Not just a cosmetic problem: facial papules in Birt-Hogg-Dubé syndrome

Clinical record

A 52-year-old man was referred for laser therapy of facial papules for cosmetic reasons. The patient presented with a history of multiple asymptomatic facial lesions that had slowly erupted over a 10-year period. Before this consultation, the patient had been referred to a dermatologist to exclude skin cancer and biopsy of a lesion showed an angiofibroma and no evidence of malignancy. Personal history was remarkable for recurrent bilateral spontaneous pneumothoraces requiring pleurodesis. His family history was positive for recurrent pneumothorax in an adult son and recent onset of similar facial lesions in another son. There was no personal or family history of renal carcinoma.

Physical examination revealed multiple dome-shaped firm whitish papules over the forehead and cheeks (Figure 1 and Figure 2). The clinical presentation of multiple facial fibrous papules occurring on a background of unexplained pneumothoraces was suggestive of the genetic condition, Birt-Hogg-Dubé syndrome (BHD). Repeat punch biopsy of a lesion revealed an infundibulum with perifollicular fibrosis suggestive of a trichodiscoma, supportive of BHD.

The patient was referred to a cancer genetic clinic for counselling, genetic testing and screening. Renal ultrasound revealed a left renal hypoechoic lesion measuring 2.5 × 2.1 × 2.4 cm. The patient underwent robotic left partial nephrectomy, and pathology revealed a hybrid oncocytic/chromophobe tumour. Although this tumour was growing in a benign manner, it displayed low-grade renal cell carcinoma features. However, as the tumour was completely excised, no further treatment was required.

Genetic testing of blood revealed a heterozygous FLCN c.853C>T mutation on chromosome 17. Genetic counselling and radiographic renal screening of family members is planned. As per suggested guidelines, our patient will undergo lifelong medical surveillance by periodic renal ultrasound and/or magnetic resonance imaging.1

BHD is a rare, autosomal dominant, hereditary cancer syndrome due to germline mutations in the folliculin gene (FLCN). The incidence of BHD is about one in 200 000 of the population; however, it is likely underdiagnosed because of low clinical awareness.1,2 Folliculin is a protein expressed on keratinocytes in the basal and spinous layer of the epidermis, dermal fibroblasts, nerve cells, lymphocytes, macrophages and mast cells. Extracutaneously, folliculin is expressed on pulmonary type-1 alveolar epithelial cells and distal nephrons.3 Folliculin is a tumour suppressor protein, important in cell signalling pathways that regulate cell growth. It is proposed that genetic mutation results in loss of a functional protein in cells, resulting in unchecked tumour growth.4 The pattern of folliculin expression correlates with the clinical features of BHD, including skin papules of varying pathologies, basal lung cysts, spontaneous pneumothorax and renal cell carcinomas.

Proposed diagnostic criteria for BHD include the presence of one major or two minor features.2 Major features are at least five adult onset fibrofollliculomas or trichodiscomas, with histological confirmation, or a pathogenic FLCN mutation. Fibrofolliculomas and trichodiscomas present as multiple small flesh-coloured or white dome-shaped papules on the face, neck and upper trunk. Angiofibromas have also been associated with BHD; however, the presence of multiple angiofibromas is more suggestive of tuberous sclerosis.5 Minor features include a history of bilateral basal lung cysts, with or without spontaneous pneumothorax, early onset (age < 50 years) renal carcinoma with multifocal or bilateral carcinomas or a mixed chromophobe/oncocytic histology, and a first-degree relative with BHD.6

Patients with BHD have a 50-fold increased risk of primary spontaneous pneumothorax development and more than 80% of affected individuals have multiple pulmonary cysts visible on a computed tomography scan, with the less common basal rather than apical predilection.6,7 Renal cell carcinomas occur in 27% of affected individuals. A wide range of renal carcinomas have been reported, with the most common pathology being the unusual mixed oncocytic/chromophobe tumour. More than 65% of patients with BHD and renal carcinoma present with multifocal, bilateral or recurrent tumours.

Early recognition of BHD is crucial, given the high risk of renal neoplasm development which, if detected early, is curable. Thus the general practitioner and dermatologist are uniquely placed to consider the diagnosis of BHD when consulted by a patient requesting removal of multiple facial papules. Unexplained spontaneous pneumothorax and basal lung cysts should also raise suspicion of BHD. Referral for genetic testing and multidisciplinary care is essential. Routine renal radiographic screening is recommended for affected individuals > 40 years and, given the likelihood of multiple tumours, nephron-sparing surgery is preferred.8

Treatment of skin lesions associated with BHD is elective. In particular, laser ablation of individual lesions may improve the appearance for cosmetic reasons.

