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An Official Publication of the Indian Association of Oral and Maxillofacial Pathologists

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Year : 2023  |  Volume : 27  |  Issue : 5  |  Page : 56-59

Frameshift mutation in exon 17 of PTCH1 gene in Nevoid basal cell carcinoma syndrome: A case report

Department of Oral Pathology and Microbiology, Amrita School of Dentistry, Amrita Vishwa Vidyapeetham, AIMS Campus, Kochi, Kerala, India

Date of Submission16-Nov-2020
Date of Acceptance19-May-2022
Date of Web Publication04-Feb-2023

Correspondence Address:
Thara Aravind
Department of Oral Pathology and Microbiology, Amrita School of Dentistry, Amrita Vishwa Vidyapeetham, AIMS Campus, Kochi - 682 041, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jomfp.jomfp_463_20

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Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. In majority of the cases, the presence of multiple and recurrent jaw cysts especially during the first two decades of life is one of the first symptoms of this syndrome. We present here a case of 14-year-old female patient who reported with a chief complaint of facial swelling for 3 weeks. The radiographs revealed multiple cysts in maxilla and mandible. Incisional biopsy of the lesions was done and the histopathologic features were suggestive of odontogenic keratocyst. Further investigations revealed the presence of falx cerebri calcifications and multiple nevi on palms and feet. Genetic study was done to confirm the diagnosis of NBCCS, which showed mutations in PTCH gene. This case stresses the importance of genetic study in suspected cases of NBCCS especially in young patients of nonsyndromic parents.

Keywords: Falx cerebri calcifications, genetic counselling, odontogenic keratocyst, PTCH1 gene

How to cite this article:
Aravind T, Savithri V, Suresh R, Subash P. Frameshift mutation in exon 17 of PTCH1 gene in Nevoid basal cell carcinoma syndrome: A case report. J Oral Maxillofac Pathol 2023;27, Suppl S1:56-9

How to cite this URL:
Aravind T, Savithri V, Suresh R, Subash P. Frameshift mutation in exon 17 of PTCH1 gene in Nevoid basal cell carcinoma syndrome: A case report. J Oral Maxillofac Pathol [serial online] 2023 [cited 2023 Mar 21];27, Suppl S1:56-9. Available from: https://www.jomfp.in/text.asp?2023/27/5/56/369184

   Introduction Top

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant inherited disease caused by heterozygous mutation in PTCH1 gene, which is mapped to chromosome 9q22.3-31.[1] This gene consists of 23 exons and encodes a transmembrane glycoprotein composed of 1447 amino acids with 12 transmembrane domains and 2 large hydrophilic extracellular loops where sonic hedgehog (SHH) ligand binding occurs.[2] It acts as a tumor suppressor, which has a fundamental function in embryonic structuring and controlling growth with varying penetrance and expressivity.[3]

The estimated prevalence varies from 1 in 57,000 to 1 in 256,000, with a male-to-female ratio of 1:1.1.[4] It is characterized predominantly by the presence of multiple odontogenic keratocysts (OKCs), basal cell carcinomas, palmar/plantar keratosis, falx cerebri calcifications and skeletal anomalies such as fused, bifid, and splayed ribs. Diagnosis can be made by having two major criteria or one major and two minor criteria put forwarded by Evans et al.,[5] later modified by Kimonis et al.[6]

Because of the wide variations in the expression of this syndrome, a confirmatory diagnosis can be made only by genetic analysis. Early diagnosis of this syndrome is of utmost importance as the affected patients have a high risk for developing neoplastic diseases.[7] We present here a case of NBCCS in a young female patient who presented with multiple OKCs, falx cerebri calcifications, multiple palmar and plantar nevi, and genetic analysis was performed to confirm the diagnosis.

   Case Report Top

A 14-year-old female patient reported to the Craniomaxillofacial Surgery Department of our institution with bilateral facial swelling which was noticed for 3 weeks. They consulted multiple dental practitioners elsewhere and were advised to undergo imaging studies, which showed the presence of multiple cystic lesions in maxilla and mandible. The patient also gave a history of foul-smelling oral discharge every morning.

