Folliculin Gene Research Articles

A novel variant in the FLCN gene in a Chinese family with Birt-Hogg-Dubé syndrome.

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. 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. 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. 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.

A Novel Mutation as a Rare Cause of Pneumothorax in a Soldier.

Birt-Hogg-Dube (BHD) is a rare cause of spontaneous pneumothorax caused by an autosomal-dominant mutation in the folliculin gene (FLCN). The syndrome can have widely variable presentations and is associated with recurrent pneumothorax, cystic lung disease, characteristic skin lesions, and renal tumors. Lung cysts have been described in over 80% of cases, and roughly 24 to 38% of patients have at least one pneumothorax and over 75% have multiple pneumothoraces. One of the defining features of this condition is fibrofolliculomas, which are benign tumors of the hair follicle. Given its rarity, the diagnosis is often missed and/or delayed for many years. This delay has clinical implications as screening for renal cancer is recommended in both the patient and affected family members. Increased recognition of this syndrome can lead to more patients receiving definitive treatment for their first pneumothorax, and being screened for renal cancers. We present a rare case of Birt-Hogg-Dubé with a never before described mutation in the FLCN gene, leading to spontaneous pneumothorax in an active duty male soldier.

Folliculin gene-negative Birt-Hogg-Dube syndrome: a case report

Introduction and importance: Birt-Hogg-Dube (BHD) is a rare genetic disorder that results from a mutation in the folliculin (FLCN) gene. Manifestations include pulmonary cysts, fibrofolliculomas, renal tumors, and pneumothoraces. Genetic testing can be used to confirm the diagnosis when suspected. BHD syndrome is diagnosed in patients with negative FLCN gene results using diagnostic criteria. Case presentation: A male in his 20s presented with recurrent pneumothoraces. A physical examination revealed bumps on his face and upper body. A chest computed tomography scan revealed cystic lesions. Blood tests, ESR, and CRP levels were unremarkable. Punch skin biopsy revealed fibrofolliculomas. Genetic testing for the FLCN mutation returned negative. His history, physical exam, imaging, and histopathology suggested BHD syndrome despite having a negative family history and genetic analysis. Eventually, the patient was diagnosed with FLCN gene-negative BHD syndrome. Clinical discussion: More than a hundred families have been identified to have BHD worldwide. There are a few cases in the literature describing patients phenotypically presenting with BHD despite having a negative genetic analysis. One study in Japan found 16 out of 157 individuals having a clinical presentation of BHD with no mutations. Also, decreased expression of the FLCN mRNA may lead to BHD. Conclusion: BHD syndrome can present with a negative FLCN gene mutation; however, patients must meet the known diagnostic criteria such as criteria made by Menko et al., Gupta et al., and Schmidt et al. in order to have a diagnosis of BHD syndrome. Also, a qualitative decrease of FLCN with the absence of mutations may also lead to BHD.

