Mandible & maxilla

Odontogenic cysts

Nevoid basal cell carcinoma syndrome

Authors: Annie S. Morrison, M.D., Kelly Magliocca, D.D.S., M.P.H.

Topic Completed: 1 February 2014

Minor changes: 21 December 2020

Copyright: 2004-2019, PathologyOutlines.com, Inc.

PubMed Search: Nevoid basal cell carcinoma syndrome [title]

Page views in 2021: 1,861

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Table of Contents

Cite this page: Morrison A. Nevoid basal cell carcinoma syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/mandiblemaxillabasalcellnevus.html. Accessed January 18th, 2022.

Definition / general

Inherited multisystem disorder due to germline mutations in the human homolog of the patched (PTCH) gene that predisposes to overgrowth, tumor formation and skeletal abnormalities

Terminology

Basal cell nevus syndrome (BCNS)
Gorlin syndrome
Gorlin-Goltz syndrome
Nevoid Basal Cell Carcinoma Syndrome (NBCCS)
Basal cell carcinoma nevus syndrome (BCCNS)
Fifth phakomatosis
Bifid-rib basal-cell nevus syndrome

Epidemiology

Prevalence estimated at 1 in 57,000
30 - 40% of cases represent a de novo mutation

Pathophysiology

Genetic basis lies in causative mutations in several genes in the sonic hedgehog signaling pathway (see Etiology and Diagrams / tables)
Sporadic cases thought to follow Knudson model such that two somatic "hits" in same cell are required for sporadic cases of NBCS
One somatic "hit" plus the inheritance of one defective allele underlies familial cases
Loss of function mutations in PTCH1, a tumor suppressor gene, result in premature termination of the PTCH protein which impacts multiple organ systems

Etiology

Autosomal dominant
High penetrance and variable expressivity
Most commonly caused by mutations in the PTCH1 gene on chromosome 9q22
Less commonly PTCH2 gene on 1p32, or the SUFU gene on 10q24-q25

Clinical features

Great deal of variability in presentation may contribute to delayed diagnosis
Prominent features may include:
- Head / neck / face / jaw: odontogenic keratocysts
- Neurologic: medulloblastoma
- Genitourinary: ovarian fibromas
- Cutaneous: basal cell carcinomas (BCC), palmar or plantar pitting
- Skeletal: rib anomalies, polydactyly of the hands or the feet, hallux valgus, pectus excavatum or pectus carinatum, syndactyly of the second and third fingers
- Cardiovascular: cardiac fibroma
- Opthalmologic: strabismus, hypertelorism, congenital cataracts

Diagnosis

Major and Minor Criteria: (eMedicine: Nevoid Basal Cell Carcinoma Syndrome Clinical Presentation [Accessed 8 June 2018])
- No studies define sensitivity and specificity of which phenotypic combination is most accurate for diagnosis
- Recent discussion to move medulloblastoma (also known as primitive neuroectodermal tumor) to major, and not a minor, criterion as this may lead to increased early detection if recognized as a potential indicator of an underlying syndrome, since it typically manifests in children 2 years of age and younger
Criteria for evaluation, "triggers" for screening:
- Odontogenic keratocysts in children < 20 years of age
- BCC in persons < 20 years of age
- Palmar or plantar pits
- Lamellar calcification of the falx cerebri
- Medullobastoma with desmoplastic histology in combination with any of the other major or minor criteria
See Laboratory for Genetic Testing

Diagrams / tables

Images hosted on other servers:

Sonic Hedgehog pathway

Diagnostic protocols

Prevalence and frequency of
major criteria in 4 studies

Laboratory

Genetic Testing:
- The positive mutation detection rate of sequence analysis for PTCH1 is approximately 75% in patients meeting clinical criteria, but has been reported as low as 60%
- Although genetic testing is considered the gold standard for diagnosis, it is also very expensive and can be cost prohibitive
- Clinical criteria are quite good in establishing a suspected diagnosis and that molecular-genetic confirmation is not warranted in all cases
- Genetic testing for PTCH1, the most common mutation, is warranted in these clinical scenarios, as the results may impact diagnosis and management within an individual or a family:
  1. Prenatal testing if known familial mutation
  2. Confirmatory diagnosis in patients with some clinical signs but not meeting criteria to allow for increased surveillance and improved patient care outcomes
  3. Predictive testing for patients with an affected family member who is at risk but does not meet clinical criteria

