Case-Control Genotyping of the c.788C>T Variant of Transforming Growth Factor-Beta 1 Gene in Otosclerosis in the South Indian Population.

BACKGROUND: Otosclerosis is a common conductive hearing loss resulting from abnormal bone metabolism. The c.788C>T variant in the transforming growth factor-beta 1 gene is associated with otosclerosis in all studied populations, except the Indian population. In this study, we predicted the functional effects of reported variants in transforming growth factor-beta 1 and analyzed the c.788C>T variant in a case-control cohort from India and in the genomes present in public databases. METHODS: Clinically confirmed otosclerosis cases (n=120) and controls (n=120) were recruited and genotyped by polymerase chain reactionrestriction fragment length polymorphism and DNA sequencing. In addition, Ensembl 1000 Genome, Ensembl NHLBI Exome, GnomAD, and Genome Asia 100K human genome databases were analyzed for allele frequency. RESULTS: Among the 3 variants studied, a significant functional effect was observed only for the c.788C>T variant. This variant was found in 1 case but absent in all others and controls. Odds ratio, 95% CI, and P-value under the dominant model were 1.00, 0.0197-50.8116, and 1.00, respectively. Analysis of genomic databases showed a frequency of 0-11.21% and 0-1.25% for the c.788C>T variant and the individuals homozygous for this variant, respectively. CONCLUSION: We did not find any genetic association between the c.788C>T variant and otosclerosis in the South Indian population; however, it was not monomorphic as had previously been reported from the Odisha population of Eastern India. Moreover, contrary to an earlier report that the c.788C>T variant was never found in a homozygous condition, homozygous individuals were found in the European, Asian, Latin American, and Ashkenazi Jews populations.

Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients.

PURPOSE: Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs. METHODS: A total of 115 patients between the age of 1 and 18 years (average: 6.6) under maintenance therapy were selected for the study. SLC19A1 (c.80G > A), MTHFR (c.677C > T; c.1298A > C), and TYMS (c.*450_*455del) genotypes were determined using PCR techniques and Sanger sequencing. Cytogenetic and SNP findings were analyzed for any association with the reported toxicities using odds ratio, chi-square test, multifactor dimensionality reduction (MDR) analysis for synergistic effect and, multinomial logistic regression analysis for the likelihood of adverse events. RESULTS: Among the evaluated genetic variations, SLC19A1 (c.80G > A) was significantly associated with TRAEs (OR = 5.71, p = 0.002). Multinomial logistic regression analysis (chi-sq = 16.64, p < 0.001) and MDR analysis (chi-sq = 10.51 p < 0.001) confirmed the finding. On the other hand, no significant association was observed between adverse events and any specific cytogenetic aberration. CONCLUSION: SLC19A1 facilitates the import of cyclic dinucleotides and reduced folates, evaluating genotypes in this gene can help in better management of patients on methotrexate treatment. Assessing a broader gene panel can help in finding more associated markers and delivering personalized medicine to the patients.

Pharmacogenetic evaluation of 6-mercaptopurine-mediated toxicity in pediatric acute lymphoblastic leukemia patients from a South Indian population.

Aim: To evaluate the variants in the genes coding for the proteins involved in thiopurine and folate metabolism with treatment related adverse effects (TRAEs). Materials & methods: Eleven variants in seven candidate genes were genotyped in 127 pediatric acute lymphoblastic leukemia patients under 6-mercaptopurine (6-MP) treatment to infer the association of selected genotypes with TRAEs. Results: Among the genotypes inspected, NUDT15 (c.415C>T) and SLC19A1 (c.80G>A) showed a significant association with the TRAEs (odds ratio = 4.01, p = 0.002 and odds ratio = 7.78, p = 0.002). Conclusion:SLC19A1 and NUDT15 play an important role in the metabolism of 6-MP and it is necessary to spot other variants in associated pathways and investigate the factors that can impact 6-MP metabolism.

Giant toxic multinodular goiter with dyspnea: A case report.

INTRODUCTION: Toxic multinodular goiter (MNG) involves an enlarged thyroid gland, is a common cause of hyperthyroidism and when it is accompanied by obstructive symptoms such as dyspnea, it carries an indication for surgery. CASE PRESENTATION: We present a case of 47-year old female with multinodular goiter with a rapid increase in size within 2 years. She also reported palpitation, breathlessness on exertion, tachycardia and hand tremor. Computed tomography scan of the neck shows a gross enlargement of thyroid gland across both sides of the neck. The fine needle aspiration cytology and final histopathological examination were suggestive of MNG with adenomatous nodules and toxic changes respectively. A total thyroidectomy was performed and the gland was dissected successfully. DISCUSSION: Toxic MNG is most effectively treated by total thyroidectomy, which achieves complete diminution from symptoms. CONCLUSION: Surgery for huge goiter is challenging and one should be careful about difficult intubation, altered anatomy and adhesions to the surrounding structures. Recognizing and treating this kind of cases are important, as they constitute a preventable cause of mortality if timely diagnosed and treated.

Pedigree Analysis and Audiological Investigations of Otosclerosis: An Extended Family Based Study.

BACKGROUND AND OBJECTIVES: To analyse the audiometric profile and the pedigree of a large family with otosclerosis to understand the inheritance pattern and its implication in clinical management of the disease. Subjects and. METHODS: Pedigree analysis was performed on the basis of family history and audiometric tests. Pure tone audiometry, tympanometry, and acoustic reflexes were evaluated for the family members. Audiometric analysis was also carried out for the individuals who have already underwent corrective surgery at the time of study. RESULTS: Out of 112 family members, 17 were affected individuals, and 11 of them were surgically confirmed. Hearing loss (HL) started unilaterally and progressed to bilateral form. Otosclerosis was presented in early 20's in the first and second generations but it was delayed to mid-late 30's in the fourth generation. An affected female was diagnosed with otosclerosis during her pregnancy. Though the disease was familial, a mother of four affected offspring in this family did not develop otosclerosis until she died at the age of 84. CONCLUSIONS: The five-generation family, which was analysed in the present study, exhibited autosomal dominant inheritance of otosclerosis with reduced penetrance. Bilateral HL and pregnancy-aggravated otosclerosis were observed in this family. It was found for the first time that the age of onset of the disease delayed in the successive generations. The current study indicated the importance of detailed pedigree analysis for better clinical management of otosclerosis.

Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India.

Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, ⩽40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.

Our Experience with Femoro-Femoral Bypass in the Management of Critical Airway Problems.

The authors present a case report of a 64 year old male patient with thyroid mass and extensive secondaries of the neck and infiltration of the trachea producing severe tracheal stenosis at the level of the thoracic inlet presenting with stridor. Due to the large mass, endotracheal intubation was ruled out; hence a femoro-femoral Cardiopulmonary Bypass was done followed by a median sternotomy, resection of the involved tracheal segment, a total thyroidectomy with neck dissection and finally a tracheal end-to-end anastomosis. The surgery was done in May 2011.

Minor's Test: Objective Demonstration of Horner's Syndrome.

To highlight the Minor's test, which is useful in demonstrating anhidrosis of Horner's syndrome. A 39 year old female presented to us with a slow growing neck swelling which was provisionally diagnosed as a probable case of cervical sympathetic chain (CSC) Schwannoma. Intra operatively, the mass was found arising from the CSC which was sacrificed. Post operatively, Horner's syndrome was expected, but was difficult to demonstrate clinically. On performing the Minor's test, the presence of anhidrosis, and thus Horner's syndrome was confirmed. Minor's test is a simple objective test to demonstrate Horner's syndrome, especially because diagnosis from the eye signs can be difficult.

Relationship between intracochlear electrode position and tinnitus in cochlear implantees.

CONCLUSION: Cochlear implant electrode position has an impact on the rate of tinnitus suppression and generation. OBJECTIVE: Suppression of pre-operative tinnitus or a generation of a new tinnitus in cochlear implantees is a known effect of cochlear implantation. The aim of the current study was to evaluate different cochlear implant electrode positions and their relationship with tinnitus suppression and tinnitus generation. METHOD: This study retrospectively evaluated four groups of CI recipients with radiologically evaluated electrode positions in relation to their subjective tinnitus quality, as evaluated by an analogue loudness scale (ALS) and a questionnaire. Group 1 consisted of 19 patients with a scalar change of the electrode position. Group 2 consisted of 18 patients with a scala tympani position and a perimodiolar electrode. Group 3 consisted of 10 patients with a scala tympani position and a lateral wall electrode. Group 4 consisted of eight patients with a scala vestibuli position. RESULTS: An overall tinnitus suppression rate of 45.9% and a generation of a new tinnitus or the deterioration of an existing one of 5.6% were observed. A significant difference in tinnitus suppression was found between groups 1 and groups 2, 3, and 4 in tinnitus suppression and tinnitus generation.

Meningo-encephalocoele of temporal lobe-management by blind SAC closure.

Brain herniation into the middle ear and mastoid is rare but is a described complication of chronic ear disease. The diagnosis is mainly clinical and requires a high index of suspicion. This can be confirmed by imaging studies. Different surgical modalities have been described in managing this condition. We present a case managed by combined trans-mastoid mini-craniotomy approach and blind sac closure.

An unusual complication of intranasal antrostomi.

Intranasal antrostomies are performed for treating maxillary simusitis. Here we present a rare case, who developed maxillary simusitis as a complication of the previous inferior meatal intranasal antrostomy. This case also proves the current concept that even though the inferior meatal antrostomy opening may be patent, the drainage is through the natural ostium.

Ectopic thyroid: A rare cause of tracheal obstruction.

The endoluminal presence of thyroid tissue in the trachea is a rare cause of airway obstruction. Only 14 well documented cases of intratracheal ectopic thyroid tissue have been reported in English Literature since 1966. These lesions are mostly benign and nearly all patients present with symptoms of respiratory obstruction. We present a case of ectopic thyroid in cervical trachea presenting with symptoms of airway obstruction. Thorough clinical examination and investigations were carried out. A right hemithyroidectomy and excision of a part of the tracheal wall through a tracheotomy was performed for removal of the ectopic thyroid tissue from trachea. The clinicians & radiologists must be aware of this entity to avoid mistaking it for evidence of invasion by a malignant neoplas, and hence this report.

Role of endoscope and microdebrider in the excision of skull base schwannoma-Arising from the sphenoid sinus.

A 54 year old lady presented with complaint of right sided nasal obstruction for the past 4 years which was persistent and total. Examination revealed a pale mass in the posterior half of the nasal cavity obscuring the choana. It was firm in consistency, pale with a smooth surface. The Cranial nerves were normal. Clinically there was no evidence of spread into the maxillary sinus or orbit or regional lymphadenopathy. Ophthalmologist's opinion was sought.

Papillary thyroid carcinoma in a thyroglossal cyst.

The incidence of Papillary Thyroid Carcinoma in a Thyroglossal Cyst is rare. Only about 160 cases have been reported in the last 85 years. We report a case of Thyroglossal Cyst who underwent Sistrunk ’s Operation. The Cyst was reported to contain a focus of papillary thyroid carcinoma. In the absence of metastases in thyroid gland and neck nodes, only thyroid suppression with Thyroxine was given. After I year of follow-up there are no metastases. The importance of Sistrunk’s operation lies not only in complete removal of Thyroglossal Cyst but also in management of small foci of Papillary thyroid Carcinoma.