Comment on Balsamo et al.: “Birt–Hogg–Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature”
BMC Medical Genomics volume 15, Article number: 85 (2022)
In this comment, we highlight the diagnosis of Birt–Hogg–Dubé (BHD) in a 60-year-old man was made from identification and removal of normochromic papular cutaneous lesions whose histological examination indicated trichodyscomas and which are considered equivalent to fibrofolliculomas, presence of bilateral renal mass suggestive of angiomyolipomas by imaging exams. A benign/likely benign variant of FLCN in the intron 13 was also detected. Still, his previous pathological history presented other relevant data such as the prior removal of vocal cord angioma, total thyroidectomy, and left parotidectomy due to a cystic lesion whose histopathological examination revealed the presence of oncocytoma and lipomatosis, in addition to basal cell cutaneous carcinoma. Simultaneous gastrointestinal hyperplastic polyposis was found in this patient. The case we reported does not have the genotypic and phenotypic expressions most present in BHDS. These facts make it important for readers to know the clinical and genetic presentation facets of this unusual syndrome.
Initially, we are grateful for the considerations offered by van de Beek and colleagues regarding our article, which allow for the discussion of this important syndrome, which, due to its etiopathogenesis, has repercussions in various organs of the human body and implies a careful clinical follow-up.
The diagnosis of Birt–Hogg–Dubé syndrome (BHDS) must be based on the fulfillment of the primary criterion (at least five fibrofolliculomas of adult-onset and with histological confirmation of at least one of them; the presence of pathogenic germline variant of the FLCN), or two minor or secondary criteria (multiple bilateral lung cysts, with or without spontaneous primary pneumothorax; multifocal or bilateral kidney tumor or kidney cancer of mixed chromophobic and oncocytic histology with onset < 50 years of age; first-degree relative with a BHDS). Even in patients who do not meet all the clinical diagnostic criteria listed above, confirmation of the pathogenic variant of FLCN would be enough for BHDS to be considered [1,2,3,4,5]. In the case of this study, the diagnosis was made (i) from identification and removal of normochromic papular cutaneous lesions whose histological examination indicated trichodyscomas and which are considered equivalent to fibrofolliculomas, (ii) presence of bilateral renal mass suggestive of angiomyolipomas by imaging exams. A benign/likely benign variant of FLCN in the intron 13 was also detected. The legend of Figures 1 and 2 of the article was mistakenly described as “fibroepithelial polyp (skin fibroma)” when, in fact, it corresponds to one of several trichodiscomas (> 5) found in the patient in this report. However, the text of the article is correct when referring to Figures 1 and 2 as “anatomopathological examination of the dorsal and frontal lesions revealed trichodiscomas.” This misunderstanding may have contributed to some of the timely comments made by van de Beek and colleagues.
Clinical manifestation and genetic findings
BHDS can also occur sporadically in individuals with no family history of the syndrome. These individual can be carrier of de novo variant in the FLCN gene . The clinical history of the patient in question did not mention any relative with similar manifestations. Still, his previous pathological history presented other relevant data such as the prior removal of vocal cord angioma, total thyroidectomy, and left parotidectomy due to a cystic lesion whose histopathological examination revealed the presence of oncocytoma and lipomatosis, in addition to basal cell cutaneous carcinoma. Moreover, solid bilateral renal masses suggestive of angiomyolipoma were observed on angiography. Consistently, lipomas [7,8,9], parathyroid adenomas , thyroid cancer [10, 11], oncocytoma, and parotid adenoma, and basal cell and squamous cell carcinoma [2, 7, 12], as well as often bilateral kidney tumors [3, 6, 7, 9] have also been described in patients with BHDS.
Also consistent with findings in BHDS [12, 13], the cutaneous manifestations identified as trichodiscomas were presented in the case we reported as multiple normochromic papules presenting on the face (frontal region) and dorsum. Although the most frequent lesions are fibrofolliculomas, found in more than 85% of patients over the age of 25 , trichodiscomas present as smooth, dome-shaped papules, measuring 2 to 4 mm in diameter, and maybe single, multiple, or merge in the form of plaques . As suggested by Schulz et al. , trichodiscomas and fibrofolliculomas are the same lesions but sectioned in different planes, which gives rise to artificial differences in histological interpretation. The follicle involved may be the same in cases labeled as fibrofolliculoma, trichodiscoma, or even acrochordon, and it may be that these skin lesions represent evolutionary stages of a single lesion.
