Enfermedades minoritarias: síndrome de Birt- Hogg- Dubé / Minority diseases: Birt-Hogg-Dubé syndrome

Presentamos el caso de una mujer de 57 años sin hábitos tóxicos y antecedentes de tres neumotórax derechos espontáneos. Antecedentes familiares de primer grado de neumotórax bilaterales de repetición, poliquistosis renal y tumor digestivo. Derivada a consulta para asesoramiento genético ante la sospecha de síndrome de Birt- Hogg-Dubé (SBHD) por diagnóstico genético confirmado en familiar de segundo grado. En la exploración se evidenciaron lesiones cutáneas compatibles con fibrofoliculomas. En la tomografía computarizada (TC) presencia de quistes pulmonares simples. El cribado genético reveló la presencia de una variante patogénica en el gen de la foliculina. El síndrome de Birt- Hogg- Dubé es una rara genodermatosis de herencia autosómica dominante caracterizada por la presencia de fibrofoliculomas y/o tricodiscomas cutáneos, quistes pulmonares, neumotórax espontáneos y tumores renales. El pronóstico depende de la gravedad de las afectaciones viscerales y del tipo de tumor renal implicado. (AU)

We present the case of a 57-year-old woman with no toxic habits and a history of three spontaneous right pneumothoraces. First-degree family history of recurrent bilateral pneumothoraces, polycystic kidney disease, and digestive tumor. Referred to consultation for genetic counseling on suspicion of Birt-Hogg-Dubé syndrome (SBHD) due to a confirmed genetic diagnosis in a seconddegree relative. The examination revealed skin lesions compatible with fibrofolliculomas. In the computed tomography (CT) presence of simple pulmonary cysts. Genetic screening revealed the presence of a pathogenic variant in the folliculin gene. Birt-Hogg-Dubé syndrome is a rare autosomal dominantly inherited genodermatosis characterized by the presence of cutaneous fibrofolliculomas and/or trichodiscomas, pulmonary cysts, spontaneous pneumothoraces, and renal tumors. The prognosis depends on the severity of the visceral involvement and the type of renal tumor involved. (AU)

Correlative analysis of lung CT findings in patients with Birt-Hogg-Dubé Syndrome and the occurrence of spontaneous pneumothorax: a preliminary study.

BACKGROUND: The diagnosis of patients with Birt-Hogg-Dubé (BHD) syndrome is always delayed (even for more than 10 years). Improving the understanding and diagnosis of this disease is vital for clinicians and radiologists. In this study we presented the chest computed tomography (CT) findings of BHD syndrome and offered suggestions for BHD cases with spontaneous pneumothorax. METHODS: Twenty-six BHD patients from 11 families (10 men, 16 women; mean age: 46 ± 12 years, 20-68 years) were included. The clinical features of the patients included pneumothorax, renal lesions, and skin lesions. Twenty-three patients underwent chest CT imaging. The cyst condition of each patient derived from reconstructed chest CT imaging was recorded, including the cyst number, size, volume, pattern, and distribution. RESULTS: Pneumothorax occurred in 54% (14/26) of patients. Among them, 43% (6/14) had pneumothorax more than twice. However, typical skin and renal lesions were absent. Four patients had renal hamartoma. CT showed that 23 (100%) patients had lung cysts. Pulmonary cysts were bilateral and multiple, round, irregular, or willow-like. And 93.6% of the large cysts (long-axis diameter ≥ 20 mm) were under the pleura, and near the mediastinum and spine. The long-axis diameter, short-axis diameter and volume of the largest cysts were associated with the occurrence of pneumothorax (all P < 0.05). CONCLUSIONS: Chest CT imaging can reveal some characteristic features of BHD syndrome. The occurrence of pneumothorax in BHD patients is closely related to their pulmonary cystic lesions.

[Two families with Birt-Hogg-Dubé syndrome:case report and literature review].

