Hidden Lung Gene Mutation Behind Recurring Collapsed Lung Finally Identified

A collapsed lung is dramatic enough the first time. Enduring one after another over fifteen years, with surgeons repeatedly cutting away portions of lung tissue and no one able to say why, is a medical odyssey that most patients should never have to face. Yet this was the reality for a 50-year-old woman whose case, now reported in the open-access journal Respirology Case Reports, has become a striking illustration of how easily one of medicine’s rarest inherited lung disorders can hide in plain sight. The woman suffered from recurrent spontaneous pneumothorax, a condition in which the lung collapses without any trauma or obvious trigger, and for years her care focused on treating each collapse as it came rather than uncovering the underlying disease driving them.

Her story began fifteen years before the referral that finally cracked the case. Over that period she underwent wedge resections of the right upper lobe, the right lower lobe, and the left upper lobe, each operation removing a wedge of lung tissue in an effort to prevent further collapse. Just two months before she arrived at the pulmonology clinic with exertional breathlessness, she had endured yet another right-sided pneumothorax, this one managed at an outside facility. When clinicians examined her, her vital signs were entirely normal, her lungs sounded clear on auscultation, and crucially, her skin was free of the small papules that might otherwise have pointed toward a diagnosis. Laboratory investigations, including a complete blood count, renal function tests, liver enzymes, D-dimer, inflammatory markers, and a broad panel of autoimmune antibodies, all came back unremarkable. Pulmonary function testing showed only mild reductions in airflow and lung capacity, with an FEV1/FVC ratio of 0.89, an FEV1 of 81 percent predicted, a forced vital capacity of 79 percent predicted, and a total lung capacity of 99 percent predicted.

The turning point came with chest computed tomography. The scan revealed multiple bilateral pulmonary cysts, thin-walled air-filled spaces scattered through both lungs, with a telling pattern: they clustered predominantly in the lower lobes and in the medial, or central, zones of the lung. That distribution matters, because it is a signature that experienced thoracic radiologists associate with a specific and rare genetic syndrome rather than with the more common cystic lung diseases. The differential diagnosis for diffuse cystic lung disease is short but consequential, encompassing lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and lymphoid interstitial pneumonia. Each mimics the others on imaging, yet each carries a profoundly different prognosis and management pathway, which is why distinguishing among them is one of the most intellectually demanding puzzles in pulmonary medicine.

The clinical team methodically eliminated the alternatives. The patient had never smoked, which argued strongly against pulmonary Langerhans cell histiocytosis, a disease overwhelmingly linked to cigarette use. Her unremarkable autoimmune serologies made lymphoid interstitial pneumonia, which typically arises in the context of autoimmune or systemic disease, unlikely as well. That left lymphangioleiomyomatosis, known as LAM, as the chief suspect. To resolve the question, the researchers went back to tissue that had been sitting in the pathology archive for years: the specimens from her prior wedge resections. Under the microscope, the lung tissue showed multiple subpleural and parenchymal cystic spaces lined by flattened epithelium, with the surrounding non-cystic lung appearing unremarkable. Immunohistochemical staining for HMB-45 and GPNMB, two molecular markers that light up in LAM, came back negative, formally excluding that diagnosis and narrowing the field dramatically.

With the imaging pattern pointing in one direction and the mimics ruled out, suspicion settled on Birt-Hogg-Dubé syndrome, an extraordinarily rare autosomal dominant disorder caused by pathogenic germline variants in the FLCN gene. The syndrome’s estimated prevalence ranges from roughly 2 in 1,000,000 to 1 in 200,000, affecting men and women equally, and experts believe the true figure is almost certainly higher because so many cases go unrecognized. Classically, the disorder is described as a triad of cutaneous fibrofolliculomas, benign hair-follicle tumors on the face, neck, and upper trunk; bilateral pulmonary cysts; and renal tumors. But as this case demonstrates vividly, the textbook triad is not the whole story. Pulmonary manifestations are among the most prevalent features of Birt-Hogg-Dubé syndrome, and they can occur entirely in isolation, without any skin lesions or kidney tumors to alert clinicians to the genetic basis of the disease.

