NEVOID BASAL CELL CARCINOMA SYNDROME (GORLIN SYNDROME)

Nevoid basal cell carcinoma syndrome (NBCCS) is an inherited neurocutaneous familial cancer condition with high penetrance and variable expressivity. 

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Nevoid basal cell carcinoma syndrome (NBCCS) is an inherited neurocutaneous familial cancer condition with high penetrance and variable expressivity. 

NBCCS is a multi-system condition characterized by the development of jaw keratocysts and/or basal cell carcinomas, typically beginning in the second or third decade of life. NBCCS affects approximately 1 in every 31,000 individuals.1 Genetic testing can assist in confirming a diagnosis and informing medical management and surveillance.

Disease Name 
Nevoid basal cell carcinoma syndrome (NBCCS)
Gorlin syndrome
Basal Cell Nevus Syndrome (BCNS)
Disease Information 

NBCCS is an autosomal dominant condition with a de novo mutation rate of approximately 20-30%, and up to 90% of affected individuals develop basal cell carcimoma. In addition, NBCCS can cause odontogenic keratocysts, congenital skeletal anomalies, cerebral calcifications, macrocephaly, polydactyly, intellectual disability, palmar epidermal pits, and cardiac and ovarian fibromas.1-5 Up to 5% of children with NBCCS develop medulloblastoma, also called primitive neuroectodermal tumor (PNET), most often the desmoplastic subtype. The diagnosis of NBCCS is typically made based on clinical features.

A clinical diagnosis of NBCCS is reached when an individual is found to have 2 major and one minor feature, or one major and 3 minor features.

Major Features Minor Features
Lamellar calcification of the falx Childhood medulloblastoma
Jaw keratocyst Lympho-mesenteric or pleural cysts
Palmar/plantar pits Macrocephaly
Multiple basal cell carcinomas (>5 in a lifetime) Cleft lip/palate
First-degree relative with NBCCS Vertebral/rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)
Preaxial or postaxial polydactyly
Ovarian/cardiac fibromas
Ocular anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium)

 

NBCCS is caused by germline mutations in PTCH1 (formerly PTCH). Somatic PTCH1 mutations are also found in sporadic cases of medulloblastoma, squamous cell carcinoma, breast and colon cancer cases.6,7 PTCH1 has also been identified as one of the infrequent genetic causes of holoprosencephaly 8,9 given its role in the sonic hedgehog (SHH) pathway.

Testing Benefits & Indication 

Genetic testing is useful for diagnostic confirmation in symptomatic individuals and for testing of at-risk asymptomatic family members (including prenatal diagnosis). Molecular testing may help direct medical screening/treatment, due to available genotype-phenotype correlations. Molecular confirmation of a diagnosis may also help avoid unnecessary testing and procedures, and allow for appropriate anticipatory guidance and medical surveillance in those at risk. When the clinical diagnosis of NBCCS is confirmed by genetic testing, implementation of periodic screening can lead to early detection of tumors, timely intervention, and improved outcome for individuals affected with this disorder.

PTCH1 testing may be considered for any of the following:

  • Any individual with suspected NBCCS that does not meet clinical criteria
  • Any asymptomatic child with a parent known to have a pathogenic PTCH1 mutation
  • Any individual with a family history of NBCCS
  • Any individual with a clinical diagnosis of NBCCS interested in pursuing preimplantation genetic diagnosis or prenatal testing for this condition
Test Description 

PTCH1 coding exons1-23 and well into the 5’ and 3’ ends of all the introns and untranslated regions are analyzed by sequencing. Gross deletion/duplication analysis determines gene copy number for coding exons 1-23. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Genomic deoxyribonucleic acid (gDNA) is isolated from the patient’s specimen using standardized methodology and quantified. Sequence enrichment of the targeted coding exons and adjacent intronic nucleotides is carried out by a bait-capture methodology, using long biotinylated oligonucleotide probes followed by polymerase chain reaction (PCR) and next generation sequencing (NGS). Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.11  Gross deletion/duplication analysis of PTCH1 using read-depth from NGS data is also performed. Any copy number changes detected by NGS are confirmed by targeted chromosomal microarray and/or multiplex ligation-dependent probe amplification (MLPA).

Mutation Detection Rate 

Mutations in PTCH1 can be detected by gene sequencing and deletion/duplication analysis for approximately 56-100% of individuals meeting the clinical diagnostic criteria for NBCCS (clinical sensitivity).10 Ambry's PTCH1 testing can detect >99.9% of described mutations, when they are present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above in the Quick Links section at the top of this page.

Since tumors associated with NBCCS have been reported in young children, testing of asymptomatic children under the age of 18 years is appropriate to consider when the disease-causing mutation in an affected parent is known.

Turnaround Time 
TEST CODE TECHNIQUE CALENDAR DAYS
5684 PTCH1 Gene Sequence and Deletion/Duplication Analysis 14-21 

 

Specialty 
Genes 
PTCH1
References 
  1. Evans DG, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–332.
  2. Soufir N, et al. PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study. Br J Cancer. 2006;95(4):548-553.
  3. Joshi PS, et al. Gorlin-Goltz syndrome. Dent Res J (Isfahan). 2012;9(1):100-106.
  4. Li TJ, et al. PTCH germline mutations in Chinese nevoid basal cell carcinoma syndrome patients. Oral Dis. 2008;14(2):174-179.
  5. Yamamoto K, et al. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature. Congenit Anom (Kyoto). 2009;49(1):8-14.
  6. Xie J, et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 1997;57(12):2369-2372.
  7. Ping XL, et al. PTCH mutations in squamous cell carcinoma of the skin. J Invest Dermatol. 2001;116(4):614-616.
  8. Ribeiro LA, et al. PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI. Am J Med Genet A. 2006;140:2584–2586.
  9. Ming JE, et al. Mutations in PATCHED-1, the receptor for sonic hedgehog, are associated with holoprosencephaly. Hum Genet. 2002;110:297–301.
  10. Evans DG and Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. In: Pagon RA, et al., editors. GeneReviews®. [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. 2002 Jun 20 [updated 2013 Mar 70.
  11. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932.