Birt-Hogg-Dubé Syndrome Research Articles

Sclerotic Fibroma in a Patient with Birt-Hogg-Dubé Syndrome

Birt-Hogg-Dubé syndrome (BHD) is a rare genetic disorder characterized by cutaneous lesions and systemic findings such as renal neoplasms, pulmonary cysts, and spontaneous pneumothoraces. Fibrofolliculomas, trichodiscomas, and acrochordons are the most common cutaneous lesions associated with BHD. Some cases with mucocutaneous lesions have also been reported. We report a sclerotic fibroma that developed over a previous thoracotomy scar of a patient with BHD.

Molecular Pathogenesis of Renal Neoplasms in Patients with Birt–Hogg–Dubé Syndrome

Birt–Hogg–Dubé syndrome (BHDS) is an autosomal dominant disease characterized by skin, lung, and renal manifestations. This syndrome is caused by a germline mutation in the FLCN gene, which leads to disruption in multiple downstream pathways. Renal cell carcinomas are one of the serious clinical manifestations of the disease, which usually presents as bilateral and multiple tumors. Morphologically, most of these tumors are classified as hybrid oncocytic tumors. Recent advances in molecular techniques have shed light on the pathogenesis of these renal tumors. In this review, we evaluate and summarize the current knowledge of BHDS, pathologic changes, and its molecular basis with the focus on the renal hybrid oncocytic tumor (HOT), their pathogenesis, and molecular underpinning.

Birt-Hogg-Dube syndrome (BHDS) detected incidentally

Birt-Hogg-Dube syndrome (BHDS) detected incidentally

Clinical and genetic characteristics of 100 consecutive patients with Birt-Hogg-Dubé syndrome in Eastern Chinese region

BackgroundAlthough an increasing number of patients with Birt-Hogg-Dubé syndrome (BHD) are being recognized in China, clinical and genetic characteristics are not well-defined. In addition, revised diagnostic criteria for the Chinese population was proposed in 2023, we aimed to explore their utility in clinical practice at a rare lung disease center.MethodsWe retrospectively analyzed the data of 100 consecutive patients with BHD diagnosed according to the revised Chinese BHD criteria, encountered at the First Affiliated Hospital of University of Science and Technology of China from Jan 2017 to June 2023.ResultsThere were 100 patients (including 63 females) from 65 unrelated families in Eastern China, mostly Anhui Province. The common manifestations were pulmonary cysts (99%), pneumothorax (60%), and skin lesions (77%). Renal cancer and renal angiomyolipoma were detected in 5 patients each. 37% of patients had no family history of BHD. In total, 25 FLCN germline mutations were detected, including 6 novel mutations. In addition to hotspot mutation c.1285delC/dupC (17%), the most common mutations were c.1015 C > T (16%), c.1579_1580insA (14%), and exons 1–3 deletion (11%) in FLCN. Higher risk of pneumothorax was associated with exons 1–3 deletion mutation and c.1177-5_1177-3de1CTC compared to the hotspot mutation c.1285dupC (91% [95% CI: 0.31, 46.82, p = 0.015] and 67% [95% CI: 0.35, 71.9, p = 0.302] vs. 30%, respectively). The average delay in diagnosis was 7.6 years after initial symptoms. Chinese diagnostic criteria were mostly consistent with typical pulmonary presentations with supportive genetic evidence.ConclusionIn the Eastern Chinese region, patients with BHD present most commonly with pulmonary cysts associated with pneumothorax and skin lesions. However, low incidence of renal cancer along with unexpected renal angiomyolipoma was observed. Genotypic spectrum differed from that reported from other global regions, and genotype association of pneumothorax warrants further research. The revised Chinese criteria for BHD seem more appropriate in diagnosing BHD in Chinese patients.

The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis.

The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.

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.

Retinal dystrophy associated with Birt-Hogg-Dubé syndrome

Purpose: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant cancer syndrome characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax, and multifocal renal carcinomas. Ophthalmologic findings associated with BHDS include flecked chorioretinopathy, choroidal melanoma, iris melanocytosis, and eyelid fibrofolliculomas. We present the case of a retinal dystrophy associated with BHDS. Methods: Observational case report. Results: A 48-year-old woman was referred for poor night vision and peripheral visual field loss. She had a past medical history of Birt-Hogg-Dubé syndrome, manifesting as multiple pulmonary cysts and atelectasis of both lungs. Best corrected visual acuity was 20/25 OU. Posterior segment examination revealed significant vessel attenuation and peripheral retinopathy consistent with a retinal dystrophy. Conclusion: This case associates BHDS with retinal pigment epithelial changes and visual field defects. Patients with BHDS should undergo ophthalmological examination as part of their care.

