TSC1 is required for iNKT cell maturation and function

Invariant Natural Killer T (iNKT) cell development is highly regulated, starting at stage 0, where DP thermocytes become committed to the iNKT cell lineage, and ending as fully mature stage 3 iNKT cells, which are capable of illiciting an immune response. iNKT cells are a subtype of T-cells that can recognise bacterial infections, viruses, and even tumours. However, upon repeated exposure, iNKT cells can become anergic and stop responding to stimuli (reviewed by Cianferoni, 2013).

Earlier this year, it was reported that the FLCN interacting protein FNIP1 was required for iNKT cells to complete the stage 2 to 3 transition, that this phenotype was cell autonomous and partially due to mTOR dysregulation (Park et al., 2014). Two studies have found that TSC1, which when mutated causes the related kidney cancer syndrome Tuberous Sclerosis Complex, is required for both iNKT cell development, and mature iNKT cell function.

In order to investigate the role of TSC1 in iNKT cell development, Wu et al. (2014a) specifically deleted TSC1 in murine T-cells using the Cd4Cre allele. They found that although these mice had similar numbers of stage 2 iNKT cells compared with wildtype mice, they had far fewer stage 3 iNKT cells, due to a higher rate of apoptosis in these cells. Therefore, similarly to FNIP1, TSC1 is required to promote the survival of mature stage 3 iNKT cells.

While the overall number of iNKT cells was reduced, a rare subset of iNKT cells which produce IL-17 (iNKT-17 cells) were present in increased numbers in the TSC1fl/fl; Cd4-Cre mice. Expression analysis showed that TSC1 causes cells to preferentially develop into iNKT rather than iNKT-17 cells by promoting the expression of T-bet and inhibiting the expression of RORɣT and ICOS.

Bone marrow transplants into irradiated mice showed using a 1:2.5 mixture of wild-type and TSC1-null bone marrow cells showed stage 1 and 2 iNKT cells were derived from both donor cell types. However, stage 3 iNKT cells were more commonly from wild-type donor cells, indicating that TSC1’s effect on iNKT cell development is cell autonomous. Furthermore, Rapamycin treatment of TSC1fl/fl; Cd4-Cre mice nearly completely reversed the block in iNKT cell development and predominance of iNKT-17 cells, meaning that dysregulated mTOR signaling was responsible for this phenotype. These results are very similar to those seen in FNIP1-null iNKT cells, suggesting that FLCN and TSC1 may co-operate to regulate iNKT cell development.

In a second study from the same team, Wu et al. (2014b) used a Tamoxifen inducible allele to delete TSC1 in mature iNKT cells. They found that, unlike wild-type iNKT cells, TSC1-null iNKT cells did not become anergic upon secondary stimulation with ɑ-galactosylceramide. The expression of the anergy promoting genes PD-1, Egr2, Egr3, Grail and p27kip were all reduced in TSC1-null iNKT cells. This suggests that TSC1 normally promotes an anergic response by activating the expression of these genes. Given the close overlap between TSC1 and FNIP1’s roles in iNKTcell development, it would also be of interest to determine whether FNIP1 or FLCN also regulate iNKT cell anergy.

Anti-cancer vaccines, like the anti-PD1 vaccine, are currently being tested in clinical trials, and preventing T-cell anergy is a significant area of interest to ensure the continued efficacy of vaccinations (Pal et al., 2014). Mice carrying TSC1-null iNKT cells developed fewer tumour nodules than wild-type mice when injected with B16F10 melanoma cells, meaning that reducing the anergic response increased iNKT cells’ ability to target tumours. These results suggest that inhibiting TSC1 in T-cells might prevent them becoming anergic, and so increase the effectiveness of cancer vaccines.

