Renal and Lung Cysts in Birt-Hogg-Dubé Syndrome: A Continuum of the Same Disorder

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Abstract

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal-dominant disorder, affecting multiple organs, mostly the skin, lungs, and kidneys. The prevalence of BHD syndrome is difficult to define given the rarity of the disease. Patients present most often with primary spontaneous pneumothorax. Renal tumors are a characteristic finding in BHD, and are often bilateral and multifocal and of the chromophobe and oncocytoma variant. Very scarce reports have highlighted the presence of simple renal cysts, as the only phenotypical renal manifestation, in BHD patients. Herein, we highlight two novel cases of bilateral multiple renal and pelvic cysts, in two females with genetically proven BHD syndrome, doubting a potential association with BHD syndrome.

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Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

Arthur R. Birt (1977)

In a sibship of nine, six members had hereditary medullary carcinoma of the thyroid. Two of those with thyroid neoplasms and two without had numerous small papular skin lesions. These proved to be a type of pilar tumor that we named fibrofolliculoma. Further investigation of the total kindred of 70 showed no other evidence of thyroid neoplasm. Skin tumors only appeared after the age of 25 years. Fifteen of 37 members older than the age of 25 years exhibited the typical skin lesions. Obviously, the original sibship was the repository of two dominantly inherited traits. The fibrofolliculoma is characterized by abnormal hair follicles with epithelial strands extending out from the infundibulum of the hair follicle into a hyperplastic mantle of specialized firbrous tissue. Associated skin lesions in this kindred were trichodiscomas and acrochordons.

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Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.

M Baba, S-B. Hong, N. Sharma … (2006)

Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.

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Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome.

B Zbar, Milagros J Toro, M. Nguyen … (2007)

Birt-Hogg-Dubé syndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibrofolliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax. We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype-pulmonary associations. Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype-pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (number of cysts, lung cyst volume, and largest cyst diameter and volume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax. Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p = 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p < 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p = 0.0002). This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax.

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Author and article information

Journal

Journal ID (nlm-ta): Cureus

Journal ID (iso-abbrev): Cureus

Journal ID (issn): 2168-8184

Title: Cureus

Publisher: Cureus (Palo Alto (CA) )

ISSN (Electronic): 2168-8184

Publication date (Electronic, pub): 18 October 2021

Publication date (Electronic, collection): October 2021

Volume: 13

Issue: 10

Electronic Location Identifier: e18878

Affiliations

[1 ] Division of Pediatric Urology, Department of Surgery, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, CAN

[2 ] Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, LBN

[3 ] Division of Nephrology and Hypertension, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LBN

[4 ] Department of Respiratory Medicine, National Coordinating Reference Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, University Hospital of Lyon, Lyon, FRA

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Mouhamad Nasser mohammad-nasser@ 123456hotmail.com

Article

DOI: 10.7759/cureus.18878

PMC ID: 8599113

PubMed ID: 34804727

SO-VID: 03b5a4af-fac8-42de-9bd7-9e886c475dbd

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date accepted : 18 October 2021

Renal and Lung Cysts in Birt-Hogg-Dubé Syndrome: A Continuum of the Same Disorder

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Most cited references 11

Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons.

Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.

Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dubé syndrome.

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