Basal cell nevoid carcinoma syndrome: A review

Abstract

Basal cell nevoid carcinoma syndrome (BCNCS) is a rare autosomal dominant genetic syndrome that is predisposed to cancer. It is characterized by the presence of multiple basal cell carcinomas (BCCs) on the skin, as well as numerous maxillary odontogenic keratocyst (QTOs), palmoplantar punctate depressions (pits), skeletal abnormalities, and other developmental defects. The genetic basis of this syndrome lies in causal mutations in the PTCH1 gene, a tumor suppressor gene located on chromosome 9. The present study aimed to review recent literature concerning SCNBC, addressing aspects such as clinical manifestations, diagnostic criteria, genetic etiology, and molecular tests used. A total of 88 articles were included, most of which were clinical cases. Among the clinical manifestations, QTOs were the most frequently mentioned major diagnostic criteria, followed by calcification of the cerebral sickle. Ocular anomalies, on the other hand, were the alterations belonging to the most prevalent minor criteria. A total of 18 clinical cases underwent molecular testing for mutations in the PTCH1 gene. The most used methods were genetic sequencing and the mutations frequently found were frameshift and nonsense mutation, which occurred in exons 2, 3, 6, 8, 11, 12, 18, and 21. Despite the existence of several mutations in the PTCH1 gene that are attributable to the etiology of SCNBC, the performance of diagnostic molecular tests were not performed in many of the studies analyzed, and even those that did not identify a correlation with the patient's phenotype or prognosis, and these are indicated only in some particular cases.

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A look at development
Basal cell nevoid carcinoma syndrome: A review
https://doi.org/10.56238/alookdevelopv1-086
Sandra Aparecida Marinho
PhD. Dental Surgeon. Professor of the Undergraduate
Course in Dentistry of the State University of Paraíba
(UEPB), Campus VIII, Araruna, PB.
ORCID: https://orcid.org/0000-0002-5379-8779
E-mail: san_mar2000@yahoo.com.br
Heglayne Pereira Vital da Silva
PhD. Pharmaceutical. Prof. of the Graduate Program in
Pharmaceutical Sciences, Federal University of Rio
Grande do Norte (UFRN), Specialization in Molecular
Biology, Natal, RN
ORCID: https://orcid.org/0000-0003-0929-6971
ABSTRACT
Basal cell nevoid carcinoma syndrome (BCNCS) is
a rare autosomal dominant genetic syndrome that is
predisposed to cancer. It is characterized by the
presence of multiple basal cell carcinomas (BCCs)
on the skin, as well as numerous maxillary
odontogenic keratocyst (QTOs), palmoplantar
punctate depressions (pits), skeletal abnormalities,
and other developmental defects. The genetic basis
of this syndrome lies in causal mutations in the
PTCH1 gene, a tumor suppressor gene located on
chromosome 9. The present study aimed to review
recent literature concerning SCNBC, addressing
aspects such as clinical manifestations, diagnostic
criteria, genetic etiology, and molecular tests used.
A total of 88 articles were included, most of which
were clinical cases. Among the clinical
manifestations, QTOs were the most frequently
mentioned major diagnostic criteria, followed by
calcification of the cerebral sickle. Ocular
anomalies, on the other hand, were the alterations
belonging to the most prevalent minor criteria. A
total of 18 clinical cases underwent molecular
testing for mutations in the PTCH1 gene. The most
used methods were genetic sequencing and the
mutations frequently found were frameshift and
nonsense mutation, which occurred in exons 2, 3, 6,
8, 11, 12, 18, and 21. Despite the existence of
several mutations in the PTCH1 gene that are
attributable to the etiology of SCNBC, the
performance of diagnostic molecular tests were not
performed in many of the studies analyzed, and
even those that did not identify a correlation with
the patient's phenotype or prognosis, and these are
indicated only in some particular cases.
Keywords: Basal cell nevus syndrome, gorlin
syndrome, odontogenic cysts, basal cell carcinoma.
1 INTRODUCTION
Basal cell nevoid carcinoma syndrome (BSCNC), also known as Gorlin syndrome, Gorlin-
Goltz syndrome, or basal cell nevus syndrome (Online Mendelian Inheritance in Men - OMIM number
109400) is an autosomal dominant neurocutaneous disease characterized by developmental
abnormalities such as palmoplantar punctate depressions (pits) ), rib anomalies, odontogenic
keratocyst (QTOs) in the maxilla or mandible, and predisposition to various tumors, including basal
cell nevoid carcinoma (BCCs), medulloblastoma, ovarome, and cardiac fibroma (FUJII; Miyashita,
2014; SPIKER et al., 2023).
SCNBC is mainly caused by mutations in the human homologous gene of the drosophila,
Patched Tumor Suppressor (PTCH, OMIM 601309), located on the long arm of chromosome 9 and
responsible for encoding the receptor for the sonic hedgehog protein (KIMONIS et al., 1997; LO
MUZIO, 2008; LO MUZIO et al., 2013; PAZDERA et al., 2022). The Hedgehog signaling pathway
(HH), in which this protein is inserted, plays a key role in the conformation of the human body, and
Basal cell nevoid carcinoma syndrome: A review
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Basal cell nevoid carcinoma syndrome: A review
tumorigenesis and its dysregulation results in various developmental defects and tumors, such as those
seen in SCNBC (FUJII; MIYASHITA, 2014).
The diagnosis of SCNBC only occurs when there is the appearance of the first signs and
symptoms (GUO et al., 2013). Patients with the syndrome usually have macrocephaly or rib anomaly
at birth and as they get older the palmoplantar pits are evident. At two years of age, 1% of patients
may present with medulloblastoma, and by 10 years of age QTOs in the jaws are evidenced (FUJII;
MIYASHITA, 2014). The presence of multiple QTOs in the jaws is the most common clinical
manifestation and, although at a late age, is highly suggestive of the syndrome, even in the absence of
cutaneous manifestations (POL et al., 2013; Hashmi et al., 2016; PACHOWICZ et al., 2017). Careful
extra clinical and intraoral examinations and cranial and chest radiographs greatly assist in the
diagnosis of SCNBC (KHALIQ et al., 2016).
Swellings in the face resulting from maxillary QTOs are often the first and only manifestations
of the syndrome and therefore, generally, the first professional to come into contact with the patient is
the dental surgeon (PEREIRA et al., 2015; KHALIQ et al., 2016). In addition, as patients have an
increased risk of developing new cysts throughout life, the health professional is responsible for the
preservation of these patients aiming at their early detection (HASHMI et al., 2016).
Because SCNBC is a condition that predisposes to cancer, it is of fundamental importance to
early diagnosis of this syndrome. Long-term complications such as malignant neoplasms, orofacial
deformations, and destruction can be reduced if diagnosis and treatment are carried out as soon as
possible (CHANDRAN et al., 2015). Despite this, most patients with SCNBC have a good prognosis
and normal life expectancy, although surgical interventions may be necessary to treat the conditions
associated with the syndrome (GARCIA de MARCOS et al., 2009).
Thus, considering the need for regular observation of patients with SCNBC by a
multidisciplinary health team, especially by dental surgeons, who are often responsible for the initial
diagnosis of these patients, and taking into account the importance of knowledge of this syndrome for
an early diagnosis of the morbidities underlying the syndrome, the present study aimed to perform a
literature review on SCNBC, addressing aspects such as clinical manifestations, diagnostic criteria,
and genetic etiology.
1.1 EPIDEMIOLOGY
The prevalence of SCNBC is 1 case for every 50 thousand - 150 thousand individuals and men
and women seem to be equally affected (PASTORINO et al., 2012; KHALIQ et al., 2016).

