Genetic Causes of a Collapsed Lung
Familial Pneumothorax, Birt-Hogg-Dubé Syndrome & Related Conditions

Most people who have a spontaneous pneumothorax are told the same thing: it happens to tall, slim young adults, more often men, and there is usually no reason for it. That description is accurate for the majority, and for most people it is the end of the story. The lung is treated, it heals, and it does not happen again.

For a minority it is not the end of the story. Around one in ten spontaneous pneumothoraces may have an underlying genetic cause. The signals that raise the question are specific rather than vague: another family member who has had a collapsed lung; a relative with cysts found on a chest scan; collapses that keep happening despite treatment; a collapse on the second side; or a first collapse in a woman, where a small number of conditions are worth excluding for reasons set out below.

The absence of a family history does not settle it. These conditions are inherited in a way that means a parent can carry the gene and never have a symptom, and they can also appear for the first time in one person with no family background at all. A great-grandparent who died young of an unexplained chest problem may be the only trace. It is common for people to be told there is nothing in the family, and for a diagnosis in one person to reveal several relatives who have been affected all along.

A chest X-ray shows that the lung has come down. It does not show why. A CT scan of the chest is the test that answers the second question, and in this context it is not looking for the collapse — it is looking at the rest of the lung tissue while the opportunity is there.

The single most useful thing on that scan is where any cysts sit. In ordinary spontaneous pneumothorax, the weak areas — blebs and bullae — are at the top of the lung. In Birt-Hogg-Dubé syndrome the cysts are characteristically low, below the level of the carina, and close to the lung surface. That distribution is the opposite of what is expected, and it is often the first clue anyone gets. Cysts spread evenly through both lungs in a woman raise a different question again.

Two practical points follow. If you already have a CT scan, the images themselves are worth more than the report, because the report may not have been written with this question in mind. And where a cystic lung condition is being considered, the scan needs to be a proper thin-section CT: ultrasound of the lung is not an adequate substitute and current guidance says so directly.

Examination matters alongside the imaging. In Birt-Hogg-Dubé syndrome the characteristic skin lesions — small, pale, dome-shaped bumps on the face, neck, chest and back — reach a penetrance of around 87 to 97 per cent by age 70. They are easily mistaken for ordinary blemishes and are rarely looked for in a chest clinic. Height, arm span and joint flexibility are recorded for a different reason, discussed further below.

Patients often assume that finding a genetic cause means a different, bigger operation. In most cases it does not. Current international guidance for Birt-Hogg-Dubé syndrome states plainly that treatment of a pneumothorax does not differ from a pneumothorax arising for any other reason, and that surgical intervention — keyhole surgery with pleurodesis, pleurectomy, or more extensive pleural covering — should be considered for recurrent episodes.

What the diagnosis changes is this:

• →Organs outside the chest come into view. In Birt-Hogg-Dubé syndrome the lifetime risk of kidney cancer is around 15 to 30 per cent, and imaging is recommended from about age 20, every one to two years and preferably annually, continuing lifelong
• →That applies even if the lung was the only thing ever affected. Guidance is explicit that people with a pathogenic FLCN variant should be offered kidney surveillance even where the personal and family history is of pneumothorax alone
• →Relatives can be tested and either monitored or released. A negative test in a family member removes the need for surveillance rather than leaving them in limbo
• →The threshold for operating changes in one condition. In lymphangioleiomyomatosis, guidance supports offering pleurodesis after a first pneumothorax rather than waiting for a recurrence
• →Follow-up is planned around a higher chance of it happening again, rather than discharge once the wound has healed

This is why the delay to diagnosis matters. Where a pneumothorax is the first feature of Birt-Hogg-Dubé syndrome, the reported time to diagnosis has a median of six years — substantially longer than when the condition declares itself through the skin or the kidneys. Those are years of kidney surveillance not happening.

