Cutaneous Expression of Familial Cancer Syndromes
DOI:
https://doi.org/10.2340/00015555-3852Keywords:
genodermatoses, familial cancer, hereditary neoplastic syndromes, genetic predisposition, skin diseases, cutaneous lesionsAbstract
Genodermatoses are inherited syndromes with cutaneous manifestations. Some genodermatoses are associated with malignancy of internal organs and tissues. Early detection of the typical signs of these syndromes is important, because those lesions are a sign of underlying predisposition to extracutaneous neoplasms. The dermatologist has an important role in the early detection of these signs and syndromes, as early detection may affect the clinical course of the disease. We report here the characteristic cutaneous findings that dermatologists should be aware of in order to identify a genodermatosis with a possible associated malignancy. An updated overview of the pathogenesis and clinical findings of these syndromes is provided. Furthermore, surveillance protocols and treatment recommendations are explored.
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Von Recklinghausen F. Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin: August Hirschwald; 1882.
Huntley C, Hodder A, Ramachandran M. Clinical and historical aspects of the Elephant Man: exploring the facts and the myths. Gene 2015; 555: 63–65.
Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 2014; 13: 834–843.
Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol 2009; 61: 1–16.
Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988; 45: 575–578.
Fenot M, Stalder JF, Barbarot S. Juvenile xanthogranulomas are highly prevalent but transient in young children with neurofibromatosis type 1. J Am Acad Dermatol 2014; 71: 389–390.
Vaassen P, Rosenbaum T. Nevus anemicus as an additional diagnostic marker of neurofibromatosis type 1 in childhood. Neuropediatrics 2016; 47: 190–193.
Doser K, Kenborg L, Andersen EW, Bidstrup PE, Kroyer A, Hove H, et al. Educational delay and attainment in persons with neurofibromatosis 1 in Denmark [published correction appears in Eur J Hum Genet 2019 Mar 22]. Eur J Hum Genet 2019; 27: 857–868.
Bergqvist C, Servy A, Valeyrie-Allanore L, Ferkal S, Combemale P, Wolkenstein P, et al. Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966. Orphanet J Rare Dis 2020; 15: 37.
Liy-Wong C, Mohammed J, Carleton A, Pope E, Parkin P, Lara-Corrales I. The relationship between neurofibromatosis type 1, juvenile xanthogranuloma, and malignancy: a retrospective case-control study. J Am Acad Dermatol 2017; 76: 1084–1087.
Denayer E, Legius E. Legius syndrome and its relationship with neurofibromatosis type 1. Acta Derm Venereol 2020; 100: adv00093.
Chamseddin BH, Le LQ. Management of cutaneous neurofibroma: current therapy and future directions. Neurooncol Adv 2019; 2: i107–i116.
Klesse LJ, Jordan JT, Radtke HB, Rosser T, Schorry E, Ullrich N et al. The use of MEK inhibitors in neurofibromatosis type 1-associated tumors and management of toxicities. Oncologist 2020; e1109–e1116.
Asthagiri AR, Parry DM, Butman JA, Kim HJ, Tsilou ET, Zhuang Z, Lonser RR. Neurofibromatosis type 2. Lancet 2009; 373: 1974–1986.
Wishart JH. Case of tumours in the skull, dura mater, and brain. Edinburgh Med Surg J 1822; 18: 393–397.
Cushing H. Tumors of the nervus acusticus and the syndrome of the cerebellopontine angle. Philadelphia: W.B. Saunders, 1917.
National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, MD, USA, 1987. Neurofibromatosis 1988; 1: 172–178.
Evans D, Huson S, Donnai D, Neary W, Blair V, Newton V, et al. A clinical study of type 2 neurofibromatosis. Q J Med 1992; 84: 603– 618.
Baser ME, Friedman JM, Joe H, Shenton A, Wallace AJ, Ramsden RT, et al. Empirical development of improved diagnostic criteria for neurofibromatosis 2. Genet Med 2011; 13: 576–581.