Immunophenotypically these dermatopathies are similar and, therefore, derived from the same histiogenic precursor, which step up this possibility [16,17,18,19,20]. Fibrofolliculomas and trichodiscomas have overlapping histological features, and skin biopsy with puncture rather than lamina biopsy is preferred to examine the general architecture of these lesions [2, 5, 20]. To diagnose the cutaneous lesions, in this case, resection and histopathological study were performed, which identified benign lesions (trichodiscomas) and malignant lesions (basal cell carcinoma). Although most patients with BHDS will have typical cutaneous manifestations, those without typical cutaneous manifestations are also at risk of developing renal tumors and pneumothorax . About 20% of patients with HBDS will not present pulmonary manifestations; therefore, the absence of symptoms or changes in chest imaging does not make the diagnosis unfeasible [12, 18, 21].
About a third of patients with BHDS have renal involvement by tumors [2, 16], often bilateral and multifocal, with slow growth and generally asymptomatic in the early stages [22, 23], usually diagnosed in males between 46 and 52 years of age. This scenario was also observed in the present case that was male, and asymptomatic kidney tumors were diagnosed by imaging at 60 years of age. In the MRI, the appearance of solid renal lesions was very suggestive of angiomyolipomas, in addition to the presence of renal cysts. This concomitant finding has also been reported in the literature [23,24,25].
Colorectal tumors, benign or malignant, are not considered a frequent phenotypic manifestation of BHDS. There were no still reports of hyperplastic colorectal polyps or in other locations in the gastrointestinal tract . We want to clarify that we were careful to use the term “simultaneous” and not the word “associated” when describing the gastrointestinal hyperplastic polyposis found in the patient in this report, as we reiterate that there is no evidence that hyperplastic polyposis is part of BHDS. In Individuals with BHDS without a pathogenic variant of FLCN have already been identified intragenic deletions and duplication in the gene . In the present case, no variants were found in other studied exons (4 to 14). Nahorski et al.  suggested that the somatic pathogenic variants of FLCN in patients with colorectal cancer are of the “transient” type and not pathogenic variants of the driver mutations. Thus, it is possible that the higher or lower risk of polyps or colorectal neoplasia in BHDS may be caused by different allelic variants of FCLN .
The tuberous sclerosis complex is known to be caused by dysregulation of the mTOR pathway, and due to phenotypic similarities with BHDS, the involvement of the mTOR pathway has been suggested to be implicated in the pathogenesis of the syndrome, although this is not the only signaling pathway implicated in the tumor suppressor action of FLCN [2, 4, 5, 28]. Some studies raise the question of why FLCN, a tumor suppressor gene, is a positive effector of the mTOR pathway. A possible explanation is that FLCN deficiency could suppress mTORC1 activity and may push other pathways to depletion, compensating the inhibition of the mTOR pathway , and which could explain the phenotypic similarity between BHDS, Cowden syndrome, tuberous sclerosis, and Peutz-Jeghers syndrome [4, 19, 29].
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- FLCN :
Magnetic resonance imaging
Mammalian target of rapamycin
Chung JY, Ramos-Caro FA, Beers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas and parathyroid adenomas in a patient with Birt–Hogg–Dube syndrome. Int J Dermatol. 1996;35:365–7.
Menko FH, van Steensel MA, Giraud S, et al. Birt–Hogg–Dubé syndrome: diagnosis and management. Lancet Oncol. 2009;10:1199–206.
Furuya M, Nakatani Y. Birt–Hogg–Dubé syndrome: clinico-pathological features of the lung. J Clin Pathol. 2013;66:178–86.
Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt–Hogg–Dubé syndrome. Fam Cancer. 2013;12:387–96.
Sasso AAD, Belém LC, Zanetti G, Souza CA, Escuissato DL, Irion KL, Guimarães MD, Marchiori E. Birt–Hogg–Dubé syndrome. State-of-the-art review with emphasis on pulmonary involvement. Resp Med. 2015;109:289–96.
Mohan Das L, Rang CE, Banka R. Birt–Hogg–Dubé syndrome: a rare cause of cystic lung diseases. BMJ Case Rep. 2013;2013:bcr2013008826.
Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, et al. Birt–Hogg–Dube syndrome: a novel marker of kidney neoplasia. Arch Dermatol. 1999;135:1195–202.
Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD mutation spectrum and phenotype analysis of a large cohort of families with Birt–Hogg–Dubé syndrome. Am J Hum Genet. 2005;76:1023–33.
Kluger N, Giraud S, Coupier L, et al. Birt–Hogg–Dubé syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010;162:527–37.
Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, et al. BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008;45:321–31.
Kunogi M, Kurihama M, Ikegami TS, et al. Clinical and genetic spectrum of Birt–Hogg–Dubé syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature. J Med Genet. 2010;47:281–7.
Rehman HU. Birt–Hogg–Dubé syndrome: report of a new mutation.Can Respir J. 2012; 19, 193–5
Bhatt JR, Richard PO, Kim NS, Finelli A, Manickavachagam K, Legere L, Evans A, Pei Y, Sykes J, Jhaveri K, Jewett MA. Natural history of renal Angiomyolipoma (AML): Most patients with large AMLs >4cm can be offered active surveillance as an initial management strategy. Eur Urol. 2016;70:85–90.
Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome. Nat Rev Urol. 2015;12:558–69.
Schulz T, Hartschuh W. Birt–Hogg–Dubé syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol. 1999; 26:55–61.
Iribe Y, Yao M, Tanaka R, Kuroda N, Nagashima Y, Nakatani Y, Furuya M. Genome-wide uniparental disomy and copy number variations in renal cell carcinomas associated with Birt–Hogg–Dubé syndrome. Am J Pathol. 2016;186:337–46.
Tobino K, Seyama K. Birt–Hogg–Dubé syndrome with renal angiomyolipoma. Intern Med. 2012;51:1279–80.
Spring P, Fellmann F, Giraud S, Clayton H, Hohl D. Syndrome of Birt–Hogg–Dubé, a histopathological pitfall with similarities to tuberous sclerosis: a report of three cases. Am J Dermatopathol. 2013;35:241–5.
Ponti G, Pellacani G, Seidenari S, Pollio A, Muscatello U, et al. Cancer associated genodermatoses: skin neoplasms as clues to hereditary tumor syndromes. Crit Rev Oncol Hematol. 2013;85:239–56.
Schimidt LS, Linehan WM. Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome. Nat Rev Urol. 2015;12:558–69.
Misagno N, Kimura T, Narisawa Y. Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/ angiofibroma): a revaluation of the histopathological and immunohistochemical features. J Cutan Pathol. 2009;36:943–51.
Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt–Hogg–Dubé syndrome. Am J Respir Crit Care Med. 2007;175:1044–53.
Byrne M, Mallipeddi R, Pichert G, Whittaker S. Birt–Hogg–Dubé syndrome with a renal angiomyolipoma: further evidence of a relationship between Birt–Hogg–Dubé syndrome and tuberous sclerosis complex. Australas J Dermatol. 2012;53:151–4.
Morrison PJ, Donnelly DE, Atkinson AB, Maxwell AP. Advances in the genetics of familial kidney cancer. Oncologist. 2010;15:532–8.
Pavlovich CP, Grubb RL, Hurley K, Glen GM, Toro J, Schimidt LS, et al. Evaluation and Management of renal tumors in the Birt–Hogg–Dube syndrome. J Urol. 2005;173:1482–6.
Happle R. Hornstein–Birt–Hogg–Dubé syndrome: a renaming and reconsideration. Am J Med Genet. 2012;158:1247–51.
Nahorski MS, Lim DHK, Martin L, Gille JJP, McKay K, et al. Investigation of the Birt–Hogg–Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. J Med Genet. 2010;47:385–90.
Nishii T, Tanabe M, Tanaka R, Matsuzawa T, Okudela K, et al. Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt–Hogg–Dubé syndrome. Pathol Int. 2013;63:45–55.
Palmirotta R, Savonarola A, Ludovici G, Donati P, Cavaliere F, et al. Association between Birt–Hogg–Dubé syndrome and cancer predisposition. Anticancer Res. 2010;30:751–7.
Furuya M, Kobayashi H, Baba M, Ito T, Tanaka R, Nakatani Y. Splice-site mutation causing partial retention of intron in the FLCN gene in Birt–Hogg–Dubé syndrome: a case report. BMC Med Genomics. 2018;11:42.
Volk C, Matwiyoff G. Birt–Hogg–Dubé syndrome caused by a novel mutation in the FLCL gene. Case Rep Genet. 2018;2018:4173704.
Kumar K, Ross C. Birt–Hogg–Dubé syndrome presenting with spontaneous pneumothorax and extensive pulmonary cysts in the absence of skin lesions or renal pathology. BMJ Case Rep. 2019;12:e231039.
Pithadia DJ, Treichel AM, Lee CR, Cowen EW, Linehan WM, Moss J, Darling TN. Birt–Hogg–Dubé syndrome initially diagnosed as tuberous sclerosis complex. JAAD Case Rep. 2019;5:368–71.
Enomoto Y, Namba Y, Hoshika Y, Komemushi Y, Mitani K, Kume H, Kobayashi E, Miyama Y, Homma Y, Ushiku T, Seyama K. A case of Birt–Hogg–Dubé syndrome implying reduced or no wild-type folliculin without mutated protein is pathogenic. Eur J Med Genet. 2020;63:103820.
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Balsamo, F., Cardoso, P.A.S., do Amaral Junior, S.A. et al. Comment on Balsamo et al.: “Birt–Hogg–Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature”. BMC Med Genomics 15, 85 (2022). https://doi.org/10.1186/s12920-022-01233-9