  • Cianferoni A (2014). Invariant Natural Killer T Cells. Antibodies, 3 (1), 16-36 doi: 10.3390/antib3010016
  • Park H, Tsang M, Iritani BM, & Bevan MJ (2014). Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America, 111 (19), 7066-71 PMID: 24785297
  • Pal SK, Hu A, Chang M, & Figlin RA (2014). Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. Clinical advances in hematology & oncology : H&O, 12 (2), 90-9 PMID: 24892254
  • Park H, Tsang M, Iritani BM, & Bevan MJ (2014). Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proceedings of the National Academy of Sciences of the United States of America, 111 (19), 7066-71 PMID: 24785297
  • Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que LG, Foster WM, Xia Z, Chi H, & Zhong XP (2014). iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. The Journal of clinical investigation, 124 (4), 1685-98 PMID: 24614103
  • Wu J, Shin J, Xie D, Wang H, Gao J, & Zhong XP (2014b). Tuberous sclerosis 1 promotes invariant NKT cell anergy and inhibits invariant NKT cell-mediated antitumor immunity. Journal of immunology (Baltimore, Md. : 1950), 192 (6), 2643-50 PMID: 24532578

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button TSC1 is required for iNKT cell maturation and function

Somatic mutations in FLCN can cause cancer

The majority of research on FLCN is within the context of BHD syndrome, which is caused by heterozygous germline mutations in the FLCN gene. However, two recent papers have reported that somatic FLCN mutations may be a factor in the development of sporadic tumours.

Sirintrapun et al. (2014) describe the case of a 74 year old man who presented with metastatic renal cancer. Molecular analysis showed that roughly a third of the primary tumour consisted of benign oncocytic cells while the remaining two thirds of the tumour was a high grade oncocytic carcinoma. The patient showed an extended 20 month progression free survival with Temsirolimus treatment.

Genetic and expression profiling revealed that both parts of the tumour had a common origin, indicating that the benign oncocytoma gave rise to the high grade tumour. A number of genomic rearrangements were present in the high grade cells only, including heterozygous loss of 17p, which contains the FLCN gene.

Thus, the authors report a rare case of somatic FLCN deletion contributing to a sporadic case of renal cell carcinoma, and the first known case of a benign oncocytoma transforming to a high grade carcinoma. However, there were additional oncogenic genomic rearrangements present in the high grade oncocytic cells, such as loss of 8p and gain of 8q, suggesting that loss of FLCN was only partly responsible for the disease progression in this patient.

In the second study, Wagle et al. (2014) describe the case of a 57 year old woman with anaplastic thyroid cancer. The patient was enrolled in a phase II clinical trial testing everolimus and had a sustained response for 18 months, at which point her tumour became resistant to treatment. Whole exome sequencing of germline, pretreatment, and resistant tumour DNA revealed that the pretreatment tumour had somatic inactivating mutations in FLCN, TSC2, and TP53, which likely lead to increased mTOR signaling in tumour cells, making the tumour particularly sensitive to treatment with mTOR inhibitiors.

The resistant tumour had developed a missense mutation (mTORF2108L) which prevents everolimus binding to mTOR. In vitro studies show that mTORF2108L is still sensitive to kinase inhibitors, such as Torin1, suggesting that kinase inhibiton may be a suitable follow up treatment for this patient. The authors suggest that sequencing tumour DNA before and during treatment may suggest the most effective treatment regimen for the patient.

These studies contain a number of interesting findings. Firstly, that somatic mutations in the FLCN gene can cause not just kidney cancer, but other tumour types when combined with additional genetic lesions. Indeed, somatic mutations in FLCN have been found in rare cases of sporadic renal cell carcinoma, colorectal cancer, and thyroid oncocytoma (Gad et al., 2007, Kahnoski et al., 2003, Khoo et al., 2003, Pradella et al., 2013). This suggests that BHD is a fundamental disease, and research insights on BHD will yield relevant results for other types of cancer.

Secondly, that FLCN mutations – and other mutations which lead to increased mTOR signaling – may indicate that the tumour will respond well to treatment with mTOR inhibitors, and indeed both patients in these studies had particularly long responses to mTOR inhibitors (20 and 18 months respectively). This is particularly exceptional in the second patient’s case, as the median survival time for anaplastic thyroid cancer is five months.