P-19 A case of Birt Hogg Dube syndrome presented with parathyroid carcinoma

Abstract Introduction The Birt Hogg Dube syndrome is an autosomal dominant genodermatosis caused by a mutation in the folliculin gene. It is characterized by benign lung cysts with spontaneous pneumothorax, kidney tumors, and hair follicle tumors. Other solid tumors may accompany. Our case is a man with Birt Hogg Dube Syndrome who has parathyroid cancer. Clinical Case A 50-year-old male was referred to our clinic for treatment of hypercalcemia and elevated parathormone; he complained of weakness, muscle, and joint discomfort. His previous medical history included Renal Cell Carcinoma, Coronary artery by-pass graft, pulmonary thromboembolism, hypertension, nephrolithiasis, and stage 4 chronic kidney disease. There was a familial history of colon cancer, with both his aunt and uncle having been diagnosed. The systemic evaluation revealed the presence of constipation, polyuria, pollakiuria. A palpable 3 cm nodular lesion was discovered in the inferior lobe of the patient's left thyroid, and the patient's vital signs were stable. There were lesions on the inner surface of the right thigh and the skull. The biopsies obtained from the lesions on the skin revealed a lipoma on the cranium and a fibrofolliculoma on the thigh upon pathological examination. Regarding laboratory exams, both the hemogram and transaminase levels were within normal limits. Serum albumin was measured at 4.9 g/L creatinine at 2.5 mg/dl, calcium at 12 mg/dl, ionized calcium at 5.9 mg/dl, phosphorus at 2.4 mg/dl, parathormone at 373 ng/dL, and 25-OH Vitamin D at 32 ng/ml. Alkaline phosphatase was determined to be 66 U/L, and 24-hour calcium output was 60 mg/day. The thyroid function test results were euthyroid, while the anterior pituitary panel was normal. The patient underwent a left inferior parathyroidectomy after thyroid ultrasonography and parathyroid scintigraphy revealed a parathyroid adenoma. The parathyroid carcinoma is identified in the pathology report. The ultrasound-observed nodule on the isthmus of the thyroid has been identified as thyroid papillary carcinoma. Bone mineral density was normal. A previously performed CT scan of the thorax for dyspnea revealed the presence of multiple cystic structures in the lungs. Taking into account the patient's history of multiple malignancies, an 18-FDG-PET CT scan was performed, revealing a significant FDG uptake (SUV Max: 22) in the patient's sigmoid colon. Pathology analysis of the removed lesion confirmed that it was a tubulovillous adenoma with high-grade dysplasia. The patient, who showed heterozygosity for the Folliculin gene, was identified as having Birt-Hogg-Dube syndrome after further genetic panel testing. Conclusion According to the most recent literature evaluation, our patient is the first Birt Hogg Dube individual to present with parathyroid carcinoma. There is some evidence in the published literature linking somatic mutation of the Folliculin gene to the development of parathyroid cancer.

THU514 Atypical Presentation Of Birt-Hogg-Dubé Syndrome With Poorly Differentiated Follicular Thyroid Cancer And Paraganglioma

Abstract Disclosure: K. Lertdetkajorn: None. J. Haw: None. J.E. Paysour: None. Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare genetic disorder typically presenting with skin hamartomas, renal tumors, and lung cysts. BHD is caused by germline mutations of the folliculin (FLCN) gene. We present the case of a patient with follicular thyroid cancer and paraganglioma diagnosed with BHDS. Case: A 64-year-old female was noted to have progressive enlargement of a neck mass over six months following admission for a hypertensive emergency. CT neck demonstrated a heterogeneous mass centered within the left thyroid lobe measuring 10.4 x 8.6 x 7.6 cm with internal calcifications. TSH was normal. FNA of this mass was suspicious for follicular neoplasm, and she underwent a total thyroidectomy. The pathology reported poorly differentiated adenocarcinoma of the thyroid gland, follicular variant, pT3aN0M0 with positive margins, and lymph-vascular space invasion (LVI). FDG-PET/CT scan showed postsurgical changes of a total thyroidectomy with ill-defined FDG uptake along the left thyroid bed, 3 x 2.8 cm portacaval lymph node (SUV of 9.6) and focal soft tissue FDG avid rectal abnormality. MRI abdomen demonstrated a 4.0 x 4.1 x 3.2 cm soft tissue mass characterized by arterial hyperenhancement and washout in the portacaval region broadly interfacing with the IVC, main portal vein, and left renal vein. EGD was unremarkable, but an EUS demonstrated 3.7 x 3.5 hypoechoic, well-circumscribed, mild-vascular hypoechoic portocaval mass. FNA of this mass was consistent with paraganglioma. Laboratory results supported the diagnosis of paraganglioma with urine metanephrine 9661 mcg/24 h (224 - 832 mcg/24 h) and urine normetanephrine 9457 mcg/24 h (122 - 676 mcg/24 h). The patient was referred for genetic testing to investigate whether the co-existence of follicular thyroid cancer and paraganglioma was secondary to a genetic disorder. The germline genetic testing revealed the pathogenic variant, c.1436dup (p.Thr481Hisfs*5), identified in the FLCN gene with no detections of VHL or SDH complex variants, confirming the diagnosis of BHDS. The patient later underwent a colonoscopy and was found to have stage I colon cancer. Some early reports have shown an association between BHDS and colon tumors. The patient decided not to have any surgery at this time. She continues to follow up in the clinic and takes levothyroxine for suppressive goals. Octreotide LAR, along with blood pressure medications including phenoxybenzamine, was started to treat her paraganglioma. Conclusion: Patients with BHDS may present with atypical clinical manifestations. Genetic testing will aid in diagnosing a germline mutation in the FLCN gene. The association between thyroid cancer and BHDS has been reported previously; however, paraganglioma as a spectrum of BHDS has not been published. Further reported cases and research may provide additional data to investigate the relationship between BHDS and paraganglioma. Presentation: Thursday, June 15, 2023

