Skip to main content

Comment on Balsamo et al.: Birt-Hogg-Dubé syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature

A Correspondence to this article was published on 15 April 2022

The Original Article was published on 14 March 2020

Abstract

The publication by Balsamo and colleagues describes a patient with Birt-Hogg-Dubé syndrome and hyperplastic polyposis throughout the gastro-intestinal tract. We question whether the diagnosis of BHD in this patient was justified. Using the previously proposed diagnostic criteria for establishing the diagnosis of BHD as a guideline, we systematically describe our concerns. In our opinion, the patient described by Balsamo and colleagues does not meet any of the proposed major and minor criteria for the diagnosis of Birt-Hogg-Dubé syndrome. Therefore, we believe that it is not justified to suggest a possible association between hyperplastic polyposis and Birt-Hogg-Dubé syndrome based on this patient, even though a higher risk for colorectal polyposis in Birt-Hogg-Dubé syndrome has not been excluded so far.

Peer Review reports

Background

Birt-Hogg-Dubé syndrome (BHD, MIM# 135,150) is a rare disorder with autosomal dominant inheritance. It is caused by mutations in the FLCN gene [1, 2]. The skin phenotype, consisting of multiple fibrofolliculomas, was first described in the 1970s [3, 4]. Fibrofolliculomas consist of proliferation of specialized connective tissue surrounding an abnormal hair follicle, in which epithelial strands extend out into the connective tissue mantle [5,6,7]. Subsequently, many case reports described several other features that could be associated with BHD. However, it was not until 2002 that the association of BHD with pneumothorax, lung cysts and renal tumours was confirmed [8]. Specifically in rare genetic diseases, case reports on associated features are of high importance and might lead to the discovery of additional phenotypic characteristics of the disease which may allow preventive measures or surveillance. It was therefore with considerable interest that we read the publication by Balsamo and colleagues, in which a patient with BHD and hyperplastic polyposis throughout the gastro-intestinal tract was described [9]. We question whether the diagnosis of BHD in this patient was correct given the absence of specific clinical features of BHD and no (likely) pathogenic FLCN mutation. Therefore the suggested association between BHD and hyperplastic polyposis might not be justified. Using the previously proposed diagnostic criteria for establishing the diagnosis of BHD as a guideline, we will further elaborate on this subject [10].

FLCN pathogenic variants

The identification of a pathogenic variant in the FLCN gene is sufficient to establish the diagnosis of BHD. FLCN sequencing was performed in the patient described by Balsamo and colleagues but revealed no (likely) pathogenic mutation. As far as we can discern, no analysis for large intragenic deletions or duplications (such as MLPA) was performed, even though these have been reported in BHD patients [11, 12]. An intronic variant was detected (c.1538 + 14 T > G), but this variant was classified as likely benign by the authors and therefore cannot be of use in the diagnosis of BHD in this patient. The variant is present in 2.4% of African healthy control alleles and can therefore likely be classified as non-pathogenic [13]. However, the lack of a mutation in FLCN does not completely exclude BHD. Pathogenic variants in FLCN are detected in up to 95% of patients with a clinical diagnosis of BHD based on the literature and our own experience [12, 14, 15]. The remaining patients might represent cases of BHD due to a currently unidentifiable variant in FLCN, for example a deep intronic one or a variant in a regulatory sequence of FLCN. In some families previously described as having BHD, another diagnosis can now be established, for example familial multiple discoid fibromas [16].

