripheral T-Cell Lymphomas: Progress in TreatmentPeripheral T-Cell Lymphomas: Progress in Treatment
Peripheral T-Cell Lymphomas: Progress in Treatment
 
Circulatingtumordna (Ctdna) in Prostate Cancer: Current Insights and New Pers...
Circulatingtumordna (Ctdna) in Prostate Cancer: Current Insights and New Pers...Circulatingtumordna (Ctdna) in Prostate Cancer: Current Insights and New Pers...
Circulatingtumordna (Ctdna) in Prostate Cancer: Current Insights and New Pers...
 
The Role of Immunity in Chemotherapy-Resistant Patient with Pembrolizumab: A ...
The Role of Immunity in Chemotherapy-Resistant Patient with Pembrolizumab: A ...The Role of Immunity in Chemotherapy-Resistant Patient with Pembrolizumab: A ...
The Role of Immunity in Chemotherapy-Resistant Patient with Pembrolizumab: A ...
 
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...
Deadenylase Expression in Small Cell Lung Cancer Related To Clinical Characte...
 
Stereotactic Radiation Therapy of Lung Cancers and Subsequent Parenchymal Alt...
Stereotactic Radiation Therapy of Lung Cancers and Subsequent Parenchymal Alt...Stereotactic Radiation Therapy of Lung Cancers and Subsequent Parenchymal Alt...
Stereotactic Radiation Therapy of Lung Cancers and Subsequent Parenchymal Alt...
 
Higher Rates of Helicobacter Pylori Infection and Gastric Intestinal Metaplas...
Higher Rates of Helicobacter Pylori Infection and Gastric Intestinal Metaplas...Higher Rates of Helicobacter Pylori Infection and Gastric Intestinal Metaplas...
Higher Rates of Helicobacter Pylori Infection and Gastric Intestinal Metaplas...
 
Critical Role of PET-Scan in Unravelling the Dual Pathology- Review of Litera...
Critical Role of PET-Scan in Unravelling the Dual Pathology- Review of Litera...Critical Role of PET-Scan in Unravelling the Dual Pathology- Review of Litera...
Critical Role of PET-Scan in Unravelling the Dual Pathology- Review of Litera...
 
Myelomastocytic Leukemia
Myelomastocytic LeukemiaMyelomastocytic Leukemia
Myelomastocytic Leukemia
 
Cavernous Sinus Metastasis of Leiomyosarcoma with Orbital Extension along the...
Cavernous Sinus Metastasis of Leiomyosarcoma with Orbital Extension along the...Cavernous Sinus Metastasis of Leiomyosarcoma with Orbital Extension along the...
Cavernous Sinus Metastasis of Leiomyosarcoma with Orbital Extension along the...
 
Analysis of Treatment Option for Synchronous Liver Metastases and Colon Recta...
Analysis of Treatment Option for Synchronous Liver Metastases and Colon Recta...Analysis of Treatment Option for Synchronous Liver Metastases and Colon Recta...
Analysis of Treatment Option for Synchronous Liver Metastases and Colon Recta...
 
An Adrenal Mass in a Patient with Lynch Syndrome
An Adrenal Mass in a Patient with Lynch SyndromeAn Adrenal Mass in a Patient with Lynch Syndrome
An Adrenal Mass in a Patient with Lynch Syndrome
 
Leiomyosarcoma of Stomach
Leiomyosarcoma of StomachLeiomyosarcoma of Stomach
Leiomyosarcoma of Stomach
 
Principles of Cancer Screening
Principles of Cancer ScreeningPrinciples of Cancer Screening
Principles of Cancer Screening
 

Recently uploaded

Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose AcademicsConnective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
MedicoseAcademics
 
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose AcademicsHistology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
MedicoseAcademics
 

Recently uploaded (20)

^In Pietermaritzburg Hager Werken Embalming +27789155305 Compound Powder in ...
^In Pietermaritzburg  Hager Werken Embalming +27789155305 Compound Powder in ...^In Pietermaritzburg  Hager Werken Embalming +27789155305 Compound Powder in ...
^In Pietermaritzburg Hager Werken Embalming +27789155305 Compound Powder in ...
 