On general examination, the patient was conscious, oriented, and her vitals were stable. Extraoral examination revealed bilateral facial swelling in the mandibular region. She has multiple nevi on palms and soles [Figure 1]a and [Figure 1]b. The nevi were present from early childhood and was dark brown in colour with the smallest measuring 0.1 × 0.2 cm and the largest measuring 0.3 × 0.4 cm and as per the parents it has not increased in size for the past 5 years. She also presented with clinical indications of macrocephaly. On intraoral examination, bilateral buccal cortical expansion was noticed in the posterior mandibular region. Moderate pus discharge was also seen associated with 36 regions. There was no paraesthesia or mobility of the teeth in relation to the swelling.
Figure 1: (a) Multiple moles on palms, (b) multiple moles on soles.

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Family history was unremarkable and her parents had a non-consanguineous marriage. Orthopantomogram revealed expansile radiolucent lesions in the mandible extending from first molar region to coronoid processes bilaterally. Impacted second and third molars were noticed within the lesion in the third quadrant. It was also seen, that the impacted third molar crown was pushed to the coronoid process in the fourth quadrant. Another smaller radiolucent lesion along with impacted third molar was observed in the first quadrant. Thinning and erosion of bone cortex was noticed at multiple sites [Figure 2]a.
Figure 2: (a) Orthopantomogram showing expansile radiolucent lesions in the mandible extending from first molar region to coronoid processes bilaterally with impacted teeth in the second and third quadrants, (b) MRI (head) showing calcifications in the falx cerebri.

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Correlating the clinical and radiographic findings, a differential diagnosis of multiple odontogenic cysts (OKC and dentigerous cyst) were considered and an incisional biopsy was performed. The lesions from all the sites had similar histopathologic features. On examination, a parakeratinized stratified squamous epithelial lining of six to eight layer thickness with surface corrugation and basal cell palisading was seen [Figure 3]a. The underlying cystic capsule was moderately collagenous. These exhibited features are characteristic of OKC. Since the mandibular lesions were larger in size, the surgeon went ahead with marsupialization of the same. After 3 months, enucleation of the mandibular and maxillary lesions was performed. Microscopically, the excisional specimen showed features of OKC similar to the incisional biopsy. In addition, the epithelial lining showed budding of basal epithelial cells in few areas [Figure 3]b. Keratin filled daughter cysts and odontogenic epithelial islands were also seen in a moderately collagenous connective tissue capsule in some of the sections [Figure 3]c. In one area, the epithelial lining showed crowding, and atypia in the basal and parabasal layers [Figure 3]d.
Figure 3: (a) Parakeratinized stratified squamous epithelial lining of six to eight layer thickness with surface corrugation and basal cell palisading, (b) epithelial lining showing budding of basal cells, (c) keratin filled daughter cysts and odontogenic epithelial island, (d) epithelial lining showing crowding and mild atypia in the basal and parabasal layers. (H&E, 200x)

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As the histopathologic diagnosis was confirmatory of multiple OKCs, the patient was sent for imaging studies. Magnetic resonance imaging (MRI) of the head revealed calcifications in the falx cerebri [Figure 2]b however, chest radiograph did not reveal any abnormal findings.

Since the patient had falx cerebri calcifications, multiple nevi on palms and soles along with the presence of multiple OKCs, the possibility of NBCCS had to be considered. To confirm the same, the patient's blood sample was sent for genetic study. Genetic analysis showed a heterozygous single base pair deletion in exon 17 of the PTCH1 gene (chr9:g. 98221976delG: Depth: 111x) that results in a frameshift and premature truncation of the protein 30 amino acids downstream to codon 932 (p.Val932SerfsTer30;ENST00000331920.6). This variation has been classified as pathogenic.

