Search Results (317)

Clear cell renal cell carcinoma (ccRCC) is characterized by marked biological heterogeneity, which limits the prognostic accuracy of conventional clinicopathological models. Increasing attention has therefore focused on identification of biomarkers that can enhance risk stratification throughout all stages of the disease. Starting from the current state of the art, this narrative review summarizes and critically appraises the evidence published over the past decade regarding prognostic biomarkers in ccRCC. The analysis is structured into four overarching domains: (i) genomic biomarkers, covering somatic alterations and transcriptomic signatures; (ii) tissue-based biomarkers, including immunohistochemical surrogates and immune microenvironment features; (iii) circulating biomarkers, such as systemic inflammation parameters and indices; and (iv) integrated predictive models, represented by emerging multi-omic approaches. Going through the broad framework of potential prognostic biomarkers, emphasis is placed on their individual and integrative value in relation to classic clinical-pathological factors and survival parameters. At the tissue level, chromosome 3p-related alterations constitute a central molecular feature of ccRCC. Among these, BAP1 loss has emerged as one of the most consistently validated indicators of aggressive tumor behavior. Disruption of the SETD2/H3K36me3 axis and immune-related biomarkers, including PD-L1 expression, have demonstrated prognostic associations in selected settings, although with variable and context-dependent performance. In the circulating compartment, plasma KIM-1 has shown prognostic relevance following nephrectomy, while postoperative detection of circulating tumor DNA (ctDNA) may identify patients at increased risk of recurrence. However, limited analytical sensitivity and methodological heterogeneity currently restrict the broader clinical applicability of ctDNA-based strategies. Systemic inflammatory indices, such as the neutrophil-to-lymphocyte ratio, show reproducible associations with outcomes but largely reflect host inflammatory status rather than tumor-specific biology. However, no single biomarker currently supports routine prognostic implementation in ccRCC. Future progress will likely depend on integrative models combining genomic, tissue-based, immune, and circulating parameters with established clinical variables. Prospective validation and clear demonstration of incremental clinical utility will be essential before such strategies can meaningfully inform therapeutic decision-making. Full article

Genetically modified (GM) lactic acid bacteria (LAB) are gaining attention as tools for innovation in the food sector, health applications, and industrial processes. LAB have long been used safely due to their GRAS/QPS status, making them suitable for improving fermentation and synthesizing specific and beneficial metabolites. Advances in genomics and gene editing have significantly expanded the available tools, ranging from classical mutagenesis to site-specific recombination, homologous recombination in non-coding regions, CRISPR-based systems, and food-grade chromosomal integration. These approaches enable the insertion of desired genes and the development of engineered strains with tailored functionalities. GM-LAB are also being studied as live delivery systems for therapeutic molecules, including cytokines, hormones, antimicrobial peptides, and vaccine antigens. Engineered strains of Lactococcus lactis and Lactobacillus spp. have yielded promising outcomes in applications such as mucosal immunization, modulation of inflammatory and metabolic responses, and inhibition of pathogenic microorganisms, including multidrug-resistant bacteria. From an industrial perspective, several studies highlight their potential for cost-effective recombinant protein production and the synthesis of high-value metabolites through fermentation. However, within the European Union, their use is subject to stringent regulatory oversight, requiring comprehensive molecular and environmental risk assessments, careful evaluation of horizontal gene transfer, and a preference for markerless chromosomal integrations. Despite these constraints, GM-LAB offer significant potential to improve food quality, sustainability, and human health. Full article