Fibrofolliculomas

The presence of fibrofolliculomas is considered pathognomonic for BHD. One of the proposed criteria for diagnosing BHD is the presence of at least five fibrofolliculomas or trichodiscomas, of which at least one is histologically confirmed [10]. Of note, fibrofolliculomas and trichodisomas in BHD are considered to be different histologic aspects of the same lesion as seen at different section levels, while trichodiscomas without the typical histological features of fibrofolliculomas have been described in individuals with familial multiple discoid fibromas [6, 16]. Balsamo and colleagues describe that their patient had skin lesions which were considered trichodiscomas at anatomopathological examination. However, the histological image in Fig. 1 in the paper is showing a fibroepithelial polyp without the typical characteristics of a trichodiscoma or fibrofolliculoma. Fibroepithelial polyps (also called skin tags or acrochordons) are very common in the general population [17]. If this image is representative for all the skin lesions of the patient, his skin lesions are, in our opinion, not consistent with the diagnosis of BHD. If the patient did actually have multiple trichodiscomas which are not shown in the original paper, the diagnosis of BHD should be considered, as well as the alternative diagnosis of familial multiple discoid fibromas.

Minor criteria

The proposed diagnostic criteria describe minor criteria of which two are required for the clinical BHD diagnosis: (1) multiple lung cysts, (2) renal cancer with early onset, multifocal, bilateral or specific histology and (3) a first-degree relative with BHD [10]. The patient described by Balsamo and colleagues has no family history of BHD and no lung cysts. He has two renal masses showing features suggestive of angiomyolipoma (AML) on MRI. Renal AMLs are not uncommon in the general population and most occur sporadically. For example, they have been detected in 0.13% of healthy adults and 2.2% of potential kidney donors [18, 19]. Renal AMLs are much more common in patients with tuberous sclerosis complex, which is caused by germline mutations in TSC1 and TSC2 [20, 21]. Several case reports have described AMLs in patients with BHD [22,23,24,25]. The involvement of both TSC1/2 and FLCN in the mTOR pathway, might be a reason to suspect a causal connection between BHD and AMLs. This has, however, not been recognized in larger studies on renal tumours in BHD patients [26,27,28,29]. Furthermore, while there is a clear activation of mTOR upon loss of TSC1 or TSC2, the effects of loss of FLCN on mTOR are dependent on the context and cell-type [30, 31]. In one of the case reports of a BHD patient with an AML, the authors show that the AML is likely sporadic, as a result of somatic loss of the TSC genes [25]. Altogether, the case reports more likely represent a coincidental co-occurrence of AML and BHD.

Hyperplastic polyposis

Hyperplastic polyposis (more recently referred to as serrated polyposis syndrome (SPS)) presents with multiple and/or large serrated polyps throughout the colon. Although RNF43 germline mutations have been shown in a small proportion of (familial) cases of SPS [32,33,34,35,36], most cases of SPS occur sporadically and seem to have a multifactorial cause since both environmental and genetic risk factors have been shown to play a role [37, 38]. The association between BHD and colorectal polyps and/or carcinoma has been unclear for a long time. In a recent study, we did not find evidence for an increased risk for colorectal carcinoma in BHD. Furthermore, the ratio between adenomatous and hyperplastic polyps in BHD patients was comparable to that in individuals without BHD [39]. Other cohort studies also did not recognize hyperplastic polyposis as an important feature of BHD [8, 12, 27]. Therefore, an association between hyperplastic polyposis and BHD seems unlikely, but cannot be excluded.

Other medical history

Although some of the other conditions in the patient described by Balsamo et al. have been reported in BHD, an association between these features and BHD has not been confirmed in larger groups and they are not useful in establishing BHD.

Conclusion

In our opinion, Balsamo and colleagues have not provided information that is enough for establishing the diagnosis of BHD in their patient. In fact, none of the proposed clinical major and minor criteria are met. Therefore, we believe that it is not justified to suggest a possible association between hyperplastic polyposis and BHD based on the provided information about this patient. If the patient would meet the diagnostic criteria for BHD based on data not yet provided, the co-occurrence of BHD and hyperplastic polyposis might still be co-incidental but could give rise to further studies.

Availability of data and materials

Not applicable.

Abbreviations

AML:

Angiomyolipoma

BHD:

Birt-Hogg-Dubé syndrome

SPS:

Serrated polyposis syndrome

References

  1. Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. 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. 2002;2(2):157–64.