Thirdly, that a personalised medicine approach – where treatment is based on the underlying metabolic abnormalities present within that tumour – will likely improve cancer survival rates. Additionally, ongoing monitoring of how tumours evolve resistance to treatment will suggest the most effective follow up treatments, even further extending lifespan following a cancer diagnosis.

When considered as a whole, these studies demonstrate the utility of genetic sequencing of tumours to determine how tumours develop and evolve, and suggest that in the future, tumours may be classified and treated according to the mutations they carry, rather than by tumour site.


  • Gad S, Lefèvre SH, Khoo SK, Giraud S, Vieillefond A, Vasiliu V, Ferlicot S, Molinié V, Denoux Y, Thiounn N, Chrétien Y, Méjean A, Zerbib M, Benoît G, Hervé JM, Allègre G, Bressac-de Paillerets B, Teh BT, & Richard S (2007). Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. British journal of cancer, 96 (2), 336-40 PMID: 17133269
  • Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, & Teh BT (2003). Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. Journal of medical genetics, 40 (7), 511-5 PMID: 12843323
  • Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjöld M, & Teh BT (2003). Inactivation of BHD in sporadic renal tumors. Cancer research, 63 (15), 4583-7 PMID: 12907635
  • Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
  • Sirintrapun SJ, Geisinger KR, Cimic A, Snow A, Hagenkord J, Monzon F, Legendre BL Jr, Ghazalpour A, Bender RP, & Gatalica Z (2014). Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization. Medicine, 93 (15) PMID: 25275525
  • Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Jänne PA, Garraway LA, & Lorch JH (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. The New England journal of medicine, 371 (15), 1426-33 PMID: 25295501

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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BHD lung cysts are not degenerative, but may cause pneumothorax

Although 90% of BHD patients develop lung cysts, there is very little information about the natural history of BHD lung cysts. In order to determine how lung cysts change over time, Johannesma et al. (2014a) compared the results of two CT scans taken at separate intervals, from six BHD patients, five of whom had suffered recurrent pneumothoraces. The time interval between scans ranged from 9 days to 44 months.

One patient developed one new lung cyst in 44 months, and the mean increase in cyst size was 0.4 mm, suggesting that BHD lung cysts do not increase in number or size particularly rapidly. Additionally, if BHD were a progressive degenerative disease, there would be a trend for older patients to develop more pneumothoraces, which has not been reported. Thus, it seems that BHD is not a degenerative disease, with respect to the lung symptoms.

This does raise the question as to when BHD lung cysts develop; there have been five reported cases of children with BHD having pneumothoraces, and FLCN has been shown to be important for alveolar development in mice. Thus, it is possible that lung cysts form during infanthood, childhood or adolescence as lungs are developing, and then remain largely stable during adulthood.

In a separate study, Johannesma et al. (2014b) found that pneumothorax was strongly correlated with the number of lung cysts, but not with their distribution, size or shape. Thus, it seems that the presence of lung cysts somehow causes pneumothoraces.

Johannesma et al. hypothesise that the heterozygous loss of FLCN in the epithelial cells lining cysts means they are more brittle due to increased cell-cell adhesion as reported by Medvetz et al. This causes cysts, and possibly the overlaying visceral pleura, to burst under the mechanical stresses of respiration, allowing air to build up in the pleural space and causing a pneumothorax.

This is similar to the hypothesis suggested by Kumasaka et al. who suggested that reduced cell-cell adhesion, as reported by Nahorski et al, made cyst walls weaker and more likely to burst under mechanical stress, also leading to a build up of air in the pleural space and potentially causing a pneumothorax.

Since the Nahorski and Medvetz studies were published in 2012, FLCN’s function has been shown to be highly cell-specific, which may account for the opposing results of the two studies. However, mouse studies have shown that deletion of FLCN in typeII alveolar lung cells leads to reduced E-cadherin localization at cell membranes, suggesting that lung cysts may indeed have weaker cell-cell contacts.

