BHD syndrome was first described in 1975 as a rare autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and renal tumors [14]. According to the BHD Foundation, over 600 families have been reported globally [4]. In the current report, we describe the clinical and genetic characteristics of 100 consecutive patients with BHD from Eastern China, which is the largest cohort reported from the Chinese population to date. Current study based on patients referred to a Rare Lung Disease Clinic with a multidisciplinary team of specialists, demonstrated that revised Chinese criteria can improve the diagnosis of BHD in China. The results of our study showed pulmonary cysts as the main manifestation with a high incidence of skin lesions, while the frequency of renal tumors was low. We also identified 5 patients with unexpected renal angiomyolipoma and 6 novel FLCN mutations. Furthermore, our study revealed that more than 90% of patients with exons 1–3 deletion experienced pneumothorax.

Pulmonary cysts are the most common presentation of BHD. Imaging findings of pulmonary cysts of variable size, irregular shape, and basal anterior distribution are considered important clues for the diagnosis of BHD [15]. Among Chinese patients with BHD, the most common manifestations were pulmonary including diffuse cysts and spontaneous pneumothorax. For example, lung cysts were noted in 92% of patients in prior report [16]. Due to the high prevalence of lung cysts in adult patients with BHD, spontaneous pneumothorax can also be a common presentation [17, 18]. In our study, almost all the patients had pulmonary cysts and 60% of them had a history of pneumothorax. This was consistent with BHD reported from other Asian countries [8]. Almost half of our patients underwent thoracic surgery for recurrent pneumothorax, which yielded pathologic result consistent with pulmonary cysts/bullae. In the setting of cystic lung disease, recurrent spontaneous pneumothorax in a non-smoker should alert the pathologist to the underlying lung pathology, which may be linked to FLCN gene mutation, in order to find further evidence of BHD.

In 2016, Furuya et al. reported 14 pulmonary neoplastic lesions in 7 patients with BHD, including adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), and atypical adenomatous hyperplasia (n = 8) [19]. We also found three cases of combined lung cancer, and all of them were pathologically suggestive of adenocarcinoma.Potential risk for colon cancer has also been reported in recent BHD studies [20, 21].However, none of these three patients underwent genetic profiling of lung cancer. Therefore, further studies clarifying the risk of malignant tumor in those with BHD seem warranted.

The incidence of characteristic skin lesions in BHD ranges from 75 to 90% in the Caucasian population [17, 20]. Prior studies had indicated that Asian patients have a notably lower incidence of skin lesions (30–48%) compared to Caucasian patients [22, 23]. However, our data showed that the incidence of skin lesions was 77%. This higher incidence may be explained by the input of experienced dermatology specialists within our multidisciplinary team, which improved the detection rate for skin lesions. As such, further investigation is needed to explore the prevalence of skin lesions in Asian patients with BHD, and it is important to encourage more patients with skin lesions to undergo skin biopsy to confirm the diagnosis.

Renal tumors occur in 25–35% of patients with BHD and are usually bilateral, multifocal, and slow-growing. Compared with the skin and lung manifestations of BHD, renal tumors are more important for the long-term prognosis of BHD patients.Thus, surveillance for early detection and diagnosis is essential for improving prognosis.Renal tumors associated with BHD consist predominantly of hybrid chromophobe/oncocytic tumors (67%), chromophobe renal cell tumors (23%), clear cell renal carcinoma (7%), and renal oncocytomas (3%) [24]. These pathological types are less common in the general population. Consequently, the possibility of BHD should be considered when the aforementioned pathological features are encountered. Previous studies indicate distinctive cytogenetic features in FLCN mutation related RCC compared to sporadic RCC [25].A study from Japan found that 34.8% of individuals carrying FLCN mutations aged over 40 had been diagnosed with renal cancers [16]. The occurrence of renal cancer in our cohort was exceptionally low compared to other reports from China. This could be explained by the limited follow-up duration. It’s noteworthy that 5 patients (6.4%) were detected with renal angiomyolipoma, which were only reported as individual cases. The incidence of AML in the general population is reported to be 0.1–0.22% [26]. Renal AMLs were found in 41% of patients diagnosed with sporadic LAM, and in 96% of individuals with TSC-LAM [27]. In 2012, Byrne et al. firstly described a 39-year-old woman diagnosed with BHD and a renal AML [28]. The reported clinical similarities between BHD and TSC may arise from the overlapping functions of FLCN (FNIP1 or FNIP2) and TSC (TSC1 or TSC2) proteins in the mTOR pathway, particularly in the assembly of the mTOR complex 1 [29]. Current guidelines recommend the use of sirolimus and other mTOR blockers in the treatment of AML, and therapeutic efficacy have been demonstrated [30, 31]. This strategy may also hold promise in the treatment of renal angiomyolipomas in patients with BHD.