Ruggieri M, Praticò AD, Serra A, Maiolino L, Cocuzza S, Di Mauro P, et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36: 345–367.
Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis 2009; 4: 16.
Lloyd SK, Evans DG. Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol 2013; 115: 957–967.
Strowd RE 3rd. Available therapies for patients with neurofibromatosis-related nervous system tumors. Curr Treat Options Oncol 2020; 21: 81.
Pringle JJ. A case of congenital adenoma sebaceum. Br J Dermatol 1890; 2: 1–14.
Jansen FE, van Nieuwenhuizen O, van Huffelen AC. Tuberous sclerosis complex and its founders. J Neurol Neurosurg Psychiatry 2004; 75: 770.
Cardis MA, DeKlotz CMC. Cutaneous manifestations of tuberous sclerosis complex and the peadiatrician’s role. Arch Dis Child 2017; 102: 858–863.
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372: 657–668.
Nathan N, Burke K, Moss J, Darling TN. A diagnostic and management algorithm for individuals with an isolated skin finding suggestive of tuberous sclerosis complex. Br J Dermatol 2017; 176: 220–223.
Treichel AM, Hamieh L, Nathan NR, Tyburczy ME, Wang JA, Oyerinde O, et al. Phenotypic distinctions between mosaic forms of tuberous sclerosis complex. Genet Med 2019; 21: 2594–2604.
Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y, Thorner AR, et al. Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLoS Genet 2015; 11: e1005637.
Northrup H, Krueger DA. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49: 243–254.
Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015; 14: 733–745.
Nathan N, Tyburczy ME, Hamieh L, Wang JA, Brown GT, Richard Lee CC et al. Nipple angiofibromas with loss of TSC2 are associated with tuberous sclerosis complex. J Invest Dermatol 2016; 136: 535–538.
Gupta N, Henske EP. Pulmonary manifestations in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet 2018; 178: 326–337.
Krueger DA, Northrup H. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49: 255–265.
Wataya-Kaneda M, Nagai H, Ohno Y, Yokozeki H, Fujita Y, Niizeki H, et al. Safety and efficacy of the sirolimus gel for TSC patients with facial skin lesions in a long-term, open-label, extension, uncontrolled clinical trial. Dermatol Ther (Heidelb) 2020; 10: 635–650.
Teng JM, Cowen EW, Wataya-Kaneda M, Gosnell ES, Witman PM, Hebert AA, et al. Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol 2014; 150: 1095–1101.
Gardner EJ. A genetic and clinical study of intestinal polyposis: a predisposing factor for carcinoma of the colon and rectum. Am J Hum Genet 1951; 3: 167–176.
Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet 1953; 5: 139–147.
Jasperson KW, Patel SG, Ahnen DJ. APC – associated polyposis conditions. 1998 Dec 18 [Updated 2017 Feb 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2020. [Accessed April 2, 2021] Available from: https://www.ncbi.nlm.nih.gov/books/NBK1345/.
Groen EJ, Roos A, Muntinghe FL, Enting RH, Vries J, Kleibeuker JH, et al. Extra-intestinal manifestations of familial adenomatous polyposis. Ann Surg Oncol 2008; 15: 2439–2450.
Kanitakis J. Adnexal tumours of the skin as markers of cancer-prone syndromes. J Eur Acad Dermatol Venereol 2010; 24: 379–387.
Rehan S, Aye K. In patients with a positive family history of familial adenomatous polyposis can the condition be diagnosed from the presence of congenital hypertrophy of the retinal pigment epithelium detected via an eye examination: a systematic review. Clin Experiment Ophthalmol 2020; 48: 98–116.
Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG Clinical Guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110: 223–263.
Slowik V, Attard T, Dai H, Shah R, Septer S. Desmoid tumors complicating familial adenomatous polyposis: a meta-analysis mutation spectrum of affected individuals. BMC Gastroenterology 2015; 15: 84.
Chenbhanich J, Atsawarungruangkit A, Korpaisarn S, Phupitakphol T, Osataphan S, Phowthongkum P. Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis. Fam Cancer 2019; 18: 53–62.