Objective: To improve the awareness of Birt-Hogg-Dubé syndrome. Methods: We performed a retrospective analysis with two families of Birt-Hogg-Dubé syndrome (BHD syndrome) diagnosed in Department of Respiratory and Critical Care Medicine, Shenzhen People's Hospital from 2020 to 2021. Clinical manifestations, imaging features, diagnosis and gene detection results were summarized. Relative literatures were reviewed in Wanfang Database and PubMed from 2015 to 2021 by using the search terms of "BHD syndrome" "Birt-Hogg-Dubé" "Birt-Hogg-Dubé syndrome", respectively. Results: The probands of both families were female, aged 37 and 34 years respectively. The onset manifestation was pulmonary bullae combined with pneumothorax. Chest computed tomography (CT) imaging showed multiple pulmonary cysts in both lobes, and no skin lesions or renal tumors were found in either case. History of pneumothorax was present in Family 1 while absent in Family 2. The FLCN gene of the two probands and their relatives showed the same mutation site. Totally 12 Chinese literatures and 394 English literatures were retrieved, among which 96 reported lung involvement only. A total of 10 literatures about Chinese population were screened out from the English literatures, and 115 patients, 31 males and 84 females, were included. The incidence of spontaneous pneumothorax was 66.95% (77/115), while a family history of pneumothorax was 88.31%(68/77). The onset age of spontaneous pneumothorax was between 30 and 44 years. The most common mutation site of FLCN was c.1285dup. Conclusions: BHD syndrome in Asian population may only have lung involvement. Patients with pneumothorax and pulmonary cystic lesions should be inquired of the family history. We speculate that there are many underdiagnosed cases in clinical practice.

Sonography of solitary fibrofolliculoma with histologic correlation.

We present a case of 15-year old male with solitary fibrofolliculoma on the ear and we demonstrate the use of ultrasound in outlining the features of this rare benign skin tumor with histological correlation. Fibrofolliculoma can be associated with a rare syndrome known as Birt-Hogg-Dubé which affects the skin, lungs and kidneys.

Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is a rare inherited autosomal dominant disorder caused by germline mutations in the tumour suppressor gene FLCN, encoding the protein folliculin. Its clinical expression typically includes multiple pulmonary cysts, recurrent spontaneous pneumothoraces, cutaneous fibrofolliculomas and renal tumours of various histological types. BHD has no sex predilection and tends to manifest in the third or fourth decade of life. Multiple bilateral pulmonary cysts are found on chest computed tomography in >80% of patients and more than half experience one or more episodes of pneumothorax. A family history of pneumothorax is an important clue, which suggests the diagnosis of BHD. Unlike other cystic lung diseases such as lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis, BHD does not lead to progressive loss of lung function and chronic respiratory insufficiency. Renal tumours affect about 30% of patients during their lifetime, and can be multiple and recurrent. The diagnosis of BHD is based on a combination of genetic, clinical and/or skin histopathological criteria. Management mainly consists of early pleurodesis in the case of pneumothorax, periodic renal imaging for tumour detection, and diagnostic work-up in search of BHD in relatives of the index patient.

Characterization of CT scans of patients with Birt-Hogg-Dubé syndrome compared with those of Chinese patients with non-BHD diffuse cyst lung diseases.

BACKGROUND AND OBJECTIVE: The purpose of this study was to create a practical CT-based algorithm to differentiate Birt-Hogg-Dubé (BHD) syndrome from other diffuse cystic lung diseases (DCLD). METHODS: The study was a retrospective review of the CT images of 33 patients with BHD syndrome, 33 patients with LAM, and 23 patients with NBNL (non-BHD and non-LAM) among DCLD patients. On the basis of the data collected, the CT images were reviewed again to evaluate the characteristics (size, number, distribution, and morphology) of pulmonary cysts. RESULTS: Lower lung-predominant cysts were more likely to be found in patients with BHD syndrome than in patients with LAM or in the NBNL DCLD group. In the axial distribution, 18 of 33 patients in BHD group had cysts that were predominantly near the mediastinum, and all the patients in the LAM and NBNL DCLD groups had diffuse cysts. The appearance of fusiform cysts was more easily observed in patients in the BHD group. In total, 58% patients in the BHD group had less than 50 lung cysts, while all patients in the non-BHD group had more than 50 lung cysts. The biggest cyst was located in the lower lobe in 28 of 33 patients in the BHD group, while 11 of 33 patients in LAM group and 10 patients in the NBNL DCLD group had the biggest cyst in the lower lobe. CONCLUSION: The pulmonary cysts in patients with BHD tended to be fusiform, less numerous and located predominantly in the lower lobe and near the mediastinum. These radiologic pulmonary features could assist physicians in differentiating BHD from other DCLDs.

A Stepwise Diagnostic Approach to Cystic Lung Diseases for Radiologists.