Birt-Hogg-Dubé syndrome is caused by a change in a gene called FLCN, which produces a protein called folliculin. It is inherited in a dominant pattern, meaning a parent with the condition has a one-in-two chance of passing it on — though whether it causes any problems, and which ones, varies widely between people and even within the same family.

Three things tend to occur together. Cysts form in the lungs, characteristically in the lower zones and near the lung surface. Small benign skin bumps appear, usually from adulthood onwards, on the face, neck, chest and back. And there is an increased risk of kidney tumours, which is the reason a diagnosis is worth having.

The reported lifetime risk of a pneumothorax sits between roughly a quarter and a half, with a median age at first collapse of around 34 years and a wide reported range on either side. People who go on to have several collapses tend to present younger than those who only ever have one. Around a third of people with the lung cysts never have a pneumothorax at all — the cysts are usually silent, and lung function is typically normal, so routine breathing tests are not recommended in people without symptoms.

The risk of a collapse is lifelong, so age is not a reason to stop considering the diagnosis. Equally, one thin-section CT at diagnosis is generally enough — there is no evidence supporting repeated routine chest scans in the absence of symptoms, and repeated imaging carries its own costs.

Familial spontaneous pneumothorax describes a collapsed lung occurring in someone who has a relative affected in the same way. Birt-Hogg-Dubé syndrome is the most common inherited condition identified in these families, but it is not the only explanation, and in a proportion of families no gene is found despite a pattern that is clearly inherited.

What is worth asking about goes wider than collapsed lungs. Relatives with cysts, blebs or bullae seen on any chest scan; relatives with kidney tumours; unexplained early deaths from chest problems in previous generations; and, because they point towards different conditions, relatives with unusual height and joint flexibility, or with problems affecting major blood vessels.

In the United Kingdom, families with recurrent or unexplained pneumothorax are increasingly discussed through a specialist familial pneumothorax service, and referrals from respiratory teams into that pathway are now routine. That route and a surgical opinion are not alternatives — they run alongside each other, and the surgical decision is usually the more urgent of the two.

One point about age. These conditions frequently declare themselves for the first time in late adolescence or early adulthood, which is also when spontaneous pneumothorax is most common generally. Genetic testing of children who have no symptoms is generally deferred until adulthood unless the result would change their care. Where a young person needs surgical assessment, the adolescent and young adult thoracic surgery page sets out the routes available.

A pneumothorax with an underlying genetic cause can return despite technically adequate surgery, and can return on the other side. These patients are followed more closely for that reason, and the operation is planned with the expectation that the lung may fail again rather than the assumption that it will not.

The reason is straightforward once the cause is known. Surgery for pneumothorax deals with the part of the lung that has failed and seals the space around it. Where the whole lung carries a process that produces cysts, or where the tissue itself is weaker than it should be, removing one area does not remove the tendency. A further collapse in that setting is not automatically evidence that something was done badly.

That has two practical consequences. Recurrence after an apparently adequate operation is one of the strongest reasons to ask whether an underlying cause was ever looked for — particularly a collapse on the second side. And where a cause is already known, the choice of how the pleural space is sealed, and how much of it, is a decision made with the recurrence risk in mind rather than by default. How pneumothorax surgery is done →

Lymphangioleiomyomatosis, usually shortened to LAM, is a rare lung condition affecting almost exclusively women, in which cysts develop throughout both lungs. It occurs on its own and also in association with tuberous sclerosis complex. A pneumothorax is one of the common ways it first comes to light.

This is the condition where the surgical decision genuinely changes. International guidance makes a conditional recommendation to offer pleurodesis after a first pneumothorax in LAM, rather than waiting for a recurrence as would be usual otherwise. The same guidance recommends against pleurodesis being used as a reason to exclude a patient from lung transplantation later — a concern that has caused real hesitation in the past and should no longer weigh against treating the pleural space properly.