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose AcademicsConnective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
Connective Tissue II - Dr Muhammad Ali Rabbani - Medicose Academics
 
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.GawadHemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
Hemodialysis: Chapter 1, Physiological Principles of Hemodialysis - Dr.Gawad
 
Stereochemistry & Asymmetric Synthesis.pptx
Stereochemistry & Asymmetric Synthesis.pptxStereochemistry & Asymmetric Synthesis.pptx
Stereochemistry & Asymmetric Synthesis.pptx
 
Overview on the Automatic pill identifier
Overview on the Automatic pill identifierOverview on the Automatic pill identifier
Overview on the Automatic pill identifier
 
Hi Fi * Surat ℂall Girls Surat Dumas Road 8527049040 WhatsApp AnyTime Best Su...
Hi Fi * Surat ℂall Girls Surat Dumas Road 8527049040 WhatsApp AnyTime Best Su...Hi Fi * Surat ℂall Girls Surat Dumas Road 8527049040 WhatsApp AnyTime Best Su...
Hi Fi * Surat ℂall Girls Surat Dumas Road 8527049040 WhatsApp AnyTime Best Su...
 
ROSE CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
ROSE  CASE SPINAL SBRT BY DR KANHU CHARAN PATROROSE  CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
ROSE CASE SPINAL SBRT BY DR KANHU CHARAN PATRO
 
Video capsule endoscopy (VCE ) in children
Video capsule endoscopy (VCE ) in childrenVideo capsule endoscopy (VCE ) in children
Video capsule endoscopy (VCE ) in children
 
SEMESTER-V CHILD HEALTH NURSING-UNIT-1-INTRODUCTION.pdf
SEMESTER-V CHILD HEALTH NURSING-UNIT-1-INTRODUCTION.pdfSEMESTER-V CHILD HEALTH NURSING-UNIT-1-INTRODUCTION.pdf
SEMESTER-V CHILD HEALTH NURSING-UNIT-1-INTRODUCTION.pdf
 
Quality control tests of suppository ...
Quality control tests  of suppository ...Quality control tests  of suppository ...
Quality control tests of suppository ...
 
Drug development life cycle indepth overview.pptx
Drug development life cycle indepth overview.pptxDrug development life cycle indepth overview.pptx
Drug development life cycle indepth overview.pptx
 
TEST BANK For Huether and McCance's Understanding Pathophysiology, Canadian 2...
TEST BANK For Huether and McCance's Understanding Pathophysiology, Canadian 2...TEST BANK For Huether and McCance's Understanding Pathophysiology, Canadian 2...
TEST BANK For Huether and McCance's Understanding Pathophysiology, Canadian 2...
 
CONGENITAL HYPERTROPHIC PYLORIC STENOSIS by Dr M.KARTHIK EMMANUEL
CONGENITAL HYPERTROPHIC PYLORIC STENOSIS  by Dr M.KARTHIK EMMANUELCONGENITAL HYPERTROPHIC PYLORIC STENOSIS  by Dr M.KARTHIK EMMANUEL
CONGENITAL HYPERTROPHIC PYLORIC STENOSIS by Dr M.KARTHIK EMMANUEL
 
Gallbladder Double-Diverticular: A Case Report المرارة مزدوجة التج: تقرير حالة
Gallbladder Double-Diverticular: A Case Report  المرارة مزدوجة التج: تقرير حالةGallbladder Double-Diverticular: A Case Report  المرارة مزدوجة التج: تقرير حالة
Gallbladder Double-Diverticular: A Case Report المرارة مزدوجة التج: تقرير حالة
 
Tips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES examTips and tricks to pass the cardiovascular station for PACES exam
Tips and tricks to pass the cardiovascular station for PACES exam
 
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptxANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
ANAPHYLAXIS BY DR.SOHAN BISWAS,MBBS,DNB(INTERNAL MEDICINE) RESIDENT.pptx
 
JOURNAL CLUB PRESENTATION TEMPLATE DOCUMENT
JOURNAL CLUB PRESENTATION TEMPLATE DOCUMENTJOURNAL CLUB PRESENTATION TEMPLATE DOCUMENT
JOURNAL CLUB PRESENTATION TEMPLATE DOCUMENT
 
