Birt-Hogg-Dubé Syndrome Research Articles

MP41-18 CLINICAL MANIFESTATIONS OF BIRT-HOGG-DUBE SYNDROME IN A LARGE CLINICAL COHORT

You have accessJournal of UrologyCME1 Apr 2023MP41-18 CLINICAL MANIFESTATIONS OF BIRT-HOGG-DUBE SYNDROME IN A LARGE CLINICAL COHORT Brian Cortese, Raju Chelluri, David Ostrowski, Daniel Roberson, Phillip Pierorazio, and Katherine Nathanson Brian CorteseBrian Cortese More articles by this author , Raju ChelluriRaju Chelluri More articles by this author , David OstrowskiDavid Ostrowski More articles by this author , Daniel RobersonDaniel Roberson More articles by this author , Phillip PierorazioPhillip Pierorazio More articles by this author , and Katherine NathansonKatherine Nathanson More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003279.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Birt-Hogg-Dube (BHD) syndrome is an underdiagnosed autosomal dominant condition caused by folliculin (FLCN) gene mutations and is characterized by fibrofolliculomas, pulmonary cysts, and renal masses. Our study characterizes our center’s cohort of BHD patients to describe the range of presentations. METHODS: A single center, retrospective cohort study of patients with BHD syndrome was performed. The medical record was queried for clinical data corresponding to renal mass, pulmonary, and dermatologic findings. Results were reported as median and inter-quartile range (IQR). Germline mutation status is reported. RESULTS: Eighty-one BHD patients were identified. Median age of BHD diagnosis was 38 [28-57] years old. Ten (12.3%) patients had a total of 15 renal masses. Age at first tumor diagnosis was 58 [50.8-60.2] years with median lesion size being 1.5 [1-2.1] cm. Six (60%) tumor patients were managed non-operatively and 4 (40%) underwent resection. Surveilled tumor growth rate was 0 [-0.02 – 0] cm/yr during a median 2.3 [2.3-5.6] year follow-up. Twenty-six (32.1%) patients had characteristic skin findings at diagnosis with fibrofolliculomas being documented in 47 (58%) total patients at a median age of 46.5 [33-58] years. Twenty-eight (34.6%) patients had a history of pneumothorax at diagnosis with pneumothorax affecting 34 (42%) total patients. Notably, 9/47 (19.1%) patients with fibrofolliculomas and 4/34 (11.8%) patients with pneumothorax history had a renal mass. Four (40%) renal tumor patients had pneumothorax history. CONCLUSIONS: Renal tumors were found to affect 12.3% of BHD patients in this clinical cohort. BHD-associated renal masses were noted to mostly small, indolent with a static growth rate. Only 19% patients with fibrofolliculomas and 12% of patients with pneumothorax developed a renal mass. Of patients with a renal mass, 40% experienced a pneumothorax in their lifetime. Limitations of this study include its retrospective nature, small sample size of BHD patients with renal lesions, and low follow-up time. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e563 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brian Cortese More articles by this author Raju Chelluri More articles by this author David Ostrowski More articles by this author Daniel Roberson More articles by this author Phillip Pierorazio More articles by this author Katherine Nathanson More articles by this author Expand All Advertisement PDF downloadLoading ...

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease. To investigate for novel genes causing parathyroid cancer. We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant. The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

Characteristic Chest Computed Tomography Findings for Birt-Hogg-Dube Syndrome Indicating Requirement for Genetic Evaluation.

