Abstract
Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30–45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease.
References
Birt AR, Hogg GR, Dube WJ (1977) Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 113:1674–1677
Toro JR, Wei MH, Glenn GM et al (2008) BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet 45:321–331
Kunogi M, Kurihara M, Ikegami TS et al (2010) Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet 47:281–287
Benusiglio PR, Giraud S, Deveaux S et al (2014) Renal cell tumour characteristics in patients with the Birt-Hogg-Dube cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis 9:163
Schmidt LS, Nickerson ML, Warren MB et al (2005) Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet 76:1023–1033
Pavlovich CP, Walther MM, Eyler RA et al (2002) Renal tumors in the Birt-Hogg-Dube syndrome. Am J Surg Pathol 26:1542–1552
Pavlovich CP, Grubb RL 3rd, Hurley K et al (2005) Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome. J Urol 173:1482–1486
Menko FH, van Steensel MA, Giraud S et al (2009) Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol 10:1199–1206
Argani P, Hicks J, De Marzo AM et al (2010) Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol 34:1295–1303
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70:93–105
Amin MB, Gupta R, Ondrej H et al (2009) Primary thyroid-like follicular carcinoma of the kidney: report of 6 cases of a histologically distinctive adult renal epithelial neoplasm. Am J Surg Pathol 33:393–400
Gunji Y, Akiyoshi T, Sato T et al (2007) Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet 44:588–593
Houweling AC, Gijezen LM, Jonker MA et al (2011) Renal cancer and pneumothorax risk in Birt-Hogg-Dube syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer 105:1912–1919
Johannesma PC, van den Borne BE, Gille JJ et al (2014) Spontaneous pneumothorax as indicator for Birt-Hogg-Dube syndrome in paediatric patients. BMC Pediatr 14:171
Bruder E, Passera O, Harms D et al (2004) Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 28:1117–1132
Wu A, Kunju LP, Cheng L, Shah RB (2008) Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical and molecular characteristics with an emphasis on the spectrum of Xp11.2 translocation-associated and unusual clear cell subtypes. Histopathology 53:533–544
Perlman EJ (2010) Pediatric renal cell carcinoma. Surg Pathol Clin 3:641–651
Khoo SK, Giraud S, Kahnoski K et al (2002) Clinical and genetic studies of Birt-Hogg-Dube syndrome. J Med Genet 39:906–912
Nickerson ML, Warren MB, Toro JR et al (2002) Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2:157–164
Benhammou JN, Vocke CD, Santani A et al (2011) Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome. Genes Chromosomes Cancer 50:466–477
Ding Y, Zhu C, Zou W et al (2015) FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax. Am J Med Genet A 167A:1125–1133
Lim DH, Rehal PK, Nahorski MS et al (2010) A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat 31:E1043–E1051
Vocke CD, Yang Y, Pavlovich CP et al (2005) High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst 97:931–935
Kim JH, Seo SI, Song C, Chung J, Kwak C, Hong SH (2015) Clinicohistological characteristics of renal cell carcinoma in children: a multicentre study. Can Urol Assoc J 9:E705–E708
Stamatakis L, Metwalli AR, Middelton LA, Marston Linehan W (2013) Diagnosis and management of BHD-associated kidney cancer. Fam Cancer 12:397–402
Acknowledgements
This work was supported by the Mildred Scheel Fellowship from the German Cancer Aid (to MS) and the Boehringer Ingelheim Fonds’ MD fellowship (to KD).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schneider, M., Dinkelborg, K., **ao, X. et al. Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. Familial Cancer 17, 135–139 (2018). https://doi.org/10.1007/s10689-017-0008-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-017-0008-8