Lung cysts are commonly seen on computed tomography (CT), and cystic lung diseases show a wide disease spectrum. Thus, correct diagnosis of cystic lung diseases is a challenge for radiologists. As the first diagnostic step, cysts should be distinguished from cavities, bullae, pneumatocele, emphysema, honeycombing, and cystic bronchiectasis. Second, cysts can be categorized as single/localized versus multiple/diffuse. Solitary/localized cysts include incidental cysts and congenital cystic diseases. Multiple/diffuse cysts can be further categorized according to the presence or absence of associated radiologic findings. Multiple/diffuse cysts without associated findings include lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome. Multiple/diffuse cysts may be associated with ground-glass opacity or small nodules. Multiple/diffuse cysts with nodules include Langerhans cell histiocytosis, cystic metastasis, and amyloidosis. Multiple/diffuse cysts with ground-glass opacity include pneumocystis pneumonia, desquamative interstitial pneumonia, and lymphocytic interstitial pneumonia. This stepwise radiologic diagnostic approach can be helpful in reaching a correct diagnosis for various cystic lung diseases.

Role of Radiologists in the Diagnosis of Unsuspected Birt-Hogg-Dubé Syndrome in a Tertiary Clinical Practice.

OBJECTIVE. Birt-Hogg-Dubé (BHD) syndrome is considered rare. Growing evidence indicates that it is underdiagnosed. The purpose of this study is to ascertain the impact of radiology reports that suggest the possibility of BHD syndrome on downstream management and a final diagnosis of BHD syndrome. MATERIALS AND METHODS. In this retrospective study, electronic medical records were searched to identify radiology reports suggesting the possibility of BHD syndrome in patients without a known or suspected diagnosis. Clinical and demographic information, the specialty of the ordering clinician, and imaging findings and confidence conveyed in the radiology report (with BHD syndrome listed as the most likely diagnosis versus one among several possibilities but not as the leading diagnosis) were recorded. The resultant downstream evaluations that were captured included referral for genetic evaluation and subsequent diagnosis of BHD. RESULTS. Between 2004 and 2016, radiologists suggested a diagnosis of BHD syndrome in 87 patients. Of these patients, 15% (13/87) underwent genetic evaluation, and 54% of those patients (7/13) had positive findings. Genetic evaluation was more likely for patients with a history of pneumothorax (p = 0.004) or involvement of the lungs and kidneys (p = 0.003). The urology department referred the highest percentage of patients (31% [4/13]) for genetic evaluation. CONCLUSION. Radiologists have a unique opportunity to suggest BHD syndrome, allowing appropriate genetic testing, screening, and counseling of patients and their families. Clinical presentation, including a history of pneumothorax and involvement of both the lungs and kidneys on imaging, may determine which patients are ultimately referred for genetic evaluation. We hope that increasing awareness that BHD syndrome is not so rare may lead to early diagnosis.

Differentiation Between Lymphangioleiomyomatosis and Birt-Hogg-Dubé Syndrome: Analysis of Pulmonary Cysts on CT Images.

OBJECTIVE: The purposes of this study were to identify diagnostic imaging markers for differentiating pulmonary cysts in lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome and to identify potential risk factors for spontaneous pneumothorax in the two diseases. MATERIALS AND METHODS: This retrospective study included 44 patients with lymphangioleiomyomatosis (44 women; mean age, 35 ± 10.9 years) and 13 patients with Birt-Hogg-Dubé syndrome (nine men, four women; mean age, 45.1 ± 10.9 years). CT findings were analyzed to determine the shape; presence of septation, wall visibility, and subpleural cysts; size; number; distribution; location of the largest cyst; and presence of cysts encircling the bronchovascular bundle ("air-cuff" sign) and of mediastinal fat indentation. Multiple logistic regression was performed to identify risk factors for spontaneous pneumothorax. RESULTS: Compared with patients with lymphangioleiomyomatosis, patients with Birt-Hogg-Dubé syndrome were significantly older, and more of them were men. The cysts in these patients had a more irregular shape, more septation, lower and more peripheral distribution, larger maximum size, and more attachment to the pleura, air-cuff sign, indentation on mediastinal fat, and subpleural cysts larger than 2 cm. The maximum diameter of cysts was the sole independent risk factor for spontaneous pneumothorax (p = 0.027; 95% CI, 1.043-1.992) in both diseases. ROC analysis showed an AUC of 0.745 (95% CI, 0.612-0.851), and the optimal cutoff value was 22 mm (sensitivity, 72.5%; specificity, 76.5%). CONCLUSION: Several CT imaging markers may help in differentiating pulmonary cysts in patients with lymphangioleiomyomatosis and those with Birt-Hogg-Dubé syndrome and in predicting spontaneous pneumothorax.

Birt-Hogg-Dubé syndrome in Korean: clinicoradiologic features and long term follow-up.