Background: Chest computed tomography (CT) findings are important for identifying Birt−Hogg−Dube (BHD) syndrome. However, the predictive power of classical criteria for chest CT findings is weak. Here, we aimed to identify more specific chest CT findings necessitating genetic examination for FLCN gene mutations. Methods: From June 2016 to December 2017, we prospectively enrolled 21 patients with multiple bilateral and basally located lung cysts on chest CT with no other apparent cause, including cases with and without spontaneous primary pneumothorax. All enrolled patients underwent FLCN mutation testing for diagnosis confirmation. Results: BHD was diagnosed in 10 of 21 enrolled patients (47.6%). There were no differences in clinical features between the BHD and non-BHD groups. Maximal cyst diameter was significantly greater in the BHD group (mean ± standard deviation; 4.1 ± 1.1 cm) than in the non-BHD group (1.6 ± 0.9 cm; p < 0.001). Diversity in cyst size was observed in 100.0% of BHD cases and 18.2% of non-BHD cases (p = 0.001). Morphological diversity was observed in 100.0% of BHD cases and 54.6% of non-BHD cases (p = 0.054). Areas under the receiver operating characteristic curves for predicting FLCN gene mutations were 0.955 and 0.909 for maximal cyst diameter and diversity in size, respectively. The optimal cut-off value for maximal diameter FLCN mutations prediction was 2.1 cm (sensitivity: 99%; specificity: 82%). Conclusions: Reliable chest CT features suggesting the need for FLCN gene mutations screening include variations in cyst size and the presence of cysts > 2.1 cm in diameter, predominantly occurring in the bilateral basal lungs.

Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene.

Previously, we reported a series of families presenting with trichodiscomas, inherited in an autosomal dominant pattern. The phenotype was named familial multiple discoid fibromas (FMDF). The genetic cause of FMDF remained unknown so far. Trichodiscomas are skin lesions previously reported to be part of the same spectrum as the fibrofolliculoma observed in Birt-Hogg-Dubé syndrome (BHD), an inherited disease caused by pathogenic variants in the FLCN gene. Given the clinical and histological differences with BHD and the exclusion of linkage with the FLCN locus, the phenotype was concluded to be distinct from BHD. We performed extensive clinical evaluations and genetic testing in ten families with FMDF. We identified a FNIP1 frameshift variant in nine families and genealogical studies showed common ancestry for eight families. Using whole exome sequencing, we identified six additional rare variants in the haplotype surrounding FNIP1, including a missense variant in the PDGFRB gene that was found to be present in all tested patients with FMDF. Genome-wide linkage analysis showed that the locus on chromosome 5 including FNIP1 was the only region reaching the maximal possible LOD score. We concluded that FMDF is linked to a haplotype on chromosome 5. Additional evaluations in families with FMDF are required to unravel the exact genetic cause underlying the phenotype. When evaluating patients with multiple trichodisomas without a pathogenic variant in the FLCN gene, further genetic testing is warranted and can include analysis of the haplotype on chromosome 5.

A rare cause of spontaneous pneumothorax: radiological findings and surgical approach

Birt-Hogg-Dubé Syndrome (BHDS) is a rare genetic condition that affects the connective tissue of kidneys, lungs, and skin, causing an aberration in the proteic folliculin (FLCN) pathway. In the lungs, the altered FLCN is found in the outer part of the alveoli, particularly in the lower lobes, causing parenchymal weakness and subsequent cystic degeneration. Because of its rarity, a comprehensive management protocol is not available yet. We present a case of a man with left recurrent pneumothorax due to bilateral multiple bullae, as revealed by a preoperative chest Computed Tomography (CT) scan. Given the characteristic radiological features of BHDS, the CT scan should always be considered for the differential diagnosis to exclude other more common cystic diseases, such as lymphoid interstitial pneumonia, Langerhans cell histiocytosis, or lymphangioleiomyomatosis. Considering the different options suitable for bullous diseases, we decided to treat the patient with a pleural abrasion through a biportal Video-Assisted Thoracic Surgery approach and sterile talc pleurodesis. No more spontaneous episodes were reported one year later. Bullectomy was not carried out because the diffuse cystic intraoperative pattern would never be solved by marginal parenchymal resections. Relapsing spontaneous pneumothorax could be a spy of a hidden genetic disease (such as BHSD), and a CT scan should be considered case-by-case because it may provide crucial information regarding the overall lung pattern. In such cases, pleural abrasion with talc pleurodesis is a considerably effective treatment.