Abstract 6265: FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors

Abstract Parathyroid carcinoma (PC) is rare, poses challenges in definitive diagnosis and treatment, and carries a high rate of recurrence and mortality. Atypical parathyroid tumors (APT) have histopathologic features of malignancy but lack unequivocal evidence of invasion and are of uncertain malignant potential. Analysis of genetic alterations that may play a role in PC development, particularly those that might serve as markers of malignant potential, is important for further understanding this disease. FLCN is a gene found on chromosome 17 that encodes folliculin, a ubiquitously expressed protein with roles in multiple cellular processes such as apoptosis and cell signaling. Inactivating FLCN mutations cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant condition characterized by benign fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, and increased risk of renal cancer. Benign parathyroid tumors had previously been reported in a few BHD patients and recently one study has reported a link between FLCN mutations and parathyroid carcinoma. Germline frameshift mutations in FLCN, accompanied by somatic loss of the normal allele, were reported in two unrelated PC patients, both with clinical features suggestive of BHD, but no established diagnosis of BHD. An identical somatic frameshift FLCN mutation was reported in one PC and one APT. Interestingly, the authors noted low coverage of FLCN on whole exome sequencing, resulting in the failure to detect variants identified by Sanger sequencing, thus raising the possibility that prior studies may have missed FLCN variants. To better understand the frequency of germline or somatic FLCN mutations in PC and APT, we performed Sanger sequence analysis of the entire coding region of the FLCN gene on available tumor DNA from 11 PCs and 15 APTs. We identified no inactivating FLCN mutations in any of the PC or APT samples examined. A germline missense variant, resulting in a p.Gly325Val change, predicted to be benign/tolerated by in silico analyses, was seen in one PC and a synonymous variant (c.1233G>A) was seen in one APT. The absence of pathogenic mutations in our series parathyroid carcinoma and atypical parathyroid tumors suggests that FLCN mutations are rare in these parathyroid tumors. Nevertheless, germline FLCN testing and/or additional screening for BHD-related lesions in parathyroid carcinoma patients merits further consideration and study. Citation Format: Callie Burke, Justin Bellizzi, Jessica Costa-Guda, Andrew Arnold. FLCN variants and their role in parathyroid cancer and atypical parathyroid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6265.

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.

Resection and Re-resection for a Clear Cell Renal Carcinoma with Sarcomatoid Features in a Patient with Birt-Hogg-Dubé Syndrome

Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic autosomal dominant disorder which is, among other disease manifestations, associated with an increased life-time risk of developing renal cell carcinoma (RCC). Sarcomatoid RCC (sRCC) is a subtype of RCC associated with poor prognosis, high recurrence rates, and a significant resistance to a variety of systemic treatments. Case Report: Here, it is reported that the first case of a sRCC with local recurrence in a 62-year-old female patient with BHDS. This patient was successfully treated with a partial robotic nephrectomy and a re-resection of the tumor recurrence resulting in good short-term oncological outcomes. Conclusions: Robotic partial nephrectomy for sRCC, and robotic re-resection for locally recurrent sRCC in BHDS patients is a feasible treatment strategy associated with good short-term oncological outcomes. Due to the high risk of local and distant recurrences in sRCC cases, a lifelong follow-up with regular imaging is recommended.

Coexistent Sjogren’s syndrome and Birt-Hogg-Dube´ syndrome: a case report

We report a rare case of Sjogren’s syndrome complicated with Birt-Hogg-Dubé syndrome (BHDS) not previously mentioned in the literature. Further, there is insufficient evidence linking the two diseases. Here, we review existing diagnostic algorithms for diagnosing diffuse cystic lung disease and provide new insights. The patient initially complained of thirst and dry eyes for ten years, and gradually developed shortness of breath. After admission, physical examination showed five missing teeth, decreased respiratory sounds in both lower lungs, and Velcro rales. Computed tomography showed multiple thin-walled cystic lesions in both lungs. Initial xerophthalmia and labial gland biopsy seemed to reveal a pulmonary cystic change associated with Sjogren’s syndrome. Before discharge, a rash suspected to indicate a fibrofollicular tumor in the neck was observed, and then FLCN variant has been found. The challenges how to clarify the diagnosis of DCLD causes are discussed.

Risk of pneumothorax in Birt-Hogg-Dubé syndrome during pregnancy and birth.

Birt-Hogg-Dubé syndrome (BHDS) is a genetic disorder characterized by fibrofolliculomas, renal cell cancer and lung cysts. Patients are at risk to develop pneumothorax but the magnitude of this risk during pregnancy is unknown. Information was obtained from 46 women with BHDS that had at least one pregnancy (BHDS-with preg), 18 female BHDS relatives without pregnancies (BHDS-no preg) and 25 non-BHDS female relatives with at least one pregnancy (noBHDS-with preg). In total, 77 pneumothoraces occurred in the BHDS-with preg group (mean 1.7/patient) and 11 in the BHDS-no preg group. Comparison of patient years for the first two groups showed pneumothorax incidence rates of 0.054 and 0.016, respectively. The incidence rate difference was significant [0.038 (CI 0.02-0.057), value of p-value 0.0001]. This difference is not caused by an increased number of patients with pneumothorax but by an increased number of pneumothoraces per patient. Pregnancy in BHDS therefore might be a risk factor for multiple pneumothoraces.

