Birt-Hogg-Dubé Syndrome - report of two cases with two new mutations.

Radiologically Indeterminate Pulmonary Cysts in Birt-Hogg-Dubé Syndrome

Birt Hogg Dube Syndrome (BHDS)

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

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant genetic disorder characterized by the development of benign cutaneous neoplasms, renal tumors, and pulmonary cysts. Caused by mutations in the folliculin (FLCN) gene on chromosome 17, the pulmonary manifestations observed in BHD include multiple subpleural cysts that are frequently associated with pneumothorax. Diffuse cystic lung disease is also commonly encountered in lymphangioleiomyomatosis (LAM), either in isolation or in the context of tuberous sclerosis complex (TS). The diagnosis of BHD is confirmed by identifying pathogenic FLCN germline mutations. Modern evidence, however, supports using serum vascular endothelial growth factor-D (VEGF-D) levels in differentiating LAM from other cystic lung diseases, including BHD, with high specificity. This case report describes the unique finding of an elevated VEGF-D serum level (1290 pg/ml) in a patient with cystic lung disease, bilateral pneumothorax and a novel disease-causing mutation (E280X) in the FLCN gene.

Birt-Hogg-Dubé syndrome (BHDS), caused by germline mutations in the folliculin (FLCN) gene, predisposes individuals to develop fibrofolliculomas, pulmonary cysts, spontaneous pneumothoraces, and kidney cancer. The FLCN mutation detection rate by bidirectional DNA sequencing in the National Cancer Institute BHDS cohort was 88%. To determine if germline FLCN intragenic deletions/duplications were responsible for BHDS in families lacking FLCN sequence alterations, 23 individuals from 15 unrelated families with clinically confirmed BHDS but no sequence variations were analyzed by real-time quantitative PCR (RQ-PCR) using primers for all 14 exons. Multiplex ligation-dependent probe amplification (MLPA) assay and array-based comparative genomic hybridization (aCGH) were utilized to confirm and fine map the rearrangements. Long-range PCR followed by DNA sequencing was used to define the breakpoints. We identified six unique intragenic deletions in nine patients from six different BHDS families including four involving exon 1, one that spanned exons 2-5, and one that encompassed exons 7-14 of FLCN. Four of the six deletion breakpoints were mapped, revealing deletions ranging from 5688 to 9189 bp. In addition, one 1341 bp duplication, which included exons 10 and 11, was identified and mapped. This report confirms that large intragenic FLCN deletions can cause BHDS and documents the first large intragenic FLCN duplication in a BHDS patient. Additionally, we identified a deletion "hot spot" in the 5'-noncoding-exon 1 region that contains the putative FLCN promoter based on a luciferase reporter assay. RQ-PCR, MLPA and aCGH may be used for clinical molecular diagnosis of BHDS in patients who are FLCN mutation-negative by DNA sequencing.

Birt-Hogg-Dubé syndrome: metalloproteinase activity and response to doxycycline

Approximately 10% patients of spontaneous pneumothorax have positive family history. Birt–Hogg–Dube syndrome (BHD) is one of the cause of familial pneumothorax. BHD syndrome is associated with hamartomas of skin,renal cancer and spontaneous pneumothorax. However there have been reports of isolated spontaneous pneumothorax and lung cysts in patients of BHD syndrome in the absence of other manifestations. Mutation in Folliculin gene (FLCN) on chromosome 17 has been reported to cause BHD syndrome. A 32 year old non-smoker female presented with left sided spontaneous pneumothorax. Her sister had previously suffered from recurrent pneumothorax (twice). High Resolution CT (HRCT) scan of chest of both the sisters revealed multiple lung cysts. We decided to evaluate these patients of familial pneumothorax and identify any genetic basis for their disease. Genetic sequencing of the FLCN gene was performed in 8 family members. We subsequently screened the family members by HRCT scan of chest for any lung cysts. Physical examination and abdominal CT scan was done to rule out any skin and renal involvement. Genetic sequencing revealed Cytosine deletion mutation in hypermutable region of exon 11 of FLCN gene in the index case, her 3 siblings, her mother and her son. HRCT scan of the patient9s sibling showed lung cysts whereas her son had normal lungs, despite having the mutation.This cytosine deletion caused a frameshift mutation resulting in a truncated folliculin protein. For cystic lung disease with an undetermined etiology or familial pneumothorax, possibility of BHD syndrome should be considered. Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement.

