Mandible / maxilla
Odontogenic cysts
Nevoid basal cell carcinoma syndrome

Author: Annie Morrison, M.D. (see Authors page)
Editor: Kelly R. Magliocca, D.D.S., M.P.H.

Revised: 21 June 2018, last major update February 2014

Copyright: (c) 2004-2018, PathologyOutlines.com, Inc.

PubMed Search: Nevoid basal cell carcinoma syndrome [title]

Cite this page: Morrison, A. Odontogenic cysts: nevoid basal cell carcinoma syndrome. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/mandiblemaxillabasalcellnevus.html. Accessed July 22nd, 2018.
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:
Missing Image

Sonic Hedgehog pathway

Missing Image

Diagnostic protocols

Missing Image

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:
Missing Image

Multiple odontogenic cysts

Missing Image Missing Image Missing Image

Odontogenic keratocysts

Missing Image

Multiple KCOTs



Missing Image

Multiple unilocular radiolucencies

Missing Image

Radiolucent area with minimum cortical plate expansion

Missing Image

Hypodense areas

Missing Image

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
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:
Missing Image

Increased inner canthal distance

Missing Image

Hyper pigmented plaques

Missing Image Missing Image

Clinical features of NBCCS




Palmar pits:
Missing Image

Multiple pits on the palm

Missing Image

Palmer pits in the hypothenar eminence

Missing Image Missing Image

Numerous tiny pits over her palms and soles

Missing Image

Small brown papules and palmar pits




Basal cell carcinoma:
Missing Image

Nodular pigmented lesion

Missing Image

Pearly, pedunculated, telangiectatic papules

Missing Image

Three papules on the neck

Missing Image

Soft, minimally hyperpigmented neoplasms

Missing Image

Skin colored papules on lateral neck

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