Due to the possibility of recurrence of OKCs the surgeon went ahead with dredging of the mandibular lesions at an interval of 6 months and the last dredging specimen did not show any pathologic finding. The patient and her parents also underwent genetic counselling regarding the syndrome. She was also referred to a dermatologist for review of the multiple nevi. The patient was prescribed UVA gel (SPF-30) for local application and asked to report immediately if there is an increase in the size of any of the nevi.

   Discussion Top

NBCCS was first reported in 1894 and later described in detail by Gorlin and Goltz in 1960. The syndrome is primarily not only attributed to the mutation in PTCH1 gene, but is also rarely associated with PTCH2 and SUFU as well.[7] PTCH1 is a tumour suppressor gene that holds a key role in SHH signalling pathway involved in cell growth and patterning.[8] Mutations in the gene results in uncontrolled cell proliferation, which explains the predisposition of NBCCS patients for benign and malignant tumours. The complex phenotype of this syndrome makes it more challenging for the clinician to diagnose it at an early stage.

The diagnosis of NBCCS is made by the presence of two major and one minor criteria or one major and three minor criteria, put forward by Evans et al.[5] and later modified by Kimonis et al.[6] These are summarised in [Table 1].[9]
Table 1: Diagnostic criteria for NBCCS

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The presence of multiple OKCs especially in the first two decades are considered to be one of the earliest manifestations of this syndrome.[10] Our patient also reported with multiple cystic lesions in the jaws which was confirmed histopathologically as OKCs and she was in her second decade. Previous studies have showed that the histopathology of multiple OKCs associated with NBCCS exhibits more aggressive features compared to non-syndromic cases of multiple OKCs.[11] These features include solid areas of epithelial proliferation and the presence of increased number of daughter cysts and/or odontogenic epithelial rests. In our case, epithelial off shoots were seen at various areas and the proliferative epithelium at one particular site also showed cytological atypia. Islands of odontogenic epithelium and keratin filled daughter cysts were also found in the connective tissue capsule showing the aggressiveness and recurrence potential of the cystic epithelium.

Other major diagnostic criterias of the NBCCS include the presence of ectopic calcifications of the central nervous system and skeletal abnormalities, mainly rib anomalies. It has been reported that bilamellar calcifications of falx cerebri was present in 70–85% of the cases.[12] MRI scan of our patient also revealed falx cerebri calcifications but there was no rib anomaly noted in the chest radiograph. Though the patient had no basal cell carcinomas, she had multiple nevi on palms and feet. Since there is no change in the size and the colour of the nevi for the past 5 years, biopsy was not advised. The patient was prescribed a sunscreen with SPF-30 and advocated a periodic follow-up for the multiple nevi. She also showed clinical indications of macrocephaly with a head circumference of 59 cm which is also a minor criteria for the syndrome.

Since our case satisfied two major and one minor criteria for the diagnosis of NBCCS, a genetic analysis was done for the confirmation of the same. On genetic study, a heterozygous single base pair deletion in exon 17 of the PTCH1 gene that results in a frameshift and premature truncation of the protein 30 amino acids downstream to codon 932 was detected and classified as a pathogenic variant. The observed variation was not published previously and has not been reported in the 1000 genomes.[13] The genetic test results were reported based on the recommendations of the American College of Medical Genetics.[14]

According to previous studies, analysis of PTCH1 mutations in NBCCS has identified deletions, insertions, splice site alterations, frameshift or nonsense and missense mutations and 86% of the mutation results in truncation of the coded protein.[15],[16] In our case, the frameshift mutation was detected which also resulted in the premature truncation of the coded protein. As the syndrome is a hereditary condition, genetic counselling and screening of the family members is mandatory. The parents were clinically evaluated for the syndromic signs and were negative. Since the features of the syndrome has an early life onset, the parents were not advised for a genetic study. Life expectancy of the patients affected with NBCCS is not seriously altered provided the diagnosis is done at the earliest.

The diagnosis depends on specific clinical criteria and confirmation was done by genetic study. Treatment requires a multidisciplinary approach depending on the patient's clinical and radiographic manifestations. Genetic counselling is compulsory for the patient and the family members.