Expert consensus on the diagnosis and management of Birt-Hogg-Dubé syndrome

A RARE AND LATE PRESENTATION OF A HEREDITARY CYSTIC LUNG DISEASE

Rationale:Birt–Hogg–Dube (BHD) syndrome is a rare autosomal dominant disorder characterized by a triad of manifestations, including recurrent spontaneous pneumothorax, multiple cutaneous fibrofolliculomas, and renal neoplasms. Familial clustering of spontaneous pneumothorax should raise clinical suspicion of BHD syndrome. This syndrome is caused by pathogenic variants of the folliculin gene (FLCN gene) encoding folliculin, which predisposes to pneumothorax through dysregulated matrix metalloproteinase activity, leading to elastic fiber degradation in the pulmonary parenchyma.Patient concerns:A 28-year-old female presented with recurrent pneumothorax and a family history of primary spontaneous pneumothorax. Emergency video-assisted thoracoscopic surgery with bullectomy and cyst resection was performed.Diagnoses:The FLCN gene mutation was confirmed by genetic testing after surgery. The clinicopathological characteristics, molecular genetics, and therapeutic strategies for BHD syndrome have been discussed in the literature. The female who experienced 3 episodes of spontaneous pneumothorax within 24 months. Notably, her multigenerational family history included her paternal uncle and cousins affected by primary spontaneous pneumothorax.Interventions:Emergency video-assisted thoracoscopic surgery revealed multiple subpleural cysts (3–15 mm in diameter), predominantly in the lower lung lobes, requiring bullectomy and cyst wall resection. Histopathological analysis revealed characteristic thin-walled cysts lined with alveolar epithelium. Postoperative genetic sequencing revealed a heterozygous splice-site variant in FLCN gene, establishing a diagnosis of BHD syndrome.Outcomes:After regular follow-up, the patient had no recurrence of spontaneous pneumothorax, such as bullae rupture, until recently. This case highlights the importance of integrating radiological findings with molecular diagnostics for the evaluation of recurrent pneumothorax. It is particularly necessary to emphasize that the patient and her legal guardian has given us informed consent. Chengdu-Shangjin Nanfu Hospital ethics Committee has approved this study.Lessons:This case shows a typical phenomenon of family clustering that should raise clinical suspicion of BHD syndrome. BHD syndrome is a rare autosomal dominant genetic disorder that caused by mutations in FLCN gene. The gene is a tumor suppressor gene that encodes the follicle-stimulating hormone folliculin. Follicle-stimulating hormone folliculin is expressed in most tissues, including the skin and its appendages, type I alveolar epithelial cells, and distal renal tubular epithelial cells, which explains why BHD syndrome occurs in the skin, lungs, and kidneys. The literature review shows that there are 12 similar cases, including the male-to-female ratio and average age. Thoracoscopic surgery had the best effect, followed by conservative treatment, and the recurrence rate was higher after closed thoracic drainage. Due to the rarity of this syndrome, this article reminds clinicians to pay attention to its familial clustering characteristics during diagnosis and treatment, and also reminds other family members to pay attention to screening for the clinical features related to this syndrome, so as to facilitate early treatment. Furthermore, this case also provides significant reference value for identifying the causes and molecular mechanisms of spontaneous pneumothorax, especially those with a familial clustering tendency.

BackgroundBirt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition characterized by dermatologic lesions, pulmonary manifestations, and renal tumors. The syndrome arises from germline mutations in the folliculin (FLCN) gene. We present findings from the single largest family BHD cohort described to date. Primary objectives were to characterize cystic lung changes on computed tomography (CT) chest scanning and identify features that stratify patients at higher risk of pneumothorax. Secondary objectives entailed description of the following: type and natural history of BHD-associated pneumothorax, pulmonary function characteristics, and relationship between cystic lung changes and pulmonary function.MethodsThe study was a retrospective chart review for a case series of a single family. Over 70 family members of a proband with documented BHD were identified, 68 of which consented to genetic testing. All those with confirmed BHD were offered a clinical assessment by the Medical Genetics and Pulmonary services which included a history, physical exam, complete pulmonary function tests, and computed tomography (CT) scan of the chest and abdomen.ResultsThirty-six individuals had a heterozygous mutation in the FLCN gene (c.59delT). Of these, 100 % (28/28) had pulmonary cysts, 41 % (13/32) had spontaneous pneumothoraces, 26 % (8/31) had kidney cysts, 3 % (1/31) had renal tumors, and 53 % (18/34) had dermatologic manifestations. Recurrent pneumothoraces were common (40 %). Cyst size (OR 3.23, 95 % CI 1.35–7.73) and extent of lower lung zone disease (OR 6.43, 95 % CI 1.41–29.2) were the only findings associated with pneumothorax. The size or extent of cystic disease did not correlate with lung function results.ConclusionsThis is the largest single family cohort of patients with BHD syndrome documented to date. We found that all individuals had pulmonary cysts, pneumothoraces were common, and cyst size and lower lobe predominant disease were associated with pneumothorax. Lung function was generally preserved and not affected by a high cyst burden.