A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

Aspergillus tracheobronchitis with Birt-Hogg-Dubè syndrome as a rare cause of chronic cough

BackgroundAspergillus tracheobronchitis (ATB) is confined as a condition of chronic superficial infection of tracheobronchial tree. Its diagnosis is difficult due to atypical manifestations and low detective rate of Aspergillus thus far.Case presentation:Herein, we presented a 45-year-old male patient with a sole chronic productive cough for five years referred to our cough specialist clinic. Chest high-resolution computed tomography showed multiple lung cysts predominantly located in the subpleural lesions and near the mediastinum. Neither bacteria nor fungi were identified by sputum culture. However, metagenomic next-generation sequencing in sputum detected Aspergillus fumigatus DNA. The genetic testing of whole blood suggested the germline mutation of the tumor suppressor gene folliculin, supporting a diagnosis of Birt-Hogg-Dubé (BHD) syndrome. His productive cough symptom significantly improved after receiving itraconazole treatment for 2 months. After discontinuation of antifungal treatment, there was no relapse for four months follow-up. A diagnosis of ATB with BHD syndrome was eventually established in this patient.ConclusionATB should be considered in any patient with prolonged unexplained productive cough. Next-generation sequencing technologies may be useful to identify ATB which is uncommon and easily ignored in clinical practice.

Abstract 15528: Indeterminate Cardiomyopathy in a Patient With Birt Hogg Dubé Syndrome and a Clinical Diagnosis of Scleroderma and Prior Atrial Tachy Arrhythmias: A Diagnostic and Therapeutic Dilemma

Birt Hogg Dubé (BHD) syndrome, tachycardia induced cardiomyopathy and scleroderma are three well defined diagnoses. A link between them has not been reported. We present a diagnostic and treatment challenge, of a patient with BHD, clinical scleroderma and prior tachycardia induced cardiomyopathy with persistent left ventricular dysfunction despite restoration of sinus rhythm. Mr. X medical history includes recurrent bilateral pneumothoraces and bullectomy, with a cystic lung disease. He was diagnosed with BHD syndrome in 2018. He was diagnosed clinically with scleroderma with myositis based on symptoms and clinical signs with paucity of inflammation on muscle biopsy and negative biomarkers. There has been a limited response to immunosuppressants. In 2020 he presented with symptomatic paroxysmal atrial fibrillation. CMRI showed biventricular dilatation with increased volumes with LVEF of 40%, ​RVEF of 25% in sinus bradycardia. LGE showed subendocardial signal in ​​the basal and mid segment of the lateral and posterolateral walls with small foci of myocardial ​​​signal at the basal and mid inferior RV-LV hinge points. A bespoke CRT-D (secondary to cavity size) was inserted following documented broad complex tachycardia, given the history of reduced ejection fraction despite medical therapy. Right and left heart catheterisations were normal. Endomyocardial biopsy showed no pathological features and no fibrosis or evidence of infiltrative disease. Genotype results are pending. BHD is a genetic disorder, affecting folliculin protein, associated with cystic lesions of the lung, kidney, and skin with an increased risk of renal cell carcinoma (1). There is no known link of BHD syndrome with cardiomyopathy. Studies have demonstrated folliculin has a role in cardiomyocyte generation (2). Given the cardiac biopsy result, not in keeping with scleroderma or tachycardia induced cardiomyopathy, he may have an independent cardiomyopathy, or a first case of cardiomyopathy secondary to BHD. Our challenge continues to be optimising available therapies ensuring the best quality of life, whilst balancing the potential need for cardiac transplant with lifelong immunosuppressant therapy in a condition which has a seven-fold increased risk of renal cancer.

RF19 | PSUN33 Adrenocortical Carcinoma as a Rare Manifestation of Birt-Hogg-Dubé Syndrome

