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Background: Birt-Hogg-Dube (BHD) syndrome is a rare genetic condition associated with the development of renal tumors. This study aims to determine typical age ranges for detecting renal abnormalities, risk factors for tumor development, and long-term outcomes based on current surveillance strategies. Methods: A single-center multi-site retrospective cohort study was performed on all patients with BHD diagnosed from 2000 to 2023. Baseline demographics, pulmonary function, laboratory, radiologic, and histopathologic findings were collected. Logistic regression was used to assess predictor variables for the development of renal tumors with survival analysis evaluated from the date of BHD diagnosis to date of death or last known follow-up. Results: The study included 149 patients with BHD, 39 (26%) with diagnosed renal tumors, of which 28 had histopathologic confirmation. Mean age at renal tumor detection was 53.61 years. Older age and male sex were predictive of renal tumor development ((odds ratio 1.05; 95% CI, 1.01–1.08, P = 0.002) and (odds ratio 2.59; 95% CI, 1.17–5.73, P = 0.02), respectively). Time to all-cause mortality appeared shorter in those with renal tumors (Log-rank P = 0.02), though no deaths were from cancer or cancer-related complications. Conclusions: Current screening protocols for renal tumors in BHD suggest the most common presenting age range for presentation is late 40s to early 50s, with older age and male sex as risk factors for tumor development. [ABSTRACT FROM AUTHOR]

Abstract Background Birt-Hogg-Dube (BHD) syndrome is a rare genetic condition associated with the development of renal tumors. This study aims to determine typical age ranges for detecting renal abnormalities, risk factors for tumor development, and long-term outcomes based on current surveillance strategies. Methods A single-center multi-site retrospective cohort study was performed on all patients with BHD diagnosed from 2000 to 2023. Baseline demographics, pulmonary function, laboratory, radiologic, and histopathologic findings were collected. Logistic regression was used to assess predictor variables for the development of renal tumors with survival analysis evaluated from the date of BHD diagnosis to date of death or last known follow-up. Results The study included 149 patients with BHD, 39 (26%) with diagnosed renal tumors, of which 28 had histopathologic confirmation. Mean age at renal tumor detection was 53.61 years. Older age and male sex were predictive of renal tumor development ((odds ratio 1.05; 95% CI, 1.01–1.08, P = 0.002) and (odds ratio 2.59; 95% CI, 1.17–5.73, P = 0.02), respectively). Time to all-cause mortality appeared shorter in those with renal tumors (Log-rank P = 0.02), though no deaths were from cancer or cancer-related complications. Conclusions Current screening protocols for renal tumors in BHD suggest the most common presenting age range for presentation is late 40s to early 50s, with older age and male sex as risk factors for tumor development.

Background: This study aimed to identify disease‐causing variants within a Chinese family affected by Birt–Hogg–Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene. Methods: A Chinese proband diagnosed with BHDS due to renal tumors underwent next‐generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant. Results: A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members. Conclusions: A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families. [ABSTRACT FROM AUTHOR]