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Basal cell nevoid carcinoma syndrome: A review
1.2 DIAGNOSTIC CRITERIA
The first description of a patient affected by SCNBC was published in 1894 when Jarisch
described a 22-year-old patient presenting with short stature, milia (small cysts filled with keratin, seen
on the face, below the eyes, or on the forehead), mental disability, marked scoliosis, and multiple BCCs
since the age of 14. But it wasn't until 1960 that SCNBC was described in detail by Robert Gorlin and
Robert Goltz, who established the classic triad of multiple BCCs, multiple QTOs, and bifid ribs
(GORLIN; GOLTZ, 1960).
In 1993, Evans et al. established the diagnostic criteria, which were later modified by Kimonis
et al. (1997). According to the researchers, the presence of two major criteria or one major criterion
plus two minor criteria is required for the diagnosis of this syndrome. (EVANS et al., 1993; KIMONIS
et al., 1997). These criteria are detailed in Table 1.
Table 1 - Diagnostic criteria of the SCNBC.
EVANS et al. (1993)
KIMONIS et al. (1997)
MAJOR CRITERIA
Multiple BCC (>2) or 1 BCC under 30 years or >
10 basal cell nevi
Multiple BCC (>2) or 1 BCC in a patient < 20
years of age
QTO in jaws (histologically proven) or polyostotic
bone cysts
QTO in jaws (histologically proven)
Palm or plantar depressions (pits) (3 or more)
Palm or plantar depressions (pits) (3 or more)
Early ectopic calcification (< 20 years) bilaminar of
the cerebral sickle
Bilaminar calcification of the cerebral sickle
Family history of SCNBC
Bifid, fused, or markedly enlarged rib
First-degree relative with SCNBC
MINOR CRITERIA
Macrocephaly
Macrocephaly
Congenital malformations such as cleft lip or
palate, frontal bossing, polydactyly, or ocular
anomalies (cataracts, coloboma, microphthalmia)
Congenital malformations such as cleft lip or
palate, frontal bossing, face coarse, and moderate
or severe hypertelorism
Congenital skeletal anomalies: such as bifida,
fused, absent, or enlarged rib; fused, absent, bifid,
wedge-shaped vertebrae; Sprengel's deformity, or
marked pectoral deformity (Pectus excavatum)
Other skeletal anomalies (Sprengel's deformity,
marked breast deformity, and marked digital
syndactyly
Medulloblastoma
Radiological abnormalities (covering of the sella
turcica, vertebral anomalies, patterned defects of
the hands, flame-shaped feet of the hands and feet
Ovarian or cardiac fibroma
Ovarian fibroma or medulloblastoma (not
applicable in male patients)
Lymphasenteric cyst
BCC: Basal cell carcinoma; QTO: Odontogenic keratocyst; SCNBC: Basal Cell Nevoid Carcinoma Syndrome
In 2011, an international multidisciplinary colloquium was organized to better define the
findings of the syndrome. According to the colloquium, a suspicious diagnosis should be considered
if there is a greater criterion and molecular confirmation; two major criteria; or a major and a minor
criterion. However, there was no consensus among participants for a formal recommendation regarding