Connor JT. Aesculapian society of London. Lancet 1895; 2: 1169.
Peutz JLA. Over een zeer merkwaardige, gecombineerde familiaire polyposis van de slijmvliezen van den tractus intestinalis met die van de neuskeelholte en gepaard met eigenaardige pigmentaties van huid en slijmvliezen. Ned Maandschr Geneeskd 1921; 10: 134–146.
Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. A syndrome of diagnostic significance. N Engl J Med 1949; 241: 1031–1036.
Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 2010; 59: 975–986.
Kopacova M, Tacheci I, Rejchrt S, Bures J. Peutz Jeghers syndrome: diagnostic and therapeutic approach. World J Gastroenterol 2009; 15: 5397–5408.
Van Lier MGF, Wagner A, Mathus-Vliegen EMH, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 2010; 105: 1258–1264.
Rajan N, Ashworth A. Inherited cylindromas: lessons from a rare tumour. Lancet Oncol 2015; 16: e460–e469.
Dubois A, Rajan N. CYLD cutaneous syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2020. [Accessed April 2, 2021] Available from: https://www.ncbi.nlm.nih.gov/books/NBK555820/.
Kazakov DV. Brooke-Spiegler syndrome and phenotypic variants: an update. Head Neck Pathol 2016; 10: 125–130.
Dubois A, Wilson V, Bourn D, Rajan N. CYLD GeneticTesting for Brooke-Spiegler syndrome, familial cylindromatosis and multiple familial trichoepitheliomas. PLoS Curr 2015; 7: ecurrents.eogt.45c4e63dd43d62e12228cc5264d6a0db.
Lloyd KM II, Dennis M. Cowden’s disease. A possible new symptoms complex with multiple system involvement. Ann Intern Med 1963; 58: 136–142.
Weary PE, Gorlin RJ, Gentry WC, Comer JE, Greer KE. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol 1972; 106: 682–690.
Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, et al. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet 1999; 7: 267–273.
Farooq A, Walker LJ, Bowling J, Audisio RA. Cowden syndrome. Cancer Treat Rev 2010; 36: 577–583.
Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 2013; 105: 1607–1616.
Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 2012; 18: 400–407.
Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, Stochholm K. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome. Eur J Med Genet 2020; 63: 103873.
The NCCN 2019 Cowden syndrome clinical practice guidelines in oncology. National Comprehensive Cancer Network. [Accessed April 2, 2021] Available from: http://www.nccn.org.
Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64: 270–283.
Bain F. Carney complex. Mayo Clin Proc 1986; 61: 508.
Stratakis CA. Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes. Pediatr Pathol Mol Med 2000; 19: 41–68.
Correa R, Salpea P, Stratakis C. Carney complex: an update. Eur J Endocrinol 2015; 173: M85–M97.
Bertherat J. Carney complex (CNC). Orphanet J Rare Dis 2006; 1: 21.
Espiard S, Bertherat J. Carney complex. Front Horm Res 2013; 41: 50–62.
Hornstein OP, Knickenberg M. Perifollicular fibromatosis cutis with polyps of the colon – a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res 1975; 253: 161–175.
Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977; 113: 1674–1677.
BHD foundation. Published BHD Families; [cited 2020 Apr 21]. Available from: https://www.bhdsyndrome.org/for-researchers/what-is-bhd/introduction/published-bhd-families/.
Gupta S, Kang HC, Ganeshan D, Morani A, Gautam R, Choyke PL, et al. The ABCs of BHD: an in-depth review of Birt-Hogg-Dubé syndrome. AJR Am J Roentgenol 2017; 209: 1291–1296.
Jensen DK, Villumsen A, Skytte AB, Madsen MG, Sommerlund M, Bendstrup E. Birt-Hogg-Dubé syndrome: a case report and a review of the literature. Eur Clin Respir J 2017; 4: 1292378.
Reese E, Sluzevich J, Kluijt I, Teertstra HJ, De Jong D, Horenblas S, Ryu J. Birt-Hogg-Dubé syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer syndromes. Bethesda (MD): National Center for Biotechnology Information (US); 2009.