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose AcademicsHistology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
Histology of Epithelium - Dr Muhammad Ali Rabbani - Medicose Academics
 
The Clean Living Project Episode 24 - Subconscious
The Clean Living Project Episode 24 - SubconsciousThe Clean Living Project Episode 24 - Subconscious
The Clean Living Project Episode 24 - Subconscious
 
NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019
NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019
NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019
 

IMG_46767.pdf

  • 1. Clinics of Oncology Review Article ISSN: 2640-1037 Volume 6 The Role of Mutations on Gene IRF6 in IRF6 Related Syndrome Asadi S* and Fayyazian E Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, USA * Corresponding author: Shahin Asadi, Medical Genetics-Harvard University, Division of Medical Genetics and Molecular Optogenetic Research, Harvard University, Boston Children’s Hospital, USA, Tel: +1-857-600-7921; E-mail: shahin.asadi1985@gmail.com Received: 25 Mar 2022 Accepted: 14 Apr 2022 Published: 20 Apr 2022 J Short Name: COO Copyright: ©2022 Asadi S. This is an open access article distribut- ed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. Citation: Asadi S, The Role of Mutations on Gene IRF6 in IRF6 Related Syndrome. Clin Onco. 2022; 6(4): 1-6 Keywords: IRF6 Related Syndrome; IRF6 gene; Genetic Mutation; Autosomal Dominant clinicsofoncology.com 1 1. Abstract IRF6-related syndrome is a group of cleft lip and palate disorders including Van der Wood Syndrome (VWS) and Popliteal Pteryg- ium Syndrome (PPS). People with VWS are at the lowest end of the spectrum. They can have cleft lip or palate or cleft palate or a combination of these abnormalities. People with PPS usually have cleft lip, cleft lip, or cleft palate, with additional skin and limb abnormalities, including dark skin on the back of both feet (papil- lary) and between the legs (between the veins), deformity, or ab- normalities of the device. Mutations in the interferon-6 regulatory factor (IRF6) gene, located on the long arm of chromosome 1 at 1q32.2, have been linked to IRF6 syndrome. 2. Generalities of IRF6 Related Syndrome IRF6-related syndrome is a group of cleft lip and palate disorders including Van der Wood Syndrome (VWS) and Popliteal Pterygi- um Syndrome (PPS). People with VWS are at the lowest end of the spectrum. They can have cleft lip or palate or cleft palate or a com- bination of these abnormalities. People with PPS usually have cleft lip, cleft lip, or cleft palate, with additional skin and limb abnor- malities, including dark skin on the back of both feet (papillary) and between the legs (between the veins), deformity, or abnormal- ities of the device. Genital warts are swollen or swollen fingers or toes (syndactyly), maxillary and mandibular adhesions (intraoral adhesions), and upper and lower eyelids (ankylobulpharon). The conical crease of the skin on the thumb nail is one of the definite findings in PPS [1, 2] Figure 1. Figure 1: Images of patients with IRF6-related syndrome.
  • 2. clinicsofoncology.com 2 Volume 6 Issue 4 -2022 Review Article 3. Clinical Signs and Symptoms of IRF6 Related Syn- drome The symptoms of IRF6 syndrome vary greatly from person to per- son. Some people with the disease may have mild clinical symp- toms, while others may have a more severe form of the disease (variable expression) [1, 3]. People with VWS can have lip sores, cleft lip or cleft palate alone, or a combination of these abnormalities. Lip sores are usually formed as a pair of dimples on the lower lip. In less common cases in VWS, a person may develop lip cone, lip pit, partial missing teeth, incomplete cleft palate, and limited tongue movement (an- gioglossia) [1, 3]. People with PPS typically have a thick network of skin on the back of both feet that extends from the hip (isial tuberosity) to the heel. In some patients, this abnormal thick skin network may be present on one foot (unilateral). Because full leg stretching may be limited or the legs may rotate abnormally (in or out), this may make it difficult to walk [1, 3]. In most patients, dark skin may also be present between the legs in the upper thigh area (intermittent fingernail). Some