Introduction: Smith-Magenis syndrome (SMS) is a rare genetic syndrome characterized by characteristic phenotypic features, developmental delay, cognitive impairment, and behavioral abnormalities. The diagnosis of SMS is established with suggestive clinical findings and either a heterozygous deletion at chromosome 17p11.2 that includes RAI1 or a heterozygous intragenic RAI1 variant. Individuals with a 17p11.2 deletion that includes FLCN may require management of features of Birt-Hogg-Dubé syndrome (BHD). The risk of cancer appears to be no greater than in the general population for most individuals with SMS. To date, renal tumors have been reported in three adults with heterozygous deletion of 17p11.2. Patient and Surgical Procedure: A 25-year-old male patient has a history of SMS, presented with back pain, and underwent abdominal ultrasound, which noted bilateral renal masses. A subsequent MRI was performed, noting 7 masses in the right kidney and 3 masses in the left kidney. He underwent renal biopsy of 3 masses on the right and 1 on the left, which were interpreted as renal hybrid oncocytic/chromophobe tumors (HOCTs). Germline genetic testing confirmed the patient carries an FLCN mutation. Haploinsufficiency of FLCN causes Birt-Hogg-Dubé (BHD), a syndrome characterized by pulmonary cysts, renal, and skin tumors. Of note, our patient only exhibits renal findings, with no characteristic skin lesions or pulmonary manifestations. Results: The operative time was 3 h with blood loss of less than 600 mLs. There were several off-clamp enucleations, followed by clamping of the renal hilum for 29 min, with resection of joint upper pole cystic masses in a traditional partial nephrectomy fashion, and enucleation of a deep hilar mass. This was followed by renorrhaphy and unclamping of the hilum. Additional small tumors were enucleated off-clamp. The patient was discharged uneventfully on post-operative day-1 (POD-1). The final pathology was notable for 6 hybrid oncocytic tumors, with the largest tumor measuring 6.6 cm (pT1b). There were no reported complications. Conclusion: In this report, we describe purely renal manifestations of a patient with Smith-Magenis syndrome with an FLCN mutation, without other findings of BHD syndrome. Given that these patients experience the same life expectancy as others with cognitive delay, they should be approached with similar care and the objective of nephron-sparing techniques. We demonstrate the feasibility of approaching the patient with a combination of enucleation off-clamp and traditional partial nephrectomy for large complex multiple renal masses. The technique emphasizes maximum preservation of renal parenchyma while minimizing the necessity for future procedures in cases of tumor growth and recurrence.

Abstract Background This study aimed to identify disease‐causing variants within a Chinese family affected by Birt–Hogg–Dubé syndrome (BHDS), which arises from an autosomal dominant inheritance pattern attributed to variants in the folliculin (FLCN) gene, recognized as a tumor suppressor gene. Methods A Chinese proband diagnosed with BHDS due to renal tumors underwent next‐generation sequencing (NGS), revealing a novel variant in the FLCN gene. Sanger sequencing was subsequently performed on blood samples obtained from family members to confirm the presence of this variant. Results A novel germline frameshift variant (NM_144997.5:c.977dup) was identified in five individuals among the screened family members, marking the first report of this variant. Additionally, a somatic frameshift variant (NM_144997.5:c.1252del) was detected in the renal tumors of the proband. No variant was detected in unaffected family members. Conclusions A novel heterozygous variant was identified in exon 9 of the FLCN gene, which broadens the spectrum of FLCN variants. We recommend that molecular analysis of the FLCN gene be performed in patients with suspected BHDS and their families.

Renal oncocytomas are commonly reported in association with Birt-Hogg-Dube (BHS) syndrome, while BHD-associated oncocytomas of the parotid gland are rare. To date, there have been only 11 cases of BHD-associated parotid gland oncocytoma, without a reported case of malignant transformation. We present the first reported case of oncocytic carcinoma of the parotid gland associated with BHD, with radiologic and histologic correlation. This case establishes that BHD-associated parotid oncocytic lesions, previously identified only as benign oncocytomas in the literature to date, can undergo malignant transformation, and should potentially be regarded with a higher index of suspicion and lower threshold for aggressive management.

Birt–Hogg–Dubé syndrome (BHDS) is a rare autosomal dominant inherited disorder caused by a mutation in folliculin (FLCN) gene transmitted via germline autosomal dominant pattern. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, spontaneous pneumothorax, and benign skin hamartomas, and its diagnosis is not easy and consequently underestimated. Several mutations have been identified in FLCN gene, among which the majority of alterations are frameshift (insertion/deletion), nonsense, or splice-site mutations that generally produce unfunctional truncated FLCN proteins. Our aim is to present a case of a BHDS family whose proband is a 56-year-old patient who has been experiencing multiple disorders, has an FLCN genetic mutation, and has also been identified to have a pathogenic variant in BRCA2 gene. Our further purpose is to emphasize the importance of the next-generation sequencing (NGS) approach to identify potential multiple germline mutations in complex and rare oncologic disorders, allowing strict and more targeted cancer screening programs. [ABSTRACT FROM AUTHOR]