In either case, it seems that increased numbers of cysts rupturing and causing air to build in the pleural space is a likely mechanism that causes pneumothoraces to develop in BHD patients. Johannesma et al. therefore suggest that eliminating the pleural space by combined pleurectomy and chemical pleurodesis will reduce the recurrence of pneumothoraces in BHD patients. They do however caution that this treatment approach should first be tested in a phase II multicenter clinical trial before becoming the standard of care.


  • Johannesma PC, Houweling AC, van Waesberghe JH, van Moorselaar RJ, Starink TM, Menko FH, & Postmus PE (2014). The pathogenesis of pneumothorax in Birt-Hogg-Dubé syndrome: A hypothesis. Respirology (Carlton, Vic.), 19 (8), 1248-50 PMID: 25302759
  • Johannesma PC,, van Waesberghe JH,, Reinhard R,, Gille J,, van Moorselaar J,, Houweling A,, Starink T,, Menko FH,, & Postmus PE (2014b). Birt-Hogg-Dube Syndrome Patients With And Without Pneumothorax: Findings On Chest CT. American Journal of Respiratory and Critical Care Medicine, 189. [Abstract]
  • Kumasaka T, Hayashi T, Mitani K, Kataoka H, Kikkawa M, Tobino K, Kobayashi E, Gunji Y, Kunogi M, Kurihara M, & Seyama K (2014). Characterization of pulmonary cysts in Birt-Hogg-Dubé syndrome: histopathological and morphometric analysis of 229 pulmonary cysts from 50 unrelated patients. Histopathology, 65 (1), 100-10 PMID: 24393238
  • Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, & Henske EP (2012). Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PloS one, 7 (11) PMID: 23139756
  • Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, Klomp JA, Teh BT, Hatzfeld M, Gissen P, & Maher ER (2012). Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Human molecular genetics, 21 (24), 5268-79 PMID: 22965878

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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The Amsterdam Patient Charter for Global Kidney Cancer Care

Kidney cancer patients face a number of challenges, such as lack of awareness both by patients and their doctors, difficulty getting a diagnosis, limited access to treatment, inappropriate treatment, lack of information and lack of support. Given that there were an estimated 338,000 new cases of kidney cancer diagnosed in 2012 alone, this is a significant problem.

Following discussions at the International Kidney Cancer Coalition’s (IKCC) 4th Expanding Circles conference in Amersterdam earlier this year, the IKCC have published the Amsterdam Patient Charter for Global Kidney Cancer Care (Giles et al., 2014) which aims to address these challenges. The Charter outlines the rights of kidney cancer patients worldwide, and consists of ten points, which you can read here, and can be broadly split into three categories: clinical care, support, and information and empowerment.

Regarding clinical care, the charter states that patients should expect timely investigation, accurate diagnosis, access to the best available evidence-based therapies and treatment from doctors with specialist knowledge about kidney cancer. These measures will all lead to improved health outcomes for people with kidney cancer.

It was recently reported that doctors consistently underestimated the number of kidney cancer patients who became depressed after their diagnosis. The Amsterdam Patient Charter recommends that patients should be offered regular follow-up care, including psychosocial support, and given information about patient support and relevant advocacy organisations. Additionally, as kidney cancer can have long term health effects, patients should be given survivorship support, and recommendations about how to preserve health. These measures will help patients to cope with their illness and treatment and will allow patients to return to their normal lives.

Finally, patients should be offered accessible information specifically written for patients about all aspects of their disease course, including treatment, clinical trials, pain control, palliative care, survivorship and available support. Furthermore, patients should be given access to their medical records, and encouraged to take an active role in any decision-making regarding their treatment. Having better knowledge about their disease, and being given the opportunity to participate in the decision-making process, will empower patients to feel they have control over their care.

