[Clinical and genetic features of Chinese patients with Birt-Hogg-Dubé syndrome]

Objective: To summarize the clinical and genetic characteristics of Chinese patients with Birt-Hogg-Dubé syndrome (BHD). Methods: We retrospectively analyzed the clinical data of patients diagnosed with BHD between January 1, 2015, and April 30, 2025, at Peking Union Medical College Hospital, Chinese Academy of Medical Science (Beijing center); the First Affiliated Hospital of USTC, University of Science and Technology of China (Hefei center); and the First Affiliated Hospital of Guangzhou Medical University (Guangzhou center). Epidemiological characteristics, clinical manifestations, genetic variants were summarized, and the correlation between genetic mutations and phenotypic presentations were explored. Statistical analyses were performed using SAS 9.4 software. Results: A total of 168 BHD families comprising 256 patients (76 from Beijing, 141 from Hefei, and 39 from Guangzhou) were enrolled, including 201 (78.5%) probands and 55 (21.5%) family screening participants. The cohort included 188 females, with a male-to-female ratio of 1∶2.8. The mean age at diagnosis was 18-81 (44.1±12.6) years, with a median misdiagnosis duration of 12 (0, 72) months. Among 256 patients, family history was present in 195 patients (76.2%), including 71 (36.4%) pulmonary cysts with pneumothorax, 60 (30.8%) pulmonary cysts alone, 53 (27.2%) pneumothorax alone, and 11 (5.6%) renal tumors. Pulmonary cysts were present in 254 patients (99.2%), most commonly presenting as extensive cysts (≥10 cysts, 68.5%, 174/254) followed by moderate cysts (5-9 cysts, 24%, 61/254). Cysts were bilateral in 248 patients (97.6%), while only 6 (2.4%) had unilateral involvement. Lower lobe predominance was noted in 237 patients (93.3%), and paramediastinal distribution in 158 (62.2%). Pneumothorax occurred in 170 patients (66.4%), with 113 (66.5%) experiencing unilateral events and 57 (33.5%) bilateral events. The mean age at first pneumothorax was (37.4±11.6) years, with an average of 2.4 episodes per patient. Cutaneous manifestations were noted in 55.9% (143/256), but only 15.4% (22/143) underwent biopsy, confirming fibrofolliculomas (9 cases) and trichodiscomas (2 cases). Significant regional differences in skin lesion prevalence were observed (Beijing 48.7% (37/76) vs. Hefei 72.3% (102/141) vs. Guangzhou 10.3% (4/39), χ²=50.01, P<0.001). Renal imaging was performed in 232 patients, revealing renal tumors in 10 patients (4.3%), including 6 cases of renal cell carcinoma and 4 cases of angiomyolipoma. Ninety-two distinct genetic variants were identified, including 38 novel mutations. The most common variants in Chinese patients were exon 11 c.1285dupC (13.5%, 27/200), exon 11 c.1285delC (7.5%, 15/200), and exon 14 c.1579_1580insA (12/200, 6.0%). Variants associated with higher pneumothorax rates included exon 9 c.929_930insTT (3/3), large deletions in exons 1-3 (8/9) and exon 6 c.469_471delTTC (4/5). Cutaneous manifestations were more common with exon 11 flanking sequence c.1177-5_1177-3delCTC (5/6), exon 6 c.469_471del TTC (4/5), and exon 9 c.1015C>T (11/14). Conclusions: Chinese patients with BHD predominantly present with pulmonary cysts and pneumothorax, with a relatively low incidence of renal tumors. Although the detection rate of skin lesions is higher than previously reported, significant regional variations persist. Multidisciplinary collaboration is recommended in medical centers to improve diagnostic accuracy. Furthermore, Chinese patients exhibit a distinct genetic variant profile, with five variants potentially associated with pneumothorax and skin lesion phenotypes; however, further studies are required to validate these findings.