Birt–Hogg–Dubé syndrome (BHDS) is a rare autosomal dominant inherited disorder caused by a mutation in folliculin (FLCN) gene transmitted via germline autosomal dominant pattern. Patients with this syndrome have an increased susceptibility to renal cell carcinoma, lung cysts, spontaneous pneumothorax, and benign skin hamartomas, and its diagnosis is not easy and consequently underestimated. Several mutations have been identified in FLCN gene, among which the majority of alterations are frameshift (insertion/deletion), nonsense, or splice-site mutations that generally produce unfunctional truncated FLCN proteins. Our aim is to present a case of a BHDS family whose proband is a 56-year-old patient who has been experiencing multiple disorders, has an FLCN genetic mutation, and has also been identified to have a pathogenic variant in BRCA2 gene. Our further purpose is to emphasize the importance of the next-generation sequencing (NGS) approach to identify potential multiple germline mutations in complex and rare oncologic disorders, allowing strict and more targeted cancer screening programs.

Multiple cystic lung diseases comprise a wide range of various diseases, some of them of genetic origin. Lymphangioleiomyomatosis (LAM) is a disease occurring almost exclusively in women, sporadically or in association with tuberous sclerosis complex (TSC). Patients with LAM present with lymphatic complications, renal angiomyolipomas and cystic lung disease responsible for spontaneous pneumothoraces and progressive respiratory insufficiency. TSC and LAM have been ascribed to mutations in TSC1 or TSC2 genes. Patients with TSC are variably affected by cutaneous, cognitive and neuropsychiatric manifestations, epilepsy, cerebral and renal tumors, usually of benign nature. Birt-Hogg-Dubé syndrome is caused by mutations in FLCN encoding folliculin. This syndrome includes lung cysts of basal predominance, cutaneous fibrofolliculomas and various renal tumors. The main complications are spontaneous pneumothoraces and renal tumors requiring systematic screening. The mammalian target of rapamycin (mTOR) pathway is involved in the pathophysiology of TSC, sporadic LAM and Birt-Hogg-Dubé syndrome. MTOR inhibitors are used in LAM and in TSC while Birt-Hogg-Dubé syndrome does not progress towards chronic respiratory failure. Future challenges in these often under-recognized diseases include the need to reduce the delay to diagnosis, and to develop potentially curative treatments. In France, physicians can seek help from the network of reference centers for the diagnosis and management of rare pulmonary diseases., (Copyright © 2023 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

No abstract available. Article truncated after the first page. Clinical History: A 48-year-old non-smoking woman with a history of hysterectomy and right oophorectomy, and cholecystectomy, otherwise previously healthy, presented with right-sided chest pain. A frontal chest radiograph (Figure 1) was performed. Which of the following statements regarding the chest radiograph is most accurate? 1. The frontal chest radiograph shows a right-sided pneumothorax; 2. The frontal chest radiograph shows abnormal mediastinal contours; 3. The frontal chest radiograph shows bilateral pleural thickening; 4. The frontal chest radiograph shows no abnormal findings; 5. The frontal chest radiograph shows small lung volumes with multiple small nodules.

Up to 5% of renal cell carcinomas (RCCs) can be associated with a known hereditary RCC syndrome. In addition to the well-characterized RCC syndromes, there are also emerging syndromes associated with increased RCC risk. In the last few years, consensus guidelines have outlined recommendations for who should be referred for genetic evaluation, and what screening should be done for early detection of RCC. Although much progress has been made, work is still needed-guidelines are still mostly based on expert opinion and the role of emerging genetic associations will need to be clarified., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant inherited syndrome caused by mutations in the folliculin coding gene (FLCN). The clinical manifestations of the syndrome involve the skin, lungs, and kidneys. Because of the rarity of the syndrome, guidelines for diagnosis and management of the patients with BHDS are lacking. Objective: To present a case story and a review of the literature on BHDS in order to give an update on genetics, clinical manifestations, diagnosis, treatment, prognosis and follow-up strategies. Design: Literature review and case story. Results: A PubMed and Embase search identified 330 papers. BHDS is characterized by small benign tumors in the skin, spontaneous pneumothoraces caused by cysts in the lungs and a seven-fold increased risk of renal cancer. A case story of a young female patient presenting with pneumothorax and a family history of recurrent pneumothoraces in many relatives illustrates how the history and the diagnostic work up resulted in a diagnosis of BHDS. Conclusion: BHDS is a rare inherited disorder. In patients with spontaneous pneumothorax or cystic lung disease without any obvious explanation, BHDS should be considered. Concomitant skin manifestations, a family history of familiar pneumothorax, renal cancers and skin manifestations supports the suspicion of BHDS. Early diagnosis is important in order to subject patients to systematic screening for renal cancers. A radiological surveillance strategy for renal cancer is proposed.