   Conclusion Top

The dental practitioner can play a very crucial role in the initial diagnosis of NBCCS as the presence of multiple OKCs is considered to be one of the earliest manifestations of this syndrome. In case of young patients who present only with multiple jaw cysts, genetic analysis need to be carried out for confirmatory diagnosis of the syndrome at an early stage. Patients should be regularly followed-up every 6 months by a dental practitioner for the recurrence of any cystic lesion and also by a dermatologist for the occurrence of any skin lesions. The patients with NBCCS should avoid direct exposure to sunlight as they are more vulnerable for developing basal cell carcinomas and should be advised to apply a sunscreen when they go outdoors. Radiation therapy for any other cause should also be avoided as it causes induction of basal cell carcinomas.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Acocella A, Sacco R, Bertolai R, Sacco N. Genetic and clinicopathologic aspects of Gorlin-Goltz syndrome (NBCCS): Presentation of two case reports and literature review. Minerva Stomatol 2009;58:43-53.  Back to cited text no. 1
Daneswari M, Reddy MS. Genetic mutations in Gorlin-Goltz syndrome. Indian J Hum Genet 2013;19:369-72.  Back to cited text no. 2
[PUBMED]  [Full text]  
Barreto DC, Gomez RS, Bale AE, Boson WL, De Marco L. PTCH gene mutations in odontogenic keratocysts. J Dent Res 2000;79:1418-22.  Back to cited text no. 3
Sahu S, Sahoo S, Banerjee R, Ghosh S. An enigma of Gorlin-Goltz syndrome: Two cases reported in mother and daughter. J Oral Maxillofac Pathol 2019;23(Suppl S1):115-21.  Back to cited text no. 4
Evans DGR, Ladusaris EJ, Rimmer S, Burnell LD, Thakker N, FarndonPA. Complications of the naevoid basal cell carcinoma syndrome: Results of a population based study. J Med Genet 1993;30:460-4.  Back to cited text no. 5
Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 1997;69:299-308.  Back to cited text no. 6
Takahashi C, Kanazawa N, Yoshikawa Y, Yoshikawa R, Saitoh Y, Chiyo H, et al. Germline PTCH1 mutations in Japanese basal cell nevus syndrome patients. J Hum Genet 2009;54:403-8.  Back to cited text no. 7
Villavicencio EH, Walterhouse DO, Iannaccone PM. The Sonic hedgehog-Patched-Gli pathway in human development and disease. Am J Hum Genet 2000;67:1047-54.  Back to cited text no. 8
Fini G, Belli E, Mici E, Virciglio P, Moricca LM, D'Itri L, et al. Nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome). Case report. G Chir 2013;34:176-9.  Back to cited text no. 9
Lo Muzio, Lorenzo. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis 2008;3:32. doi: 10.1186/1750-1172-3-32.  Back to cited text no. 10
Auluck A, Suhas S, Pai KM. Multiple odontogenic keratocysts: Report of a case. J Can Dent Assoc 2006;72:651-6.  Back to cited text no. 11
Bahadure RN, Jain ES, Badole GP. Gorlin and Goltz syndrome: A case report with surgical review. Int J Clin Pediatr Dent 2013;6:104-8.  Back to cited text no. 12
Reinders MG, van Hout AF, Cosgun B, Paulussen AD, Leter EM, Steijlen PM, et al. New mutations and an updated database for the patched-1 (PTCH1) gene. Mol Genet Genomic Med 2018;6:409-15.  Back to cited text no. 13
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med 2015;17:405-24.  Back to cited text no. 14
Boutet N, Bignon YJ, Drouin-Garraud V, Sarda P, Longy M, Lacombe D, et al. Spectrum of PTCH1 mutations in French patients with Gorlin syndrome. J Invest Dermatol 2003;121:478-81.  Back to cited text no. 15
Schultz Tanner K. Novel de novo mutation in woman with clinical Gorlin syndrome: A case study. SN Compr Clin Med 2019;1:928-30.  Back to cited text no. 16


  [Figure 1], [Figure 2], [Figure 3]

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