SAT562 Metastatic Oncocytic (Formerly Hürthle Cell) Thyroid Carcinoma in a Patient With Birt-Hogg-Dubé Syndrome

Abstract Disclosure: S. Vaid: None. R. Klein: None. P. Veeraraghavan: None. D.M. Blakaj: None. A. Agrawal: None. J. Sipos: None. S.I. Sherman: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Introduction: Birt-Hogg-Dubé syndrome (BHD) is a rare, autosomal dominant disorder due to a germline loss-of-function mutation in the folliculin (FLCN) gene. Clinical manifestations include pulmonary cysts, renal cell carcinoma, and skin tumors, while tumors of other sites such as thyroid are uncommon. Here, we report an extremely rare case of oncocytic thyroid carcinoma (OTC) in a patient with BHD. Clinical case: A 55-year-old male with BHD noted a lump in his neck which was identified as a 3 cm right thyroid nodule on sonogram. Medical history only included BHD, which was diagnosed based on the presence of pulmonary cysts and two family members with BHD. No family members had thyroid tumors, and the patient denied any history of radiation exposure. Fine needle aspiration biopsy was indeterminate (Bethesda III). A total thyroidectomy and central lymph node (LN) dissection was performed as LN metastases were identified on intraoperative frozen section. Histopathology revealed 3 foci of OTC, largest being 3.8 cm, with extrathyroidal extension into fibroadipose tissue, 3/31 LN metastases with the largest deposit of 0.5 cm without extranodal extension. A 156.6 mCi dose of I-131 radioiodine (RAI) was administered. No uptake was noted on the post-therapy scan. Four months later, new right lateral cervical lymphadenopathy was noted on computed tomogram (CT). A right lateral selective neck dissection was performed, which identified 3/28 metastatic LNs without extranodal extension. Next generation gene sequencing testing of the metastatic tumor revealed the pathogenic FLCN (H429fs*27) variant, along with TP53 (R248Q), and DAXX (L666fs*29) pathogenic variants. Over the next 20 months, serum thyroglobulin increased from 1.8 ng/ml to 121 ng/mL (normal: 1.6 - 59.9 ng/mL). Several sub-centimeter lung nodules and new right cervical lymphadenopathy were noted on CT, and these lesions demonstrated increased uptake on fluorodeoxyglucose positron emission tomography (PET/CT) and on Ga-68 DOTATATE PET/CT scans. Due to close proximity to the right internal jugular vein, the cervical lymphadenopathy was deemed to be inoperable. Stereotactic radiation was administered to the neck, which resulted in substantial shrinkage of the neck metastases. The patient continues to be on active surveillance, with tyrosine kinase inhibitors or peptide receptor radionuclide therapy being potential future systemic therapy options in case of disease progression. Conclusion: Thyroid tumors have been occasionally reported in BHD. While most of them are papillary or follicular tumors, only one case of OTC in BHD has been previously reported in the literature [1]. This report underscores the importance of screening for thyroid neoplasms in patients with BHD. Reference: 1. Panagiotidis et al. World J Nucl Med. 2018;17(2):123-125 Presentation Date: Saturday, June 17, 2023

Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians' understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Exons 1–3 deletion in FLCN is associated with increased risk of pneumothorax in Chinese patients with Birt-Hogg-Dubé syndrome