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Basal cell nevoid carcinoma syndrome: A review
the syndrome (BREE et al., 2011). The criteria established by the colloquium are presented in Chart
2.
Table 2 - Diagnostic criteria of the SCNBC, according to the multidisciplinary colloquium of 2011.
MAJOR CRITERIA
MINOR CRITERIA
BCC before 20 years of age or an excessive number of
BCCs, disproportionate to previous sun exposure and
skin type
Rib anomalies
QTO of jaws before 20 years
Macrocephaly
Palm or plantar depressions
Other specific skeletal malformations and radiological
changes (vertebral anomalies, chyphoscoliosis, small
fourth metacarpal bone, postaxial polydactyly)
Lamellar calcification of the cerebral sickle
Cleft palate or lip
Medulloblastoma typically desmoplastic
Ovarian/cardiac fibroma
First-degree kinship with SCNBC bearer
Lymphosenteric cysts
Eye abnormalities (strabismus, hypertelorism,
congenital cataracts, glaucoma, coloboma)
BCC: Basal cell carcinoma; QTO: Odontogenic keratocyst; SCNBC: Basal Cell Nevoid Carcinoma Syndrome
The diagnosis should be made as early as possible, and in addition to the importance of clinical
findings, radiographic examinations are crucial for the same (THOMAS et al., 2016; PACHOWICZ
et al., 2017).
According to Lo Muzio (2008), the protocol for diagnosing the syndrome should take into
account the following aspects:
• Family history: previous dental and medical histories.
• Clinical examination: skin, oral, central nervous system, head circumference; interpupillary
distance, eyes, genitourinary, cardiovascular, respiratory, and skeletal systems.
• Imaging tests:
o Radiographs of the chest (posteroanterior and anteroposterior), lateral of the skull,
cervical and thoracic vertebrae; pan; hands (for pseudocysts); pelvis (women).
o Ultrasound: ovary (women) to check for ovarian fibroma.
o Echocardiogram: (child) to check for cardiac fibroma.
• Genetic testing.
1.3 COMMON MANIFESTATIONS
The clinical presentation of SCNBC differs between individuals, even within the same family
or in different families. The presence of multiple QTOs is the most common and representative
manifestation of the syndrome and is usually detected in the first and second decades of life (POL et
al., 2013; MANJIMA et al., 2015; SUBRAMANYAM et al., 2015; KAMIL; TARAKJI, 2016;
THOMAS et al., 2016). The QTOS may present an average of five per patient (ranging from 1 to 30),
presenting a high recurrence rate after removal, justified by the presence of satellite cysts (daughter

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Basal cell nevoid carcinoma syndrome: A review
cysts). These, in turn, are located on the periphery of the lesion and have a friable coating. In syndromic
patients, the recurrence rate is higher. Preservation is recommended for a long period, being annual for
five years and then, every two years, for the entire life of the patient (KAMIL; TARAKJI, 2016;
KHALIQ et al., 2016; THOMAS et al., 2016).
BCCs associated with the syndrome are often reported in young patients in unexposed areas of
the body. In general, the diagnosis occurs, on average, at 25 years of age (LO MUZIO, 2008;
THOMAS et al., 2016). BCCs range clinically from pigmented papules to ulcerated plaques, with
diameters of 1 to 10 mm, most commonly located on the face, back, and chest. The number ranges
from 2 to 1000 BCCs (LO MUZIO, 2008; CHEN et al., 2015).
Evans et al. (1993), when studying 84 members of 29 families, found a prevalence of 71% of
cases of palmoplantar depressions (which did not turn into carcinomas); 66% presence of QTOs in the
jaws; 47% of BCC cases; 26% of ocular anomalies, the most common being strabismus; 24% of
ovarian fibromas in women and no cases of cardiac fibroma. Only 5% of cases of medulloblastoma
were diagnosed. The authors stated that the screening of cases should be initiated in the prenatal care
of mothers or fathers with the syndrome, and cardiac tumors and cleft palates can be detected early.
These children should be treated with periodic examinations, including DNA tests, for early diagnosis,
before puberty, of any change related to the syndrome, avoiding complications.
Santos et al. (2016), when studying 10 Brazilian individuals from the same family with the
syndrome, found that all had calcification of the cerebral sickle, hypertelorism, and prominent frontal
bossing. Multiple QTOs occurred in 90% of patients, palmoplantar depressions in 40%, and multiple
BCCs in 20% of patients.
Other alterations, such as skeletal anomalies, are quite frequent in syndromic patients. Above
60% of patients have rib anomalies (PACHOWICZ et al., 2017). The most frequently found
radiographic alteration is calcification of the cerebral sickle (LO MUZIO, 2008; CHEN et al., 2015),
and in addition to this, the presence of multiple QTOs can be considered pathognomonic radiographic
findings of the syndrome, observed using computed tomography (HAJALIOGHLI et al., 2015)
1.4 PTCH1 AND GENETICS
SCNBC exhibits an inherited autosomal dominant characteristic of complete penetrance and
variable expressivity (GARCIA de MARCOS et al., 2009). Mutations in PTCH1 are known to be
associated with the etiology of SCNBC (HOOPER et al., 2013; THOMAS et al., 2016). However,
causal mutations in other genes of the signaling pathway HHhow SUFU and PTCH2 have already been
identified in patients with the syndrome (EVANS et al., 2017).

