Birt–Hogg–Dubé: beyond the clinical manifestations

Clinicians and scientists understand the medical implications of BHD; however, what may not be apparent to clinicians and scientists are the psycho-social aspects of living with BHD. Although medical reality differs among people who have Birt–Hogg–Dubé, they often share multiple non-medical ramifications ranging from economic and physical insecurity to interruptions in familial communication patterns and relationships. Physicians cognizant of the psycho-social aspects of having BHD are in a position to offer enhanced and meaningful non-medical interventions and care to their patient with BHD.     

Genetically diagnosed Birt–Hogg–Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report

When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt–Hogg–Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595–597,  10.1007/s10689-015-9807-y, 2015) but it is not yet clear whether they represent a genuine part of that conditions’ phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed.     

Birt–Hogg–Dubé: tumour suppressor function and signalling dynamics central to folliculin

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.     

Novel germline mutations in FLCN gene identified in two Chinese patients with Birt–Hogg–Dubé syndrome

Birt–Hogg–Dubé (BHD) syndrome, a hereditary renal cancer syndrome caused by mutations in the folliculin (FLCN) gene, is characterized by the presence of fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cell carcinoma (RCC). Few BHD syndrome cases have been reported in Asian countries, and cutaneous presenta-tions are relatively rare in Asian patients. Asian BHD patients may be misdiagnosed due to their atypical manifesta-tions. Here, we report two Chinese BHD patients with novel FLCN mutations (c.946-947delAG in exon 9 and c.770-772delCCT in exon 7). Both of them had RCC and spontaneous pneumothorax without fibrofolliculomas. In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pulmonary cysts (pneumothorax).     

Guillain-Barré syndrome and glioblastoma

Guillain-Barré syndrome (GBS) is defined as an acute demyelinating peripheral neuropathy. We describe a case of GBS in a patient with glioblastoma undergoing chemotherapy treatment. A 57 year old woman diagnosed with glioblastoma developed a subacute progressive history of bilateral symmetric numbness of her fingers and toes, belt-type neuropathic pain, a left facial droop and upper and lower extremity muscle weakness. There was no evidence of a tumor mass or leptomeningeal disease in the spine. Electrophysiological studies confirmed the diagnosis. Although rare, GBS should be considered in primary brain tumor patients with generalized acute-subacute progressive weakness that is inconsistent with the location of their tumor, particularly if they are also on chemotherapy contributing to their immunosuppressive state.     

Guillain-Barré syndrome and myelodysplasia--a possible association

We report on three cases of Guillain-Barré syndrome (GBS) occurring in patients with myelodysplasia, two with autoimmune manifestations. In two cases the myelodysplasia was diagnosed during the treatment of the GBS, while in the third case the myelodysplasia preceded its diagnosis. We discuss possible underlying mechanisms for the previously unreported finding.     

Antioxidants and basal cell carcinoma of the skin: A nested case–control study

Objective To investigate the relationship between basal cell carcinoma (BCC) and antioxidant nutrients, specifically carotenoids, vitamin E and selenium.Methods The Nambour Skin Cancer Study is an ongoing, community-based study of randomly selected adult residents of a township in sub-tropical Queensland, Australia. Using a nested case–control design, incident cases of BCC (n=90) were compared with age and sex matched controls (n=90). Dietary exposure was measured using food frequency questionnaire estimates of intake as well as serum biomarkers. Other determinants of skin cancer including sun exposure were also considered. Dietary intakes were adjusted for energy intake, and serum carotenoids and vitamin E were adjusted for serum cholesterol. Odds ratios were calculated across quartiles of dietary intake and serum biomarkers and linear trends were assessed using logistic regression, adjusting for age, sex and supplement use.Results and conclusions In this prospective study no significant associations were found between BCC and carotenoids, vitamin E or selenium, as measured by serum biomarkers or dietary intake, although there was a suggestion of a positive association with lutein intake.     

Case–control study of smoking and non-melanoma skin cancer

Objective  

To investigate the association between cigarette smoking and basal and squamous cell carcinomas (BCC and SCC) of the skin, a clinic-based case–control study was conducted in Tampa, FL.     

Pulmonary manifestations of Birt-Hogg-Dubé syndrome

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.     

Mycosis fungoides and the Sézary syndrome

PURPOSE OF REVIEW: Mycosis fungoides and the Sézary syndrome represent a heterogeneous group of good-to-intermediate-risk non-Hodgkin lymphomas that have recently been identified as distinct histopathologic and clinical entities by the World Health Organization and European Organization for Research on the Treatment of Cancer lymphoma classification systems. Significant progress has been made in identifying and categorizing patients based on clinical prognostic factors, but there is little information regarding the etiology, molecular biology, and molecular genetics of these diseases. This review outlines recent advances in clinical diagnosis and prognosis as well as novel therapeutic approaches. RECENT FINDINGS: A number of reports have further defined clinical prognostic subgroups among early-stage patients and those with circulating Sézary cells. The recent availability and demonstrated efficacy of the oral RXR retinoid, bexarotene, has altered the treatment paradigm of early-stage patients who would not otherwise be exposed to systemic therapies. Novel targeted agents and receptor-directed therapies, including the fusion toxin, denileukin diftitox, histone deacetylase inhibitors, and novel nucleoside analog therapies, have demonstrated promising activity and are undergoing further clinical evaluation. The evolution of immunotherapy has been augmented by studies demonstrating the efficacy of peptide-loaded dendritic cells as well as the use of photopheresis to generate an anti-idiotype cytotoxic T-cell response. SUMMARY: This review will enumerate the most recent findings with respect to clinical staging, prognosis, and treatment of patients with mycosis fungoides and the Sézary syndrome. Novel treatment options will be reviewed and treatment paradigms will be outlined.