ABSTRACT
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.
Subject(s)
Birt-Hogg-Dube Syndrome , Kidney Neoplasms , Birt-Hogg-Dube Syndrome/pathology , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/diagnosis , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/genetics , Prognosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/analysis , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/genetics , Tumor Suppressor Proteins/genetics , Proto-Oncogene ProteinsABSTRACT
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.
Subject(s)
Birt-Hogg-Dube Syndrome , Salivary Gland Neoplasms , Humans , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/pathology , Birt-Hogg-Dube Syndrome/complications , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/pathology , Middle Aged , Adult , Male , Female , Aged , Young AdultABSTRACT
BACKGROUND: This study aimed to identify disease-causing variants within a Chinese family affected by Birt-Hogg-Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene. METHODS: A Chinese proband diagnosed with BHDS due to renal tumors underwent next-generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant. RESULTS: A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members. CONCLUSIONS: A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.
Subject(s)
Birt-Hogg-Dube Syndrome , Frameshift Mutation , Pedigree , Proto-Oncogene Proteins , Tumor Suppressor Proteins , Humans , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/pathology , Tumor Suppressor Proteins/genetics , Proto-Oncogene Proteins/genetics , Male , Female , Adult , Middle Aged , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Germ-Line Mutation , Heterozygote , East Asian PeopleABSTRACT
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.
Subject(s)
Birt-Hogg-Dube Syndrome , Carcinoma, Renal Cell , Kidney Neoplasms , Neoplastic Syndromes, Hereditary , Tuberous Sclerosis , von Hippel-Lindau Disease , Humans , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/therapy , Tuberous Sclerosis/genetics , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Kidney Neoplasms/therapy , Kidney/pathology , Birt-Hogg-Dube Syndrome/genetics , von Hippel-Lindau Disease/genetics , von Hippel-Lindau Disease/therapyABSTRACT
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.
Subject(s)
Birt-Hogg-Dube Syndrome , Kidney Neoplasms , Proto-Oncogene Proteins , Tumor Suppressor Proteins , Aged , Female , Humans , Asymptomatic Diseases , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/diagnosis , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/diagnosis , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/surgery , Genetic Testing , Germ-Line Mutation , Heterozygote , Kidney Neoplasms/genetics , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Nephrectomy , Pedigree , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/geneticsSubject(s)
Birt-Hogg-Dube Syndrome , Humans , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/complications , Birt-Hogg-Dube Syndrome/pathology , Birt-Hogg-Dube Syndrome/diagnosis , Female , Male , Middle Aged , Skin Neoplasms/pathology , Skin Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Proto-Oncogene Proteins/geneticsSubject(s)
Birt-Hogg-Dube Syndrome , Mutation , Proto-Oncogene Proteins , Tumor Suppressor Proteins , Humans , Birt-Hogg-Dube Syndrome/genetics , Birt-Hogg-Dube Syndrome/diagnosis , Birt-Hogg-Dube Syndrome/complications , Proto-Oncogene Proteins/genetics , Male , Tumor Suppressor Proteins/genetics , Female , Adult , Middle AgedABSTRACT
Presentamos el caso de una mujer de 57 años sin hábitos tóxicos y antecedentes de tres neumotórax derechos espontáneos. Antecedentes familiares de primer grado de neumotórax bilaterales de repetición, poliquistosis renal y tumor digestivo. Derivada a consulta para asesoramiento genético ante la sospecha de síndrome de Birt- Hogg-Dubé (SBHD) por diagnóstico genético confirmado en familiar de segundo grado. En la exploración se evidenciaron lesiones cutáneas compatibles con fibrofoliculomas. En la tomografía computarizada (TC) presencia de quistes pulmonares simples. El cribado genético reveló la presencia de una variante patogénica en el gen de la foliculina. El síndrome de Birt- Hogg- Dubé es una rara genodermatosis de herencia autosómica dominante caracterizada por la presencia de fibrofoliculomas y/o tricodiscomas cutáneos, quistes pulmonares, neumotórax espontáneos y tumores renales. El pronóstico depende de la gravedad de las afectaciones viscerales y del tipo de tumor renal implicado. (AU)
We present the case of a 57-year-old woman with no toxic habits and a history of three spontaneous right pneumothoraces. First-degree family history of recurrent bilateral pneumothoraces, polycystic kidney disease, and digestive tumor. Referred to consultation for genetic counseling on suspicion of Birt-Hogg-Dubé syndrome (SBHD) due to a confirmed genetic diagnosis in a seconddegree relative. The examination revealed skin lesions compatible with fibrofolliculomas. In the computed tomography (CT) presence of simple pulmonary cysts. Genetic screening revealed the presence of a pathogenic variant in the folliculin gene. Birt-Hogg-Dubé syndrome is a rare autosomal dominantly inherited genodermatosis characterized by the presence of cutaneous fibrofolliculomas and/or trichodiscomas, pulmonary cysts, spontaneous pneumothoraces, and renal tumors. The prognosis depends on the severity of the visceral involvement and the type of renal tumor involved. (AU)
