Genetic insight into Birt-Hogg-Dubé syndrome in Indian patients reveals novel mutations at FLCN.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families. RESULTS: Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS. CONCLUSION: Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.

A Case of Sirolimus-Induced Interstitial Lung Disease After Liver Transplantation.

Mammalian target of rapamycin inhibitors (mTORis) are immunosuppression agents that are commonly used in solid organ transplantation. Available mTORis include sirolimus and everolimus. Interstitial lung disease (ILD) is an uncommon side effect of mTORis in liver transplantation. A high index of suspicion is needed, and timely intervention can reverse the disease. We present a case of sirolimus-induced ILD that improved after discontinuation of sirolimus.

Bullet in tracheobronchial tree without lung contusion removed by fibreoptic bronchoscopy in two parts.

A person presented with multiple gunshot injury. Chest x-ray & CT whole body trauma protocol was done which showed multiples pellets of bullet in abdomen and one bullet in elbow according to entry wound. There was an entry wound without any bullet in left maxillofacial region however there was no exit wound. A bullet was noticed in tracheobronchial tree. There was no pneumothorax any signs of chest trauma or any pneumomediastinum. It is assumed that the bullet first hit the left cheek (maxilla) and lost its momentum. As the patient lost consciousness and had a fall leading to inhalation (aspiration) of bullet in the airway. As per ballistic experts it was basically a jacketed metallic bullet. As bullet moved in airway, the outer metallic core reached the trachea near carina and the soft metallic core slipped more distally to right main bronchus and bronchus intermedius. While inspection the outer metallic capsule was seen in trachea just above carina which was hollow and was gently removed with the help of foreign body forceps. The core was removed with dormia basket without any mucosal tear. The favorable outcome can be attributed as patient had no lung contusion or chest trauma and bullet was inhaled which was not very old. The evolution of bronchoscopy started with rigid one but the fibreoptic bronchoscopy (FOB) has revolutionized the pulmonary interventions. The FOB can be used with minimal traumas under local anesthesia resulting in markedly reduced morbidity and mortality.

The clinical utility of cycle of threshold value of GeneXpert MTB/RIF (CBNAAT) and its diagnostic accuracy in pulmonary and extra-pulmonary samples at a tertiary care center in India.

BACKGROUND: There are knowledge gaps in the in-depth analysis of the most promising and robust diagnostic tool, GeneXpert MTB/RIF (CBNAAT). The cycle of threshold (CT) value of the CBNAAT test and its clinical implications has not been explored much. AIMS AND OBJECTIVES: The study aimed at (a) estimating the diagnostic accuracy and incremental yield of Xpert MTB/RIF in various specimens (b) establishing the association between CT value category (high, medium, low, very low) and culture time-to-positivity (TTP). METHODS: A total of 1000 samples, both pulmonary and extra-pulmonary were collected from presumptive TB cases in a large tertiary care hospital. Sensitivity and specificity of CBNAAT was calculated with culture as the gold standard. The association of CT value with culture TTP was also studied. RESULTS: The overall sensitivity of CBNAAT was 88.5%, with bronchial washing specimen being the most sensitive (92.3%) and pleural fluid being the least (66.7%). In smear negative individuals, the sensitivity of CBNAAT was 80.9%. The additional yield of CBNAAT over smear microscopy was 10.9%. It was observed that as we move from high to very low CT category, culture positivity decreases significantly (p<0.001), whereas time taken for culture growth increases (p<0.001). CONCLUSION: CBNAAT is a robust test for accurate diagnosis of tuberculosis both pulmonary and extra-pulmonary, smear negative as well, especially in resource-limited settings. The correlation between CT value and culture TTP has potential in predicting bacillary load, though further studies are required.