Background: Congenital heart disease (CHD) represents a major cause of perinatal morbidity and mortality, and fetal echocardiography is essential for its early diagnosis and management. Maternal smoking has been suggested as a potential teratogenic factor affecting fetal cardiovascular development; however, findings regarding its association with CHD remain inconsistent. This study aimed to evaluate the relationship between maternal smoking during pregnancy and the risk of CHD. Methods: A total of 2715 pregnant women and 2784 fetuses who underwent fetal echocardiography at ≥20 weeks’ gestation between 1 January 2024 and 1 November 2025 were analyzed. Pregnancies complicated by known chromosomal or syndromic abnormalities, significant teratogenic exposure, duplicate assessments, or nonstandard examinations were excluded. Maternal smoking status during pregnancy was recorded and categorized according to daily cigarette consumption. The prevalence of CHD and the distribution of CHD subtypes were evaluated and compared according to smoking status. Fetal cardiac diagnoses were classified based on the classical morphological classification system. Results: A total of 2715 pregnancies (2784 fetuses) were analyzed, including 2530 fetuses in the non-smoking group and 254 in the smoking group. Congenital heart disease was detected in 12.5% of fetuses in the non-smoking group and 14.2% in the smoking group, with no statistically significant difference (p = 0.442). According to the classical morphological classification, the distribution of fetal echocardiographic pathologies did not differ significantly between groups (p = 0.607). Septal defects were the most common subtype in both groups. Although conotruncal defects were proportionally more frequent in the smoking group, this difference did not reach statistical significance. After reclassifying daily cigarette consumption into four exposure categories, no association was detected between maternal smoking and CHD risk (OR = 1.04; 95% CI: 0.86–1.26; p = 0.691). Conclusion: In this cohort referred for fetal echocardiographic evaluation, no association was detected between maternal smoking during pregnancy and the risk of congenital heart disease or alterations in CHD subtype distribution. No consistent dose–response relationship was observed. These findings suggest that no association was detected between maternal smoking exposure and CHD. Further large-scale prospective studies are needed to clarify phenotype-specific associations. Full article

Background/Objectives: Idiopathic epilepsy is a lifelong neurologic disorder in dogs, but its genetic basis remains incompletely understood in many breeds. This study aimed to identify risk-associated markers in Siberian Huskies, quantify their effects, assess potential risk modifiers, and characterize the shared haplotype background of the associated signal. Methods: A genome-wide association study was conducted in 113 Siberian Huskies genotyped on the Illumina CanineHD array, integrating association, regression, and haplotype/IBD analyses. An independent follow-up cohort of 57 additional dogs was genotyped at the lead marker by Sanger sequencing. Sex and gonadectomy status/timing were also evaluated as potential modifiers of risk, using multivariable regression and time-to-event analyses. Results: A strong, localized association was identified on canine chromosome 3 (CFA3) within KCNIP4. The lead intronic marker was significantly enriched in cases, with all risk-allele homozygotes affected, most heterozygotes affected, and no control homozygotes observed. Risk-associated chromosomes shared extended haplotypes across the region, consistent with carriers inheriting a common risk haplotype from a relatively recent shared ancestor. Among carriers, male sex was associated with higher odds of epilepsy and earlier seizure onset, with more tentative evidence for a similar association with gonadectomy before 5 years of age. Conclusions: These findings prioritize a CFA3 region encompassing KCNIP4 as a major risk locus for idiopathic epilepsy in Siberian Huskies. Fine-mapping with high-coverage sequencing and functional follow-up will be required to pinpoint the causal variant(s) and support development of risk assessment tools. Until those studies are completed, this marker should be regarded as a research finding rather than a predictive test. Full article

Nitrogen is an essential element for plant growth, and low nitrogen stress significantly restricts crop yield. Therefore, cultivating crop varieties that are tolerant to low nitrogen is crucial for agricultural production. The AT-hook motif nuclear localization protein (AHL) family is vital for plant stress resistance. To investigate the potential regulatory mechanisms of the AHL family in maize under low nitrogen stress, 35 ZmAHL genes were identified from the maize genome using bioinformatics methods. The results indicated that these genes encode proteins with lengths ranging from 203 to 573 amino acids, with relative molecular weights between 20.68 and 59.68 kDa, and they are unevenly distributed across 10 chromosomes. Most proteins encoded by these genes are alkaline hydrophilic proteins, primarily localized in the nucleus. Family expansion occurred through tandem and fragment repeats, which exhibited evolutionary conservation with rice homologous genes. Transcriptome analysis revealed that the majority of ZmAHL genes in drought-tolerant maize inbred lines were significantly up-regulated under drought and low nitrogen stress, with the ZmAHL10 gene displaying the most pronounced response to low nitrogen conditions. Experiments involving transgenic Arabidopsis thaliana further confirmed that the growth status, nitrogen uptake, and photosynthetic pigment content of ZmAHL10 overexpression strains under low nitrogen conditions were superior to those of the wild type, while the mutant exhibited significant growth inhibition. Overall, this study delineated the fundamental characteristics of the maize ZmAHL gene family and established that ZmAHL10 enhances low nitrogen tolerance in plants by improving nitrogen absorption capacity and maintaining the stability of the photosynthetic system. This research provides candidate genes and a theoretical foundation for the molecular breeding of maize with enhanced low nitrogen tolerance. Full article

