Abstract
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental defects and tumorigenesis. The gene responsible for NBCCS is PTCH1. The development of meningioma in NBCCS patients is a rare event. Here, we report two cases of NBCCS in which meningiomas did develop. The first patient carried a germline mutation in one allele of PTCH1, c.290dupA (p.N97KfsX43). In addition, the meningioma sample carried a somatic mutation, c.307delG (p.Val103LeufsX15), in the other allele of the same gene, suggesting a second hit. This is the first case of NBCCS-associated meningioma explained by the standard two-hit hypothesis. The second patient had a germline nonsense mutation in the SUFU gene, c.550C>T (p.Q184X). SUFU is located downstream of PTCH1 in the sonic hedgehog signaling pathway. This is the second time a germline mutation in SUFU has been found to cause NBCCS. Together with the previous report describing three cases of non-NBCCS medulloblastoma carrying a germline mutation in this gene, individuals with a SUFU germline mutation are expected to have a markedly high risk of developing medulloblastoma and probably meningioma.
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References
Gorlin RJ, Goltz RW (1960) Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib a syndrome. N Engl J Med 262:908–912
Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA (1993) Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet 30:460–464
Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, Martin N, Wicking C, Chenevix-Trench G (1994) Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet 50:282–290
Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ (1997) Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 69:299–308
Endo M, Fujii K, Sugita K, Saito K, Kohno Y, Miyashita T (2012) Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. Am J Med Genet A 158A:351–357
Fukushima Y, Oka H, Utsuki S, Iwamoto K, Fujii K (2004) Nevoid Basal cell carcinoma syndrome with medulloblastoma and meningioma—case report. Neurol Med Chir (Tokyo) 44:665–668
Pribila JT, Ronan SM, Trobe JD (2008) Multiple intracranial meningiomas causing papilledema and visual loss in a patient with nevoid Basal cell carcinoma syndrome. J Neuroophthalmol 28:41–46
Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671
Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, Leffell DJ, Gerrard B, Goldstein AM, Dean M, Toftgard R, Chenevix-Trench G, Wainwright B, Bale AE (1996) Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85:841–851
Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087
Dunaeva M, Michelson P, Kogerman P, Toftgard R (2003) Characterization of the physical interaction of gli proteins with SUFU proteins. J Biol Chem 278:5116–5122
Svärd J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergström A, Ericson J, Toftgård R, Teglund S (2006) Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 10:187–197
Fujii K, Kohno Y, Sugita K, Nakamura M, Moroi Y, Urabe K, Furue M, Yamada M, Miyashita T (2003) Mutations in the human homologue of Drosophila patched in Japanese nevoid basal cell carcinoma syndrome patients. Hum Mutat 21:451–452
Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823
Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EHJ, de Sauvage FJ (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–92
Tamoney HJ Jr (1969) Basal cell nevoid syndrome. Am Surg 35:279–283
Stoelinga PJ, Peters JH, van de Staak WJ, Cohen MM Jr (1973) Some new findings in the basal-cell nevus syndrome. Oral Surg Oral Med Oral Pathol 36:686–692
Southwick GJ, Schwartz RA (1979) The basal cell nevus syndrome: disasters occurring among a series of 36 patients. Cancer 44:2294–2305
Mortimer PS, Geaney DP, Liddell K, Dawber RP (1984) Basal cell naevus syndrome and intracranial meningioma. J Neurol Neurosurg Psychiatry 47:210–212
Aumaitre O, Sampoux P, Georget AM, Mondie JM, Thieblot P, Dordain G (1986) Neurologic manifestations of basal cell nevomatosis. A case. Presse Med 15:2105–2107
Jones KL, Wolf PL, Jensen P, Dittrich H, Benirschke K, Bloor C (1986) The Gorlin syndrome: a genetically determined disorder associated with cardiac tumor. Am Heart J 111:1013–1015
Albrecht S, Goodman JC, Rajagopolan S, Levy M, Cech DA, Cooley LD (1994) Malignant meningioma in Gorlin’s syndrome: cytogenetic and p53 gene analysis. Case report. J Neurosurg 81:466–471
O’Malley S, Weitman D, Olding M, Sekhar L (1997) Multiple neoplasms following craniospinal irradiation for medulloblastoma in a patient with nevoid basal cell carcinoma syndrome. Case report. J Neurosurg 86:286–288
Tate G, Li M, Suzuki T, Mitsuya T (2003) A new germline mutation of the PTCH gene in a Japanese patient with nevoid basal cell carcinoma syndrome associated with meningioma. Jpn J Clin Oncol 33:47–50
Campbell RM, Mader RD, Dufresne RG Jr (2005) Meningiomas after medulloblastoma irradiation treatment in a patient with basal cell nevus syndrome. J Am Acad Dermatol 53:S256–S259
Evans DG, Birch JM, Orton CI (1991) Brain tumours and the occurrence of severe invasive basal cell carcinoma in first degree relatives with Gorlin syndrome. Br J Neurosurg 5:643–646
Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–310
Pastorino L, Ghiorzo P, Nasti S, Battistuzzi L, Cusano R, Marzocchi C, Garrè ML, Clementi M, Scarrà GB (2009) Identification of a SUFU germline mutation in a family with gorlin syndrome. Am J Med Genet A 149A:1539–1543
Evans DG, Farndon PA, Burnell LD, Gattamaneni HR, Birch JM (1991) The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer 64:959–961
Amlashi SF, Riffaud L, Brassier G, Morandi X (2003) Nevoid basal cell carcinoma syndrome: relation with desmoplastic medulloblastoma in infancy. A population-based study and review of the literature. Cancer 98:618–624
Schofield D, West DC, Anthony DC, Marshal R, Sklar J (1995) Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas. Am J Pathol 146:472–480
Cowan R, Hoban P, Kelsey A, Birch JM, Gattamaneni R, Evans DG (1997) The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br J Cancer 76:141–145
Acknowledgments
We greatly appreciate Hiromi Hatsuse for her technical assistance. We are grateful to the participating family members, whose contributions made this study possible. This research was supported by Science Research Grants for intractable diseases in Japan (H22-intractable diseases-120) from the Ministry of Health, Labour and by a Grant-in-Aid for Science Research (20591261) from the Ministry of Education, Culture, Sports, Science and Technology.
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Kijima, C., Miyashita, T., Suzuki, M. et al. Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. Familial Cancer 11, 565–570 (2012). https://doi.org/10.1007/s10689-012-9548-0
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DOI: https://doi.org/10.1007/s10689-012-9548-0