BackgroundThe pathogenic variants responsible for Birt-Hogg-Dubé syndrome (BHDS) in folliculin (FLCN) gene mostly consist of point mutations. Although large intragenic deletions/duplications have been reported in several case reports, the relationship between large intragenic deletions/duplications and phenotype in BHDS remains unclear.MethodsWe retrospectively identified and reviewed patients with a large intragenic deletion spanning exons 1–3 and analyzed their phenotypic features to compare with those of point mutation carriers in our hospital from January 1, 2017 to August 31, 2022.ResultsTwenty unique point mutations (including 4 novel mutations) were detected in 62 patients from 45 families (90%). Exons 1–3 deletion were identified in 8 patients from 5 families (10%) that resided in the same region, Feidong County of Anhui Province, China. Breakpoint analysis indicated that all the deletion breakpoints were flanked by Alu repeats. The prevalence of exons 1–3 deletion carriers in Feidong County was 8.1-times higher than that for BHDS in Anhui Province, suggesting a clustered phenomenon of exons 1–3 deletion. Significantly increased risk of pneumothorax was observed in those with exons 1–3 deletion compared with point mutations (91% vs. 58%, p value 0.047). The risk of renal cancer may be higher in those with exons 1–3 deletion than for those with point mutations (18% vs. 4%, p > 0.05).ConclusionsLarge intragenic deletion of exons 1–3 in FLCN was identified as a local aggregation phenomenon in Feidong County, China, and was associated with a significantly higher risk of pneumothorax compared to those with point mutations.

Folliculin Prevents Lysosomal Degradation of Human Papillomavirus To Support Infectious Cell Entry.

Human papillomavirus (HPV) infects epithelial basal cells in the mucosa and either proliferates with the differentiation of the basal cells or persists in them. Multiple host factors are required to support the HPV life cycle; however, the molecular mechanisms involved in cell entry are not yet fully understood. In this study, we performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout (KO) screen in HeLa cells and identified folliculin (FLCN), a GTPase-activating protein for Rag GTPases, as an important host factor for HPV infection. The introduction of single guide RNAs for the FLCN gene into HeLa, HaCaT, and ectocervical Ect1 cells reduced infection by HPV18 pseudovirions (18PsVs) and 16PsVs. FLCN KO HeLa cells also exhibited strong resistance to infection with 18PsVs and 16PsVs; nevertheless, they remained highly susceptible to infections with vesicular stomatitis virus glycoprotein-pseudotyped lentivirus and adeno-associated virus. Immunofluorescence microscopy revealed that the numbers of virions binding to the cell surface were slightly increased in FLCN KO cells. However, virion internalization analysis showed that the internalized virions were rapidly degraded in FLCN KO cells. This degradation was blocked by treatment with the lysosome inhibitor bafilomycin A1. Furthermore, the virion degradation phenotype was also observed in Ras-related GTP-binding protein C (RagC) KO cells. These results suggest that FLCN prevents the lysosomal degradation of incoming HPV virions by enhancing lysosomal RagC activity. IMPORTANCE Cell entry by human papillomavirus (HPV) involves a cellular retrograde transport pathway from the endosome to the trans-Golgi network/Golgi apparatus. However, the mechanism by which this viral trafficking is safeguarded is poorly understood. This is the first study showing that the GTPase-activating protein folliculin (FLCN) protects incoming HPV virions from lysosomal degradation and supports infectious cell entry by activating the Rag GTPases, presumably through the suppression of excessive lysosomal biosynthesis. These findings provide new insights into the effects of small GTPase activity regulation on HPV cell entry and enhance our understanding of the HPV degradation pathway.