joints may become permanently bent (joint contraction), especially the knees. Babies with PPS may also have swelling or swelling of one or more toes and / or toes (syndactyly), and some children may have a triangular (pyramidal) crease in the toenails, especially the big toe. To cover. There may also be dimples on the skin of the elbows and knees [1, 4]. PPS may also be associated with facial abnormalities, including incomplete closure of the roof of the mouth (cleft palate) or upper lip (cleft lip) in most infants. Children with cleft palate may also be prone to recurrent middle ear infections (otitis media). Children with PPS may have abnormal bands of fibrous tissue on the gums (gums) or between the upper (maxillary) and lower (mandible) bones of the jaws (syngenatia), which can cause problems with opening the mouth. In addition, some people with the disease may have abnormal fibrous tissue that connects the edges of the eye- lids (filiform ankylosing spondylitis) and may show limited tongue movement (angioglossia). Many of these facial abnormalities, es- pecially cleft palate, can contribute to eating problems, breathing problems, or speech disorders. [1, 4] Figure 2. People with PPS may also have genital abnormalities. In some women, two long folds of skin on either side of the vaginal open- ing (large lips) or uterus may not have grown (hypoplastic). In some patients, the clitoris may not grow enough. In some men with this disorder, the scrotum may split abnormally (bifid). In rare cas- es, the scrotum may be small (hypoplastic) or absent, leaving the testicles in the abdomen (undescended testicles). In approximately 40% of men with testicular disorder, the testicles may also not be able to descend from the abdomen to the scrotum (cryptorchidism) [1, 5]. In severe cases of PPS, abnormalities of the hands and feet (limbs) may be present, including the absence (agenesis) or insufficient growth (hypoplasia) of the fingers or toes, abnormal bending of the outside (valgus), or Bending inside (varus) of the foot, or de- formity (dysplasia) of the nails. It is worth noting that growth and intelligence are usually normal in IRF6 syndrome [1, 5]. Figure 2: Images of disorders associated with IRF6-related syndrome.
  • 3. clinicsofoncology.com 3 Volume 6 Issue 4 -2022 Review Article 4. Etiology of IRF6-Related Syndrome Mutations in the interferon-6 regulatory factor (IRF6) gene, locat- ed on the long arm of chromosome 1 at 1q32.2, have been linked to IRF6 syndrome [1, 6]. IRF6-related syndrome follows an autosomal dominant inheri- tance pattern. Therefore, a copy of the IRF6 mutant gene (either parent) is required to cause the syndrome, and the chance of hav- ing a child with the autosomal dominant syndrome is 50% for each possible pregnancy [1, 6] Figure 3. Figure 3: Schematic of chromosome 1 where the IRF6 gene is located in the long arm of this chromosome as 1q32.2. 5. Frequency of IRF6-Related Syndrome VWS is the most common cause of a single cleft lip and palate gene. The prevalence of this syndrome in Europe and Asia is es- timated at 1 in 35,000 to 1 in 100,000. The prevalence of PPS is approximately 1 in 300,000 [1, 7]. 6. IRF6-Related Syndrome Disorders The symptoms of the following disorders may be similar to those of IRF6 syndrome. A comparison may be useful for the differential diagnosis of this syndrome: Van der Woude 2 Syndrome (VWS2) is an autosomal dominant cleft palate disorder that is almost identical to VWS. They differ in two ways. First, the phenotypic spectrum of VWS2 is the same as VWS. Therefore, it is impossible to distinguish an individual case of VWS from VWS2 based on clinical criteria alone. However, people with VWS2 are more prone to cleft palate and less likely to develop cleft lip and palate. Second, VWS2 is a GRHL3-related disorder because it is caused by a mutation in the gene encoding the GRHL3 transcription factor. While 70% of VWS cases are due to mutations in IRF6, 5% of VWS cases are due to mutations in GRHL3 [1, 8] Figure 4. Kabuki Syndrome, also known as Nikawa-Kuruki Syndrome, is a rare genetic disorder characterized by mental retardation, short stature, unusual facial features (reminiscent of Kabuki makeup in Japanese theater), skeletal abnormalities, and prominent skin pat- terns