Introduction: Birt-Hogg-Dubé syndrome (BHD), is a rare inherited autosomal dominant disorder characterized by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal tumors, caused by germline mutations in the FLCN gene, which encodes folliculin. BHD has no sex predilection and tends to manifest in the third or fourth decade of life. A family history of pneumothorax is an important clue, along with physical exam and unique imaging findings. This case discusses an individual who had multiple criteria required to diagnosis BHD but had a hindrance in treatment due to its delayed diagnosis. Case presentation: A 43-year-old female with a past medical history of obstructive sleep apnea (not on CPAP), active smoker (∼20 pack year), and recurrent spontaneous pneumothoraces (three prior since 2022, some requiring chest tube insertion) presented for dyspnea. Chest xray revealed a small right apical pneumothorax. She was alert and oriented, SpO2 96% on room air, respiratory rate 12, heart rate 80 bpm, blood pressure 147/82 mmHg, and afebrile. White blood cell count was 12,320 with lymphocyte predominant differential. Physical exam was notable for facial fibrofolliculoma. Review of CT scan exhibited diffuse cystic lung disease with a basilar predominant pattern, subpleural cysts, and renal cysts. Upon further questioning regarding family history, she eluded her sisters and aunt had Birt Hogg Dube syndrome. Due to the patient being clinically stable with a small pneumothorax, she was placed on a non-rebreather mask for nitrogen washout therapy and chest xray the following day showed resolution. She was encouraged to follow up with interventional pulmonary for possibility of pleurodesis and to obtain genetic testing for FLCN gene. Discussion: The prevalence of BHD is about two cases per million, although this may be underestimated. Menko, et al (2009) published diagnostic criteria for BHD, of which this patient met two minor criteria. While she is still pending genetic and histopathologic testing, it is important to note that negative FLCN gene testing does not exclude the diagnosis, as up to 40% of patients with negative testing still meet diagnostic criteria. Imaging includes bilateral pulmonary cysts with a basilar predominance, +/- pneumothorax, and bilateral renal cysts with a high tendency of becoming malignant. Unlike other cystic lung diseases, BHD usually does not lead to progressive loss of lung function. It is crucial to keep BHD in the differential when evaluating patients with cystic lung disease and a strong family history of pneumothoraces.

Birt–Hogg–Dubé syndrome (BHDS), which is also called Hornstein-Knickenberg syndrome (HKS), is a hereditary autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN, NM_144997). More pulmonary manifestations (pulmonary cysts and recurrent pneumothoraxes) but fewer skin fibrofolliculomas and renal malignancy are found in Asian BHDS patients compared with other BHDS patients. The atypical manifestation can easily lead to a missed or delayed diagnosis. Here, we report a Chinese family with BHDS that presented with primary spontaneous pneumothorax (PSP) and extensive pulmonary cysts in the absence of skin lesions or renal neoplasms. Next-generation sequencing (NGS) was used to sequence the FLCN gene, and Sanger sequencing was carried out on the samples to confirm the presence of these variants. Among the 13 family members, a novel frameshift variant of FLCN (c.912delT/p.E305KfsX18) was identified in seven individuals. This variant has not been reported before. Bioinformatics analysis showed that the novel variant might lead to a premature stop codon after 18 amino acid residues in exon 9, and this may affect the expression level of FLCN. The identification of this novel frameshift variant of FLCN not only further confirms the familial inheritance of BHDS in the proband but also expands the mutational spectrum of the FLCN gene in patients with BHDS.

Introduction: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic disorder characterized by dermatologic, pulmonary, and renal manifestations. It is an inherited autosomal dominant disorder caused by folliculin (FLCN) gene mutations. It is characterized by a triad of lung cysts leading to recurrent pneumothorax, skin lesions, and increased risk of renal neoplasia. Given its varied manifestations, BHD syndrome poses a diagnostic challenge. Case Presentation: We present a 60-year-old female with history of type 1 diabetes with diabetic nephropathy, recurrent spontaneous pneumothorax, who presented with shortness of breath and pleuritic chest pain. She was found to have right-sided spontaneous pneumothorax, making this her third episode of the year. Chest imaging found multiple multiloculated, irregular paraseptal lung cysts, most pronounced at the lung bases. Chest tube was inserted with complete resolution of the pneumothorax. Right-sided pleurodesis was performed to manage her recurrent pneumothorax. As recurrent spontaneous pneumothorax is a hallmark of BHD syndrome, genetic testing was done, which revealed positive FLCN gene mutation, confirming the diagnosis. Family genetic testing found positive FLCN gene mutation in her mother and sister. Thorough physical examination revealed wart-like growth on her left shoulder. She also had a family history of skin lesions in multiple members. Biopsy of the lesion was consistent with squamous cell carcinoma. Although skin cancer is not directly linked to BHD syndrome, it can present with benign skin lesions, like fibrofolliculomas and trichodiscomas. As individuals with BHD syndrome have a significantly increased risk of renal neoplasms, she underwent routine screening for renal carcinoma with regular abdominopelvic CTs, which did not show any evidence of renal masses. The patient and her family undergo annual pulmonary, dermatological and renal surveillance for detection of new or enlarging lung cysts, malignant transformation of skin lesions, or renal cancer. Management of lung manifestations include pleurodesis vs observation. The patient and family were educated on preventive strategies, such as avoiding activities that increase risk of lung injury. In case renal tumors are identified, nephron-sparing surgery is recommended. Discussion: BHD syndrome is diagnosed based on clinical presentation, family history, and genetic testing for FLCN mutations, which can delay diagnosis. This case underscores the importance of comprehensive family history and genetic testing in at-risk individuals. Due to predisposition for multisystem involvement, multidisciplinary management for individualized care is warranted. Although there is no cure for BHD syndrome, proactive surveillance is essential in reducing morbidity, and preventive strategies can significantly improve quality of life.

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.