Subject(s)
Humans , Female , Middle Aged , Birt-Hogg-Dube Syndrome/diagnostic imaging , Birt-Hogg-Dube Syndrome/diagnosis , Birt-Hogg-Dube Syndrome/genetics , Pneumothorax , Tomography, X-Ray Computed , Kidney NeoplasmsABSTRACT
No disponible
Subject(s)
Humans , Male , Adult , Birt-Hogg-Dube Syndrome/diagnosis , Birt-Hogg-Dube Syndrome/genetics , Pneumothorax/complications , Pleurodesis/methods , Mutation/genetics , Lung Neoplasms/diagnostic imaging , Asthma/complications , Radiography, Thoracic , Tomography, Emission-Computed , Cysts/diagnostic imaging , Lung Neoplasms/physiopathologySubject(s)
Humans , Male , Middle Aged , Birt-Hogg-Dube Syndrome/diagnosis , Birt-Hogg-Dube Syndrome/genetics , Kidney NeoplasmsABSTRACT
A 45-year-old woman with a history of renal carcinoma was observed for facial, cervical and truncal flesh-colored papules. Relatives had similar skin findings and a brother had repeated episodes of pneumothorax. The computerized tomography scan revealed multiple cysts on both lungs. A skin biopsy revealed a perifollicular fibroma. The clinical diagnosis of Birt-Hogg-Dubé syndrome (BHDS) was corroborated by identification of a novel frameshift c.573delGAinsT (p.G191fsX31) mutation in heterozygosity on exon 6 of the folliculin gene. The presence of multiple and typical benign hair follicle tumors highlights the role of the dermatologist in the diagnosis of this rare genodermatosis that is associated with an increased risk of renal cell cancer and pulmonary cysts, warranting personal and familial follow-up and counseling.
Uma mulher de 45 anos com história de carcinoma renal foi observada por pápulas cor da pele, faciais, cervicais e tronculares. Referia história familiar de achados cutâneos semelhantes e irmão com episódios repetidos de pneumotórax. Identificaram-se múltiplos quistos pulmonares por tomografia computorizada. Uma biópsia cutânea revelou fibroma perifolicular. O diagnóstico clínico de síndrome de Birt-Hogg-Dubé (BHDS) foi contudo corroborado pela identificação de uma nova mutação frameshift c.573delGAinsT (p.G191fsX31) em heterozigotia no exão 6 do gene da foliculina. A presença de múltiplos e típicos tumores benignos do folículo piloso, realça o papel do dermatologista no diagnóstico desta rara genodermatose, que está associada a um risco aumentado de tumores de células renais e cistos pulmonares, exigindo seguimento e aconselhamento pessoal e familiar.
Subject(s)
Female , Humans , Middle Aged , Birt-Hogg-Dube Syndrome/pathology , Skin/pathology , Biopsy , Birt-Hogg-Dube Syndrome/genetics , Mutation , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
OBJECTIVE: Our aim is to present a novel mutation of the Birt-Hogg-Dubé Syndrome. METHODS: We present a case report of a 70-year-old male with three solid nodulary lesions of 4, 2.6, and 3 cm each in the right kidney, and two lesions of 1.5 and 1.3 cm in the left kidney. RESULTS: Needle biopsy was performed. The pathological analysis of right kidney lesions revealed a renal tumor suggestive of chromophobe renal cell carcinoma and medullar tumor with zones that suggested oncocytosis. Genetic test results were positive for a novel heterozygous mutation c.1198G>A; p.V400I in exon 11 of the FLCN gene. CONCLUSION: In patients presenting with bilateral multifocal renal tumors of oncocytic hybrid histology, Birt-Hogg-Dubé syndrome should be the first diagnosis in mind. The mutation found in this patient has not been previously described in the literature in the context of BHD
OBJETIVO: Presentar una nueva mutación del Sindrome de Birt-Hogg-Dubé (BHD). MÉTODOS: Presentamos el caso de un varón de 70 años con tres lesiones nodulares sólidas en el riñón derecho de 4, 2,6 y 3 cm, y dos lesiones de 1,5 y 1,3 cm en el riñón izquierdo. RESULTADOS: Se realizó biopsia con aguja. El estudio patológico de las lesiones del riñón derecho reveló un tumor renal sugestivo de carcinoma renal cromófobo y tumor medular con zonas que sugerían oncocitosis. Las pruebas genéticas fueron positivas para una nueva mutación heterocigótica c.1198G>A; p.V400I en el exón 11 del gen FLCN. CONCLUSIONES: En pacientes que presentan tumores renales bilaterales multifocales de histología oncocítica híbrida, el primer diagnóstico a tener en cuenta es el Síndrome de Birt-Hogg-Dubé. La mutación hallada en este paciente no ha sido descrita previamente en la literatura en el contexto del BHD
Subject(s)
Humans , Male , Aged , Birt-Hogg-Dube Syndrome/genetics , Carcinoma, Renal Cell/pathology , Nephrectomy/methods , Heterozygote , Mutation/genetics , Biomarkers, Tumor/analysisABSTRACT
No disponible
Subject(s)
Humans , Male , Adult , Birt-Hogg-Dube Syndrome/genetics , Hair Follicle/pathology , Mutation/genetics , BiopsyABSTRACT
No disponible