FLCN mutation profiles have been reported with some variations in different populations. In the Caucasian populations, a cytosine insertion/deletion in a C8 tract in exon 11 is a mutation hotspot for BHD. Most BHD mutations are expected to result in truncation of the BHD protein, folliculin [32].In Japanese populations, the common mutations were c.1285dupC, c.1533_1536delGATG, and c.1347_1353dupCCACCCT [11]. By the end of 2021, there were 287 patients with BHD from 143 families reported in China. As reported in previous studies, the most frequent mutation was the single deletion, duplication of cytosine in codon 1285 of exon 11 (25%), following by the mutation of c.1579_1580ins in exon 14 (4.2%), and c.1015 C > T in exon 6 was the third most common mutation (3.3%) [14]. In total, 25 FLCN mutations were detected in the present study, and one-quarter of FLCN mutations were novel. Except for hotspot mutation c.1285delC/dupC, the other frequent mutations in our cohort were different from other areas in China. For example, the mutations percentage of c.1015 C > T, c.1579 and 1580insA were higher than that of previous report [9].

The relationship between gene mutation sites and clinical phenotypes has always been a focus of attention in various studies. A recent study from Germany found mutation c.924_926del to be associated with a 39% risk for pneumothorax, which increased to 60% for mutation c.1285dup, and 73% for mutation c. 1579_1580ins [33]. Our results showed that c.1285delC, c.1177_5 1177_3de1CTC and exon 1–3 deletion were associated with a high incidence of pneumothorax. In particular, the incidence of pneumothorax in exon 1–3 deletion patients was significantly higher than that in mutation hotspot c.1285dup patients reported in previous study [34]. Thus, BHD in Eastern China presented different genotypic characteristics from other areas and its association of pneumothorax phenotype warrants further research.

The delay in diagnosis remains a challenge both in China and in the rest of the world. The average time of diagnostic delay was 7.6 years in this study and almost 10 years in China overall [35]. In 2009, the European BHD Syndrome Consortium introduced the diagnostic criteria for BHD, which have since become widely utilized in clinical settings [12]. The European BHD diagnostic criteria suggest that a minimum of five fibrofolliculomas or trichodiscomas (with at least one confirmed histologically, occurring in adulthood) and the presence of a pathogenic FLCN germline mutation to be major criteria. Minor diagnostic criteria include multiple pulmonary cysts, renal cancer, and first-degree relatives diagnosed with BHD. Currently, Chinese patients with BHD have a lower frequency of positive family history and a low biopsy rate of skin lesions, plus low incidence of renal cancer. According to the European BHD diagnostic criteria, only few Chinese cases met the major criterion of skin lesions, which is not conductive to early diagnosis of BHD in China. Therefore, in 2023, a revised criterion for BHD proposed by China Alliance for the Rare Lung Disease and experts from the related disciplines in China [13]. Considering the clinical characteristics and realities of BHD in China, it optimized the diagnostic criteria by adding family history of first-degree relatives as a genetic criterion and adjusting skin lesion as a clinical criterion. In general, the diagnosis of hereditary diseases is usually based on the clinical phenotype and ultimately supported by the positive genetic mutation. Therefore, as a hereditary disease, BHD could also be characterized in this fashion. The Chinese diagnostic criteria summarize the clinical and genetic manifestations, which is more in line with the characteristics of hereditary diseases and is suitable for Chinese patients with low skin biopsy rate. Our study also confirmed the revised diagnostic criteria might be more applicable for Chinese patients with BHD (Table 3), the difference was statistically significant when skin pathology was used as a main diagnostic criterion (95%CI: 3.48, 27.85, p < 0.001).

Nevertheless, we acknowledge the limits of the present study, such as its retrospective design and the significant number of patients who did not undergo skin lesion biopsy. In addition, there may have been selection bias associated with most of our patients being diagnosed through referral to the Rare Lung Disease Clinic. A more accurate assessment of this issue could be performed in a multi-center prospective study using a standard protocol in family screening and systemic follow-up evaluation for this rare disease. Nonetheless, considering the rarity of BHD disease, we have collected the largest number of cases up to date. Therefore, our findings offer valuable insights to improve the understanding and diagnosis of this rare disease in China.