Lessons from practice

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition caused by germline mutations in the folliculin gene.
Phenotypical features of this rare syndrome include multiple white dome-shaped facial papules and bilateral basal lung cysts, predisposing to spontaneous pneumothorax.
Diagnosing BHD early is important, as the genetic defect is also associated with early onset renal cell carcinomas, of varying pathology.
As there are variations in presentation, a combination of multiple facial papules, spontaneous pneumothorax and a personal or family history of renal cell carcinoma should trigger consideration of BHD.

Figure 1 –

Figure 1: Patient’s facial fibrofolliculomas and trichodiscomas presenting as innumerable small white papules on the forehead, cheeks and chin.

Figure 2 –

Figure 2: Close-up image of fibrofolliculomas and trichodiscomas.

[Comment] Offline: Chronic diseases—the social justice issue of our time

It would be normal to be anxious at a meeting about chronic diseases. Even overwhelmed. Non-communicable diseases (NCDs) are many—cardiovascular, cancer, diabetes, respiratory, liver, renal, neurological. The list goes on. And then there are risk factors: tobacco, diet, physical inactivity, high blood pressure, air pollution. The context only adds to the complexity—rapid globalisation, urbanisation, an ageing society. If you were a minister of health amid this extraordinary diversity of challenges, where would you begin? Last week, WHO held a “dialogue” to discuss the Global Coordination Mechanism on the Prevention and Control of Non-communicable Diseases.

Health neglected in climate talks

More than half of governments around the world are yet to develop national plans to protect their citizens from the health effects of climate change despite increasing warnings it will cause more extreme weather, spread disease and put pressure on food and water supplies.

As leaders from around the world attending the United Nations Climate Change Conference in Paris reaffirmed their commitment to provide $139 billion a year by 2020 to the UN’s Green Climate Fund and other climate initiatives, an international survey of 35 countries, including Australia, has found a general lack of focus and urgency around the looming threat of climate change to health, with most governments doing little work on likely effects and how to mitigate them.

The survey results underline calls from the AMA, the World Medical Association and other national medical organisations for the health effects of climate change to be made a priority.

AMA President Professor Brian Owler said that while much of the Paris talks were about carbon emission targets, there should be equal emphasis on equipping health systems to cope with the extra burden of problems created by climate change.

“Climate change will dramatically alter the patterns and rate of spread of diseases, rainfall distribution, availability of drinking water and drought,” Professor Owler said. “The incidence of conditions such as malaria, diarrhoea and cardio-respiratory problems is likely to rise.”

The AMA President’s comments came as a survey coordinated by the World Federation of Public Health Associations (WFPHA) found almost 80 per cent of governments are yet to comprehensively assess the threat climate change poses to the health of their citizens, two-thirds had done little to identify vulnerable populations and infrastructure or examine their capacity to cope, and less than half had developed a national plan.

The result underlines the importance of repeated AMA calls for the Federal Government to do much more to prepare for the effects of climate change, which Professor Owler said were “inevitable”.

Earlier this year the AMA released an updated Position Statement on Climate Change and Human Health that warned of multiple risks including increasingly frequent and severe extreme weather events, deleterious effects on food production, increased pressure on scarce water resources, the displacement of people and an increase in health threats such as vector-borne diseases and climate-related illnesses.

“There are already significant health and social effects of climate change and extreme weather events, and these effects will worsen over time if we do not take action now,” Professor Owler said.

“Nations must start now to plan and prepare. If we do not get policies in place now, we will be doing the next generation a great disservice.

“It would be intergenerational theft of the worst kind — we would be robbing our kids of their future.”

In May, the AMA and the Australian Academy of Science jointly launched the Climate change challenges to health: Risks and opportunities report that detailed the likely health effects of climate change and called for the establishment of a National Centre of Disease Control to provide a national and coordinated approach to threat.

The WFPHA said the results of its survey should serve as a wake-up call for governments to do much more.

“The specifics of these responses provide insight into the lack of focus of national governments around the world on climate and health,” the Federation said.

Disturbingly, the survey found that Australia was one of the laggards in addressing the health effects of climate change, having done little to assess vulnerabilities and long-term impacts, develop an early warning system or adaptation responses, and yet to establish a health surveillance plan.

On many of these measures, the nation was lagging behind countries like the United States, Sweden, Taiwan, New Zealand and even Russia and China.

Climate and Health Alliance Executive Director Fiona Armstrong, who helped coordinate the survey, said the results showed the Federal Government needed to place far greater emphasis on human health in its approach to climate change.

“As a wealthy country…whose population is particularly vulnerable to the health impacts of climate change, it is very disappointing to see this lack of leadership from policymakers in Australia,” Ms Armstrong said.