on the fingers. Hands, toes, and palms are marked. Disorders of the palms of the hands and soles of the feet, cleft lip and palate are relatively common findings in Kabuki syndrome. In addition, cases of Kabuki syndrome, cleft palate, and cleft lip have been reported, as seen in IRF6 syndrome [1, 8]. Hirschsprung's Disease (HSCR) is characterized by aganglonic megacolon. However, it has been reported that the cases include cleft palate and in one case, cleft palate and lip cavity [1, 9]. Oro-Facio-Digital syndrome (OFD) is a predominantly X-related disorder that is fatal in men. Affected women have a highly vari- able phenotype characterized by abnormalities of the mouth, face, and fingers, and can include kidney and brain abnormalities. Oral abnormalities include an arched palate or cleft palate or cleft lip. In one reported case, an infected person had an internal pit in the lower lip [1, 9]. Branchio-Oculo-Facial Syndrome (BOFS) is a very rare genetic disease that is evident from birth (congenital). This disorder may be characterized by low birth weight. An abnormal pit, seen as a cleft lip, or a tumor-like skin abnormality (hemangiomatous or atrophic skin lesion) occur behind both ears (postauricular area) in this syndrome. Specific abnormalities in the head and face (skull and face); Eye abnormalities; Premature graying of the scalp during adolescence or other abnormalities also occur in this syn- drome. Some people with BOFS have cleft lip or cleft palate, while others may have unusually wide, prominent upper lip protrusion (filtrum) that resembles surgery-repaired cleft lip. Additional skull and facial abnormalities may include a large, dysplastic nose and defective ears. In people with this disorder, characteristic eye ab- normalities may include abnormally small eyes (microphthalmia). Blurring of the lenses of the eyes (cataracts); Congenital ocular stenosis (congenital strabismus); Wide distance of eyes from each other (hyperthermia); Or the absence of tissue (coloboma) from the colored part of the eye (iris), gives the iris an appearance like a "keyhole". BOFS is inherited as an autosomal dominant genetic trait [1, 10]. Bartsocas-Papas syndrome is a disorder that can include cleft lip or palate and dark skin similar to that seen in PPS. This is a more severe phenotype and in some cases, but not all, is fatal. This is an autosomal recessive inherited pattern and has been shown to have mutations in the RIPK4 gene, at least in some cases. In addition, a recent molecular study showed that RIPK4 activates IRF6 func- tion [1, 11]. Isolated cleft lip and palate (iCLP), also called non-syndrom- ic cleft lip and palate, is a disorder that involves only the cleft lip and palate and has no other abnormal features of a syndrome. Isolated CLP is special because it is related to IRF6 syndrome in two phenotypic and genotypic ways. This is phenotypically relat- ed because up to 15% of people with VWS do not have dimples. Because these people with VWS only have an oral-facial cleft, their phenotype is the same as that of people with iCLP. In most cases, they were diagnosed with VWS because another affected family member had a lip sore with a cleft lip. Therefore, physi- cians can diagnose these two disorders only by careful analysis of the family tree. Isolated CLP is genotypically related to IRF6 syndrome because common types of DNA in IRF6, although not
  • 4. clinicsofoncology.com 4 Volume 6 Issue 4 -2022 Review Article causing IRF6-related syndrome, can increase the risk of cleft lip and palate. The role of IRF6 mutations in iCLP is less clear due to the phenotypic overlap between iCLP and IRF6-related syn- drome. Data from 2472 families identified rare IRF6 mutations in 0.24-0.44% of apparently iCLP families. The ability to distinguish between autosomal dominant disorders associated with IRF6 and iCLP is significant because the risk of recurrence for an individual with iCLP (3%) while much higher than the general population risk (0.1%) is much lower than the risk of recurrence [1, 12]. Figure 4: Schematic of the dominant autosomal inherited pattern that IRF6-related syndrome follows. 