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Basal cell nevoid carcinoma syndrome: A review
O gene PTCH1, whose chromosomal location is 9q22, consists of 23 exons encoding a
transmembrane glycoprotein composed of 1447 amino acids, with 12 domains and two large turns
(loops) hydrophilic extracellular, which function as receptors for the sonic hedgehog protein (SHH).
The SHH protein is inserted in the family HH of regulatory factors responsible for repressing
the transcription of certain genes encoding signaling proteins belonging to the transforming growth
factor (TGF-β) and Wnt families. During embryogenesis, the SHH pathway plays an important role in
the ongoing development of the stem cell population, also adjusting the development of hair follicles
and sebaceous glands. In adults, the SHH pathway is deactivated and aberrant activation of this
pathway is associated with several neoplasms including BCCs.
Under normal conditions, the PTCH1 constitutively inhibits SMO (a signal-transducing protein
of the SHH pathway), however, the binding of PTCH1 the SHH protein drives the release of SMO
which activates transcription factors (Gli1, Gli2, and Gli3) that are transported to the nucleus and there
activate target genes involved in cell growth and proliferation including PDGFRA, FOX gene family,
MYCN, cyclins, CTNNB1, beta-cateninas e RUNX3 (LO MUZIO, 2008; SÁ'S BELT; SILVA; Lopes,
2015).
O gene PTCH1 acts both as a developmental gene and as a tumor suppression gene. Mutations
in PTCH1 They result in the non-formation of the second hydrophilic extracellular turn of the
transmembrane receptor to which the SHH protein would bind, resulting in a non-inhibition of several
genes that control the cell cycle and genes responsible for the fate, patterning, and growth of cells.
Genetic analysis of patients with SCNBC identified more than 230 mutations in the PTCH1, including
deletions, insertions, Splicing, and mutations nonsense and missense, and more than 80% of the
mutations are related to the error during the reading phase of the codons (frameshift), or related to the
insertion of a premature stop codon, which implies a non-functional protein (LO MUZIO, 2008).
Being a tumor suppressor gene, PTCH1 follows the model of the two activations of tumor
suppressor genes to occur disordered tumor growth. According to this model, there is a need for two
distinct episodes of DNA damage, with the inactivation of both alleles of the tumor suppressor gene,
for tumor development (KNUDSON, 1971).
The occurrence of two mutations in both alleles or a mutation in one allele of the tumor
suppressor gene accompanied by allelic loss of the wild remnant is required for the development of
neoplasm. In patients with SCNBC, the first activation is a germline mutation of the PTCH1 gene, and
the second activation involves somatic mutation that inactivates it, or deletion, resulting in constitutive
activation of signals from the HH signaling pathway (AGARWAL et al., 2014; TATE et al., 2014).
All PTCH1 mutations cause changes in this signaling pathway during development. There are more
than 100 germline mutations of PTCH1 associated with the syndrome (RODRIGUES et al., 2014).

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Basal cell nevoid carcinoma syndrome: A review
According to Tate et al. (2014), the two inactivations of PTCH1 were highly prevalent in BCC
specimens from patients with the syndrome, although cases of absence of any activation of PTCH1
may also exist. In the cases evaluated by the authors, there was interruption∕ biallelic rupture in all 16
BCC specimens examined from two sisters with the syndrome.
The first was the germline mutation of c.2313delC and the second was the somatic loss of the
wild allele of the PTCH1 gene, resulting in the lack of expression of the PTCH1 protein and then
leading to activation of the HH pathway and finally, the formation of BCC. All BCC specimens showed
loss of the wild allele of exon 16 of PTCH1, indicating that the loss of heterozygosity resulted in
biallelic disruption of PTCH1 in multiple BCCs of the same patient.
These results indicated that the single-base germline deletion of PTCH1 (c.2613 delC) is the
first activation and the loss of heterozygosity of the wild allele is the second activation, implying that
all 16 BCCs of the two sisters fit the two-activation carcinogenesis model.
Although genetic testing is considered the gold standard for the diagnosis of SCNBC, it has a
high cost and demands time because it is laborious, due to the PTCH1 gene presenting 23 exons (LO
MUZIO, 2008; HOOPER et al., 2013; THOMAS et al., 2016).
It was determined by the multidisciplinary colloquium that the genetic testing of the PTCH1
gene is indicated only in prenatal testing if there is any mutation of this gene in the family; for
confirmation of the diagnosis in patients with some clinical signs, but who do not meet all the criteria,
allowing greater vigilance; and as a predictive test for patients with an affected family member, that is
at risk but does not meet clinical criteria (BREE et al., 2011).
Guo et al. (2013), when analyzing 14 patients with the syndrome, carriers of QTOs, identified
34 mutations in 11 (78.6%) of the syndromic patients (11 germinative and four somatic), and in 13
(44.8%) of the 29 patients without the syndrome (all of them somatic), presenting sporadic QTOs. The
predominant germline mutation was the mutation that causes protein truncation PTCH (mutation
nonsense). In addition, 29 new mutations were identified, including 20 truncations, five non-
truncations, and four splices.
The mutations were widely distributed across the entire gene sequence: 12 in the two large
extracellular turns (Large extracellular loops), eight in the sterol-sensitive domain (sterol-sensing
domain - SSD), four in the N-terminal region, three in the eighth to tenth transmembrane regions (TM8-
10), and two in intracellular turns 4 and 5 (ICL4 and ICL5).
The presence of germline mutations in individuals with the syndrome justifies the appearance
of QTOs at early, multifocal ages in both jaws, while sporadic QTOs are unique and appear in older
patients, and preferably located in the mandible. The authors suggested that the syndrome may also be
caused by genes other than the PTCH1, with interference from environmental factors.