Objective: This study examined the frequency of entosis in solid tumors of various origins (colorectal cancer, breast cancer, and lung cancer) and its association with clinical and pathological characteristics. It also examined survival and copy number alterations (CNAs) in genes associated with stem cells. The aim was to assess the potential prognostic value of entotic events in tumors. Methods: A total of 238 patients were included: 96 with colorectal cancer (CRC), 45 with lung cancer (LC), and 97 with breast cancer (BC). Entotic cell-in-cell (CIC) structures were evaluated on hematoxylin–eosin–stained slides using Mackay’s criteria. A CIC frequency >0.1 per 20 high-power fields was considered positive. Clinicopathological parameters, overall survival (CRC), metastasis-free survival (LC and BC), and CNA profiles of stemness-related genes were analyzed. Amplifications of MAP1LC3A and other chromosomal loci were assessed. Results: CRC demonstrated the highest entosis rate, more than two-fold higher compared with BC and LC (p < 0.05). Entosis correlated with high tumor grade (G3) in CRC (p = 0.03). In LC, CIC-positive tumors were more frequent in patients with lymph-node metastases (p = 0.02), whereas in BC, the opposite trend was observed (p = 0.02). It was noted that in patients with stage III–IV LC, the frequency of entosis was significantly higher than in patients with stage I–II cancer (p = 0.03). CIC-positive status was associated with poorer overall survival in CRC (p = 0.03) and reduced metastasis-free survival in LC (p = 0.011). In breast cancer, no statistically significant survival differences were observed. Tumors harboring two or more stemness-gene amplifications showed significantly higher entosis frequency regardless of tumor site. A strong association was identified between entosis and MAP1LC3A amplification. Conclusions: Enosis is not a random morphological phenomenon but a process associated with unfavorable tumor characteristics, high malignancy, reduced survival, and amplification of stem cell-related genes. The results of this study confirm the working hypothesis that entosis may contribute to the emergence of aneuploid clones of tumor cells, including those containing amplifications of stem cell-associated genes. This positions entosis as a potential factor in tumor genetic heterogeneity, which is particularly important in the context of therapeutic selection pressure. The observed association between high entosis frequency and the presence of ≥2 stem cell gene amplifications, as well as its association with poor prognosis in colorectal and lung cancer, highlights its potential value as a prognostic indicator. Furthermore, MAP1LC3A amplification data may serve as a molecular marker of entotic activity and a potential therapeutic target. Full article

We present a case of a patient in their 80s initially presenting with myelodysplastic syndromes (MDS). Chromosomal analysis showed an abnormal female karyotype with a complex karyotype. Metaphase FISH confirmed four copies of KMT2A (MLL) in 24.5% [49/200] and amplification of KMT2A (MLL) with more than four copies in 22% [44/200]. FISH also revealed the presence of MYC (8q24) on the long arm of chromosome 2 at 2q33 locus, two copies of BCR on each homolog 22, and two additional copies of BCR on a derivative chromosome 22. Flow cytometric analysis revealed a population of aberrant myeloid blasts (15–17%). Bone marrow analysis showed hypercellular marrow with a significant increase in myeloid blasts (~50%) and trilineage dysplasia. Eventually, these findings were consistent with a final diagnosis of acute myeloid leukemia non-M3 and a complex karyotype, correlating with cytogenetics, flow cytometry, molecular, and clinical findings. The patient’s clinical course was marked by a rapid deterioration, including recurrent arrhythmias, hypoxic respiratory failure, and septic shock. Given their poor clinical status and adverse-risk molecular profile, care was transported to hospice. The presence of KMT2A amplification is a rare event in AML and is present in ~1% of AML and MDS cases. MYC translocation, KMT2A (MLL) amplification, and 5q/20q losses suggest secondary therapy-related AML and categorize this case in the adverse risk prognosis under the ELN 2022 guidelines. Full article