Of particular interest to BHD patients, point 10 of the charter highlights the fact that 10% of kidney cancer cases are caused by hereditary syndromes, and that these cases must be managed differently to sporadic cases. As these patients carry a genetic predisposition to develop kidney cancer, tumours must be treated more conservatively by partial rather than total nephrectomy, and patients require specialised care throughout their lifetime.

This initiative comes in same year as European Cancer Patients’ Bill of Rights, which aims to improve health outcomes by ensuring every European cancer patient has access to the best care, evidence-based treatment, and information. Although it is unclear how these charters will be enforced, their existence demonstrates the commitment of doctors, patient advocates, researchers and policy makers to improving the experience of cancer patients in Europe and kidney cancer patients worldwide.


  • Giles RH, Maskens D, & the International Kidney Cancer Coalition (2014). Amsterdam Patient Charter for Global Kidney Cancer Care. European urology PMID: 25257033

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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Routine screening of lung resections taken during surgery for pneumothorax may help identify unrecognised cases of BHD

In many cases, early diagnosis means treatments are more effective, cost less and save more lives. Screening programmes aid early diagnosis and can be used to screen whole populations, such as the fetal anomaly screening given to all pregnant women in the UK, or smaller groups of people with specific risk factors or symptoms, such as bowel cancer screening given to older men and women in the UK. A recent study by Sauter and Butner (2014) suggests that pathological analysis should be performed routinely on all lung tissue resected during surgery to repair a pneumothorax.

The authors identified 94 patients who had lung tissue resected during surgery for spontaneous pneumothorax at Fletcher Allen Health Care, a teaching hospital in Vermont, USA, between 1st January 2002 and 31st December 2012. 22 patients were eliminated from this study as the cause of their lung disease was known. For the remaining 72 cases of primary spontaneous pneumothorax, slides were reviewed for histopathological features, and cross referenced with each patient’s medical records.

61.5% of cases had recurrent episodes of pneumothorax, 96.2% of cases affected the upper lobes of the lung, and all cases had blebs. Six patients (8.3%) showed unexpected clinically significant findings: one patient’s sample revealed the presence of an adenocarcinoma; one patient had cystic lung disease consistent with pulmonary stromal endometriosis (Boyle and McCluggage, 2009); three patients showed lung damage likely to be caused by marijuana use; and one patient had multiple cysts in the lower lobes, and was later diagnosed with BHD.

In the US, routine pathological screening following appendectomy, herniorrhaphy, and cholecystectomy is under debate, with clinically significant findings in 1%, 1.4% and 2% of cases respectively (Lohsiriwat et al., 2009). Thus, Sautner and Butner advocate performing routine screening in lung resections taken following pneumothorax, as their rate of clinically significant findings was much higher at 8.3%.

In in this particular cohort the BHD patient would benefit most from an early diagnosis, as this allows the patient to have kidney surveillance screening, thus reducing their chances of developing advanced kidney cancer. Not only would this obviously be beneficial to the patient, but the authors state that the cost of treating just one case of advanced renal cancer would exceed the costs of screening all 72 samples analysed in this study. Furthermore, diagnosing the individual will also allow family members to get diagnosed, potentially avoiding further cases of advanced kidney cancer.

Further analysis of additional cohorts in different hospitals will be required to determine whether this screening would be truly cost effective. However, this study underscores the important role histopathologists play in diagnosing patients with rare diseases. There are a number of histological clues that suggest a patient has BHD: fibrofolliculomas; choromophobe, oncocytic or hybrid kidney tumours; the presence of intratumoral peripheral small papillary tufts in the kidneys; and small, irregularly-shaped cysts in the basal region of the lung. Thus, teaching histopathologists to recognise these clues and to refer these patients for genetic testing may improve diagnosis rates of BHD.