BACKGROUND/AIMS: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder that is characterized by skin fibrofolliculomas, pulmonary cysts, and renal tumors. The objective of this study was to describe the features of Korean patients with BHD syndrome. METHODS: Clinical data were retrospectively reviewed in 12 patients (10 confirmed by direct sequencing of the folliculin (FLCN) gene and two confirmed by clinical diagnosis) diagnosed from 2004 to 2016 at Asan Medical Center, Seoul, South Korea. Criteria proposed by the European BHD consortium were used for diagnosis. RESULTS: The median follow-up was 52 months. The mean age was 41.3 years and 66.7% were female. Eight patients (66.7%) had a history of pneumothorax, which was recurrent in 75%. Skin lesions were detected in 25.0% and renal cancer in 25.0%. Among mutations of the FLCN gene, the duplication of cytosine in the C8 tract of exon 11 (c.1285dupC) was the most common (40%); however, a novel heterozygous sequence variant of c.31T>C (p.C11R) in exon 4 was detected in one patient. All patients had multiple and bilateral pulmonary cysts, distributed in predominantly lower, peripheral and subpleural regions of the lungs. Most patients showed preserved lung function that remained unchanged during follow-up, and two (16.7%) developed cancers (renal cancer in one and breast cancer in one). CONCLUSION: Our data suggest that Korean patients with BHD syndrome may have a higher risk of pneumothorax, less frequent skin lesions, and a novel FLCN mutation compared to previous reports. Multiple bilateral and basal-predominant cysts were the most common radiologic features.

Dermoscopy of Adnexal Tumors.

Cutaneous adnexal tumors include lesions with apocrine, eccrine, follicular, sebaceous, and mixed differentiation. Most are benign and sporadic, although malignant forms are occasionally observed and some cases develop in the setting of inherited syndromes. These tumors often cause immense diagnostic difficulty. Dermoscopy is a noninvasive technique that has greatly improved the diagnostic accuracy of different skin lesions, including these tumors. We provide a review of the literature on the dermoscopic structures and patterns associated with adnexal tumors. Most patterns associated with this kind of tumor are nonspecific and are observed in other nonadnexal tumors, especially in basal cell carcinomas.

Imaging findings of hereditary renal tumors, a review of what the radiologist should know.

It is estimated that up to 8% of currently diagnosed renal cancers are part of a hereditary syndrome. The radiologist may be the first person to associate a renal tumor presenting during an imaging study to other manifestations of a hereditary syndrome. This diagnosis can have broad implications for the patient but also for other family members. This update reviews the current known associations and emerging mutations of hereditary renal cancers from a radiologist's perspective. Renal manifestations, as well as associated radiological findings and pitfalls are discussed. Additionally, screening and surveillance recommendations are also discussed to aid radiologists in the decision-making process for patient management.

Novel clinical scoring system to identify patients with pneumothorax with suspicion for Birt-Hogg-Dubé syndrome.

BACKGROUND AND OBJECTIVE: Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary disease that presents with multiple lung cysts and pneumothorax (PTX). Although some reports propose that findings from chest computed tomography enable one to distinguish BHDS from primary spontaneous pneumothorax (PSP), it is still unclear whether clinical features are useful for identifying patients with suspicion of BHDS from those with PTX. METHODS: We retrospectively reviewed the medical records of patients with PTX who underwent video-assisted thoracoscopic surgery at Nissan Tamagawa Hospital from January 2012 to December 2015. RESULTS: We identified a total of 1141 patients with PTX, including 54 with BHDS and 517 with PSP. Among them, logistic regression analysis segregated five features that were significantly associated with BHDS: familial history of PTX, past history of bilateral PTX, age at the first episode of PTX (≥25 years old (y.o.)), body mass index (≥18.5) and gender (female). We assigned scores of 3, 3, 2, 2 and 1 to the five features, respectively, to establish a system with a calculated score from 0 to 11. The cut-off value of a calculated score ≥ 4 yielded the highest sensitivity of 93% and specificity of 86%. Receiver operating characteristic (ROC) analysis showed the area under the curve reflecting an accuracy of this diagnostic test as 0.953. CONCLUSION: BHDS has several clinical features distinct from PSP. Our scoring system consists of only five clinical variables that are easily evaluated and efficiently separate BHDS patients from those who have PTX without relying on an imaging study. Further prospective study is needed to confirm our findings.