7. Diagnosis of IRF6-Related Syndrome The diagnosis of IRF6 syndrome is based on physical characteris- tics confirmed by molecular genetic testing. If a baby is born with cleft lip or palate, a diagnosis of VWS should be considered, even if there are no cleft lip and palate. However, the current method does not include the IRF6 sequence for such individuals because the cost is very high and the performance is very low (<0.5). Mo- lecular genetic testing can be used to confirm a diagnosis based on physical characteristics. Traditionally, molecular genetic test- ing of the Sanger method has been used to sequence each of the 9 IRF6 exons. For VWS, more mutations were detected in exons 3, 4, 7 and 9, suggesting a two-tier method for optimal screen- ing. For PPS, almost all mutations were detected in exons 3, 4, and 9, and a rationale for a two-tier screening method is provided. In addition, mutations in MCS9.7 were observed in a family with VWS. MCS9.7 is a 600 bp sequence that is 9.7 KB upstream of the IRF6 gene. Studies have shown that MCS9.7 is an amplifying element, a DNA sequence that acts as a regulatory key to the pro- duction of IRF6 gene products. Mutations detected in this VWS family reduce MCS9.7 enhancer activity, suggesting that it may be the cause of the phenotype in infected individuals. Thus, recent molecular genetic testing protocols include the MCS9.7 region. To date, approximately 70% of people with VWS have detectable mutations in the IRF6 gene. Approximately 97% of people with PPS have detectable mutations in the IRF6 gene [1, 13]. If the suspected diagnosis of IRF6-related disorder is not molecu- larly confirmed, there are at least two hypotheses for the inability to detect all mutations. First, traditional methods for molecular genetic testing do not screen the entire IRF6 and surrounding re- gion for mutations in potential regulatory sequences. In support of this hypothesis, a highly penetrating mutation in the MCS9.7 amplifier of IRF6 was detected in a family with VWS. Second, mutations in other genes may be IRF6-related phenotypes in some families. This includes 5% of VWS families that have mutations in the VWS2 locus in GRHL3 and 2-3% of PPS cases with mutations in RIPK4 or other genes associated with this syndrome (e.g., SFN and IKKA). Over time, molecular genetic plates are becoming next-generation sequencing platforms that allow the sequencing of whole organisms (all exons in the genome) and whole genomes. These platforms provide a more complete evaluation of the IRF6 gene and regulatory elements in order to detect any mutations in the IRF6 syndrome [1, 14]. If the diagnosis of IRF6 syndrome is confirmed, the affected per- son should have a thorough physical examination to determine if they have any symptoms of the disorder. For example, the pres- ence of an abnormality in the lower lip or the presence of a pyra- midal skin fold on the toenail [1, 15]. If an IRF6 gene mutation is detected, prenatal diagnosis and pre- implantation genetic diagnosis are available for IRF6 syndrome. Molecular genetic testing for IRF6 gene mutations can be per- formed on amniocentesis-induced embryonic cells at 18-16 weeks of gestation or placental aberrations at 12-12 weeks of gestation. Pre-implantation genetic diagnosis involves in vitro fertilization and testing for gene mutations in blastocyst-derived cells. Only embryos that do not have mutations are implanted [1, 16]. 8. Treatment Routes for IRF6-Related Syndrome Genetic counseling is an important intervention for sufferers and their families. The risk of recurrence for IRF6-related disorders is up to 50%, as expected for autosomal dominant inheritance with high permeability. In addition, a specific set of mutations in the IRF6 gene (unpleasant mutations that alter amino acids predicted to interact directly with DNA) are associated with PPS, but are not identified. In other words, people with VWS who have one of these PPS-related mutations are potentially at risk of having a child with a more severe PPS phenotype. Conversely, people with PPS can have a child with a low-intensity VWS phenotype. At this time, the factors that modify the phenotype in both directions are