To confirm the diagnosis, the team performed germline whole-exome sequencing, a technology that reads the protein-coding regions of a patient’s entire genome. The analysis identified a heterozygous frameshift variant in the FLCN gene, designated NM_144997.7:c.1579_1580insA, resulting in a truncated protein labeled p.Arg527GlnfsTer75. Under American College of Medical Genetics and Genomics guidelines, the variant was classified as pathogenic, delivering a definitive molecular diagnosis of Birt-Hogg-Dubé syndrome. Formal dermatologic evaluation subsequently found no fibrofolliculomas, and abdominal imaging showed no renal tumors, cementing the conclusion that this was an isolated pulmonary presentation of the disease. Formal genetic counseling followed, in which the patient learned about the autosomal dominant inheritance pattern, meaning each of her children has a fifty percent chance of carrying the same mutation. Cascade genetic testing was offered to her first-degree relatives, and she was enrolled in annual renal surveillance using magnetic resonance imaging, a precaution taken because of the lifetime risk of kidney malignancy that accompanies the syndrome.

At the molecular level, the story of Birt-Hogg-Dubé syndrome is a story about a tumor suppressor gone missing. The FLCN gene encodes folliculin, a protein that regulates mTORC1, a master cellular signaling complex that controls growth, metabolism, and proliferation. When loss-of-function variants disable folliculin, mTORC1 activity becomes dysregulated, and evidence from human Birt-Hogg-Dubé tissue and mouse models implicates this deranged signaling in the formation of the alveolar cysts that weaken the lung and predispose carriers to spontaneous pneumothorax. In other words, the same genetic lesion that raises the specter of kidney cancer also, through a distinct downstream pathway, slowly riddles the lungs with fragile air spaces that can rupture without warning, collapsing the lung and squeezing it away from the chest wall.

The epidemiology of the pulmonary disease underscores why early recognition is so valuable. Spontaneous pneumothorax develops in approximately 30 to 50 percent of patients with Birt-Hogg-Dubé syndrome, typically at a median onset age of 30 to 38 years, and it recurs frequently, exactly as it did in this patient over a decade and a half. The cysts themselves have characteristic features on imaging: they tend to be thin-walled and lentiform, meaning lens-shaped or oval, and they favor the lower lobes and medial lung zones, in contrast to the upper-lobe and peripheral distribution seen in many other cystic lung diseases. Diagnostic criteria for the syndrome require either one major criterion, such as at least five fibrofolliculomas or a pathogenic FLCN variant, or two minor criteria, which include unexplained bilateral pulmonary cysts, early-onset multifocal renal tumors before the age of 50, or a first-degree relative with the syndrome. Perhaps the most sobering statistic attached to the disease is the diagnostic lag: the mean delay from symptom onset to diagnosis has been reported at more than seven years, a window in which patients may undergo repeated chest tubes, repeated surgeries, and repeated collapses without ever learning that a single inherited gene variant lies at the root of it all.

For now, there is no approved disease-modifying therapy for Birt-Hogg-Dubé syndrome, which makes surveillance and prevention the cornerstones of care. Acute pneumothorax is managed with standard approaches, and for patients with recurrent episodes, as in this case, surgical intervention or pleurodesis, a procedure that adheres the lung to the chest wall to prevent future collapse, should be considered. Because renal malignancy, though typically indolent, is the most serious complication of the syndrome, lifelong annual renal surveillance with MRI beginning at age 20 is recommended, allowing tumors to be detected while they are small and treatable. Patients are strongly advised never to smoke, since smoking compounds the threat to already vulnerable lungs. And as this case makes clear, the reach of a diagnosis extends beyond the individual patient: cascade genetic testing of first-degree relatives is essential to identify asymptomatic carriers before cysts form, lungs collapse, or kidney tumors develop. For a woman who spent fifteen years in a cycle of collapse and surgery, a single blood test grounded in a sharp radiological eye finally delivered an answer, a management plan, and a warning that may protect her entire family.

Subject of Research: Birt-Hogg-Dubé syndrome presenting with isolated pulmonary manifestations causing recurrent spontaneous pneumothorax

Article Title: An Underrecognized Cause of Recurrent Spontaneous Pneumothorax: Birt‐Hogg‐Dubé Syndrome With Isolated Pulmonary Manifestation

Article References: An Underrecognized Cause of Recurrent Spontaneous Pneumothorax: Birt‐Hogg‐Dubé Syndrome With Isolated Pulmonary Manifestation. (n.d.). https://doi.org/10.1002/rcr2.70703

Image Credits: AI Generated

DOI: 10.1002/rcr2.70703

Keywords: Birt-Hogg-Dubé syndrome, FLCN gene, pneumothorax, cystic lung disease, folliculin, mTORC1 signaling, genetic testing, lymphangioleiomyomatosis, renal surveillance, whole-exome sequencing, pulmonary cysts, rare disease