Skin lesions of Birt-Hogg-Dubé syndrome: Clinical and histopathological findings in 31 Japanese patients who presented with pneumothorax and/or multiple lung cysts.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) (OMIM #135150) is an autosomal dominant disease, characterized by fibrofolliculomas (FFs) of the skin, pulmonary cysts with/without pneumothorax, and renal tumors. The prevalence of skin manifestations reported for Japanese BHDS patients is lower (<30%) compared with that of Western countries (75∼90%), which appear to be underestimated. OBJECTIVE: To precisely examine the prevalence of skin lesions with dermoscopy and histopathology with reference to genetic analyses. METHODS: We studied 31 patients (47.0±13.2years old, range 15-71) consisting of 26 unrelated families consecutively from May 2013 to June 2015 specifically for skin-colored papules on their faces and cervicothoracic regions. Patients initially suspected of BHDS from multiple pulmonary cysts that resulted in pneumothorax (30/31; 96.8%) received dermoscopic examinations and skin biopsies if applicable. The diagnosis of BHDS was established by folliculin (FLCN) genetic testing, and the results were compared to the histopathological findings of FFs or trichodiscomas (TDs). RESULTS: FLCN germline mutation was demonstrated in 25/26 (96.2%) unrelated families tested and 28/29 patients (96.6%) tested. Skin lesions were recognized in 26/31 patients (83.9%); skin biopsies were performed in 23 patients of whom FFs and/or TDs were histologically demonstrated in 17 (73.9%). Although our study population included patients whose skin manifestations were evaluated prior to or after FLCN genetic testing, skin lesions were clearly prevalent and recognizable irrespective of whether genetic testing was or wasn't done. When examined with dermoscopy, distinct FFs appeared as well-demarcated areas of pallor with central follicular openings in 13 of 15 FF-bearing patients (86.7%); however, those manifestations were not recognized for TD. CONCLUSIONS: Skin lesions appear to be more prevalent than previously reported (<30% vs.73.9%) in Japanese BHDS patients. Dermoscopy is a useful diagnostic aid for finding FFs.

Difference of the progression of pulmonary cysts assessed by computed tomography among COPD, lymphangioleiomyomatosis, and Birt-Hogg-Dubé syndrome.

Many groups developed the methods to quantitatively analyze low attenuation area (LAA) on chest CT in patients with cystic lung diseases. Especially in COPD, it was reported that the cumulative size distribution of LAA clusters follows a power law characterized by the exponent D, which reflect the fractal dimension of terminal airspace geometry. We hypoyhesized that the quantitative charateristics of LAA clusters including fractal property might indicate the different features of the progression of cysts in cystic lung diseases. The aim of this study was to apply the CT image-based method of characterizing the size distribution of LAA clusters for lymphangioleiomyomatosis (LAM) and Birt-Hogg-Dubé syndrome (BHDS) to disclose their features of the progression of pulmonary cysts. 40 patients with COPD, 52 patients with LAM, and 18 patients with BHDS who had undergone CT scans at our institute between January 2002 and August 2009 were included. Differences among these diseases in the quantitative characteristics of LAA clusters {i.e., extent, number, size, fractal property, and the relationship between these quantitatives} were assessed. The Chi-sqsuare test, unpaired t-test, and one-way analyses of variance with Tukey post-hoc tests were used to compare groups, spline model with an interaction terms were used to assess the relationship between extent and number, and exponential regression model was used to assess the relationship between extent and size. Statistically significant differences separated the three diseases in extent and number (P < 0.001). Number was significantly correlated with extent in COPD (P < 0.001), but was not so in LAM and BHDS when extent exceeded 11.5% and 20.8%, respectively. Size was significantly correlated with extent in COPD and LAM (P < 0.001), but was not so in BHDS. The percentage of CT images with fractal property was higher in COPD than that in LAM and BHDS (95.8%, 92.9% and 63.0%, respectively). In conclusion, our study has demonstrated for the first time the different characteristics of the size distribution of LAA clusters among COPD, LAM and BHDS, and indicated that this method is useful for exploration of the pathophysiology in cystic lung diseases.

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function.

Cystic lung diseases constitute a distinct group of rare lung disorders, among which two result from monogenic defects affecting tumor suppressor genes: lymphangioleiomyomatosis, either sporadic or associated with tuberous sclerosis complex, and Birt-Hogg-Dubé syndrome. These disorders have similarities in their clinical expression, including occurrence in young adults, multiple pulmonary cysts, recurrent pneumothorax, skin hamartomas, and renal tumors. However, they markedly differ in their gender distribution, pathogenesis, disease course, and prognosis. Our knowledge on these two rare conditions is rapidly expanding. Management of lymphangioleiomyomatosis has substantially improved in the past decade with the understanding of its pathogenic mechanisms, the discovery of an effective therapy, and development of large cohorts and international guidelines. Birt-Hogg-Dubé syndrome has been described more recently and still awaits deeper understanding of its pathophysiology.