Received date: September 04, 2013; Accepted date: October 30, 2013; Published date: November 01, 2013
Citation: Zeybek A, Sahan L, Çelik ÖI, Özbudak IH, Kalemci S (2013) Birt Hogg Dubè Syndrome: A Case Report. J Pulmon Resp Med S14:008. doi:10.4172/2161-105X.S14-008
Copyright: © 2013 Zeybek A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Birt Hogg Dubè syndrome; Cancer predisposition
Birt-Hogg-Dubè syndrome (BHDS), a rare hereditary condition, was initially identified (in 1977) as a skin condition where small skin lesions were found to be distributed particularly around scalp, forehead, face and neck regions. In recent years, more symptoms such as renal and pulmonary cyst, kidney cancer and non-cancerous fibrofolliculomas have been linked with BHDS. This hereditary autosomal dominant inherited syndrome is known to be caused by the mutation in the gene of localized folliculin in 17p11.2 chromosome . The cases have been mostly reported from America, Italy and Ireland. Although the exact incidence of this disease is yet to be known, 200 families with BHDS were affected to be reported with this condition .
On clinical examination, patients with BHDS show benign dermatologic lesions on upper body, nucha, neck and face named as fibrofolliculoma or trichodiscoma, and these patients are at the increased risk of developing renal cyst or tumor, pulmonary bullous lesion and recurrent spontaneous pneumothorax attacks . It is matter of great concern that this syndrome has been found to increase the predispositions of certain types of cancer such as lung, gastrointestinal, ovarian, breast, pancreatic cancers, and especially the renal cancer . Therefore, it is necessary to check the family history for patients with pulmonary cysts and/or spontaneous pneumothorax. If occurrences of BHDS syndrome have been found in family history, a close follow up is recommended due to increased cancer risk in renal or other systems. We present here a case of 56 year old female suspected for BJD syndrome.
A 56-year-old female patient with the complaints of mild shortness of breath and right side pain was evaluated by thoracic Computerized Tomography (CT). Thin-walled bullous lesion 13 cm in diameter was observed in the lower lobe of the right lung in the thoracic computerized tomography (Figure 1A and B). The patient, although without a history of chronic systemic disease, had been operated on bulla resection 20 years ago as the patient was diagnosed with bullous lesion with left spontaneous pneumothorax. Upon checking the family history, we found that the sister, brother and nephew of the patient had a history of pneumothorax. The patient was examined genealogically for the evidence of familial cancer and pneumothorax (Figure 2).
The patient was mild dyspneic on the physical examination; the oxygen saturation was 96% in room air. Fibrofolliculoma and acrochordon lesions were observed on the face, around the nose and especially on the neck (Figure 3). The patient was evaluated with abdominal CT and USG because of hematuria detection in the preoperative urine samples performed before the surgery. In the left renal, 7 cm cyst and 2 mm calculus were reported (Figure 4). It was followed after urologic consultation.
Thyroid function tests were within normal limits, and these were being followed after thyroid biopsy due to multinodular goiter.
Left hemithorax volume was decreased due to the earlier surgery that the patient had. In pulmonary function test, FEV1 (forced expiratory volume in one second) and FVC (forced vital capacity) were found to be 88% and 92%, respectively. Respiratory sound was not heard from the lower lobe of right lung in the respiratory system auscultation. Other system examinations were evaluated as normal.
Thin-walled bullous lesion of 13*10 cm diameter was explored in the lower lobe of the right lung with right thoracotomy operation (Figure 5). Bulla was resected using a 3, 5*60 mm tissue supported endoGIA stapler. As the patient did not develop any postoperative complication, she was discharged from the hospital in the first week. The skin lesions biopsy of the patient revealed the leisons as acrochordon (Figure 6). The lesion was very small (3mm in diameter) with a polipoid appearance. It was fixed in 10% formalin, sampled in a cassette and after the routine tissue processing, it was embedded in paraffin. The block was sectioned in 5 μm thickness and stained with Hematoxylin-eosin. The slides were examined with the light-microscope. Some sections of the lesion were covered with a normal epidermis surrounding a core of fibrovascular tissue with dense collagen fibers (Figure 6).
Pathological specimen of the patient with a history of familial pneumothorax was forwarded to an external pathology clinic for the advanced histochemical evaluation. Histological examination of patient’s lung bullae showed typical emphysematous changes. However, unlike other causes of spontaneous pneumothorax, bullae located basilar (right lower lobe).
The patient was screened and followed-up closely for three years in terms of renal and other system cancers.
BHD syndrome, first identified in 1977, is an autosomal dominant inherited genodermatosis. It has a clinical triad comprising of skin lesions, renal tumor/cyst, pulmonary bullous lesions or spontaneous pneumothorax attacks. The reasons for the development of cysts and pneumothorax in the lung cannot be fully explained. Folliculin gene has a strong effect on lung fibroblasts and macrophages. Pulmonary structure depends on the interaction of the collagen and elastin fibers in the extracellular matrix forming the structure of alveolus wall. The proteases and cytokines, which were caused by matrix destruction as a result of the inflammatory processes and restructure, have been known to cause mutation of folliculin gene 7 .