Radiology description

MRI / CT: paramount concern in patients with syndrome is exposure to radiation; therefore, imaging should be selected carefully:
- Bilateral hyperplasia of coronoid process of mandible, odontogenic keratocysts, mandibular prognathism
- Calcification of falx cerebri, medulloblastoma
- Fused vertebrae, kyphosis, lumbarized sacrum, scoliosis
- Marfanoid habitus
- Polydactyly, short metacarpals, flame shaped radiolucencies of the hands and feet
- Spontaneous fractures

Radiology images

Images hosted on other servers:

Multiple odontogenic cysts

Odontogenic keratocysts

Multiple KCOTs

Multiple unilocular radiolucencies

Radiolucent area with minimum cortical plate expansion

Hypodense areas

Well defined round cystic mass

Echocardiogram

Cardiac fibromas have an incidence as high as 3% in some studies (rarer in other studies)
In patients with NBCCS, one might consider a baseline echocardiogram at birth or within the first year of life and then subsequently, primarily if clinical suspicion arises for a cardiac fibroma

Pelvic ultrasound

At puberty as a baseline, and later in life if symptoms are present, for the diagnosis of ovarian fibroma

Prognostic factors

Morbidity and premature mortality primarily related to the syndrome related development of skin cancers and other tumors
Actual mortality rates are unavailable
Morbidity from multiple skin cancers and their treatment may be severe