The article presents a case study of a 64-year-old man with nephrectomy of the right kidney for multifocal adenocarcinoma, clear-cell, and oncocytic differentiation. Topics include follow-up computed tomography (CT) scans showing multiple stable suspicious lesions in the left kidney and multiple thin-walled cystic lesions in both lungs; and showing progressive pulmonary cystic disease with cysts growing, contracting, fusing, ascending, and increasing in number without causing pneumothorax.

Hereditary forms of kidney carcinoma account for 5-8% of all malignant kidney neoplasms. The renal tumors are often multiple and bilateral and occur at an earlier age. Each of the hereditary kidney carcinoma syndromes is associated with specific gene mutations as well as a specific histologic type of kidney carcinoma. The presence of associated extrarenal manifestations may suggest a hereditary kidney cancer syndrome. Radiology is most commonly used to screen and manage patients with hereditary kidney cancer syndromes. This manuscript reviews the clinical and imaging findings of well-defined inherited kidney cancer syndromes including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary papillary renal carcinoma syndrome, hereditary leiomyomatosis and RCC syndrome, tuberous sclerosis complex, and Lynch syndrome. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations in the folliculin gene (FLCN) on chromosome 17p cause Birt–Hogg–Dube syndrome (BHD), which is associated with cystic lung disease. The risk of lung collapse (pneumothorax) in BHD patients is 50-fold higher than in the general population. The cystic lung disease in BHD is distinctive because the cysts tend to be basilar, subpleural and lentiform, differentiating BHD from most other cystic lung diseases. Recently, major advances in elucidating the primary functions of the folliculin protein have been made, including roles in mTOR and AMPK signaling via the interaction of FLCN with FNIP1/2, and cell–cell adhesion via the physical interaction of FLCN with plakophilin 4 (PKP4), an armadillo-repeat containing protein that interacts with E-cadherin and is a component of the adherens junctions. In addition, in just the last three years, the pulmonary impact of FLCN deficiency has been examined for the first time. In mouse models, evidence has emerged that AMPK signaling and cell–cell adhesion are involved in alveolar enlargement. In addition, the pathologic features of human BHD cysts have been recently comprehensively characterized. The “stretch hypothesis” proposes that cysts in BHD arise because of fundamental defects in cell–cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in regions of the lung with larger changes in alveolar volume and at weaker “anchor points” to the pleura. This hypothesis ties together many of the new data from cellular and mouse models of BHD and from the human pathologic studies. Critical questions remain. These include whether the consequences of stretch-induced cyst formation arise through a destructive/inflammatory program or a proliferative program (or both), whether cyst initiation involves a “second hit” genetic event inactivating the remaining wild-type copy of FLCN (as is known to occur in BHD-associated renal cell carcinomas), and whether cyst initiation involves exclusively the epithelial compartment versus an interaction between the epithelium and mesenchyme. Ultimately, understanding the mechanisms of cystic lung disease in BHD may help to elucidate the pathogenesis of primary spontaneous pneumothorax, with more than 20,000 cases reported annually in the United States alone. [ABSTRACT FROM AUTHOR]

Patients with the Birt-Hogg-Dubé cancer susceptibility syndrome are at high risk of developing renal cell carcinoma, pulmonary cysts and pneumothorax, and skin lesions called fibrofolliculomas. Here we report the case of a Birt-Hogg-Dubé patient with a primary clear cell carcinoma of the thyroid (a very rare type of thyroid cancer), and FLCN loss of heterozygosity within the tumour, providing molecular evidence for this association. Our findings expand the tumour spectrum associated with this syndrome. It is paramount to identify individuals with Birt-Hogg-Dubé so that they, and subsequently their affected relatives, can benefit from tailored cancer screening and prevention.