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Basal cell nevoid carcinoma syndrome: A review
Ponti et al. (2013) found that the protein profiles of fibroblasts obtained from BCCs had
statistically significant differences when they came from missense and nonsense mutations of the
PTCH1 gene.
These fibroblasts could play a role in the development of BCC, even without sun exposure,
with the production of different proteins (cytokines and growth factors), promoting the proliferation
of basal cells.
There was no evidence of a transcriptome-associated PTCH1 nonsense mutation, but the
authors hypothesized that the mutations were coding for degradation mRNA bound to cytosolic
variants of the PTCH protein, rather than transmembrane proteins.
The absence of the transmembrane protein receptor may be related to the constitutional
activation of the HH signaling pathway, which increases protein synthesis and secretion. Conversely,
missense mutation of the gene should lead to the production of defective receptors, which should
explain the poor ability of fibroblasts to synthesize.
Morita et al. (2015) screened 15 individuals (10 affected and 5 non-syndromic relatives) with
a history of SCNBC (six families) looking for genetic changes using hybridization and PCR by next-
generation sequencing (next-generation sequencing-NGS).
Through the re-sequencing of all coding exons in the junction regions between exon and intron,
as well as evaluation of the status of changes in the number of copies (copy number alterations-CNA),
using alignment map files obtained via NGS, the authors found that several mutations in the PTCH1,
including large deletions, could explain the different phenotypes of the syndrome.
According to the authors, as it is advisable to examine the CNAs, in cases of absence of
mutations, the methodology NGS, which simultaneously screens all exons of the signaling pathway
genes HH, is useful because it simultaneously detects single nucleotide variations (single nucleotide
variations-SNVs) and CNAs in the regions of the target genes.
The authors found that SNVs of PTCH1 caused amino acid changes in four families (seven
individuals), while the CNAs in or flanking PTCH1 were found in two families, in which SNVs were
not detected. Numerous germline mutations of PTCH1, including errors in reading frameshift
mutations Nonsense, Missense and Splicing, as well as large insertions and gross deletions, were
observed.
1.5 PATIENT MANAGEMENT AND AVAILABLE TREATMENTS
The management of patients with the syndrome should be multidisciplinary, involving dental
surgeons; pediatricians, radiologists, otolaryngologists, urologists, cardiologists, gynecologists,
ophthalmologists, surgeons, plastic surgeons, neurologists, oncologists and geneticists (ACHARYA et

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Basal cell nevoid carcinoma syndrome: A review
al., 2013; GUPTA et al., 2013; CHANG et al., 2014; CHEN et al., 2015; RAMESH et al., 2015;
SKODRIC-TRIFUNOVIK et al., 2015; KAMIL, TARAKJI, 2016; KHALIQ et al., 2016).
Dermatologists should also be involved in the early detection of BCCs (HASHMI et al., 2016;
TANDON et al., 2016).
Genetic counseling with or without genetic testing should be considered for family members
of the patient with the syndrome (LO MUZIO, 2008; KIRAN et al., 2012; ACHARYA et al., 2013;
DONG-UK et al., 2016; HASHMI et al., 2016; SANTOS et al., 2016). The family should be carefully
informed about the changes responsible for the disease, prognosis and risks of more individuals
affected by the syndrome since each child of a syndromic has a 50% chance of inheriting the defective
gene (LO MUZIO, 2008; SANTOS et al., 2016).
The treatment of QTOs has been performed by several modalities, one of them being the
Carnoy solution (absolute alcohol, chloroform, glacial acetic acid, ferric chloride), which can be used
as an adjunct to surgical enucleation, its most common treatment.
A systematic review by Diáz-Belenguer et al. (2016) revealed that only enucleation presented
a recurrence rate from 0 to 58.8% and using Carnoy's solution as the only adjuvant, recurrences ranged
from 0 to 100%. With the use of more than two adjuvant treatments, the recurrence rate was from 0 to
7.9%.
However, studies using more than two adjuvants involved fewer patients and their proservation
time was different, which may induce bias. Another type of treatment is the surgical removal of the
QTOs in which it requires exposure of the lesion utilizing an osteotomy in the jaw under local or
general anesthesia, for the meeting of the cyst wall and its total removal. Only in extreme cases is it
necessary to remove the entire region of the affected jaw.
The treatment of BCCs with radiation is contraindicated for patients with syndromes that
predispose to cancer (FECHER; SHARFMAN, 2015). Another important factor is that due to the
strong positive correlation of BCCs with sun exposure, it is indicated that patients avoid excessive sun
exposure, also using sunscreen and glasses during sun exposure.
As a treatment of superficial BCCs without follicular involvement, there is an indication for
the topical use of Tretinoin 0.1% cream. Surgical excision is only indicated when the number of lesions
is limited and other treatments may be more efficient than surgical removal of multiple lesions such as
ablation, photodynamic therapy, and topical chemotherapy.
Another form of treatment for BCCs is photodynamic therapy (PDT), which involves the use
of a photosensitive pigment given intravenously or topically that preferentially accumulates inside
malignant cells and is then activated by a red light that kills the cells. Interferon therapy has also been
proposed in experimental studies (LO MUZIO, 2008).

