BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant syndrome with different skin, lung, and renal manifestations. It is diagnosed commonly in the third decade of life, and patients have an increased risk for pneumothorax and renal carcinomas.
METHODS: Articles published in PubMed, and Medline from 1977 to September 2023, were included in the systematic review. Inclusion criteria were applied to case reports, case series, and a retrospective cohort study, describing clinical, histopathological, and genetic findings in patients with BHDS with oral and/or parotid lesions.
RESULTS: Sixteen families/individuals with BHDS were identified for analysis. Patients ranged in age from 20 to 74 years, with an average of 49.4 years. Males were affected 52.2% of the time and females, 39.1%. Skin fibrofolliculomas were reported in 87% of cases, and oral lesions were documented in 47.8%. Parotid tumors were documented in 43.5% of patients, 30.4% of which were oncocytomas, 4.3% bilateral oncocytomas, and 4.3% \"oncocytic carcinoma\".
CONCLUSIONS: Because BHDS is uncommon, its spectrum of clinical manifestations may be underrecognized, especially as the disease is mostly reported at advanced stage. And some of the patients with BHDS may have oncocytic parotid tumors and oral lesions. In this regard, patients presenting these lesions and other indications of BHDS should be considered for renal screening.

暂无摘要。

BACKGROUND: Diffuse cystic lung disease (DCLD) represents a heterogeneous group of conditions, typically characterized by the presence of multiple thin-walled, predominantly round parenchymal lucencies. The increased accessibility of computed tomography (CT) underscores the growing relevance of a relatively rare group of diseases as more clinicians are confronted with the presence of multiple lung cysts on the chest CT scan. Although the etiology of these conditions is very diverse, the focus of the differential diagnosis revolves around four primary causative factors - Lymphangioleiomyomatosis (LAM), Pulmonary Langerhanscell histiocytosis (PLCH), Birt-Hogg-Dubé (BHD) and lymphoid interstitial pneumonia (LIP). Achieving an accurate diagnosis poses a challenge and typically necessitates lung biopsies; however, it is crucial for ensuring proper management.
UNASSIGNED: Cystische Lungenerkrankungen.
UNASSIGNED: Zusammenfassung: Diffuse zystische Lungenerkrankungen (DCLD) stellen eine heterogene Gruppe von Erkrankungen dar, die typischerweise durch das Vorhandensein mehrerer dünnwandiger, überwiegend runder parenchymatöser Läsionen gekennzeichnet sind. Die zunehmende Zugänglichkeit der Computertomographie (CT) unterstreicht die wachsende Bedeutung dieser relativ seltenen Krankheitsgruppe, da immer mehr Kliniker mit dem Vorhandensein multipler Lungenzysten auf dem Thorax-CT-Scan konfrontiert werden. Obwohl die Ätiologie dieser Erkrankungen sehr vielfältig ist, konzentriert sich die Differentialdiagnose auf vier primäre Auslöser: Lymphangioleiomyomatose (LAM), pulmonale Langerhanszell-Histiozytose (PLCH), Birt-Hogg-Dubé (BHD) und lymphoide interstitielle Pneumonie (LIP). Eine genaue Diagnose zu stellen, ist eine Herausforderung und erfordert in der Regel Lungenbiopsien; sie ist jedoch entscheidend für die Gewährleistung einer angemessenen Behandlung.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). It is characterized by skin tumors, multiple lung cysts, and renal tumors. Active genetic testing and appropriate periodic examinations of family lines of patients with BHD syndrome have not been widely performed. In this report, we present our experience regarding the diagnosis of asymptomatic family members with BHD syndrome. The proband was a 65-year-old female with a family history of colorectal cancer and spontaneous pneumothorax that affected her father. Computed tomography revealed an approximately 10 cm-sized tumor protruding from the upper pole of the left kidney, a buried tumor approximately 1.5 cm in length in the right kidney, and multiple pulmonary cysts. The patient underwent laparoscopic radical left nephrectomy. Pathological examination indicated that the resected tumor was a chromophobe renal cell carcinoma. After the surgery, there was no evidence of local recurrence or metastasis. The size of the tumor in the right kidney was monitored, but it did not increase. On FLCN genetic examination, targeted next generation sequencing revealed a partial deletion of exon 14, thus confirming the diagnosis of the patient to be BHD syndrome that caused the previously unreported pathogenic variant. Three years after the surgery, we conducted genetic counseling for the proposita and her three children. Genetic examination, performed at the request of the second daughter, confirmed that she carried the same genetic variant as her mother. This diagnosis prompted the second daughter to begin managing her health via periodic imaging tests.

80% of renal carcinomas (RC) are diagnosed incidentally by imaging. 2-4% of \"sporadic\" multifocality and 5-8% of hereditary syndromes are accepted, probably with underestimation. Multifocality, young age, familiar history, syndromic data, and certain histologies lead to suspicion of hereditary syndrome. Each tumor must be studied individually, with a multidisciplinary evaluation of the patient. Nephron-sparing therapeutic strategies and a radioprotective diagnostic approach are recommended. Relevant data for the radiologist in major RC hereditary syndromes are presented: von-Hippel-Lindau, Chromosome-3 translocation, BRCA-associated protein-1 mutation, RC associated with succinate dehydrogenase deficiency, PTEN, hereditary papillary RC, Papillary thyroid cancer- Papillary RC, Hereditary leiomyomatosis and RC, Birt-Hogg-Dubé, Tuberous sclerosis complex, Lynch, Xp11.2 translocation/TFE3 fusion, Sickle cell trait, DICER1 mutation, Hereditary hyperparathyroidism and jaw tumor, as well as the main syndromes of Wilms tumor predisposition. The concept of \"non-hereditary\" familial RC and other malignant and benign entities that can present as multiple renal lesions are discussed.