The term cystic lung disease encompasses a heterogeneous group of entities characterised by round lung lesions that correspond to cysts with fine walls, which usually contain air. The differential diagnosis of these lesions can be challenging, requiring both clinical and radiological perspectives. Entities such as pulmonary emphysema and cystic bronchiectasis can simulate cystic disease. High-resolution computed tomography (HRCT) is the imaging technique of choice for the evaluation and diagnosis of cystic lung disease, because it confirms the presence of lung disease and establishes the correct diagnosis of the associated complications. In many cases, the diagnosis can be established based on the HRCT findings, thus making histologic confirmation unnecessary. For these reasons, radiologists need to be familiar with the different presentations of these entities. A wide variety of diseases are characterised by the presence of diffuse pulmonary cysts. Among these, the most common are lymphangioleiomyomatosis, which may or may not be associated with tuberous sclerosis, Langerhans cell histiocytosis, and lymphocytic interstitial pneumonia. Other, less common entities include Birt-Hogg-Dubé syndrome, amyloidosis, and light-chain deposit disease. This article describes the characteristics and presentations of some of these entities, emphasizing the details that can help differentiate among them., (Copyright © 2022 SERAM. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome. Methods: We studied French Birt-Hogg-Dubé patients with a history of renal tumour. Results: We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it. Conclusions: Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers. [ABSTRACT FROM AUTHOR]

Birt-Hogg-Dubé syndrome (MIM #135150) is characterized by the development of benign skin tumours called fibrofolliculomas, pulmonary cysts that may lead to pneumothorax and a high risk of developing kidney cancer. BHD is caused by mutations affecting the highly conserved protein folliculin (FLCN), which probably has a role in intracellular transport. Most of the research effort directed towards BHD has focused on understanding how loss of FLCN causes kidney cancer. The cutaneous manifestations have received comparatively little attention. Although understandable, it is unfortunate, as the fibrofolliculomas are highly accessible and thus potentially are an excellent system for trying to understand the basic pathobiology of BHD. Also, patients can be very much burdened by the cosmetic consequences of having hundreds of facial skin tumours. Our lack of insight into what drives fibrofolliculoma growth translates into a very limited therapeutic arsenal. Thus, paying attention to fibrofolliculomas has both basic science and practical benefits. In this review, we will discuss the state of the art regarding our understanding of fibrofolliculoma pathogenesis and indicate future directions for research. [ABSTRACT FROM AUTHOR]

The cellular function of folliculin (FLCN) is a mystery that still needs to be solved. It is known that mutation of FLCN can predispose Birt-Hogg-Dubé (BHD) patient's to renal cell carcinoma , renal and lung cysts, as well as skin fibrofolliculomas. FLCN has been classed as a tumour suppressor, but it is probable that cystic and the skin manifestations do not occur as a consequence of FLCN loss of heterozygosity. Discovery that FLCN is a direct substrate of AMP dependent protein kinase (AMPK) placed FLCN on the cell signalling map, downstream of AMPK. This breakthrough suggested that FLCN might be involved in cell energy homeostasis. Over these more recent years, BHD research has become much more complicated and interesting from a cell signalling perspective. Folliculin has been linked to numerous cell pathways that are known to cause cancer, involving cell growth, metabolism, cell adhesion, cell motility, cytokinesis, and cell survival. The collective evidence implies that FLCN may have a broader housekeeping role in the cell. Of particular importance, FLCN was recently been reported to have guanine exchange factor activity towards the small G protein Rab35 and implicates FLCN in vesicular trafficking and/or membrane sorting. This newer discovery will undoubtedly help in the continued challenge of solving the signalling puzzle that shrouds FLCN function. [ABSTRACT FROM AUTHOR]