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Basal cell nevoid carcinoma syndrome: A review
Vismodegib is an orally administered drug approved by the U.S. Food and Drug
Administration (FDA), used to treat metastatic, locally advanced, and unresectable BCCs, and is
effective and safe (CHANG et al., 2016). It is an inhibitor of the HH signaling pathway, acting through
its interaction with themothened s protein (smo), inhibiting the SMO gene pathway. Ally et al. (2014)
found that Vismodegib also could decrease the size (by 50%) of QTOs of patients with the syndrome.
However, four patients had decreased QTOs and in two there was no change in lesion size (ALLY et
al., 2014).
The approximate monthly cost of treatment with Vismodegib is $7,500.00, and considering that
it lasts for many months, it becomes unfeasible for patients (MOHAN; CHANG, 2014). Added to this
is the presence of the many adverse effects of the drug, such as cramps and muscle spasms; loss of
weight, taste and hair; fatigue and dysgeusia (TANG et al., 2012; CHANG et al., 2014; BOOMS et
al., 2015), which lead to discontinuity of treatment. More than half of the patients studied by Tang et
al. (2012) discontinued the use of Vismodegib due to its adverse effects.
Kis et al. (2012) performed treatment with electrochemotherapy (use of electric current and
administration of antineoplastic drugs) as intravenous bleomycin, in three patients who had 99 BCCs
located on the face and trunk and obtained a positive response in 99% of the lesions, with 87% of these
with complete response. Numerous tumors can be treated in the same session and the sessions can be
repeated if necessary.
Chaudhary et al. (2015) in a study with murine mice, reported that the administration of
inhibitors (vismodegib∕itraconazole∕cyclopamine) of the SMO pathway or nonsteroidal anti-
inflammatory drugs (sulindac∕sulfasalazine) separately resulted in partial resolution of Ultraviolet
(UVB)-induced BCCs. The combined administration of these inhibited the growth of BCCs by 90%.
For the authors, SKH-1 mice are relevant and viable animal models for the study of SCNBC,
accelerating the development of therapeutic modalities to be used in affected patients.
2 MATERIAL AND METHODS
This is a review of the recent literature on SCNBC. The bibliographic survey was performed
through the NCBI online database (PubMed) (https://www.ncbi.nlm.nih.gov/pubmed/), the term "
being usedGorlin Goltz Syndrome" as a search engine. Articles published on the subject in the last five
years were included in the review and, from these, only those freely available in their full version were
selected (Free Full Text). After the initial screening, the downloaded articles were sequentially
numbered and read to verify the adequacy of the theme, and those that did not refer strictly to the theme
were excluded. The remaining articles were then classified according to the type of article: research
articles, literature reviews, clinical case, and clinical case associated with the review. Subsequently,

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Basal cell nevoid carcinoma syndrome: A review
the articles were also evaluated for the number of clinical cases per article, the most frequently cited
clinical criteria among the clinical cases, as well as the performance of molecular tests and
corresponding methodology.
In addition to the articles mentioned, we sought to include ref-classical rerences necessary for
discussion of the topic, such as Gorlin; Goltz (1960), Knudson (1971), Lo Muzio (2008), Bree et al.
(2011) and Evans et al. (2013, 2017).
3 FINDINGS
Out of a total of 115 full-text articles available, located by the database PubMed, 27 articles
(23.5%) were excluded because they did not refer strictly to the theme, resulting in a final number of
88 articles included in the study.
Of the 88 articles used, 21 (23.9%) were classified as research articles; 14 (15.9%) as literature
review articles, 45 (51.1%) as clinical cases, and eight (9.1%) as concomitant clinical case articles and
literature reviews.
The articles containing clinical cases alone (n=45) added to those associated with the review
(n=8) resulted in a total of 53 (60.2%) articles, of which the majority were from a single case report
(n=49, 92.4%), four articles reported more than one clinical case (7.6%). Most cases were reports of
the syndrome affecting males (n=33, 55%) and 27 (45%) were reported in females. Two (3.8%) articles
did not report gender.
The clinical manifestations of the syndrome reported in the 53 articles of clinical cases surveyed
are presented in chart 4. Regarding the phenotypic manifestations of the syndrome, of the major
criteria, the most prevalent cited was the QTO (n=45, 84.9%), followed by calcification of the cerebral
sickle (n=31, 58.4%), palmoplantar depressions (pits) (n=28, 52.3%). BCCs had a prevalence of 41.5%
(n=22). Regarding the minor criteria, the most prevalent manifestations were ocular anomalies (n=30,
56.6%), followed by skeletal and radiological alterations (n=27, 50.9%) and rib anomalies (n=26,
49%). Of the ocular anomalies, hypertelorism was the most prevalent (n=25, 83.3%). Other phenotypic
clinical alterations were mentioned by 36 articles (67.9%), which may or may not be related to the
syndrome.