Public Health Association of Australia Chief Executive Officer Mike Moore said the increasing number and ferocity of bushfires and storms underlined the urgent need for action.

“It is time to ensure that health-related climate issues are part of our national planning and budgeting if we are to pre-empt many avoidable illnesses and injuries,” Mr Moore said.

Read the AMA’s Position Statement on Climate Change and Human Health.

Adrian Rollins

[Comment] Japan’s vision for a peaceful and healthier world

Health is fundamentally a global issue. Recent outbreaks of Ebola virus disease and Middle East respiratory syndrome have reminded us that global health issues require collective action. The world must unite and countries must establish resilient and sustainable health systems, ensuring that each individual is secure and receives the highest attainable standard of health. Japan has been a longstanding advocate of human security1 and has taken concrete action on the ground in support of this principle.

[Obituary] Howard Wilbur Jones

Gynaecologist, oncologist, and pioneer of in-vitro fertilisation in the USA. He was born in Baltimore, MD, USA, on Dec 30, 1910, and died of respiratory failure in Norfolk, VA, USA, on July 31, 2015, aged 104 years.

[Perspectives] The politics of global health security

Disease Diplomacy by Sara Davies, Adam Kamradt-Scott, and Simon Rushton delves into the high politics of global health security. They trace this new disease diplomacy to the severe acute respiratory syndrome (SARS) epidemic of 2003. Ever since that time, and indeed long before, political leaders took notice of the security and economic effects of new infections spanning national borders.

Govts doing little to tackle climate health threat

Picture: paintings%20/%20Shutterstock.com“>paintings / Shutterstock.com

As leaders from around the world meet in Paris for UN climate talks, an international survey of 35 countries, including Australia, has found a general lack of focus and urgency around the looming threat of climate change to health, with most governments doing little work on likely effects and how to mitigate them.

The survey results underline calls from the AMA, the World Medical Association and other national medical organisations for the health effects of climate change to be made a priority at the climate talks.

AMA President Professor Brian Owler said that while much of the Paris talks will be about carbon emission targets, there should be equal emphasis on equipping health systems to cope with the extra burden of problems created by climate change.

He said the Paris Conference was “the perfect place” to develop and implement plans to deal with these effects.

The result underlines the importance of repeated AMA calls for the Federal Government to do much more to prepare for the effects of climate change, which Professor Owler said were “inevitable”.

“There are already significant health and social effects of climate change and extreme weather events, and these effects will worsen over time if we do not take action now,” Professor Owler said.

“Nations must start now to plan and prepare. If we do not get policies in place now, we will be doing the next generation a great disservice.

“It would be intergenerational theft of the worst kind — we would be robbing our kids of their future.”

The WFPHA said the results of its survey, released little more than two weeks before the United Nations Climate Change Conference in Paris, should serve as a wake-up call for governments to do much more.

“The specifics of these responses provide insight into the lack of focus of national governments around the world on climate and health,” the Federation said.

On many of these measures, the nation was lagging behind countries like the United States, Sweden, Taiwan, New Zealand and even Russia and China.

Public Health Association of Australia Chief Executive Officer Mike Moore said the increasing number and ferocity of bushfires and storms underlined the urgent need for action.

“It is time to ensure that health-related climate issues are part of our national planning and budgeting if we are to pre-empt many avoidable illnesses and injuries,” Mr Moore said.

The AMA’s Position Statement on Climate Change and Human Health can be viewed at: position-statement/ama-position-statement-climate-change-and-human-health-2004-revised-2015

Adrian Rollins

[Correspondence] Key donors to reinstate health funding to Zambia

In her World Report (Aug 8, p 519),1 Ann Danaiya Usher noted that key donors intend to reinstate health funding to Zambia 6 years after a corruption scandal that led them to withdraw funding. It is true that an immediate decline in health indicators—such as antenatal coverage, tuberculosis, malaria, and diarrhoeal and respiratory infections—was seen after the loss of funding. However, between 2007 and 2013, Zambia recorded huge reductions in maternal and child mortality—with under-5 mortality declining by 37% and maternal mortality by 33%—and improvements in several other service delivery indicators and health outcomes (eg, family planning, deliveries by skilled providers, treatment of fevers and acute respiratory infections in under-5 children, use of insecticide-treated bednets, total fertility rate, and prevalence of chronic malnutrition among children younger than 5 years).

[Perspectives] The experiences of a black doctor in the USA: a searing journey

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[Comment] Respiratory medicine and critical care: a call for papers

As health care becomes ever more complex and the approach to treatment more personalised, research is a vital component in our mission to help improve the lives of patients living with respiratory diseases. From understanding the genetic links to disease to cutting-edge treatments, high-quality research helps us to navigate the intricate path to optimum care for patients.