Gmehlin, C.G.

Abstract Introduction: Birt-Hogg-Dube (BHD) is a rare autosomal dominant genetic disorder caused by mutations in the FLCN tumor suppressor gene. Clinically, BHD is characterized by development of cutaneous fibrofolliculomas/trichodiscomas, renal tumors, and pulmonary cysts, the latter which can result in recurrent, spontaneous pneumothoraces. We present a case of BHD in which diagnosis was delayed given absence of dermatologic and renal manifestations. Case Report: A 66-year-old female never smoker with a past medical history of left-sided breast cancer treated with lumpectomy and chemoradiation and osteoporosis presented for evaluation of recurrent pneumothoraces. Her first pneumothoraces occurred in her 20s-30s and required doxycycline pleurodesis (right side) and video-assisted thoracoscopic pleurodesis (left side). The most recent pneumothorax was in her 50s and resolved with chest tube placement. She reported repeated episodes of pneumonia which prompted pulmonary re-evaluation. A non-contrast CT chest was obtained which demonstrated middle and lower lobe predominant irregular thin-walled cystic changes with paramediastinal involvement. Pulmonary function testing revealed mild hyperinflation but otherwise no evidence of obstruction, restriction, or diffusion limitations (FEV1 113% predicted, FEV1/FVC of 0.72 predicted, FVC 109% predicted, TLC 108% predicted, DLCO 90% predicted). Immunoglobulins and alpha-1 antitrypsin were obtained and normal. A lung biopsy was discussed for definitive diagnosis but never performed. Upon presentation to our clinic, she reported no symptoms such as cough, shortness of breath, pleuritic chest pain, fevers, arthralgias, myalgias, rashes, dry mouth, or dry eyes. A broad differential was considered and a connective tissue disease cascade, VEGF-D testing, and SPEP/UPEP were sent and negative/normal. Given the distribution of cysts on her CT, BHD was considered, and she was referred to clinical genetics for germline testing which identified a heterozygous FLCN variant (c.837dup, p.Glu280Argfs[asterisk]12) consistent with BHD. Discussion: BHD is a rare and underdiagnosed cause of cystic lung disease as it has a broad range of clinical manifestations. Recognizing the disease without either renal or dermatologic manifestations as in our patient can be challenging and requires a high degree of suspicion. Clues to the diagnosis include a family history of spontaneous pneumothorax, which can be highly predictive of BHD as it is the most common cause of hereditary pneumothorax. Definitive diagnosis of BHD depends on a combination of clinical features and germline testing for mutations in the FLCN gene.