Colon adenocarcinoma and Birt–Hogg–Dubé syndrome in a young patient: case report and exploration of pathologic implications

ABSTRACT Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN) that result in the functional loss of the tumor suppressor folliculin. It is classically associated with cutaneous hamartomas, pulmonary cysts with spontaneous pneumothorax, and various renal cancers. In this case, we present a patient initially diagnosed with chromophobe renal cell carcinoma and subsequently found to have colorectal cancer (CRC). The presence of two separate malignancies in a young patient with a strong family history of CRC (father and paternal grandfather) led to genetic testing, which revealed an FLCN c.1177–5_1177-3del mutation, and a diagnosis of BHD was made. Out of the more than 300 known unique mutations of the FLCN coding region, the c.1285dupC mutation on exon 11 has been the only one convincingly associated with CRC thus far. While larger cohort studies are needed to further clarify this association, we present the first patient with CRC to our knowledge with an FLCN c.1177–5_1177-3del mutation and loss of heterozygosity implicating it as an initiating factor in tumorigenesis. We further explore the studies supporting and refuting the connection between BHD and CRC and highlight the molecular signaling pathways that may play a role in pathogenesis.

A Case of Birt-Hogg-Dube Syndrome with Folliculin Gene Mutation

A Case of Birt-Hogg-Dube Syndrome with Folliculin Gene Mutation

Phosphoproteomic Analysis of FLCN Inactivation Highlights Differential Kinase Pathways and Regulatory TFEB Phosphoserines

In Birt–Hogg–Dubé (BHD) syndrome, germline loss-of-function mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address how FLCN inactivation affects cellular kinase signaling pathways, we analyzed comprehensive phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15,744 phosphorylated peptides were identified from 4329 phosphorylated proteins. INKA analysis revealed that FLCN loss alters the activity of numerous kinases, including tyrosine kinases EGFR, MET, and the Ephrin receptor subfamily (EPHA2 and EPHB1), as well their downstream targets MAPK1/3. Validation experiments in the BHD renal tumor cell line UOK257 confirmed that FLCN loss contributes to enhanced MAPK1/3 and downstream RPS6K1/3 signaling. The clinically available MAPK inhibitor Ulixertinib showed enhanced toxicity in FLCNNEG cells. Interestingly, FLCN inactivation induced the phosphorylation of PIK3CD (Tyr524) without altering the phosphorylation of canonical Akt1/Akt2/mTOR/EIF4EBP1 phosphosites. Also, we identified that FLCN inactivation resulted in dephosphorylation of TFEB Ser109, Ser114, and Ser122, which may be linked to increased oxidative stress levels in FLCNNEG cells. Together, our study highlights differential phosphorylation of specific kinases and substrates in FLCNNEG renal cells. This provides insight into BHD-associated renal tumorigenesis and may point to several novel candidates for targeted therapies.

Epidemiology and clinical features of Birt-Hogg-Dubé syndrome: A nationwide population-based study in South Korea.

Birt-Hogg-Dubé (BHD) syndrome is an ultrarare lung disease with unclear prevalence and incidence. Our study aimed to identify the epidemiological and clinical features of BHD syndrome by using nationwide claims data from the Korean Health Insurance Review and Assessment service. Patients with BHD syndrome who had the following criteria were included: 1) tested for folliculin gene mutation, and 2) had at least one of the conditions: other specified malformation syndromes, fibrofolliculoma, acrochordon, lung cyst, cancer, and pneumothorax based on International Classification of Disease-10 code. We found 26 patients with BHD syndrome from 2017 to 2019. The prevalence of BHD syndrome was 5.67 per 107 population, with no peak age. Among incidence cases, the median age of diagnosis was 51 years, with slightly more females than males (n = 15, 57.7%). Over half of the patients (n = 14, 53.8%) experienced pneumothorax, and 10 (38.5%) developed malignant neoplasm within the clinical course. The prevalence of BHD syndrome in Korea is extremely low. However, affected patients manifest several comorbidities, including malignant neoplasm and repetitive pneumothorax.