  • Boyle DP, & McCluggage WG (2009). Peritoneal stromal endometriosis: a detailed morphological analysis of a large series of cases of a common and under-recognised form of endometriosis. Journal of clinical pathology, 62 (6), 530-3 PMID: 19155237
  • Lohsiriwat V, Vongjirad A, & Lohsiriwat D (2009). Value of routine histopathologic examination of three common surgical specimens: appendix, gallbladder, and hemorrhoid. World journal of surgery, 33 (10), 2189-93 PMID: 19669232
  • Sauter JL, & Butnor KJ (2014). Pathological findings in spontaneous pneumothorax specimens: does the incidence of unexpected clinically significant findings justify routine histological examination? Histopathology PMID: 25234592

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

pf button Routine screening of lung resections taken during surgery for pneumothorax may help identify unrecognised cases of BHD

Telomere shortening may cause genetic anticipation in VHL syndrome

Genetic anticipation describes the situation where younger generations of a family with a genetic disease develop symptoms at a younger age, develop more severe symptoms, or both. A study earlier this year showed that there is evidence of genetic anticipation in the genetic kidney cancer syndrome Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) (Wong et al., 2014), and more recently a study suggests that this phenomenon is also seen in another hereditary kidney cancer syndrome, Von Hippel-Lindau syndrome (VHL) (Ning et al., 2014).

The authors analysed 34 parent-child pairs who were diagnosed with VHL at Peking University First Hospital in Bejing between 2009 and 2012. They found that 31 out of 34 parent-child pairs showed earlier onset of disease and that, on average, disease onset was 16.8 years earlier in the younger generation. This is similar to the results of the HLRCC study, which found that children were diagnosed with renal cell carcinoma roughly 18.6 years earlier than their affected parent.

In order to investigate the cause of the genetic anticipation seen in these families, the authors analysed telomere length, as telomere shortening has been found to cause genetic anticipation in other genetic diseases (Martinez-Delgado et al., 2011). DNA was available from 29 VHL patients, corresponding to 10 of the parent-child pairs, and 9 additional patients. 23 of the 29 patients showed a shorter than average telomere length compared with 325 healthy control samples. Furthermore, in all 10 parent-child pairs, relative telomere length was shorter in the younger generation. All of these families showed earlier age of disease onset in the younger generation, suggesting that shortened telomere length is associated with genetic anticipation in VHL.

In order to conclusively define the role of telomere shortening in VHL, it would be interesting to measure telomere length in those VHL families that do not show genetic anticipation. If no telomere shortening was seen in these families, this would strengthen the hypothesis that telomere shortening causes genetic anticipation in families with VHL. However, this would not explain why some VHL families get telomere shortening and subsequently show genetic anticipation, and other families do not. Alternatively, it is possible that the VHL protein is required to elongate telomeres during embryonic development, and that all people with VHL tend have shortened telomeres. As telomere length lies on a spectrum, it could be that telomere length must fall below a certain threshold before genetic anticipation between generations becomes evident.

This study does not rule out ascertainment bias, where subsequent generations are simply diagnosed at a younger age due to higher awareness of the disease and better diagnostic technology, rather than because they are truly developing symptoms earlier. Furthermore, similarly to the HLRCC study, it only analyses a small number of families from the same population, and does not rule out birth cohort or environmental effects that might cause the younger generation to develop symptoms at a younger age.

Thus more data are required in order to determine how common genetic anticipation is in VHL, HLRCC and other related syndromes like BHD, and what the underlying mechanism is. Indeed, The Cancer in our Genes International Databank for hereditary kidney cancers may be able to identify families showing genetic anticipation, allowing further research into this phenomenon.


  • Martinez-Delgado B, Yanowsky K, Inglada-Perez L, Domingo S, Urioste M, Osorio A, & Benitez J (2011). Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS genetics, 7 (7) PMID: 21829373
  • Ning XH, Zhang N, Li T, Wu PJ, Wang X, Li XY, Peng SH, Wang JY, Chen JC, & Gong K (2014). Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families. Cancer research, 74 (14), 3802-9 PMID: 24986515
  • Wong MH, Tan CS, Lee SC, Yong Y, Ooi AS, Ngeow J, & Tan MH (2014). Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC). Familial cancer, 13 (2), 281-9 PMID: 24526232

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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Air travel may cause pneumothorax in BHD patients

One concern many BHD patients have is whether it is safe to take commercial flights, or whether this would increase the chances of a pneumothorax. A recently published study, by Professor Pieter Postmus and his team at the VU Medical Center in the Netherlands, sheds some light on this issue.