The characteristics of the pulmonary cysts on the high-resolution computed tomography (HRCT) chest images are an important diagnostic clue to distinguish among cystic lung diseases. The diagnostic accuracy of HRCT was reported to be as high as 90% by experienced pulmonologists and radiologists. Herein, we report the case of an elderly woman with Birt-Hogg-Dubé syndrome (BHDS) whose HRCT images displayed lymphangioleiomyomatosis-like features of the pulmonary cysts, rendering it difficult for us to diagnose BHDS. This case illustrates the significance of a thorough anamnesis, physical examination, and skin biopsy of facial papules to establish an accurate diganosis.

Familial kidney tumors represent a rare variety of hereditary cancer syndromes, although systematic gene sequencing studies revealed that as many as 5% of renal cell carcinomas (RCCs) are associated with germline pathogenic variants (PVs). Most instances of RCC predisposition are attributed to the loss-of-function mutations in tumor suppressor genes, which drive the malignant progression via somatic inactivation of the remaining allele. These syndromes almost always have extrarenal manifestations, for example, von Hippel-Lindau (VHL) disease, fumarate hydratase tumor predisposition syndrome (FHTPS), Birt-Hogg-Dubé (BHD) syndrome, tuberous sclerosis (TS), etc. In contrast to the above conditions, hereditary papillary renal cell carcinoma syndrome (HPRCC) is caused by activating mutations in the MET oncogene and affects only the kidneys. Recent years have been characterized by remarkable progress in the development of targeted therapies for hereditary RCCs. The HIF2aplha inhibitor belzutifan demonstrated high clinical efficacy towards VHL-associated RCCs. mTOR downregulation provides significant benefits to patients with tuberous sclerosis. MET inhibitors hold promise for the treatment of HPRCC. Systematic gene sequencing studies have the potential to identify novel RCC-predisposing genes, especially when applied to yet unstudied populations.

Birt-Hogg-Dubé syndrome (BHD) represents a rare autosomal dominant tumor predisposition syndrome characterized by skin lesions, lung cysts, and renal tumors. The predominant histological subtypes of BHD-related renal tumors include hybrid oncocytoma-chromophobe tumors, oncocytomas, and chromophobe renal cell carcinomas, all exhibiting eosinophilic/oncocytic features. Immunohistochemistry staining for KIT (CD117) and CK7 exhibits variability in these tumor types. Germline mutations in FLCN have been consistently identified. Generally, patients with BHD demonstrate a favorable prognosis with minimal metastatic potential. Nonetheless, the comprehensive elucidation of pathological characteristics of BHD remains incomplete, particularly in BHD-associated renal tumors that deviate from the previously identified subtypes, thereby complicating the differential diagnosis. In this review, we provide a comprehensive overview of BHD encompassing epidemiology, clinical manifestations, genetic and molecular pathogenesis, as well as clinical diagnostic modalities. Emphasis is placed on clinicopathological features, specifically focusing on BHD-associated renal tumors. Collectively, this review aims to present the latest insights into BHD which benefits in the early detection, therapeutic decision-making, and prognosis prediction in BHD cases, and deepen the understanding of sporadic renal tumors.

Multiple hereditary syndromes predispose to kidney cancer, including Von Hippel-Lindau syndrome, BAP1-Tumor Predisposition Syndrome, Hereditary Papillary Renal Cell Carcinoma, Tuberous Sclerosis Complex, Birt-Hogg-Dubé syndrome, Hereditary Paraganglioma-Pheochromocytoma Syndrome, Fumarate Hydratase Tumor Predisposition Syndrome, and Cowden syndrome. In some cases, mutations in the genes that cause hereditary kidney cancer are tightly linked to similar histologic features in sporadic RCC. For example, clear cell RCC occurs in the hereditary syndrome VHL, and sporadic ccRCC usually has inactivation of the VHL gene. In contrast, mutations in FLCN, the causative gene for Birt-Hogg-Dube syndrome, are rarely found in sporadic RCC. Here, we focus on the genes and pathways that link hereditary and sporadic RCC.

Birt-Hogg-Dubé (BHD) syndrome is associated with an increased risk of multifocal renal tumors, including hybrid oncocytic tumor (HOT) and chromophobe renal cell carcinoma (chRCC). HOT exhibits heterogenous histologic features overlapping with chRCC and benign renal oncocytoma, posing challenges in diagnosis of HOT and renal tumor entities resembling HOT. In this study, we performed integrative analysis of bulk and single-cell RNA sequencing data from renal tumors and normal kidney tissues, and nominated candidate biomarkers of HOT, L1CAM, and LINC01187 , which are also lineage-specific markers labeling the principal cell and intercalated cell lineages of the distal nephron, respectively. Our findings indicate the principal cell lineage marker L1CAM and intercalated cell lineage marker LINC01187 to be expressed mutually exclusively in a unique checkered pattern in BHD-associated HOTs, and these 2 lineage markers collectively capture the 2 distinct tumor epithelial populations seen to co-exist morphologically in HOTs. We further confirmed that the unique checkered expression pattern of L1CAM and LINC01187 distinguished HOT from chRCC, renal oncocytoma, and other major and rare renal cell carcinoma subtypes. We also characterized the histopathologic features and immunophenotypic features of oncocytosis in the background kidney of patients with BHD, as well as the intertumor and intratumor heterogeneity seen within HOT. We suggest that L1CAM and LINC01187 can serve as stand-alone diagnostic markers or as a panel for the diagnosis of HOT. These lineage markers will inform future studies on the evolution and interaction between the 2 transcriptionally distinct tumor epithelial populations in such tumors.