Background and Clinical Significance: Over the last two decades, glucagon-like peptide-1 (GLP-1) receptor agonists have dramatically improved the management of type 2 diabetes mellitus and obesity. Currently, little is known about the use of semaglutide (a second-generation GLP-1 receptor agonist) in patients with X chromosome abnormalities. Herein, we describe the therapeutic use of semaglutide in a woman with a partial deletion of the X chromosome long arm (partial Xq deletion) and comorbid obesity. We also conducted a narrative mini-review on overweight, obesity and common metabolic derangements in patients with partial Xq deletions and Turner syndrome. Case Presentation: A 65-year-old Italian woman with a partial Xq deletion, class 1 obesity, insulin resistance, prediabetes, hypercholesterolemia and metabolic dysfunction-associated steatotic liver disease (MASLD) was referred to our Institution for persistent difficulty in managing excess body weight despite regular adherence to different structured physical activity programs and hypocaloric diets. Therefore, we prescribed a combination therapy based on low-dose metformin (500 mg/day) and once-weekly subcutaneous semaglutide (as an adjunct to lifestyle intervention). At 5 months after initiation of the combination therapy, blood tests showed metabolic improvements, including improvement of prediabetes (0.3-percentage-point reduction in glycated hemoglobin [HbA1c] values) and normalization of markers of insulin sensitivity and insulin resistance (QUICKI, HOMA-IR and TyG index). At 8 months, the patient showed substantial weight loss, which amounted to 13.8 kg (percent total body weight loss: 20.95%), and was accompanied by a notable reduction in waist circumference (−14.1 cm). Moreover, body mass index (BMI)-based weight status improved from class 1 obesity to overweight: BMI value of 25.1 kg/m² at 8 months vs. 31.8 kg/m² at baseline (near-normalization of BMI values). Bioelectrical impedance analysis (BIA) revealed that the patient’s overall weight loss consisted of 74.6% fat mass (FM) loss (−10.3 kg) and 25.4% fat-free mass (FFM) loss (−3.5 kg). Despite the expected FFM reduction in absolute terms, percent FFM increased at 8 months (+9.6%). This increase in percent FFM was accompanied by a reduction in percent FM at 8 months (−9.6%), indicating an overall improvement in body composition. Normalization of percent FM and FFM values (28.6% and 71.4%, respectively) was also achieved at 8 months. These body composition changes are in line with those observed in clinical trials investigating the use of semaglutide in patients with overweight or obesity. At 6 months, an abdominal ultrasound also showed the disappearance of the sonographic characteristics suggestive of mild-to-moderate hepatic steatosis. Low-dose metformin (500 mg/day) and subcutaneous semaglutide (up to a weekly dose of 1.7 mg) were well tolerated by the patient. Conclusions: To the best of our knowledge, this is the first case documenting the effective use of once-weekly subcutaneous semaglutide plus low-dose metformin combination therapy for the treatment of obesity and prediabetes in a woman with a partial Xq deletion. Large prospective cohort studies are warranted to better investigate the safety and efficacy profile of semaglutide (alone or in combination with metformin) in patients with numerical and structural X chromosome abnormalities, comorbid overweight/obesity and related metabolic disorders. Full article

Pulmonary arterial hypertension (PAH) is marked by vascular remodeling, yet the role of adventitial fibrosis—and its modulation by sex and hormonal status—remains unclear. We examined stage-specific adventitial remodeling and pulmonary artery adventitial fibroblast (PAAF) mechanosensitivity in male, ovary-intact female, and ovariectomized (OVX) female Sprague–Dawley rats with SuHx-induced PAH. Hemodynamics, pulmonary artery histology, and adventitia-specific transcriptional profiling were integrated with in vitro assays of PAAFs exposed to defined substrate stiffness and stretch. All groups developed comparable increases in mean pulmonary arterial pressure, but vascular resistance shift and adventitial fibrosis diverged by sex: intact females showed attenuated increase in pulmonary vascular resistance and transient collagen accumulation, whereas OVX females mirrored the sustained, male-like progression. Extracellular matrix (ECM) gene activation occurred without smooth muscle actin induction, suggesting noncanonical fibrotic pathways. In vitro, intact female PAAFs required higher substrate stiffness to induce profibrotic gene expression, indicating a hormone-modulated stiffness threshold. OVX PAAFs showed persistent transcriptional reprogramming, while stretch-induced ECM upregulation occurred predominantly in male-derived PAAFs. These findings demonstrate that adventitial fibrosis in PAH is shaped by both hormonal and chromosomal sex, independent of hemodynamic severity, and highlight fibroblast mechanosensitivity as a potential target for stage- and sex-specific interventions. Full article