    CAS  Article  PubMed  Google Scholar 

  2. Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene. 2001;20(37):5239–42.

    CAS  Article  PubMed  Google Scholar 

  3. Birt AR, Hogg GR, Dube WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol. 1977;113(12):1674–7.

    CAS  Article  PubMed  Google Scholar 

  4. Hornstein OP, Knickenberg M. Perifollicular fibromatosis cutis with polyps of the colon–a cutaneo-intestinal syndrome sui generis. Arch Dermatol Res. 1975;253(2):161–75.

    CAS  Article  PubMed  Google Scholar 

  5. Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dube syndrome: a review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol. 2003;49(4):698–705.

    Article  PubMed  Google Scholar 

  6. Schulz T, Hartschuh W. Birt-Hogg-Dube syndrome and Hornstein-Knickenberg syndrome are the same. Different sectioning technique as the cause of different histology. J Cutan Pathol. 1999;26(1):55–61.

    CAS  Article  PubMed  Google Scholar 

  7. Collins GL, Somach S, Morgan MB. Histomorphologic and immunophenotypic analysis of fibrofolliculomas and trichodiscomas in Birt-Hogg-Dube syndrome and sporadic disease. J Cutan Pathol. 2002;29(9):529–33.

    Article  PubMed  Google Scholar 

  8. Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev. 2002;11(4):393–400.

    PubMed  Google Scholar 

  9. Balsamo F, Cardoso PAS, do AmaralJ unior SA, Theodoro TR, de Sousa Gehrke F, da Silva Pinhal MA et al. Birt-Hogg-Dube syndrome with simultaneous hyperplastic polyposis of the gastrointestinal tract: case report and review of the literature. BMC Med Genet. 2020; 21(1):52.

  10. Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol. 2009;10(12):1199–206.

    CAS  Article  PubMed  Google Scholar 

  11. Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, et al. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome. Genes Chromosomes Cancer. 2011;50(6):466–77.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Houweling AC, Gijezen LM, Jonker MA, van Doorn MB, Oldenburg RA, van Spaendonck-Zwarts KY, et al. Renal cancer and pneumothorax risk in Birt-Hogg-Dube syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families. Br J Cancer. 2011;105(12):1912–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q et al. The mutational constraint spectrum quantified from variation in 141,456 humans. bioRxiv. 2020:531210.

  14. Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, et al. 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. 2008;45(6):321–31.

    CAS  Article  PubMed  Google Scholar 

  15. Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet. 2005;76(6):1023–33.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Starink TM, Houweling AC, van Doorn MB, Leter EM, Jaspars EH, van Moorselaar RJ, et al. Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dube syndrome not linked to the FLCN locus. J Am Acad Dermatol. 2012;66(2):259.

    Article  PubMed  Google Scholar 

  17. Banik R, Lubach D. Skin tags: localization and frequencies according to sex and age. Dermatologica. 1987;174(4):180–3.

    CAS  Article  PubMed  Google Scholar 

  18. Rule AD, Sasiwimonphan K, Lieske JC, Keddis MT, Torres VE, Vrtiska TJ. Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis. 2012;59(5):611–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Fujii Y, Ajima J, Oka K, Tosaka A, Takehara Y. Benign renal tumors detected among healthy adults by abdominal ultrasonography. Eur Urol. 1995;27(2):124–7.

    CAS  Article  PubMed  Google Scholar 

  20. Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9(2):88–100.

    CAS  Article  PubMed  Google Scholar 

  21. Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet. 2005;13(6):731–41.

    CAS  Article  PubMed  Google Scholar 

  22. Dow E, Winship I. Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex. Am J Med Genet A. 2016;170(12):3323–6.

    CAS  Article  PubMed  Google Scholar 

  23. Tobino K, Seyama K. Birt-Hogg-Dube syndrome with renal angiomyolipoma. Intern Med. 2012;51(10):1279–80.

    Article  PubMed  Google Scholar 

  24. Byrne M, Mallipeddi R, Pichert G, Whittaker S. Birt-Hogg-Dube syndrome with a renal angiomyolipoma: further evidence of a relationship between Birt-Hogg-Dube syndrome and tuberous sclerosis complex. Australas J Dermatol. 2012;53(2):151–4.

