Nevoid Basal Cell Carcinoma Syndrome
- Author: Daniel Berg, MD; Chief Editor: Dirk M Elston, MD more...
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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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.
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.
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." . Its wide-reaching activity accounts for the myriad findings in patients with NBCCS.[3, 4, 5, 6, 7]
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.
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.
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. Recent Japanese data also showed a lower rate of skin cancer with a later age of onset compared with whites. Full expression of the non–skin cancer features of the syndrome is found in patients of all skin types.
Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008 Oct. 8(10):743-54. [Medline].
Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 2004 Nov-Dec. 6(6):530-9. [Medline].
Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996 Jun 14. 85(6):841-51. [Medline].
High A, Zedan W. Basal cell nevus syndrome. Curr Opin Oncol. 2005 Mar. 17(2):160-6. [Medline].
Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996 Jun 14. 272(5268):1668-71. [Medline].
Goldstein AM, Bale SJ, Peck GL, DiGiovanna JJ. Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol. 1993 Jul. 29(1):34-41. [Medline].
Titinchi F, Nortje CJ, Parker ME, van Rensburg LJ. Nevoid basal cell carcinoma syndrome: a 40-year study in the South African population. J Oral Pathol Med. 2013 Feb. 42(2):162-5. [Medline].
Endo M, Fujii K, Sugita K, Saito K, Kohno Y, Miyashita T. Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. Am J Med Genet A. 2012 Feb. 158A(2):351-7. [Medline].
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].
Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore). 1987 Mar. 66(2):98-113. [Medline].
Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. 1994 Apr 15. 50(3):282-90. [Medline].
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 Mar 31. 69(3):299-308. [Medline].
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].
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].
Kimonis VE, Mehta SG, Digiovanna JJ, Bale SJ, Pastakia B. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med. 2004 Nov-Dec. 6(6):495-502. [Medline].
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].
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].
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].
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].
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].
Tang JY, Mackay-Wiggan JM, Aszterbaum M, Yauch RL, Lindgren J, Chang K. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012 Jun 7. 366(23):2180-8. [Medline].
Wolfe CM, Green WH, Cognetta AB Jr, Hatfield HK. Basal cell carcinoma rebound after cessation of vismodegib in a nevoid basal cell carcinoma syndrome patient. Dermatol Surg. 2012 Nov. 38(11):1863-6. [Medline].
Maybury CM, Craythorne EE, Urbano TG, Mallipeddi R. Systemic therapy for advanced basal cell carcinoma. Lancet Oncol. 2015 Jun. 16 (6):608-10. [Medline].
Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012 Jun 7. 366(23):2171-9. [Medline].