A novel missense mutation in the folliculin gene associated with the renal tumor-only phenotype of Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé syndrome is an autosomal dominant disease caused by germline mutations in the folliculin gene (FLCN), characterized by skin fibrofolliculomas, pulmonary cysts, and multiple renal tumors. We report the case of a 51-year-old woman with multiple bilateral renal tumors resected by bilateral open partial nephrectomy. Following pathological diagnosis of hybrid oncocytic/chromophobe tumors, targeted next-generation sequencing of FLCN of the patient's blood revealed a novel missense mutation (c.602A>C, p.Gln201Pro) in exon 6. Sanger sequencing revealed that this mutation was heterozygous. In silico prediction programs consistently indicated the mutation as pathogenic. Western blot analysis and immunohistochemistry revealed suppressed FLCN expression and the upregulation of glycoprotein nonmetastatic B, a downstream target negatively regulated by FLCN, in the tumor tissue, suggesting that the mutation resulted in reduction of functional FLCN expression. Whole-genome sequencing of one of the tumors identified another frameshift mutation in exon 4, suggesting a “second hit” leading to tumorigenesis. We recommend that gene sequencing should be considered in patients with multiple renal tumors to identify their genetic predisposition to renal tumors.

Cigarette smoking is a secondary cause of folliculin loss

BackgroundBirt-Hogg-Dubé syndrome (BHD) is a clinical syndrome manifesting with cystic lung disease and pneumothorax. Features of BHD result from the loss-of-function mutations of the folliculin (FLCN) gene. Chronic obstructive pulmonary...

Clinical Characteristics and Genetic Analysis of a Family With Birt-Hogg-Dubé Syndrome and Congenital Contractural Arachnodactyly.

Background: Birt-Hogg-Dubé (BHD) syndrome and congenital contractural arachnodactyly (CCA) or Beals-Hecht syndrome are clinically rare autosomal dominant genetic diseases. In this study, we describe an extremely rare family with BHD syndrome and CCA. Objective: To investigate the clinical and genetic characteristics of a family with BHD syndrome and CCA. Methods: We describe the clinical characteristics, family history, and clinical manifestations of the patient’s family members. The patient underwent a blood test, computed tomography (CT) of the chest, color Doppler ultrasound of the abdomen and heart, and digital radiography of the hands. Whole exome sequencing was performed on his family members. Results: Two years ago, the male proband developed chest tightness and shortness of breath that was accompanied by an irritating cough as well as repeated (four times) spontaneous pneumothorax. The chest CT indicated spontaneous pneumothorax on the right side and cyst and bullae in both lungs. He had no kidney tumors or skin lesions. His son had a history of pulmonary bullae and experienced spontaneous pneumothorax twice. The proband, his mother, and his son were all born with a hand deformity. The sequencing results demonstrated that both the proband and his son had heterozygous variations of the folliculin (FLCN) gene c.1015C > T (p. Gln339Ter) and fibrillin-2 (FBN2) gene c.3485G > A (p. Cys1162Tyr), which are associated with BHD syndrome and CCA, respectively. Conclusion: For patients with chest tightness, shortness of breath, recurrent spontaneous pneumothorax, and congenital hand deformity without inducement, genetic testing should be carried out as soon as possible to make a clear diagnosis, which can then guide treatment and genetic counseling.

