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Nevoid Basal Cell Carcinoma Syndrome

  • Author: Daniel Berg, MD; Chief Editor: Dirk M Elston, MD  more...
 
Updated: Sep 04, 2015
 

Background

Nevoid basal cell carcinoma syndrome (NBCCS) represents a series of multiorgan abnormalities known to be the consequence of abnormalities in the PTCH gene. The syndrome has been documented for 50 years, but more recent developments in molecular genetics have dramatically increased understanding of its pathophysiology and opened up molecular avenues for treatment in the future.

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Pathophysiology

Multiple organ systems may be impacted in nevoid basal cell carcinoma syndrome (NBCCS). Abnormalities of the skin, the skeletal system, the genitourinary system, and the central nervous system (CNS) are the most common. Other less common neoplasms and abnormalities are also associated with the disease and are well documented.[1]

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Etiology

NBCCS, also known as basal cell nevus syndrome (BCNS), is an autosomal dominant syndrome caused by mutations in the PTCH (patched) gene found on chromosome arm 9q. The disease has complete penetrance and variable expressivity. Although clinical features vary more among families than within families, no clear-cut link exists between specific mutations and phenotype. Approximately one third of cases are new mutations.

Genetics

First elucidated in fruit flies, the protein product of the PTCH gene is important in determining segment polarity of wings and limbs (anterior-posterior relationships in developing embryos). In mammals, PTCH is an important inhibitor in the so-called hedgehog (HH) signaling pathway, whose downstream proteins can lead to cell growth. PTCH is frequently mutated on 1 allele in sporadic basal cell carcinomas (BCCs), and according to Epstein, "upregulation of HH signaling is the pivotal abnormality in all BCCs."[2] . Its wide-reaching activity accounts for the myriad findings in patients with NBCCS.[3, 4, 5, 6, 7]

Ultraviolet exposure

Ultraviolet (UV) light exposure appears to be an important cofactor. BCCs are much more common in sun-exposed areas and are much more common in white individuals with the syndrome. Nevertheless, molecular genetic studies looking for UV-related mutations in BCCs obtained from patients with NBCCS leave the possibility that agents other than UV-B may cause alterations to the gene.[8]

Radiation

Patients are particularly sensitive to ionizing radiation (radiation therapy; XRT), and reports have described multiple BCCs in the radiation portal developing in patients treated with XRT for medulloblastoma. Reports of more aggressive BCCs occurring in sites of previous XRT for BCC also exist. Radiobiologic studies on fibroblasts suggest an abnormal response to radiation in fibroblasts obtained from patients with NBCCS.

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Epidemiology

The approximate prevalence of NBCCS is reported to be 1 case per 56,000-164,000 population. The prevalence is likely to be considerably higher in individuals younger than 20 years who present with BCCs.

The syndrome is found in all races, and men and women are affected about equally (1:1.3). However, a definite but smaller percentage of black individuals present with skin cancer and have fewer skin cancers than affected white individuals. This decreased number of skin cancers, a diagnostic hallmark, may account for the comparatively fewer patients with darker skin ascertained in reviews of the syndrome. The lone study evaluating an African cohort found that only 20% with NBCCS had basal cell carcinoma.[9] Recent Japanese data also showed a lower rate of skin cancer with a later age of onset compared with whites.[10] Full expression of the non–skin cancer features of the syndrome is found in patients of all skin types.

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Contributor Information and Disclosures
Author

Daniel Berg, MD Clinical Professor of Dermatology, University of Washington School of Medicine

Daniel Berg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Mohs Surgery, American Academy of Dermatology, American Society for Dermatologic Surgery

Disclosure: Received honoraria from Genentech for review panel membership; Received honoraria from DUSA Pharmaceuticals for review panel membership.

Coauthor(s)

Jonathan M Olson, MD Fellow, Division of Dermatology, University of Washington Medical Center

Jonathan M Olson, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

R Stan Taylor, MD The JB Howell Professor in Melanoma Education and Detection, Departments of Dermatology and Plastic Surgery, Director, Skin Surgery and Oncology Clinic, University of Texas Southwestern Medical Center

R Stan Taylor, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Medical Association

Disclosure: Nothing to disclose.

References
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  12. Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA. Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. 1993 Jun. 30(6):460-4. [Medline]. [Full Text].

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  16. Kimonis VE, Singh KE, Zhong R, Pastakia B, Digiovanna JJ, Bale SJ. Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome. Genet Med. 2013 Jan. 15(1):79-83. [Medline].

  17. Veenstra-Knol HE, Scheewe JH, van der Vlist GJ, van Doorn ME, Ausems MG. Early recognition of basal cell naevus syndrome. Eur J Pediatr. 2005 Mar. 164(3):126-30. [Medline].

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  19. Ferreres JR, Macaya A, Jucglà A, Muniesa C, Prats C, Peyrí J. Hundreds of basal cell carcinomas in a Gorlin-Goltz syndrome patient cured with imiquimod 5% cream. J Eur Acad Dermatol Venereol. 2006 Aug. 20(7):877-8. [Medline].

  20. Wolfe CM, Green WH, Cognetta AB Jr, Hatfield HK. A possible chemopreventive role for photodynamic therapy in Gorlin syndrome: a report of basal cell carcinoma reduction and review of literature. Australas J Dermatol. 2013 Feb. 54(1):64-8. [Medline].

  21. Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg. 2004 Jul. 30(7):1054-61. [Medline].

  22. Oseroff AR, Shieh S, Frawley NP, Cheney R, Blumenson LE, Pivnick EK, et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Arch Dermatol. 2005 Jan. 141(1):60-7. [Medline].

  23. Migden MR, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015 Jun. 16 (6):716-28. [Medline].

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Multiple basal cell carcinomas on the back of a patient with nevoid basal cell carcinoma syndrome.
Multiple small papules on the neck and upper trunk in a 10-year-old patient. Biopsy confirmed basal cell carcinoma.
Palmar pits in an adult.
Syndactyly is noted in some affected persons such as this 8-year-old boy.
 
 
 
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