  • 5. clinicsofoncology.com 5 Volume 6 Issue 4 -2022 Review Article unknown. Thus, while the risk of having a child with IRF6 syn- drome is predictable, the severity of the phenotype for children at risk is unpredictable [1, 17]. Cleft lip and palate are treated with surgery and orthodontics. Peo- ple with cleft palate usually need speech therapy and hearing tests. Lip pits can be surgically cut for cosmetic or lip function reasons [1, 17]. Treatment for PPS is specific to the symptoms that are specific to each individual. Treatment may require the coordinated efforts of a team of specialists, including pediatricians; Plastic, orthopedic and maxillofacial surgeons, speech pathologists; And specialists who treat the ear, nose and throat (ENT specialists) may need reg- ular and comprehensive planning to diagnose and treat the affected child [1, 18]. Dark skin on the back of the legs (papillary) may be removed sur- gically. Corrective surgery should be performed as soon as possi- ble because the skin networks may limit the injured person's ability to stretch their legs and inhibit normal gait. In many cases, how- ever, surgery can be complicated because it can block nerves (for example, the sciatic nerve and its branches) and blood vessels that run down through the legs (vascular bundles). Is located in the skin tissue. In these cases, surgeons must remove the nerves and blood vessels from the extra skin and try to place them in their natural place inside the legs [1, 19]. The extra skin network between the legs may also be surgically re- moved, as it may limit a person's ability to open and close the legs and move the legs independently, interfering with normal walking. Swelling or fusion of one or more fingers or toes (syndactyly) may also be corrected with surgery [1, 19]. Abnormal fibrous fibers of the mouth (oral syncytia), such as those that connect the jaws (syngathia) or the gums (synechiae gums) and abnormal fibrous tissue that connects the edges of the eyelids (ankyloblepharon phylliform) It may also be corrected with sur- gery [1, 20]. Surgery may also be performed to correct genital abnormalities that may be associated with PPS but lead to infertility. In women, plastic surgery may help regenerate the vagina and related struc- tures (big lip, clitoris). In men, surgery can be performed to trans- fer the undescended testicles to the scrotum and attach them to prevent them from contracting (archipexia). Plastic surgery may also be performed to correct the abnormal division of the scrotum. Treatment with an endocrinologist may be necessary to remove any small penis (micropenis) that may be present [1, 21]. Movement support (dynamic splint) or surgery may be used to treat joint contractions. Physiotherapy is also useful for children with joint contractions [1, 22]. A team approach for infants with the disorder may be helpful and may include special social support, speech therapy, physiotherapy and other medical services. Other treatments are symptomatic and supportive. All babies born with cleft lip and palate are best moni- tored by a cleft or skull and face medical team [1, 22]. 9. Discussion and Conclusion People with VWS are at the lowest end of the spectrum. They can have cleft lip or palate or cleft palate or a combination of these abnormalities. People with PPS usually have cleft lip, cleft lip, or cleft palate, with additional skin and limb abnormalities, includ- ing dark skin on the back of both feet (papillary) and between the legs (between the veins), deformity, or abnormalities of the device. Genital warts are swollen or swollen fingers or toes (syndactyly), maxillary and mandibular adhesions (intraoral adhesions), and up- per and lower eyelids (ankylobulpharon). Van der Woude 2 Syn- drome (VWS2) is an autosomal dominant cleft palate disorder that is almost identical to VWS. They differ in two ways. First, the phe- notypic spectrum of VWS2 is the same as VWS. Therefore, it is impossible to distinguish an individual case of VWS from VWS2 based on clinical criteria alone. However, people with VWS2 are more prone to cleft palate and less likely to develop cleft lip and palate. Genetic counseling is an important intervention for suf- ferers and their families. The risk of recurrence for IRF6-related disorders is up to 50%, as expected for autosomal dominant inher- itance with high permeability. Treatment may require the coordi- nated efforts of a team of specialists, including pediatricians; Plas- tic, orthopedic and maxillofacial