Birt-Hogg-Dubé syndrome (BHD) is a rare, autosomal dominant disorder characterized by the development of hair follicle tumors, renal tumors and pulmonary cysts. BHD is caused by heterozygous, predominantly truncating mutations in the folliculin ( FLCN) gene located on chromosome 17, which encodes a highly conserved tumor suppressor protein. Although management of renal tumors of low malignant potential is the primary focus of longitudinal care, pulmonary manifestations including cyst formation and spontaneous pneumothorax are among the most common manifestations in BHD. Due to the lack of awareness, there is commonly a delay in the pulmonary diagnosis of BHD and patients are frequently mislabeled as having chronic obstructive lung disease, emphysema or common bullae/blebs. A family history of pneumothorax is present in 35 % of patients with BHD. Certain imaging characteristics of the cysts, including size, basilar and peripheral predominance, perivascular and periseptal localization, and elliptical or lentiform shape can suggest the diagnosis of BHD based on inspection of the chest CT scan alone. Recurrent pneumothoraces are common and early pleurodesis is recommended. A better understanding of role of FLCN in pulmonary cyst formation and long term studies to define the natural history of the pulmonary manifestations of BHD are needed. [ABSTRACT FROM AUTHOR]

In addition to the associated cutaneous and pulmonary manifestations, individuals with the Birt-Hogg-Dubé (BHD) syndrome have an increased risk of developing kidney cancer, which is often bilateral and multifocal. The risk of developing a renal tumor in this population does not decrease with age and therefore warrants a lifelong screening approach. We recommend abdominal imaging every 36 months in individuals without renal lesions at initial screening. Once renal tumors are identified, they should be followed with interval imaging studies until the largest tumor reaches 3 cm in maximal diameter, at which point nephron-sparing surgery should be ideally pursued. While the histology of renal tumors can vary in the BHD syndrome, most tumors possess a relatively indolent natural history and do not require adjuvant therapy if resected when localized to the kidney. With this approach, the vast majority of patients will achieve a curative oncologic outcome and avoid the medical sequelae of chronic renal insufficiency that could otherwise result from total nephrectomy. [ABSTRACT FROM AUTHOR]

Birt-Hogg-Dube syndrome (BHDS) is a rare form of classically cystic lung disease that may present with spontaneous pneumothorax. The associated skin manifestations (fibrofolliculomas) are not always present. This article describes a case of spontaneous pneumothorax secondary to bullous emphysema in an otherwise healthy gentleman caused by a novel mutation in the folliculin ( FLCN ) gene. [ABSTRACT FROM AUTHOR]

The article provides an overview on kidney cancer. It notes that renal cancer is caused by different gene including von Hippel-Lindau (VHL), a gene for the hereditary cancer syndrome. It also offers information on the genetic defect underlying hereditary papillary renal carcinoma (HPRC) which is known as MET, the cell surface receptor for hepatocyte growth factor. Moreover, it discusses BHD gene also known as folliculin or FLCN, a gene for Birt-Hogg-Dube (BHD) syndrome.

Birt-Hogg-Dubé syndrome, first described in 1977, is a rare autosomal dominant condition that commonly presents with skin lesions, including fibrofolliculomas and trichodiscomas; pulmonary cysts; spontaneous pneumothoraces; and renal cancer. We present the only known cases of intracranial vascular pathologies in patients with Birt-Hogg-Dubé syndrome. We present three cases (three female; age range 18-50) of intracranial vascular lesions in Birt-Hogg-Dubé patients, including two aneurysms and one arteriovenous malformation, and review one previously reported case of carotid aplasia. Due to the rarity of Birt-Hogg-Dubé syndrome and significant variations in its clinical presentation, it is difficult to assess whether or not Birt-Hogg-Dubé patients are predisposed to intracranial vascular pathologies. We hypothesize that increased transcription of hypoxia-inducible factor 1-alpha, resulting from a mutated form of the protein folliculin transcribed by the Birt-Hogg-Dubé gene, may be associated with vascular pathogenesis in Birt-Hogg-Dubé patients and thus provide a possible molecular basis for a link between these two conditions. [ABSTRACT FROM AUTHOR]