Abstract Adrenocortical carcinoma (ACC) can occur as part of hereditary cancer syndromes, particularly Lynch syndrome and Li-Fraumeni syndrome. Here we describe 5 patients (3 women) with adrenal tumors and Birt-Hogg-Dubé syndrome (BHDS). BHDS is a hereditary tumor syndrome characterized by fibrofolliculomas/trichodiscomas, renal tumors, lung cysts, and spontaneous pneumothoraces. All five patients had a confirmed germline FLCN pathogenic variant. One case was previously reported by our institution. Age of diagnosis (AD) ranged from 36 to 62 years with a mean AD of 46 years. All patients identified as Caucasian. Three patients had non-functioning adrenal tumors, while the remaining two patients did not undergo biochemical assessment preoperatively but did not have symptoms or history of adrenal hormone excess. Histologically, four patients had confirmed ACC while one had an adrenocortical tumor of uncertain malignant potential, most consistent with an oncocytoma. All patients were initially treated with mitotane. Three patients developed metastatic disease requiring additional systemic chemotherapy, immunotherapy, and/or radiation. A total of 8 confirmed ACCs in patients with BHDS have been reported to date, raising suspicions that these tumors might be a part of the BHDS tumor spectrum. When BHDS patients are screened for renal malignancies, special attention should be paid to the adrenal glands. Adrenal nodules should undergo prompt assessment as &amp;gt;50% of reported cases developed metastatic disease. Given possible association with BHDS, testing for FLCN pathogenic variants should be considered during the genetic evaluation of patients with ACC. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.

Birt-Hogg-Dubé syndrome: Another mTOR phenomenon.

Birt-Hogg-Dubé syndrome is an uncommon autosomal dominant systemic disorder with cutaneous findings notable for fibrofolliculomas or trichodiscomas on the scalp, face, neck, and trunk. These cutaneous signs are associated with bilateral renal cell carcinoma, benign renal cysts, pulmonary cysts, and spontaneous pneumothorax. Given its autosomal dominant inheritance pattern, the successful diagnosis of Birt-Hogg-Dubé syndrome (BHDS) may elucidate a diagnosis in family members. BHDS results from a mutation in the FLCN gene encoding the folliculin protein, a transcriptional regulator of the mammalian target of rapamycin signaling pathway. Like tuberous sclerosis, BHDS's clinical features may subside with the use of oral rapamycin for mammalian target of rapamycin inhibition, a theoretical concept meriting exploration. Although its prevalence in the general population has been estimated at 2 cases per million, BHDS has been detected in a few patients from the nearby Portuguese-lineage quarter of the city of Newark, a disproportionate prevalence possibly explained by the founder effect.

Diffuse cystic lung diseases: Imaging spectrum and diagnostic approach using high-resolution computed tomography.

The lung cyst is an air-containing lucent area surrounded by thin imperceptible walls. Other lucent lung lesions like centrilobular emphysema, cavity, cystic bronchiectasis, honeycomb cyst, and pneumatoceles are close mimics of a lung cyst on high-resolution computed tomography (HRCT). Various diseases with multiple lung cysts throughout both the lungs are classified as diffuse cystic lung diseases (DCLDs). HRCT is considered the imaging of choice for diagnosis of such diffuse cystic lung diseases. Common DCLDs like lymphangioleiomyomatosis, Birt-Hogg-Dubé syndrome (BHS), Langerhans cell histiocytosis (LCH), lymphocytic interstitial pneumonia (LIP), and desquamative interstitial pneumonia (DIP) can be confidently diagnosed on HRCT without further requirement of histopathological confirmation. The imaging also helps in differentiation of uncommon DCLDs and exclusion of the mimics. This review describes a simple algorithmic approach for DCLDs on HRCT based on scrutinizing the cyst's distribution, size, and shape, background parenchymal changes, and its correlation with clinical features and extrapulmonary imaging findings.

Percutaneous Thermal Ablation for Renal Tumors in Patients with Birt-Hogg-Dubé Syndrome.