For BJD syndrome, we came up with final diagnosis based on the detection of mutation in folliculin gene in DNA analysis. Following diagnostic criteria, both major and minor criteria were considered . Major criteria include the presence of fibrofolliculoma or trichodiscoma, confirmed histologically on at least 5 cervical or facial areas, and the detection of mutation in folliculin gene as confirmed by the DNA analysis . Minor criteria include the multiple lung cysts localized in the basals that may develop or may not develop primary spontaneous pneumothorax and of which underlying reasons cannot be detected. History of renal cancer and diagnosis of BHD syndrome in the first degree relatives are also considered as minor criteria. Diagnosis is confirmed if one of major criteria or two of minor criteria occur. Development of bullous lesions localized in the bilateral lower lobe on patient without history of smoking and the existence of familial history led to screening for multiple cystic lung diseases. Our patient did not have history of smoking.
It is difficult to diagnose BHD syndrome from symptoms alone, because hereditary renal cancers, pneumothorax, and cutaneous tumors may also occur with other syndromes for example, hereditary recurrent pneumothorax or pulmonary cysts are associated with Marfan syndrome, while Tuberous Sclerosis Complex (TSC), alpha1- antitrypsin deficiency, and cystic fibrosis are found to be associated with Ehlers-Danlos syndrome. On the other hand, non-hereditary recurrent pneumothorax and/or pulmonary cysts may occur with Langerhans cell histiocytosis and lymphangioleiomyomatosis. Definitive diagnosis of TSC is important as similar symptoms such as angiofibroma on the face, lung cysts and pneumothorax, renal cysts and tumor are associated with other syndromes, especially with BHD. Occurrence of TSC, especially in female patients, is associated with central nervous system symptoms and diffuse distribution of the lung cysts, and these show distinctive features from BHD .
Though fibrofolliculomas are unique to BHD, they may present with an ambiguous appearance, and must be confirmed histologically. Other diseases can mimic the dermatologic manifestations of BHD including TSC, Cowden syndrome, familial trichoepitheliomas, and multiple endocrine neoplasia type 1 .
Hereditary bilateral, multifocal kidney tumors similar to those seen in BHD may also occur with von Hippel-Lindau disease (clear cell renal cell carcinoma), hereditary papillary renal cancer (papillary renal cell carcinoma), and hereditary leiomyomatosis and renal cell cancer syndrome. However, they can be differentiated with examination of the tumors’ histology .
We confirmed the diagnosis of our patient as BHDS on the basis of fulfilling one major (presence of fibrofolliculoma or trichodiscoma confirmed histologically) and one minor (presence of multiple lung cysts localized in the basals) criteria.
Folliculin gene plays an active role in renal distal nephrons, lung type 1 pneumocytes and stromal cells; epithelial canal of the breast, pancreatic acinar cells, and in the serous glands of parathyroid and ovary . Therefore, the mutation of folliculin gene takes a part in the development of tumors associated with these tissues. Renal cancer risk for the patients especially with BHD syndrome is nine times higher . Renal tumors can manifest in multiple types of renal cell carcinoma, however, certain pathological subtypes (including chromophobe, oncocytoma, and oncocytic hybrid tumors) are more commonly seen.
Thyroid nodules have been associated with the BHD phenotype, and present in 65% of individuals and 90% of families with the syndrome. However, a connection between BHD and thyroid cancer has not yet been substantiated. Other conditions have been reported to be associated but may not be caused by the mutation in FLCN or may not be related at all. These include multinodular goiter, medullary thyroid carcinoma, parotid oncocytoma, colonic polyposis, connective tissue nevus, lipomas, angiolipomas, parathyroid adenomas, flecked chorioretinopathy, neurothekeoma, meningiomas, angiofibromas of the face, trichoblastomas, cutaneous focal mucinosis, cutaneous leiomyoma, breast cancer, tonsillar cancer, colorectal cancer, sarcoma of the leg, lung cancer, melanoma, dermatofibrosarcoma protuberans, basal cell carcinoma, cutaneous leiomyosarcoma, and squamous cell carcinoma. These conditions can be differentiated from Birt-Hogg- Dubé through examining the patient history and performing a physical examination . For women, suspected to have BHD syndrome, ruling out pulmonary or thoracic endometriosis may be necessary .
In the literature, no specific treatment for BHD syndrome is mentioned. However, treatments for BHD syndrome are actually the treatments for the associated symptoms. Therefore, the different manifestations of BHD syndrome are controlled in different ways. The fibrofolliculomas can be removed surgically, through curettage, shave excision, skin resurfacing, or laser ablation; however, this is not a permanent solution as the tumors often recur. The renal and pulmonary symptoms are managed preventatively: CT scans, ultrasounds, or MRIs of the kidneys are recommended regularly, and family members are advised not to smoke . MRI is the preferred method for surveillance of the kidneys in patient with BHD, because MRI does not carry the same risk of radiation complications as CT scans, and is more sensitive than ultrasounds. Smokers with BHD syndrome have more severe pulmonary symptoms than non-smokers.6 although nephrectomy is sometimes indicated; kidney tumors in case of BHD syndrome are often removed without taking the whole kidney, in a procedure called partial nephrectomy . Knockout mouse studies have shown that administration of rapamycin may mitigate the effects of FLCN mutations on kidneys and improve renal cancer prognoses because of folliculin’s interaction with the mTOR pathway .
Patients with recurren primary spontaneous pneumothorax along with familial history of pneumothorax and with having atypical bullae localization must be evaluated clinically, radiologically and histologically in detail in terms of BDH syndrome, and they must be followed regularly in terms of cancer predisposition.