Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan.

BACKGROUND: Breast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally. Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5-10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored. METHODS: Retrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020. Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher's exact, Pearson's chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05. RESULTS: Out of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5-48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42-5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers. CONCLUSIONS: In our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase.

DO NOT FALL to the VAPE TRAP!

INTRODUCTION: Whilst the use of combustible tobacco products continues to decline in the United States, the use of e-cigarettes has seen an explosive rise in recent years. In 2019 an outbreak on EVALI was seen across the country, highlighting the fact that e-cigarettes may not be as harmless as previously perceived. CASE DESCRIPTION: A 22-year-old male came to the emergency department complaining of vomiting and shortness of breath. Patient reported using a "pod" a day of a "JUUL" e-cigarette. Patient's oxygen requirement continued to increase and was eventually shifted to the intensive care unit and mechanically ventilated. After a course of intravenous glucocorticoids, the patient was successfully weaned off the mechanical ventilation to oral glucocorticoids and discharged. DISCUSSION: Our patient's clinical course can be described as a "classic" case of EVALI. But in contrast to previously reported cases, our patient did not use e-cigarettes known to contain vitamin E acetate or THC two common substances implicated in EVALI. Our patient exclusively used a JUUL e-cigarette at a rate much higher than the typical user. The widespread use of JUUL and e-cigarettes especially amongst the younger demographics is especially concerning. CONCLUSION: Research efforts must be directed towards the substances utilized in e-cigarettes, and their use should be actively discouraged.

Compound heterozygosity for a whole gene deletion and p.R124C mutation in CYP21A2 causing nonclassic congenital adrenal hyperplasia.

We present a family with 2 members who received long-term steroid treatment for presumed classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, until molecular testing revealed nonclassic CAH, not necessarily requiring treatment. A 17-year-old male presented to our clinic on glucocorticoid and mineralocorticoid treatment for classic CAH. He was diagnosed at 4 years of age based on mild-moderate elevations of 17-hydroxyprogesterone (17-OHP) and adrenocorticotropic hormone (ACTH), but without evidence of precocious adrenarche/puberty. Due to his diagnosis, his clinically asymptomatic 3-year-old sister was tested and also found to have elevated ACTH and 17-OHP levels and was started on glucocorticoids for classic CAH. Family history revealed a healthy sibling who had no biochemical evidence of CAH and consanguineous healthy parents. We questioned the diagnosis of classic CAH and performed an ACTH1-24 stimulation test, which showed a level of 17-OHP in the borderline range between classic and nonclassic CAH. Molecular testing, using sequencing and multiplex ligation-dependent probe amplification analysis of CYP21A2, revealed that both affected siblings were compound heterozygotes for a whole-gene deletion and a, likely pathogenic (nonclassical), sequence variant, p.R124C. The asymptomatic father had the same genotype, while the mother showed one deleted copy and 2 active copies, making her an asymptomatic carrier. Our report demonstrates the importance of molecular testing in atypical cases of CAH, as well as the importance of both sequencing and deletion analysis. The results of molecular testing should be interpreted in clinical context, and treatment should be prescribed according to guidelines when available.

Differences in symptoms and presentation delay times in myocardial infarction patients with and without diabetes: A cross-sectional study in Pakistan.

OBJECTIVE: A short pre-hospital delay, from the onset of symptoms to rapid initiation of reperfusion therapy, is a crucial factor in determining prognosis of myocardial infarction (MI). The purpose of this study was to evaluate symptoms and presentation delay times in MI patients with and without diabetes. METHODS: This cross-sectional study was conducted in 3 tertiary care hospitals of Pakistan over a period of 6 months. The study sample consisted of 280 consenting individuals diagnosed with ST-elevation MI (STEMI) or Non-ST elevation MI (NSTEMI), out of which 130 were diabetic and 150 were non-diabetic. Data was collected using a standardized questionnaire, investigating MI symptoms along with causes and duration of pre-hospital delay within 72hours of admission. RESULTS: No significant difference was found in the intensity of chest pain between diabetics and non-diabetics. Atypical symptoms of MI such as anxiety (p<0.001), cold sweats (p=0.034) and epigastric pain (p=0.017) were more frequently reported in diabetics. MI patients with diabetes had a significantly longer presentation delay time with 75% of the patients presenting after elapse of 3h. Only a few patients reported to the hospital within an hour of onset of symptoms (n=23, 8.2%), out of which majority were non-diabetics (n=18). A majority of patients (n=146, 52%) in both groups did not use emergency medical services. CONCLUSION: This study provides an incentive for further research, aiming to reduce pre hospital delay along with investigating the effectiveness of emergency medical services.