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

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

SAT179 Germline And Somatic Inactivating FLCN Variants In Parathyroid Cancer and Atypical Parathyroid Tumors

Abstract Disclosure: S. Jha: None. J. Welch: None. R. Tora: None. J. Lack: None. A. Warner: None. J. Del Rivero: None. S.M. Sadowski: None. N. Nilubol: None. L. Schmidt: None. W.M. Linehan: None. L.S. Weinstein: None. W.F. Simonds: None. S.K. Agarwal: None. Background: 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. Methods: We analyzed the germline DNA of 19 patients with “sporadic” (PC) and 2 with atypical parathyroid tumors (APT) 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 two patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. FIindings: We identified germline FLCN variants in three unrelated patients with PC. The two 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 impact on post-translational modification. All three patients with germline FLCN variants were noted to have renal cysts and two had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (one 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, LOH at the locus was demonstrated in 2 of 3 patients with identified germline FLCN variant. Interpretation: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy. Presentation: Saturday, June 17, 2023

Metastatic Clear Cell-Renal Cell Carcinoma in Birt-Hogg-Dube Syndrome

Abstract The Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant genodermatosis harboring a mutated gene encoding for a protein known as folliculin. BHD is associated with increased risk of renal cell carcinoma (RCC), especially chromophobe/oncocytic hybrid tumors. The mutations driving clear cell RCC (ccRCC) in BHD remain investigational. We describe a case of BHD syndrome with a metachronous metastatic ccRCC and genomic alterations.

A splicing mutation of the FLCN gene is associated with Birt-Hogg-Dubé syndrome characterized by familial and recurrent spontaneous pneumothorax: A case report.

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal recessive genetic disorder caused mainly by mutations in the tumor suppressor FLCN gene. Tumors caused by FLCN mutations are frequently benign and develop in skin, lungs, kidney, and other organs, leading to a variety of phenotypes that make early diagnoses of BHD challenging. A 51-year-old female was admitted to Shanghai Seventh People Hospital due to chest congestion and dyspnea that had persisted for 3 years and aggravated for 1 month. She had been diagnosed with pneumothorax prior to this submission, but the etiology was unknown. Chest computed tomography (CT) revealed multiple pulmonary cysts and pneumothorax, and her family members shared similar manifestation. Whole-exome sequencing analysis indicated a heterozygous FLCN splicing mutation (c.1432 + 1G > A; rs755959303), which was a pathogenic variant indicated in ClinVar. Based on FLCN mutation and the family history of pulmonary cysts and pneumothorax, BHD syndrome was finally diagnosed, which had been delayed for 3 years since her first pneumothorax. Pulmonary bullectomy and pleurodesis were finally conducted due to the poor effects of thoracic close drainage. Her pneumothorax was resolved, and no recurrence was found in 2 years. Our study highlights the importance of genetic analysis in diagnosis and clinical management of BHD syndrome.

BIRT-HOGG-DUBÉ SYNDROME: A CASE REPORT WITH ORAL MANIFESTATION

Birt-Hogg-Dubé Syndrome (BHDS) is a rare autosomal dominant disorder characterized by cutaneous papules (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary cysts, and renal tumors. A 38-year-old man presented with pain in the right upper molars. His medical history included lung cysts due to BHDS, which also affected his mother. Extraoral examination revealed multiple skin-colored dome-shaped papules on his face, neck, ears, and upper thorax. Intraorally, there was mandibular prognathism, abfraction mainly in the posterior teeth, and asymptomatic whitish papules located on the ventral tongue. The panoramic radiograph revealed bone loss around the upper molars. The oral papules were conservatively removed, and microscopic diagnosis was consistent with fibrous hyperplasia covered by stratified epithelium with prominent rete pegs. The patient was submitted to periodontal treatment and long-term follow-up was recommended. We present an illustrative case of BHDS with oral manifestation, which is considered very rare in the literature. Birt-Hogg-Dubé Syndrome (BHDS) is a rare autosomal dominant disorder characterized by cutaneous papules (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary cysts, and renal tumors. A 38-year-old man presented with pain in the right upper molars. His medical history included lung cysts due to BHDS, which also affected his mother. Extraoral examination revealed multiple skin-colored dome-shaped papules on his face, neck, ears, and upper thorax. Intraorally, there was mandibular prognathism, abfraction mainly in the posterior teeth, and asymptomatic whitish papules located on the ventral tongue. The panoramic radiograph revealed bone loss around the upper molars. The oral papules were conservatively removed, and microscopic diagnosis was consistent with fibrous hyperplasia covered by stratified epithelium with prominent rete pegs. The patient was submitted to periodontal treatment and long-term follow-up was recommended. We present an illustrative case of BHDS with oral manifestation, which is considered very rare in the literature.

Recurrent Pneumothoraxes From Rare Birt-Hogg-Dube Syndrome

Birt-Hogg-Dubé syndrome (BHD) or Hornstein-Knickenberg syndrome is a rare autosomal dominant inherited syndrome. It is caused by the mutation in the folliculin coding gene (FLCN). The condition manifests as cystic lung disease presenting with spontaneous pneumothoraces. It predisposes to skin lesions such as fibrofolliculomas in the head and neck region. The most serious consequence is renal cell carcinoma.

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.