Case reports

Oral cavity / gnathic:
- 19 year old man with undifferentiated sinonasal carcinoma (Int J Surg Pathol 2007;15:303)
- 24 year old man with oral diffuse B cell non-Hodgkin lymphoma (Indian J Pathol Microbiol 2011;54:388)
- 38 year old man with associated unicystic ameloblastoma associated with the novel K729M PTCH1 mutation (Cancer Genet 2012;205:177)
- 39 year old man presenting with myolipoma of tongue base (J Laryngol Otol 2008;122:1130)
- 44 year old patient with concurrent adenoid cystic carcinoma of salivary gland (J Am Acad Dermatol 2003;48:S64)
- 55 year old man with resolution of odontogenic keratocysts of the jaw in basal cell nevus syndrome with GDC-0449 (Arch Dermatol 2011;147:839)
- Bilateral hyperplasia of mandibular coronoid processes (Am J Med Genet 2002;110:400)
- Basal cell carcinoma of the buccal mucosa (Int J Surg Pathol 2011;19:348)
- Tonsillar inclusion cysts (Ear Nose Throat J 2006;85:818)
Skin:
- 6 month old infant with congenital linear unilateral basal cell nevus (J Cutan Pathol 2007;34:65)
- 19 year old man with apocrine poroma (Am J Dermatopathol 1999;21:31)
- 23 year old woman with linear unilateral basal cell nevus (Cutis 2006;78:122)
- 63 year old woman with chronic hip pain and diffuse skin lesions throughout her body (Arch Pathol Lab Med 2004;128:819)
- 72 year old man with multiple skin cysts in nevoid basal cell carcinoma syndrome (Dermatology 2008;216:159)
- Cutaneous keratocysts (Int J Surg Pathol 2003;11:36)
- Eosinophilic pustular folliculitis (Acta Derm Venereol 2001;81:202)
- Associated with a palmar epidermoid cyst, milia and maxillary cysts (Br J Dermatol 2001;145:508)
- BerEP4 negative basal cell carcinoma on palm (J Dtsch Dermatol Ges 2011;9:140)
- Patched mutations and hairy skin patches (Am J Med Genet A 2006;140:2625)
- Unusual cystic scalp lesions (Pediatr Dermatol 2010;27:204)
Gastrointestinal:
- 52 year old man with associated small bowel carcinoma and mesenchymal proliferation of GI tract (BMC Cancer 2010;10:360)
- With concomitant ulcerative colitis and rectal cancer (Inflamm Bowel Dis 2009;15:488)
Skeletal
- Hypoplastic thumb in Gorlin syndrome (J Plast Reconstr Aesthet Surg 2007;60:440)
Neuro / Ocular
- 11 year old girl with spontaneous recovery from medulloblastoma (Pediatr Neurol 2003;28:231)
- 13 year old girl with conjunctival ganglioglioma as a feature of basal cell nevus syndrome (J AAPOS 2011;15:387)
- 13 to 19 year old patients with empty sella syndrome (Brain Dev 2000;22:272)
- 20 year old woman with meningeal calcification (BMJ Case Rep 2013;2013)
- 24 year old man with combined hamartoma of retina and retinal pigment epithelium in Gorlin syndrome (Arch Ophthalmol 2000;118:1004)
- 34 year old man with bilateral epiretinal membranes in Gorlin syndrome associated with a novel PTCH mutation (Am J Ophthalmol 2007;143:346)
- Intracranial calcifications in childhood medulloblastoma (AJNR Am J Neuroradiol 2000;21:790)
Chest:
- Mediastinal fetal rhabdomyoma (Virchows Arch 2011;459:235)
- Presenting as prenatal chylothorax in a girl (Prenat Diagn 2005;25:997)
Other:
- 11 year old boy with testicular thecoma and nevoid basal cell carcinoma syndrome (J Pediatr Surg 2010;45:E1)
- Atlanto-occipital ligament calcification: a novel sign in nevoid basal cell carcinoma syndrome (Anticancer Res 2010;30:4265)
- Two unusual cases of recurrent, bilateral, multinodular, calcified ovarian fibromas with conservative surgical treatment (J Minim Invasive Gynecol 2012;19:248)
- Bilateral adrenal cystic lymphangiomas in nevoid basal cell carcinoma (Gorlin-Goltz) syndrome (J Comput Assist Tomogr 1999;23:562)

Treatment

Requires multidisciplinary approach including evaluations by specialists to assess and manage abnormalities as they develop: possible / probable consultations with dermatology, genetics, pediatrics, neurology, cardiology, gynecology, oral and maxillofacial surgeon
Involves surveillance for and treatment of associated findings
Most of findings involve tumors (benign and malignant), so treatment is often surgical, but in some cases, pharmaceutical agents (see N Engl J Med 2012;366:2180) may be available for certain manifestations

Clinical images

Images hosted on other servers:

Facial features:

Increased inner canthal distance

Hyper pigmented plaques

Clinical features of NBCCS

Palmar pits:

Multiple pits on the palm

Palmer pits in the hypothenar eminence

Small brown papules and palmar pits

Basal cell carcinoma:

Nodular pigmented lesion

Differential diagnosis

Multiple basal cell carciomas are listed as a prominent feature in these syndromes: Gorlin, Bazex-Dupré-Christol, Rombo, xeroderma pigmentosum
Basal cell carcinoma may represent a relatively common, although less specific finding in these genodermatoses and medical conditions:
- Arsenic exposure, Bloom, Brooke-Spiegler, cartilage-hair hypoplasia, Cowden, epidermodysplasia verruciformis, melanin biosynthesis disorders (oculocutaneous albinism and Hermansky-Pudlak syndrome), Muir-Torre syndromes, Rothmund-Thomson, Schöpf-Schulz-Passarge, Werner

Additional references

eMedicine: Nevoid Basal Cell Carcinoma Syndrome [Accessed 8 June 2018], OMIM: Basal Cell Nevus Syndrome [Accessed 8 June 2018], Am J Med Genet A 2011;155A:2091, Eur J Hum Genet 2013 Oct;21(10)