Birt-Hogg-Dubé Syndrome

HomeRadiologyVol. 302, No. 3 PreviousNext Reviews and CommentaryFree AccessImages in RadiologyBirt-Hogg-Dubé SyndromeSubha Ghosh , Carol F. FarverSubha Ghosh , Carol F. FarverAuthor AffiliationsFrom the Section of Thoracic Imaging, Imaging Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195 (S.G.); and Department of Pathology, University of Michigan, Ann Arbor, Mich (C.F.F.).Address correspondence to S.G. (e-mail: [email protected]).Subha Ghosh Carol F. FarverPublished Online:Nov 30 2021https://doi.org/10.1148/radiol.2021211972MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In A 47-year-old man with a 30-pack-year smoking history presented with a chronic nonproductive cough and multiple dome-shaped, smooth, whitish facial papules (Figure, A). His family history was negative for renal neoplasms, pneumothorax, and seizures, and his spirometry results were normal. CT showed multiple peripheral, lentiform, perifissural, and intraparenchymal thin-walled cysts in both lungs (Figure, C). Skin biopsy of the facial papules showed fibrofolliculomas (Figure, B), which is a major diagnostic criterion for Birt-Hogg-Dubé syndrome. Notably, one major criterion or two minor criteria are needed to confirm diagnosis (1). Abdominal imaging showed no renal mass.Images in 47-year-old man with 30-pack-year smoking history who presented with chronic nonproductive cough. (A) Photograph of patient’s face shows multiple dome-shaped, smooth, whitish facial papules (arrows). (B) Photomicrograph (hematoxylin-eosin stain; original magnification, ×40) of excisional biopsy of papule shows typical findings for fibrofolliculoma. These are characterized by proliferation of follicular epithelium with prominent epithelial strands, with whirling architecture (open arrow), surrounded by perifollicular fibrous sheath (solid arrow). (C) Thin-section axial chest CT scan shows multiple thin-walled peripheral lentiform cysts (arrows) in both lungs characteristic of Birt-Hogg-Dubé syndrome.Download as PowerPointOpen in Image Viewer Birt-Hogg-Dubé syndrome is an autosomal dominant, multisystem disorder caused by a mutation in the folliculin gene, FLCN (17p11.2). This inherited disease is characterized by cutaneous lesions, renal tumors, cystic lung disease, and spontaneous pneumothorax (1). Skin lesions include fibrofolliculomas, trichodiscomas, and acrochordons (2). MRI of the kidneys is recommended every 3 years to exclude the known propensity for the development of chromophobe cell cancer and oncocytomas in these patients. Pleurodesis is frequently performed after the initial episode of spontaneous pneumothorax because of a high incidence of recurrence (3).Disclosures of Conflicts of Interest: S.G. No relevant relationships. C.F.F. No relevant relationships.Reference1. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: diagnosis and management. Lancet Oncol 2009;10(12):1199–1206. Crossref, Medline, Google Scholar2. Aivaz O, Berkman S, Middelton L, Linehan WM, DiGiovanna JJ, Cowen EW. Comedonal and Cystic Fibrofolliculomas in Birt-Hogg-Dubé Syndrome. JAMA Dermatol 2015;151(7):770–774. Crossref, Medline, Google Scholar3. Gupta N, Kopras EJ, Henske EP, et al. Spontaneous Pneumothoraces in Patients with Birt-Hogg-Dubé Syndrome. Ann Am Thorac Soc 2017;14(5):706–713. Crossref, Medline, Google ScholarArticle HistoryReceived: Aug 5 2021Revision requested: Sept 1 2021Revision received: Sept 3 2021Accepted: Sept 9 2021Published online: Nov 30 2021Published in print: Mar 2022 FiguresReferencesRelatedDetailsRecommended Articles Cardiopulmonary and Gastrointestinal Manifestations of Eosinophil- associated Diseases and Idiopathic Hypereosinophilic Syndromes: Multimodality Imaging ApproachRadioGraphics2016Volume: 36Issue: 2pp. 433-451Imaging Evaluation of Pediatric Parotid Gland AbnormalitiesRadioGraphics2018Volume: 38Issue: 5pp. 1552-1575Hereditary Renal Cystic Disorders: Imaging of the Kidneys and BeyondRadioGraphics2017Volume: 37Issue: 3pp. 924-946Case 291: Amyloid-associated Cystic Lung Disease and Coexistent Mucosa-associated Lymphoid Tissue LymphomaRadiology2021Volume: 300Issue: 1pp. 237-242Imaging of Histiocytosis in the Era of Genomic MedicineRadioGraphics2018Volume: 39Issue: 1pp. 95-114See More RSNA Education Exhibits Lung Cysts: Uncommon and Rare Etiologies with Clinical and Pathological CorrelationDigital Posters2019Radiologic-Pathologic Correlation of Cystic Lung DiseasesDigital Posters2020Imaging Overview Of Cystic Lung Diseases and Their MimicsDigital Posters2020 RSNA Case Collection LymphangioleiomyomatosisRSNA Case Collection2021Pneumothorax Ex VacuoRSNA Case Collection2022Pulmonary HamartomaRSNA Case Collection2021 Vol. 302, No. 3 Metrics Altmetric Score PDF download