The article presents medical research into the genetic basis of kidney cancer and the formulation of a model for development of molecular-targeted therapeutics. Inherited forms of kidney cancer include Von Hippel-Lindau (VHL) gene, hereditary papillary renal carcinoma (HPRC), and the Birt-Hogg-Dube (BHD) genodermatosis.

Abstract: Birt–Hogg–Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by benign hamartomatous skin lesions and an increased risk of pneumothorax and renal tumors. Many of the patients harbor insertion/deletion mutations in the hypermutable poly(C)8 tract in exon 11 of the BHD gene. This mutational hot spot is also reported to be a target of mutation in microsatellite instability (MSI) sporadic colorectal tumors. To test if the BHD gene is a potential mutational target in gastric cancer, we screened for mutations in all of the coding exons of the BHD gene in 30 cases of MSI gastric cancer as well as 50 cases of microsatellite stable (MSS) gastric cancer. Mutations in the poly(C)8 tract of BHD were detected in 3 of 19 MSI-high cases (15.8%), and none of 11 MSI-low cases. All BHD mutated cases also showed mutations of both BAX and TGFβRII. No mutations were detected in the other exons of the BHD gene. No BHD mutations were found in MSS gastric cancer cases. Taken together, these findings show that the BHD gene is a rare target in MSI-high gastric cancer, and BHD mutation tends to occur downstream in the mutational events of other major MSI-high target genes. [Copyright &y& Elsevier]

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague-Dawley (Crl:CD® (SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague-Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3-13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) has the highest rate of occurrence within the US when compared with other countries. Recent advances in the basic research and molecular diagnostics of this malignancy have revealed that RCC is not a single disease, but it is a mixture of several types of malignancies with unique molecular mechanisms and pathological attributes. RCC is now divided into clear cell carcinoma (80% of all kidney cancers), papillary type 1 and papillary type 2 neoplasms (10–15% of all RCC patients) and RCC with chromophobic and oncocytic features, called the Birt-Hogg-Dube (BHD) subtype, in roughly 5% of all patients. Apart from these, neoplasms such as the tuberous sclerosis (TSC) syndrome may occur with a mixed pathological features with a renal presentation. In this review, molecular evidence, both direct and indirect, published so far on all these RCC subtypes have been analyzed to find out whether there is any common thread that could run through these disparate malignancies that happen to occur in a single organ, i.e., the kidney. We believe that the role played by the expression and certain non-traditional activities of the cabonic anhydrase (CA) family members, along with the differing levels of hypoxia induced within these tumors may be the most common denominators. Evidence is presented focusing on how the CA family members could participate in the genesis and progression of each and every one of these RCC subtypes and how their function could be influenced by hypoxia, activities of receptor type protein tyrosine kinases and certain other pre-disposing factors. These rationalizations point towards a unified hypothesis that may help explain the occurrence of all these RCC subtypes in a molecular manner. We hope that these analyses would a) stimulate further studies aimed toward a better understanding of the role played by carbonic anhydrases in RCC subtypes and b) would pave way to a better and rationally designed therapies to interfere with their function to benefit patients with RCC and possibly other cancers. [ABSTRACT FROM AUTHOR]

Abstract Resources for rare diseases are lacking. Patients do not have the information and support that they need, and researchers struggle to make progress due to a shortage of skills and collaborations within the field. One way to overcome these hurdles is to host annual Symposia, focused on a specific rare disease. Here, we use the example of Birt-Hogg-Dubé Symposia to discuss the practical issues of such meetings, including the importance of timing and the choice of invited speakers. We highlight the ways in which rare disease symposia can create a single community, removing barriers between patients, clinicians and researchers.