Simple SummaryPercutaneous thermal ablation (TA) could be a safe and efficient nephron-sparing treatment for treating renal cell carcinoma (RCCs) associated with Birt–Hogg–Dubé (BHD) syndrome, a rare hereditary condition at greater risk of repeated treatments, even in the case of advanced chronic kidney disease, and should be systematically discussed as a treatment option. Indications for nephron-sparing management of these tumors in BHD patients depends on many factors, including size, number, and location of the tumor(s) in each kidney, patient surgical history, and renal function. The role of the tumor board including radiologists, interventional radiologists, urologists, and oncologists is essential.BHD syndrome is characterized by an increased risk of bilateral and multifocal renal cell carcinoma (RCCs), but is rarely metastatic. Our report aims to analyze the outcome of patients with BHD syndrome who underwent percutaneous thermal ablation (TA). The present report included six BHD syndrome patients (five men) with a mean age of 66 ± 11 (SD) years who had a proven germline FLCN gene mutation and underwent TA for a renal tumor. Nineteen renal tumors (median two tumors per patient; range: 1–3), including seven chromophobe RCCs, five clear-cell RCCs, four papillary RCCs, two clear-cell papillary RCC, and one hybrid oncocytic/chromophobe tumor were treated in 14 ablation sessions. The mean size of the tumors was 21 ± 11 (SD) mm (median: 20 mm; interquartile range (IQR): 14–25 mm) for a mean volume of 7 ± 11 (SD) mL (median: 3; IQR: 1–5 mL). Technical success was achieved in all ablation sessions (primary success rate, 100%). The procedure was well tolerated under conscious sedation with no significant Clavien–Dindo complication (grade 2, 3, 4). All patients were alive with no distant metastasis during a median follow-up period of 74 months (range: 33–83 months). No local tumor progression was observed. The mean decrease in estimated glomerular filtration rate was 8 mL/min/1.73 m2. No patients required dialysis or renal transplantation. In this case series, percutaneous TA appeared as a safe and efficient nephron-sparing treatment for treating RCCs associated with BHD syndrome, even in the case of advanced chronic kidney disease.

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.

Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with non-chromophobe RCC (nonchrRCC): Impact of FLCN genomic alteration (GA) status.

4550 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with nonchrRCC. Methods: 109 chrRCC and 5,862 nonchrRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female (37 [34%] vs. 1,817 [31%]) and younger than pts with nonchrRCC (median age 58 vs 62 years, p &lt;.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in the nonchrRCC cases only at 2.3% with 37% of the GA being germline. 1/109 (0.9%) of chrRCC featured a germline FLCN GA. GA/tumor were slightly higher in nonchrRCC vs chrRCC (3.6 vs 2.4; NS). There were no significant differences in gLOH, genomic signatures or ancestry between the groups. GA more frequent in chrRCC included TP53, RB1, PTEN. GA more frequent in the nonchrRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Biomarkers of immune checkpoint inhibitor (ICPI) drug response revealed higher mean TMB, TMB ≥10 mutations/Mb and PBRM1 inactivating mutation frequencies in the nonchrRCC than the chrRCC indicating possible differences in IO drug response. Conclusions: FLCN mutations that are associated with familial incidence of chrRCC are rarely associated with sporadic chrRCC. Sporadic chrRCC has a substantially different genomic profile from nonchrRCC and appears to harbor fewer opportunities for both targeted and immunotherapies. [Table: see text]

Frequency of truncating FLCN variants and Birt-Hogg-Dubé–associated phenotypes in a health care system population

Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes. Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed using Firth's logistic regression. P/LP truncating FLCN variants were identified in 35 individuals (1 in 3234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). A total of 4 (11.4%) individuals had prior clinical BHD diagnoses. In this health care population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

Birt-Hogg-Dubé syndrome encountered at rare lung disease clinic in Anhui province, China

BackgroundDiagnosis of rare diseases remains a challenge in China. We describe our experience with Birt-Hogg-Dubé syndrome (BHDS) encountered at a Rare Lung Disease Clinic recently established in China.MethodsAfter the first patient with BHDS was recognized in 2017, a Rare Lung Disease Clinic with a multidisciplinary team of specialists was established. We retrospectively analyzed the data of consecutive patients with BHDS encountered from inception to December 2021.ResultsThere were 1, 1, 15, 12 and 21 cases with BHDS diagnosed from year 2017 to 2021, respectively. All 50 patients (34 women) were of Han race with a mean age of 47.4 years. The common manifestations were pulmonary cysts (98%), pneumothorax (54%) and skin lesions (68%). Renal cancer was detected in two patients and renal angiomyolipoma in four other patients. The main presentations leading to diagnosis were pneumothorax (42%), family screening (36%), and lung cysts identified on radiologic imaging (20%). The average delay in diagnosis was 8.3 years, and 4.7 years in patients with only pulmonary cysts. The most frequent pathogenic variant was c.1285del/dup on exon 11 (23%) among 44 patients confirmed by genetic testing. Renal cancer has not been found on follow-up surveillance thus far.ConclusionsIncreasing number of patients with BHDS are being recognized in China, facilitated by establishment of a Rare Lung Disease Clinic. Pulmonary cysts and pneumothorax were commonly encountered features, but skin lesions appeared to be more prevalent in Chinese subjects than previously reported in other Asian countries.