Sattler EC, Ertl-Wagner B, Pellegrini C, Peris K, Reithmair M, Schädle N, et al. Cutaneous melanoma in Birt–Hogg–Dube syndrome: part of the clinical spectrum? Br J Dermatol 2018; 178: e132–e133.
Sattler EC, Reithmair M, Steinlein OK. Kidney cancer characteristics and genotype- phenotype-correlations in Birt-Hogg-Dube ́ syndrome. PLoS One 2018; 13: e0209504.
Daccord C, Good JM, Morren MA, Bonny O, Hohl D, Lazor R. Birt-Hogg-Dubé syndrome. Eur Respir Rev 2020; 29: 200042.
Blum P, Jean L. Besnier’s eruptive leiomyoma. Bull Soc Fr Dermatol Syphiligr. 1954; 61: 349–350.
Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 1973; 53: 409–416.
Launonen V, Vierimaa O, Kiuru M, Isola J, Roth S, Pukkala E, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 2001; 98: 3387–3392.
Hansen AW, Chayed Z, Pallesen K, Codruta Vasilescu I, Bygum A. Hereditary leiomyomatosis and renal cell cancer. Acta Derm Venereol 2020; 100: adv00012.
Patel VM, Handler MZ, Schwartz RA, Lambert WC. Hereditary leiomyomatosis and renal cell cancer syndrome: an update and review. J Am Acad Dermatol 2017; 77: 149–158.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3: 721–732.
Schierbeck J, Vestergaard T, Bygum A. Skin cancer associated genodermatoses: a literature review. Acta Derm Venereol 2019; 99: 360–369.
AlSabbagh MM, Baqi MA. Bazex-Dupré-Christol syndrome: review of clinical and molecular aspects. Int J Dermatol 2018; 57: 1102–1106.
Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis 2011; 6: 70.
Hengge UR, Emmert S. Clinical features of xeroderma pigmentosum. Adv Exp Med Biol 2008; 637: 10–18.
Arora H, Chacon AH, Choudhary S, McLeod MP, Meshkov L, Nouri K, et al. Bloom syndrome. Int J Dermatol 2014; 53: 798–802.
Larizza L, Roversi G, Volpi L. Rothmund-Thomson syndrome. Orphanet J Rare Dis 2010; 5: 2.
Larsen AK, Mikkelsen DB, Hertz JM, Bygum A. Manifestations of Gorlin-Goltz syndrome. Dan Med J 2014; 61: A4829.
Eckerle Mize D, Bishop M, Resse E, Sluzevich J. Familial Atypical Multiple Mole Melanoma Syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes. Bethesda (MD): National Center for Biotechnology Information (US); 2009. [Accessed April 2, 2021] Available from: https://www.ncbi.nlm.nih.gov/books/NBK7030/.
Ellis A, Risk JM, Maruthappu T, Kelsell DP. Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms. Orphanet J Rare Dis 2015; 10: 126.
Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis 2016; 11: 159.
Mehta PA, Tolar J. Fanconi Anemia. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsâ. Seattle (WA): University of Washington, Seattle; 1993–2020. [Accessed October 10, 2020] Available from: https://www.ncbi.nlm.nih.gov/books/.
Savage SA. Dyskeratosis congenita. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsâ. Seattle (WA): University of Washington, Seattle; 1993–2020. [Accessed September 4, 2020] Available from: https://www.ncbi.nlm.nih.gov/books/.
Oshima J, Sidorova JM, Monnat RJ. Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Res Rev 2017; 33: 105–114.
Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 2010; 18: 8–14.
Chandra S, Bronicki L, Nagaraj CB, Zhang K. WAS-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsâ. Seattle (WA): University of Washington, Seattle; 1993–2020. [Accessed April 2, 2021] Available from: https://www.ncbi.nlm.nih.gov/books/.
Chrzanowska KH, Gregorek H, Dembowska-Baginska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis 2012; 7: 13.
Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med 2011; 13: 755–764.
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