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Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disease characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, a putative tumor suppressor, which result in loss of function of the folliculin protein and may cause cancer predisposition. In a 45-year-old woman with anemia, lymphadenopathy, and a history of recurrent spontaneous pneumothorax,F-18-FDG PET/CT detected diffuse and slight (18)F-FDG accumulation in the bone marrow, enlarged spleen, and systemic multiple enlarged lymph nodes. Genetic examination identified a germline nonsense mutation [c.998C > G (p.Ser333*)] on exon 9 of FLCN. Pathological examination of the lymph node revealed a diffuse neoplastic proliferation of plasmacytoid lymphocytes. The neoplastic lymphoid cells were positive for CD20, CD138, and light chain kappa as per immunohistochemistry and mRNA in situ hybridization, and a MYD88g ene mutation [c.755T > C (p.L252P)] was identified. Accordingly, she was diagnosed with lymphoplasmacytic lymphoma concomitant with BHD syndrome. To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.

Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome in which carriers are at an increased risk of developing a variety of tumors in multiple organ systems. A clinical diagnosis of VHL is determined by the presence of specific clinical manifestations while a molecular genetic diagnosis results from a pathogenic variant in the VHL gene. The majority of mutations occur in VHL coding exons and DNA analysis of these regions has a reported sensitivity of nearly 100%. However, rare variants in the VHL gene promoter may be detected in some cases of suspected VHL disease. We report two cases where VHL promoter variants were detected and describe the role of multi-step mRNA and protein analysis in the diagnostic evaluation of these cases.

It is estimated that up to 40% of all head and neck paragangliomas (HNPGL) have a hereditary background with the most common mutations being found in the succinate dehydrogenase (SDH) genes. SDHAF2 mutation leads to the rare paraganglioma syndrome 2. The authors present the case of a 15-year-old male patient with 2, non-secretory HNPGLs, presenting with left-sided, pulsatile tinnitus, and hearing loss. Imaging led to the suspicion of a jugulotympanic paraganglioma on the left, as well as a carotid body tumor on the right. After resection of the jugulotympanic tumor, histology confirmed the presence of a paraganglioma; immunohistochemistry furthermore suggested a loss of SDHB expression. Genetic testing revealed a rare germline, loss-of-function mutation in the SDHAF2 gene, previously described to cause hereditary paraganglioma syndrome 2. Twenty months after the first operation, the patient underwent a resection of the right carotid body paraganglioma. Plasma-free metanephrines/catecholamines always remained within the reference range; the patient is under regular follow-up, and his relatives will be screened. Our findings emphasize the relevance of genetic testing in patients with HNPGL, also with negative family history, especially when the patients present at a young age and with multiple lesions.

Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence-based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2-3 per 100,000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence-based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrolment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions, data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.

// Svetlana O. Zhikrivetskaya 1,* , Anastasiya V. Snezhkina 1,* , Andrew R. Zaretsky 2 , Boris Y. Alekseev 3 , Anatoly V. Pokrovsky 4 , Alexander L. Golovyuk 4 , Nataliya V. Melnikova 1 , Oleg A. Stepanov 1,3 , Dmitry V. Kalinin 4 , Alexey A. Moskalev 1 , George S. Krasnov 1 , Alexey A. Dmitriev 1 and Anna V. Kudryavtseva 1,3 1 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia 2 M.M. Shemyakin - Yu.A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia 3 National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Moscow, Russia 4 A.V. Vishnevsky Institute of Surgery, Moscow, Russia * These authors have contributed equally to this work Correspondence to: Anna V. Kudryavtseva, email: // Keywords : paragangliomas, pheochromocytomas, molecular markers, germline and somatic mutations, signaling pathways Received : August 02, 2016 Accepted : January 23, 2017 Published : February 08, 2017 Abstract Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year. Approximately 40% of cases are due to genetic mutations in at least one out of more than 30 causative genes. About 25–30% of pheochromocytomas/paragangliomas develop under the conditions of a hereditary tumor syndrome a third of which are caused by mutations in the VHL gene. Together, the gene mutations in this disorder have implicated multiple processes including signaling pathways, translation initiation, hypoxia regulation, protein synthesis, differentiation, survival, proliferation, and cell growth. The present review contemplates the mutations associated with the development of pheochromocytomas/paragangliomas and their potential to serve as specific markers of these tumors and their progression. These data will improve our understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful for early diagnostics, malignancy prognostics, and the determination of new targets for disease therapeutics.

Background Pheochromocytomas and Paragangliomas (PCC/PGL) are rare endocrine tumors that are mostly benign, but often hormone producing, causing significant morbidity and mortality due to excess catecholamine secretion and cardiovascular crises. It is estimated that 30% of PCC/PGL are due to germline mutations, including Neurofibromatosis type 1 (NF1). There is little published data describing the phenotype of NF1-associated PCC/PGL and there are no established recommendations for PCC/PGL screening in NF1. Methods We conducted a retrospective chart review of 17 patients with NF1-associated PCC/PGL who received care at a large academic referral center between the years of 1992–2016. Results Average age of diagnosis was 42 years old. Both genders were equally affected. Average tumor size was 3.9 cm. Nine patients were hypertensive; one had orthostatic hypotension; three had tachycardia; the remaining two patients had normal BP and HR. Most tumors were benign, unilateral adrenal tumors that were hormonally active. Two had metastatic disease. Six patients experienced cardiovascular crises; three of which occurred during elective surgeries for neurofibroma removal, and a fourth occurred during labor and delivery. Conclusion These data highlight the importance of screening for PCC/PGL in NF1, especially prior to surgical procedures and pregnancy, labor and delivery as these events can trigger a cardiovascular crisis. Screening is easily accomplished with plasma or urine free fractionated metanephrine levels. Electronic supplementary material The online version of this article (10.1186/s40842-018-0065-4) contains supplementary material, which is available to authorized users.

Background The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. Case presentation We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. Discussion and conclusions We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure. Electronic supplementary material The online version of this article (10.1186/s12881-018-0651-4) contains supplementary material, which is available to authorized users.

Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.

Importance Recently, a group of melanocytic tumors with loss of BAP1 expression has been described. The lesions may occur sporadically or as part of a familial cancer syndrome. They have distinct histopathologic features characterized by a nevuslike silhouette and cytologic composition of large epithelioid melanocytes with oval vesicular nuclei, distinct nucleoli, and abundant cytoplasm. The large melanocytes are immunohistochemically characterized by loss of nuclear labeling for BAP1. Observations We describe a 21-year-old patient with multiple combined melanocytic proliferations composed of both a nevus component with strong BAP1 expression and a large epithelioid melanocyte population with loss of BAP1 expression. The occurrence of multiple BAP1 loss melanocytic lesions raised concerns about a possible germline mutation. Sequence analysis of DNA from lesional and nonlesional skin confirmed a BAP1 germline mutation. Conclusions and Relevance The presence of multiple clinically banal–appearing melanocytic lesions with childhood onset suggests that the combined lesions with BAP1 loss large epithelioid melanocytes described herein are probably combined nevi. Our findings also illustrate how the detection of a histopathologically distinct melanocytic lesion, coupled with knowledge of its possible association with a hereditary tumor syndrome, can lead to the suspicion and confirmation of a germline mutation.