Background: Optical genome mapping (OGM) detects genome-wide structural variants (SVs), including balanced rearrangements and complex copy-number alterations beyond standard-of-care cytogenomic assays. In chronic lymphocytic leukemia (CLL), cytogenetic and genomic risk stratification is traditionally based on fluorescence in situ hybridization (FISH), karyotyping, targeted next-generation sequencing (NGS), and immunogenetic assessment of immunoglobulin heavy chain variable region (IGHV) somatic hypermutation status, each of which interrogates only a limited aspect of disease biology. Methods: We retrospectively evaluated fifty patients with CLL using OGM and integrated these findings with cytogenomics, targeted NGS, IGHV mutational status, and clinical time-to-first-treatment (TTFT) data. Structural variants were detected using OGM and pathogenic NGS variants were derived from a clinical heme malignancy panel. Clinical outcomes were extracted from the electronic medical record. Results: OGM identified reportable structural variants in 82% (41/50) of cases. The most frequent abnormality was del(13q), observed in 29/50 (58%) and comprising 73% (29/40) of all OGM-detected deletions with pathologic significance. Among these, 12/29 (42%) represented large RB1-spanning deletions, while 17/29 (58%) were focal deletions restricted to the miR15a/miR16-1 minimal region, mapping to the non-coding host gene DLEU2. Co-occurrence of adverse lesions, including deletion 11q/ATM, BIRC3 loss, trisomy 12, and deletion 17p/TP53, were recurrent and strongly associated with shorter TTFT. OGM also uncovered multiple cryptic rearrangements involving chromosomal loci that are not represented in the canonical CLL FISH probe panel, including IGL::CCND1, IGH::BCL2, IGH::BCL11A, IGH::BCL3, and multi-chromosomal copy-number complexity. IGHV data were available in 37/50 (74%) of patients; IGHV-unmutated status frequently co-segregated with OGM-defined high-risk profiles (del(11q), del(17p), trisomy 12 with secondary hits, and complex genomes whereas mutated IGHV predominated in OGM-negative or structurally simple del(13q) cases and aligned with indolent TTFT. Integration of OGM with NGS further improved genomic risk classification, particularly in cases with discordant or inconclusive routine testing. Conclusions: OGM provides a comprehensive, genome-wide view of structural variation in CLL, resolving deletion architecture, identifying cryptic translocations, and defining complex multi-hit genomic profiles that tracked closely with clinical behavior. Combining OGM and NGS analysis refined risk stratification beyond standard FISH panels and supports more precise, individualized management strategies in CLL. Prospective studies are warranted to evaluate the clinical utility of OGM-guided genomic profiling in contemporary treatment paradigms. Full article

Ormosia henryi, a rare and endemic timber tree in China, possesses exceptional economic and ecological value, but it has experienced a critical decline in wild populations. We integrated PacBio HiFi and Hi-C technologies to generate a superior, chromosome-level genome assembly, establishing a more robust genetic foundation than existing draft sequences. The resulting assembly (2.64 Gb; Contig N50 = 39.17 Mb; and Scaffold N50 = 338.40 Mb) exhibits high continuity and completeness, effectively overcoming the assembly challenges associated with high heterozygosity (1.37%) and repetitive sequence content (83.89%). Comparative genomic analysis revealed that O. henryi diverged from Lupinus albus approximately 53.82 million years ago and underwent two independent whole-genome duplication events. The historical accumulation of evolutionary resilience is reflected in the significant expansion of 276 gene families enriched in photosynthesis and phenylpropanoid biosynthesis, alongside 122 genes under positive selection involved in DNA repair and proteostasis. These genomic signatures elucidate a stable genetic foundation. While wild populations have sharply declined in recent decades, this suggests that this status underscores the overwhelming impact of intense external anthropogenic pressures, such as overexploitation and habitat fragmentation, which may have overridden the species’ inherent adaptive capacity and slow life-history strategy. This high-quality genomic resource identifies key candidate loci, such as the PIF1 helicase for growth regulation, and provides a critical framework for screening elite germplasm for population restoration. Consequently, this study establishes a theoretical and molecular basis for transitioning from fundamental research to the precision conservation and sustainable industrial application of this high-value woody species. Full article