surgeons, speech pathologists; And specialists who treat the ear, nose and throat (ENT specialists) may need regular and comprehensive planning to diagnose and treat the affected child. Surgery may also be performed to correct genital abnormalities that may be associated with PPS but lead to infertility. In women, plastic surgery may help regenerate the vagi- na and related structures (big lip, clitoris). In men, surgery can be performed to transfer the undescended testicles to the scrotum and attach them to prevent them from contracting (archipexia) [1-22]. References 1. Asadi S. Pathology in Medical Genetics Book, Vol 18, Amidi Publi- cations Iran 2021. 2. Rincic M, Rados M, Krsnik Z, et al. Complex intrachromosomal re- arrangement in 1q leading to 1q32.2 microdeletion: a potential role of SRGAP2 in the gyrification of cerebral cortex. Mol Cytogenet. 2016; 9: 19. 3. Mangold E, Bohmer AC, Ishorst N, et al. Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft. Am J Hum Genet. 2016; 98: 755-62. 4. Ikwa MQ, Huynh J, Reynolds EC, Hamilton JA, Scholz GM. Dis- ease-associated mutations in IRF6 and RIPK4 dysregulate their sig- nalling functions. Cell Signal. 2015; 27(7): 1509-16. 5. Leslie EJ1, O’Sullivan J, Cunningham ML, Singh A, Goudy SL, Ababneh F, et al. Expanding the genetic and phenotypic spectrum of popliteal pterygium disorders. Am J Med Genet A. 2015; 167A(4): 545-52.
  • 6. clinicsofoncology.com 6 Volume 6 Issue 4 -2022 Review Article 6. Fakhouri, W, Rahimov F, Attanasio C, et al. An etiologic regulatory mutation in IRF6 with loss- and gain-of-function effects. Hum Mol Genet. 2014; 23: 2711-20. 7. Peyrard-Janvid, M, Leslie EJ, Kousa YA, et al. Dominant mutations in GRHL3 cause Van der Woude syndrome and disrupt periderm de- velopment. Am J Hum Genet. 2014; 94: 23-32. 8. Leslie EJ, Mancuso JL, Schutte BC, et al. Search for genetic mod- ifiers of IRF6 and genotype-phenotype correlations in Van der Woude and popliteal pterygium syndromes. Am J Med Genet. 2013; 161A(10): 2535-44. 9. Tan E-C, Lim ECP, Lee S-T. De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus. Mol Cytoge- net. 2013; 6: 31-36. 10. Mitchell K, O’Sullivan J, Missero C, et al. Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus. Am J Hum Genet. 2012; 90(1): 69-75. 11. Kalay E, Sezgin O, Chellappa V, dt al. Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. Am J Hum Genet. 2012; 90(1): 76-85. 12. Salahshourifar I, Halim AS, Sulaiman WA, Zilfalil BA. De novo interstitial deletion of 1q32.2-q32.3 including the entire IRF6 gene in a patient with oral cleft and other dysmorphic features. Cyogenet Genome Res. 2011; 134(2): 83-87. 13. Desmyter L, Ghassibe M, Revencu N, et al. IRF6 Screening of Syn- dromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign. Mol Syndromol. 2010; 1(2): 67-74. 14. Jones JLP, Canady JW, Brookes JT, et al. Wound Complications after cleft repair in children with Van der Woude syndrome. J Craniofac Surg. 2010; 21: 1350-3. 15. de Lima RL, Hoper SA, Ghassibe M, et al. Prevalence and nonran- dom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. Genet Med. 2009; 11(4): 241-7. 16. Houweling AC, Gille JJP, Baart JA, van Hagen JM, Lachmeijer AM. Variable phenotypic manifestation of IRF6 mutations in the Van der Woude syndrome and popliteal pterygium syndrome: implications for genetic counseling. Clin Dysmorphol. 2009; 18: 225-7. 17. Yeetong P, Mahatumarat C, Siriwan P, Rojvachiranonda N, Suphap- eetiporn K, Shotelersuk V. Three novel mutations of the IRF6 gene with one associated with an unusual feature in Van der Woude syn- drome. Am J Med Genet A. 2009; 149A: 2489-92. 18. Rahimov F, Visel A, Pennacchio LA, et al. Disruption of a transcrip- tion factor AP-2a binding site in an IRF6 enhancer is commonly as- sociated with nonsyndromic cleft lip and palate. Nat Genet. 2008; 40: 1341-7. 19. Schutte BC, Saal HM, Goudy S, et al. IRF6-Related Disorders. 2003. 20. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Van Der Woude Syndrome 1; VWS1. Entry No: 119300. Last Update 2015. 21. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Popliteal Pterygium Syndrome; PPS. Entry No: 119500. 22. Online Mendelian Inheritance in Man (OMIM). The Johns Hop- kins University. Interferon Regulatory Factor 6; IRF6 . Entry No: 607199.