Postmus et al. (2014) describe the case of a 38 year-old man with BHD who developed a pneumothorax after taking a speed lift to the top of one of the highest towers in the world. This episode was also two days following a trans-Atlantic flight. Upon his return home, the patient reviewed when his previous episodes of pneumothorax had occurred in relation to his flight pattern and found that both of his previous pneumothoraces had occurred within ten days of his return flights.

The authors also conducted a survey of 190 BHD patients and found that 12 patients (6.3%) suffered 13 episodes of pneumothorax within one month of flying. Of these, six cases occurred within 10 days; 4 cases between 10-20 days; and 3 cases between 20-30 days of their flight. Interestingly, although the authors concluded there was no link between air travel and increased risk of pneumothorax, a Japanese study found a similar proportion of BHD patients (3/48 or 6.3%) reported chest tightness following air travel although they were not diagnosed with pneumothorax (Hoshika et al., 2012).

It is thought that BHD-associated pneumothoraces are caused by lung cysts rupturing, which allows air to escape into the pleural cavity (Furuya and Nakatani, 2012). Thus, it is possible that the air pressure change experienced on the flight causes lung cysts to rupture. The long time lag – up to 30 days – between travel and symptoms developing suggests that pneumothorax does not occur instantaneously following cysts rupturing, but that it takes time for enough air to build up in the pleural space to collapse the lung.

Postmus et al. suggest that flying may cause a small pneumothorax to develop, which is then aggravated by further air pressure changes, most commonly the return flight. Thus, they recommend that patients are assessed for pneumothorax before making the return flight, although realistically this may not always be possible.

These results suggest that roughly 1 in 16 BHD patients are at risk of developing a pneumothorax within a month of flying, meaning that the risk is small but not insignificant. It is likely that a BHD patient’s precise risk will depend on the extent that BHD has affected their lungs, whether they have had previous episodes of pneumothorax, and how often they fly. It would also be of interest to determine whether the 12 BHD patients who reported having a pneumothorax within a month of flying had any shared characteristics such as gender, height, or FLCN mutation, to more accurately predict patient risk.

The most unexpected result of this study is the potentially large time lag between air travel and a collapsed lung becoming apparent. This may have confounded previous studies investigating the risks of air travel for BHD patients, as researchers may have only thought the two were linked if the pneumothorax occurred within a day or two of the flight. Thus, any future studies should take this into account to conclusively calculate the risk to BHD patients.

Additionally, patients should be aware of this risk and should be particularly alert to any symptoms of pneumothorax that develop up to 30 days after their flight. It may also be prudent for patients to avoid flying too frequently if possible; while British guidelines recommend that pneumothorax patients can fly 1 week after their pneumothorax has resolved, the BHD patient described in this study flew within a month of his first collapsed lung resolving, and subsequently suffered a second pneumothorax.


  • Furuya M, & Nakatani Y (2013). Birt-Hogg-Dube syndrome: clinicopathological features of the lung. Journal of clinical pathology, 66 (3), 178-86 PMID: 23223565
  • Hoshika Y, Kataoka H, Kurihara M, Anod K, Sato T, Seyama K, & Takahashi K. (2012). Features of pneumothorax and risk of air-travel in Birt-Hogg-Dube´ syndrome [abstract]. American Journal of Respiratory and Critical Care Medicine, 185 DOI: 10.1164/ajrccm-conference.2012.185.1_MeetingAbstracts.A4438
  • Postmus PE, Johannesma PC, Menko FH, & Paul MA (2014). In-Flight Pneumothorax: Diagnosis May Be Missed because of Symptom Delay. American journal of respiratory and critical care medicine, 190 (6), 704-5 PMID: 25221882

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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