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Basal cell nevoid carcinoma syndrome: A review
Table 3. Criteria for the diagnosis of SCNBC (BREE et al., 2011), observed in the case report articles.
BCC: Basal cell carcinoma; QTO: Odontogenic keratocyst; SCNBC: Basal Cell Nevoid Carcinoma Syndrome *See
references
It can also be verified that a total of 18 (34%) articles of clinical cases performed molecular
tests in search of mutations in the PTCH1 gene. Of these, 8 (44.4%) did not detail them, and only one
of them mentioned the presence of a new insertion mutation. The mutations frequently found are
described in chart 4 and were mostly reading errors (frameshift) and premature stop codons (nonsense
mutation), affecting different exons, such as 2, 3, 6, 8, 11, 12, 18, 21.
Os métodos moleculares utilizados citados nos artigos foram sequenciamento genético,
sequenciamento de nova geração, hibridização genômica (Array-based comparative genomic

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Basal cell nevoid carcinoma syndrome: A review
hybridization-a-CGH), Multiplex ligation-dependent probe amplification (MLPA), Polymerase Chain
Reaction em tempo real (PCR-Real Time), Método Nanostring, Reverse-Transcriptase Polymerase
Chain Reaction (RT-PCR), quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR),
Fluorescent in situ Hybridization (FISH), Whole Exome Sequencing (WES), imunofluorescência e
imunohistoquímica.
Table 4: Mutations found in clinical case articles (n=18).
Author and year
Type of
mutation
Strain
reached
Mutation
specification
Location of the
mutation
Result
Ishitsuka et al.
(2012)
Nonsense
mutation
c.584G>A
Exon 3
Aberrant
splicing
Chang et al. (2013)
Increase in gli1,
ptch1, pik3c
proteins
Hooper et al. (2013)
Heterozygou
s deletion
Gentzsch et al.
(2014)
Heterozygou
s deletion
Frameshift
Exon 11 e 12
Frameshift,
Premature stop
codon
Rodrigues et al.
(2014)
Frameshift
Germinative
c290dupA
Éxon 2
Protein
truncation, with
loss of function
Diociaiuti et al.
(2015)
Inappropriat
e splicing
c585-1G>A
Íntron 3
Transcribed
without exon 4
Gururangan et al.
(2015)
Mutations
espontânean
onsense
missense
Germinative
C>T
G>A
c.1670 C>G
Éxon 18
Exon 12 in the
splice
of the
donor site
Éxon 12
Hettmer et al. (2015)
Germinative
IVS15-1G>A;
c2560+1G>A
Splice do Íntron
15
Destruction of
the canonical
splicing
acceptor site,
with abnormal
splicing
Rajan et al. (2015)
Deletions
Germinative
c.456_460del
Éxon 3
Premature stop
codon
Skodric-Trifunovik
et al. (2015)
Mutation
Frameshift,
nonsense
Somatic
Germination
c.903delT
c.3524delT
c.1148C>A
Éxon 6
Exon 21
Exon 8
Premature stop
codon, truncated
protein, mRNA
degradation
Ozcan al. (2016)
New
insertion
mutation
No details
Fini et al. (2013),
Nakamura et al.
(2013), Saulite et al.
(2013), Chen et al.
(2015), Hajalioghli
et al. (2015)
Hashmi et al. (2016),
Jiang et al. (2016)
Genetic
testing
No details