For a woman having her first spontaneous pneumothorax, there are therefore two separate questions worth asking rather than one. Whether the collapses follow the menstrual cycle, which points to thoracic endometriosis and catamenial pneumothorax; and whether the lungs contain cysts, which points here. They are different conditions with different treatments, and the second is easily missed if only the first is considered. Chest symptoms that follow your cycle →

A group of inherited conditions affect the connective tissue that gives the body its structure, and some of them are associated with pneumothorax. Marfan syndrome is the best known. Vascular Ehlers-Danlos syndrome is the subtype of Ehlers-Danlos in which pneumothorax is a recognised feature, and it matters for a further reason: the tissue itself is fragile, which is directly relevant to anyone planning an operation. Loeys-Dietz syndrome, homocystinuria and the cutis laxa syndromes are rarer still.

One distinction is worth making clearly, because it causes a great deal of confusion. Being generally flexible — hypermobile — is common, and on its own it is not an established cause of collapsed lung. The association with pneumothorax is recognised in the vascular form of Ehlers-Danlos, which is a different condition, diagnosed on the behaviour of tissue and confirmed genetically rather than by a flexibility score. Many people with recurrent collapses and hypermobility are tested and found to have neither Marfan syndrome nor a connective tissue disorder of any kind.

That is why arm span, height and joint assessment are recorded in clinic. Not because a number diagnoses anything, but because the pattern either supports a line of enquiry or points away from it. A measured, documented assessment that concludes a connective tissue disorder is unlikely is a useful result, not a wasted appointment — and it is one this group of patients is rarely given.

A great many people in this position are told, once, that they should never fly again — and then organise the next twenty years around that sentence. It is worth knowing what the evidence actually shows.

In Birt-Hogg-Dubé syndrome, the estimated risk of a pneumothorax has been put at around 0.63 per cent per flight and 0.33 per cent per episode of diving, and the risk appears lower in people who have had a pleurodesis. That is not zero, and it is not nothing — but it is a long way from a permanent prohibition. Anyone with extensive cystic disease, impaired lung function, a recent collapse, or unexplained chest pain or breathlessness before travelling is in a different position, and specialist advice before flying is sensible.

Diving is treated more strictly than flying, and the distinction is often lost. A history of spontaneous pneumothorax is regarded as a contraindication to scuba diving even after pleurodesis, and anyone diving regularly or professionally should take specialist advice rather than assume that surgery has resolved the question. Those who fly professionally are in the same category.

The standard timing advice after any collapse still applies before a first flight. Flying after a collapsed lung →

Testing is usually a blood test, arranged through a clinical genetics service rather than ordered from a chest clinic, and accompanied by a discussion about what the result will mean for you and for your relatives. That conversation is part of the test, not an optional extra, because a positive result has implications for people who have not asked for it.

Dr Okiror has treated patients whose pneumothorax was caused by Birt-Hogg-Dubé syndrome, lymphangioleiomyomatosis and familial spontaneous pneumothorax, including patients referred from specialist rare lung disease clinics for a surgical opinion. Where an underlying condition is suspected or already confirmed, he refers to clinical genetics at Guy's and, for private patients, to consultant geneticists in independent practice.

A negative result is a real result. It does not mean nothing was found — it narrows the field, it usually ends the search, and it releases relatives from surveillance they would otherwise have been offered. Many people with recurrent collapses are tested and found to have no identifiable condition, and that is a legitimate place to arrive at rather than a failure of the process. Where a strong family pattern persists without a gene being identified, the family may still be managed as though a cause exists, because the pattern is the evidence.

Referrals are accepted for surgical assessment of recurrent or bilateral pneumothorax where an underlying genetic or familial cause is suspected or established, including patients already under a rare lung disease or familial pneumothorax service. A joint clinic appointment alongside a respiratory review can usually be arranged where that is more practical for the patient.

Where imaging is available, please send the CT images rather than the report alone — cyst distribution is the finding that changes the assessment and is frequently not remarked upon. Clinic letters are sent electronically within two working days.

Contact Jo Mitchelson, PA, on 020 7952 2882 or pa@lungsurgeon.co.uk. Information for referring clinicians →