    Article  PubMed  Google Scholar 

  25. Sager RA, Woodford MR, Shapiro O, Mollapour M, Bratslavsky G. Sporadic renal angiomyolipoma in a patient with Birt-Hogg-Dube: chaperones in pathogenesis. Oncotarget. 2018;9(31):22220–9.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sattler EC, Reithmair M, Steinlein OK. Kidney cancer characteristics and genotype-phenotype-correlations in Birt-Hogg-Dube syndrome. PLoS One. 2018; 13(12):e0209504.

  27. Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, et al. Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. Clin Genet. 2016;90(5):403–12.

    CAS  Article  PubMed  Google Scholar 

  28. Benusiglio PR, Giraud S, Deveaux S, Mejean A, Correas JM, Joly D, et al. Renal cell tumour characteristics in patients with the Birt-Hogg-Dube cancer susceptibility syndrome: a retrospective, multicentre study. Orphanet J Rare Dis. 2014;9:163.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Johannesma PC, van de Beek I, van der Wel T, Reinhard R, Rozendaal L, Starink TM et al. Renal imaging in 199 Dutch patients with Birt-Hogg-Dube syndrome: Screening compliance and outcome. PLoS One. 2019; 14(3):e0212952.

  30. Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A et al. Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells. Physiol Rep. 2014; 2(8).

  31. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4(9):648–57.

    CAS  Article  PubMed  Google Scholar 

  32. Buchanan DD, Clendenning M, Zhuoer L, Stewart JR, Joseland S, Woodall S, et al. Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study. Gut. 2017;66(6):1170–2.

    CAS  Article  PubMed  Google Scholar 

  33. Gala MK, Mizukami Y, Le LP, Moriichi K, Austin T, Yamamoto M, et al. Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas. Gastroenterology. 2014;146(2):520–9.

    CAS  Article  PubMed  Google Scholar 

  34. Quintana I, Mejias-Luque R, Terradas M, Navarro M, Pinol V, Mur P, et al. Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis. Gut. 2018;67(12):2230–2.

    CAS  Article  PubMed  Google Scholar 

  35. Taupin D, Lam W, Rangiah D, McCallum L, Whittle B, Zhang Y, et al. A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Hum Genome Var. 2015;2:15013.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Yan HHN, Lai JCW, Ho SL, Leung WK, Law WL, Lee JFY, et al. RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation. Gut. 2017;66(9):1645–56.

    CAS  Article  PubMed  Google Scholar 

  37. JE IJ, Bossuyt PM, Kuipers EJ, Stegeman I, de Wijkerslooth TR, Stoop EM et al. Smoking status informs about the risk of advanced serrated polyps in a screening population. Endosc Int Open. 2016; 4(1):E73–78.

  38. Arnau-Collell C, Soares de Lima Y, Diaz-Gay M, Munoz J, Carballal S, Bonjoch L et al. Colorectal cancer genetic variants are also associated with serrated polyposis syndrome susceptibility. J Med Genet. 2020.

  39. van de Beek I, Glykofridis IE, Wolthuis RMF, Gille H, Johannesma PC, Meijers-Heijboer HEJ, et al. No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dube syndrome. Br J Cancer. 2020;122(4):590–4.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

Drafting the manuscript: IvdB, ACH. Critical revision and interpretation of histology data: MAMS. All authors read and approved the manuscript.

Corresponding author

Correspondence to Irma van de Beek.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

van de Beek, I., van Steensel, M.A.M. & Houweling, A.C. 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, 84 (2022). https://doi.org/10.1186/s12920-022-01229-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12920-022-01229-5

Keywords

  • Birt-Hogg-Dubé syndrome
  • Hyperplastic polyposis