FOLLICULIN GENE MUTATION IN A YOUNG WOMAN WITH RECURRENT PNEUMOTHORAX

TOPIC: Genetic and Developmental Disorders TYPE: Medical Student/Resident Case Reports INTRODUCTION: Folliculin (FLCN) gene mutation, commonly linked with Birt-Hogg-Dube (BHD) syndrome, is associated with primary spontaneous pneumothorax (PSP). PSP is defined by air in the pleural space in those without a history of lung disease or trauma. A pneumothorax (PTX) can be a life-threatening condition that requires immediate tube thoracostomy placement. Here, we present a case of recurrent PSP in a woman presenting with dyspnea. CASE PRESENTATION: A 36-year-old woman non-smoker with a history of unclassified bullous lung disease and recurrent PTX status post right video assisted thoracoscopic surgery (VATS) with mechanical pleurodesis and left VATS with talc pleurodesis presented to the emergency department (ED) with progressive dyspnea. Family history was notable for bullous lung disease and PTX in her maternal grandfather and mother. Days prior to ED, she developed right sided pleuritic chest pain after yoga that self-resolved. Chest radiography revealed right sided pleural effusion without signs of PTX. A day prior to the ED, she developed dyspnea with exertion. On admission, she was at 100% saturation on room air, normotensive and had decreased breath sounds in her right lower lung field. Computed tomography (CT) revealed a new large right basilar, anterior, medial PTX and redemonstration of multiple bilateral bullae unchanged from prior imaging. VATS was recommended but refused. A 10.3 French chest tube was placed to wall suction overnight. Repeat CT revealed near complete resolution of the PTX with unchanged bullae. Genetics workup revealed an FLCN mutation c.1584del; p.Glu530Argfs*7 suggesting the cause of recurrent PTX. DISCUSSION: A diagnosis of PSP requires the exclusion of lung diseases such as cystic fibrosis and alpha-1-antitrypsin, connective tissue disorders such sjogren's and marfan syndromes, rare conditions such as lymphangioleiomyomatosis and tuberous sclerosis. PSP commonly occurs due to rupture of subpleural bullae and can be a complication of BHD syndrome. BHD syndrome is a hereditary cancer disorder characterized by renal cell cancer, colonic polyps, hair follicle hamartomas, lung cysts and PTX. It is associated with a FLCN gene mutation, which is expressed in type I pneumocytes that form the structure of alveoli. FLCN mutation lung cysts are hypothesized to be due to a defect in cell-cell adhesion resulting in expansion of alveolar spaces. FLCN mutation patients can rarely present with a purely spontaneous PTX. PSP treatment options include a chest tube (recurrence rate (RR) 26.4%), VATS pleurectomy (RR 0.4%), VATS abrasion (RR 2.3%) and lung transplantation. CONCLUSIONS: A FLCN gene mutation should be excluded in those with recurrent PTX. Genetic testing should be considered as well as appropriate cancer screening with renal ultrasound and colonoscopy given its association with BHD. REFERENCE #1: Boone, P. M. et al. (2019). The genetics of pneumothorax. AJRCCM, 199(11), 1344-1357. REFERENCE #2: Daccord, C. et al. (2020). Birt–Hogg–Dubé syndrome. European Respiratory Review, 29(157), 200042. REFERENCE #3: Frohlich, B. et al. (2008). Novel mutations in the folliculin gene associated with spontaneous pneumothorax. European Respiratory Journal, 32(5), 1316-1320. DISCLOSURES: No relevant relationships by George Moran, source=Web Response No relevant relationships by Hekmat Nasiri, source=Web Response No relevant relationships by Sudhir Rajan, source=Web Response

Novel folliculin gene mutations in Polish patients with Birt\u2013Hogg\u2013Dub\xe9 syndrome

BackgroundBirt–Hogg–Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS.Materials and methodsThe first case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 families have been identified. Thirteen patients were confirmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations.ResultsBHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of first pneumothorax and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respectively. Five patients (33%) were ex-smokers (2.1 ± 1.37 packyears), and 10 (67%) had never smoked cigarettes. Twelve patients (83%) had a history of recurrent symptomatic pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Different mutations of the FLCN gene were identified (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41).ConclusionsAll analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identified.