The ε4 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer’s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying TOMM40–APOE and APOE–APOC1 interactions. We further developed a digital PCR assay to quantify APOE–APOC1 interaction strength and measured APOC1 mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated APOC1 transcription in AD specimens. Genotypic analysis showed that ε3/ε4 carriers had strong chromatin interaction and transcriptional activation, whereas ε4/ε4 homozygotes exhibited minimal chromatin remodeling despite similar APOC1 expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, APOE genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study APOE-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development. Full article

Polemonium L. (Polemoniaceae) is a widespread genus native to subarctic and arctic regions of the Northern Hemisphere. The taxonomy and genome relationships within Polemonium are still unclear. We analyzed genomes of three species from each Polemonium caeruleum and Polemonium pulcherrimum complex using bioinformatic analysis by RepeatExplorer2/TAREAN pipelines of next-generation sequencing data. The repeatomes of all studied species were similar in type and number of repeats. Satellite DNAs (satDNAs) demonstrated high sequence identity within the studied species. FISH chromosome mapping of 45S rDNA, 5S rDNA, and two satDNAs Pol_C 33 and Pol_C 46 allowed us to construct the species karyograms and assess the genome diversity within the P. caeruleum complex and P. pulcherrimum complex, and also confirm the taxonomic status of P. kiushianum as an independent species. Our findings demonstrate a close genomic relationship among the species from P. caeruleum and P. pulcherrimum complexes, indicating the presence of a common ancestral genome; additionally, our results provide cytogenetic evidence for the monophyletic origin of these sections and also complex evolutionary history of the genus Polemonium. The developed approach may be a valuable framework for further investigation of the chromosomal organization of karyotypes in other species of the genus Polemonium. Full article

Homologous recombination deficiency (HRD) resulting from inactivation of BRCA1/2 genes promotes chromosomal instability and renders tumor cells susceptible to platinum derivatives and PARP inhibitors (PARPi). The contribution of alterations in other homologous recombination repair (HRR) genes to HRD remains understudied. This investigation aimed to analyze the spectrum of mutations in 34 HRR genes in prostate carcinomas (PCs) and study the relationship between HRR status and HRD. HRR mutations and HRD scores were examined by NGS in 1131 and 680 PCs, respectively. Pathogenic or likely pathogenic variants in HRR genes were detected in 216/1131 cases (19.1%). HRD, defined by an HRD score cut-off of ≥42, was observed more frequently in HRR-mutated than in wild-type tumors (23/120 (19.2%) vs. 29/560 (5.2%), p < 0.0001). The highest HRD scores were detected in PCs with biallelic inactivation of the BRCA2 or PALB2 genes, as well as in tumors with BRIP1 mutations. HRD was also occasionally seen in PCs with ATM, NBN, FANCM, BRCA1 and CDK12 alterations, but never in cases with CHEK2 mutations. HRD was significantly more associated with aggressive PC features than HRR mutations. The majority of CDK12-mutated tumors exhibited a distinct type of copy number variations (CNV)–a tandem duplication phenotype. Our study suggests that the selection of PC patients for PARPi treatment requires a significant revision of existing attitudes towards tumor genetic profiling. Full article

Birt–Hogg–Dubé (BHD) syndrome is a rare genetic disease, inherited in an autosomal dominant manner, that was first described in the mid-1970s and occurs due to pathogenic variants in the folliculin gene (FLCN) on chromosome 17p11.2. The syndrome has numerous clinical manifestations and primarily affects the lungs, kidneys, and skin. As far as the pulmonary features are concerned, more than 80% of patients appear to develop bilateral pulmonary cysts located in the lower lung zones, in the subpleural area, with cumulative risk of spontaneous pneumothorax depending on the number of cysts in the lungs. Another serious feature of the syndrome is the increased risk of renal cell carcinoma, which is often an incidental finding on screening or medical imaging. Cutaneous manifestations include benign fibrofolliculomas, trichodiscomas, and acrochordons (skin tags), which primarily affect the patients’ emotional status as a result of their cosmetic defects. BHD syndrome is generally an underdiagnosed condition due to the great variability of its clinical picture, thus highlighting the importance of genetic testing for FLCN mutations in suspected cases. The application of ERN GENTURIS guidelines in clinical practice can facilitate early, accurate diagnosis of the disease and optimal personalized management of the patients. Full article