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Basal cell nevoid carcinoma syndrome: A review
4 DISCUSSIONS
SCNBC is a rare syndrome with wide phenotypic heterogeneity, which makes it difficult to
identify until the presence of QTOs or BCCs becomes apparent. The diagnostic challenge lies in
identifying some of the more than 100 clinical manifestations that affect many organs and systems.
These are characterized by the presence of skeletal, craniofacial anomalies, neurological,
oropharyngeal, dermal, sexual, ophthalmic, and cardiac (ACHARYA et al., 2013; CHEN et al., 2015;
SAINTS et al., 2016). The clinical presentation of SCNBC differs between individuals, even within
the same family or in different families.
Consistent with the literature, QTOs were the most prevalent manifestations in the articles of
clinical cases consulted in this study. When in the presence of multiple QTOs, SCNBC should initially
be suspected considering the protocol proposed by Lo Muzio et al. (2008) and the classifications of
Bree et al. (2011) (MANJIMA et al., 2015; SUBRAMANYAM et al., 2015). Khaliq et al. (2016), in
a clinical-pathological study of seven syndromic patients, found that all had multiple QTOs as the first
manifestation of the syndrome, most of them being located in the mandible (77%), with unilocular
pattern (71%) and associated with teeth (88%). All patients also had calcification of the cerebral sickle.
As the treatment is multidisciplinary, the referral of the patient is of fundamental importance,
for the diagnosis of other alterations and possible interventions, as early as possible. The patient should
be proservated by different specialists, especially the dermatologist, due to the high predisposition to
BCC and other neoplasms (KIRAN et al., 2012). Despite naming the syndrome, the presence of BCCs
reported in the articles of clinical cases surveyed was not very frequent, being cited in less than half of
the articles.
Generally, the clinical diagnosis of the syndrome is already sufficient, without the need for
genetic confirmation (PIRSCHNER et al., 2012). This was verified in the case-reporting articles
surveyed, where a minority reported the use of genetic tests as a diagnostic tool, and only clinical
criteria were used for the diagnosis of cases. PTCH1 is the only gene in which mutations are known to
cause SCNBC, but because it has many exons, its sequencing becomes costly (HOOPER et al., 2013;
THOMAS et al., 2016). Although sequenced, there is no genotype correlation of the PTCH1 gene with
the patient's phenotype, and the detection of mutations does not provide information about the
prognosis or clinical manifestations of the disease (RODRIGUES et al., 2014).
Because it is a hereditary condition, counseling and genetic testing are important for
clarification of the patient and search for relatives at risk, especially children. As the syndrome is of
autosomal dominant inheritance, the offspring have a 50% risk of being affected by the syndrome (LO
MUZIO, 2008; ACHARYA et al., 2013; SUBRAMANYAM et al., 2015). The high mutation detection
rate of the PTCH1 gene enables a molecular diagnosis to become a tool of great value in establishing

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Basal cell nevoid carcinoma syndrome: A review
an early diagnosis, especially in atypical phenotypes or even in unaffected family members
(ACHARYA et al., 2013; SKODRIC-TRIFUNOVIC et al., 2015). However, the high cost of
molecular tests makes it impossible to perform them as a routine.
Among the mutations most commonly reported in clinical cases are frameshift, nonsense and
splicing site mutations. While the frameshift mutation is usually caused by the insertion or deletion of
nucleotides, modifying the mRNA reading sequence and as a consequence, altering the synthesized
protein, the nonsense mutation entails a premature stop codon and can predict a truncated protein,
usually of smaller size than desired. Mutations in the splicing sites (exon/intron junctions) result in the
alteration of exon and intron excision and different transcripted mRNA and generation of different
proteins, which may or may not be functional. Such mutations have been found in germ cells and also
in somatic cells. Germline mutations are the most common in the syndrome, and there are more than
100 related to the syndrome (RODRIGUES et al., 2014), and are inherited by the next generation. The
somatic ones will not be passed to the progeny (LO MUZIO, 2008; RODRIGUES et al., 2014). Above
80% of mutations occur in the reading phase, causing error (frameshift), or leading to premature
truncation of the encoded protein. The remaining mutations lead to the production of an abnormal
receptor (LO MUZIO, 2008).
The most used techniques for detecting PTCH1 mutations identified in the articles were PCR
amplification followed by genetic sequencing. Sequencing is important since most patients have a new
spontaneous mutation, with no history of an affected family member (CHEN et al., 2015). The
sequencing recommended by Sanger et al. (1977) is based on the controlled interruption of DNA
enzyme replication and is considered first-generation. There is new generation sequencing, and the
more sophisticated the technique, the more expensive the method (PILLAI et al., 2017).
The limitations of the study were the use of only freely available articles in the database, which
may represent a bias of the present study since more relevant and current research articles might not
have been included. This fact is made more concrete by the observation that the vast majority of the
articles surveyed are clinical cases, considered to have low scientific impact, and the presence of few
available research articles.
5 FINAL CONSIDERATIONS
From the results found in this literature review it can be concluded that SCNBC is a syndrome
still little studied given its rarity in the population and its description in the literature, mostly in the
form of clinical cases. The most prevalent sex reported in clinical cases was male. Although quite
numerous, clinical manifestations still constitute the main means of diagnosing the syndrome. It was
found that, among the major criteria for diagnosis, QTOs were the most cited clinical manifestations,

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Basal cell nevoid carcinoma syndrome: A review
followed by calcification of the cerebral sickle. Ocular anomalies were the most prevalent minor
criteria. For many of these criteria, imaging tests function as a complementary diagnostic tool of great
value.
The molecular tests most commonly verified in the articles were the sequencing of the PTCH1
gene, and germline and somatic mutations can be detected in it. Despite the existence of several
mutations in the PTCH1 gene that are attributable to the etiology of SCNBC, the performance of
diagnostic molecular tests was not performed in many of the studies analyzed, and even in those in
which the mutations were identified, there was no correlation with the patient's phenotype or with the
prognosis, which makes the performance of molecular tests is indicated only in some particular cases.

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Basal cell nevoid carcinoma syndrome: A review
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