Clinical and Genetic Comparison of Birt-Hogg-Dubé Syndrome (Hornstein-Knickenberg Syndrome) in Chinese: A Systemic Review of Reported Cases.

BackgroundBirt–Hogg–Dubé syndrome (BHD), also named Hornstein–Knickenberg syndrome, is a rare autosomal dominant disease characterized by lung cysts, recurrent pneumothoraxes, renal cell carcinoma and skin fibrofolliculomas.PurposeThis study summarizes the clinical and genetic information of Chinese BHD patients from all available reported cases and explores the relationship between the clinical and genetic spectrum in the hope of improving the prognosis of Chinese BHD patients.MethodsRelative studies were collected by searching PubMed, Cochrane Library, Embase, OVID medicine, SinoMed, Web of Science, China National Knowledge Infrastructure, Wanfang Data and China Hospital Knowledge Database from January 1, 1977 to December 31, 2021. The search strategy included the following term keys: (Birt–Hogg–Dubé syndrome OR Hornstein-Kinckenberg syndrome OR familial pulmonary cysts OR familial spontaneous pneumothorax OR fibrofolliculomas OR trichodiscomas OR inherited renal cancer syndromes OR FLCN) AND (Chinese OR China).ResultsIn total, 287 Chinese patients from 143 families described in 31 references were included in this article. Chinese BHD patients tended to present more pulmonary symptoms but fewer skin lesions and renal malignancies, which appeared to be atypical when compared with Caucasian patients. The FLCN mutation spectrum among Chinese BHD patients was established with the mutational hot spot c.1285depC/delC as the most frequent mutation. In addition, this mutation spectrum also showed some differences from other races, with a relatively frequent large deletion c.872–429_1740+1763del (exon 9–14 deletion) reported only in Chinese individuals but no observation of the two mutational hot spots found in Japanese individuals. We also attempted to establish potential pheno-genotype correlations in Chinese BHD patients, but the results were negative.ConclusionTo improve the prognosis of BHD patients, physicians need to increase their awareness of BHD by focusing on the family history of pneumothorax as well as skin lesions in patients with lung cysts and promptly advising patients on genetic sequencing.

Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status.

292 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p &lt;.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in only 2.3% of the ccRCC cases with 37% of the GA predicted to be germline. chrRCC did not reveal somatic or germline FLCN GA. GA/tumor were slightly higher in ccRCC vs chrRCC (3.6 vs 2.4; NS). GA more frequent in chrRCC included TP53, RB1 and PTEN. GA more frequent in the ccRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Putative biomarkers of immune checkpoint inhibitor (ICPI) response were infrequent in both groups with only a slightly higher, but still low, mean TMB in ccRCC vs chrRCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chrRCC group. Conclusions: FLCN mutations that are associated with the familial incidence of chrRCC were not associated with sporadic chrRCC. Sporadic chrRCC has substantially different genomic profile from ccRCC and may harbor a few ‘targetable’ GA. The prediction of response to ICPI in RCC remains challenging with chrRCC featuring slightly higher PD-L1 expression and ccRCC featuring higher PBRM1 GA and higher TMB.[Table: see text]

A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population.

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome.

Seventh BHD international symposium: recent scientific and clinical advancement.

The 7th Birt-Hogg-Dubé (BHD) International Symposium convened virtually in October 2021. The meeting attracted more than 200 participants internationally and highlighted recent findings in a variety of areas, including genetic insight and molecular understanding of BHD syndrome, structure and function of the tumor suppressor Folliculin (FLCN), therapeutic and clinical advances as well as patients’ experiences living with this malady.