Cerebral venous sinus thrombosis and SCN1A, a novel association?

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. Acquired and inherited prothrombotic conditions are the most common risk factors for CVST. Sometimes, an etiology is not found. Wide utilization of next generation sequencing technologies in clinical practice may lead to identification of risk factors other than those classically associated with CVST. METHOD AND RESULTS: This retrospective clinical-laboratory observational study has a reference patient who presented with CVST as an adolescent. Work up for prothrombotic conditions showed high homocysteine level secondary to homozygosity for a common polymorphism, c.677 C > T in the methylenetetrahydrofolate reductase (MTHFR) gene. His older unaffected brother has a similar MTHFR genotype and high homocysteine. The whole exome sequencing revealed a likely pathogenic variant in the sodium voltage gated channel, alpha subunit 1(SCN1A) gene. CONCLUSION: CVST is a multifactorial disease. Prothrombotic conditions are the most common risk factors for CVST. High homocysteine due to the common MTHFR polymorphisms was previously attributed to various thrombotic conditions including CVST. Although high homocysteine due to MTHFR polymorphism may be a contributing factor, additional risk factors such as blood flow abnormalities during SCN1A related seizures may be needed for thrombosis.

Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome.

Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing. We describe six patients (two not previously reported) with molecularly confirmed Myhre syndrome and neoplasia. Loss-of-function pathogenic variants in SMAD4 cause juvenile polyposis syndrome and we hypothesize that the gain-of-function pathogenic variants observed in Myhre syndrome may contribute to neoplasia in the patients reported herein. The frequency of neoplasia (9.8%, 6/61) in this series (two new, four reported patients) and endometrial cancer (8.8%, 3/34, mean age 40 years) in patients with Myhre syndrome, raises the possibility of cancer susceptibility in these patients. We alert clinicians to the possibility of detecting this syndrome when cancer screening panels are used. We propose that patients with Myhre syndrome are more susceptible to neoplasia, encourage increased awareness, and suggest enhanced clinical monitoring.

Can urinary nitrites or other urinalysis findings be a predictor of bacterial resistance of uncomplicated urinary tract infections?

BACKGROUND AND OBJECTIVES: To evaluate whether initial urinalysis (UA) and urinary nitrite results can be used as a proxy for choosing empiric antibiotic therapy. MATERIALS AND METHODS: A retrospective study was conducted in an urban inner city community hospital in New York City (NYU Woodhull Medical Center). We reviewed the charts of patients seen in the Emergency Department and Pediatric Clinic who had a diagnosis of urinary tract infection (UTI) during a 3 year time period (January 2010-December 2012). Statistical analysis was performed using SPSS 20.0 statistical software. RESULTS: Between January 2010 and December 2012, a total of 378 patients had a diagnosis of UTI. Seventy-five (19.8%) were males and 203 (80.2%) were females. Of the 378 patients with a diagnosis of UTI, the most common isolated pathogen was Escherichia coli, which was detected in 283 (74.9%) isolates. Other bacteria included Klebsiella spp 30 (7.9%), Proteus 21 (5.6%), Enterococcus 14 (3.7%), and others 30 (7.9%). The resistance rate was higher in the nitrite positive group for the following antibiotics: TMP/SMX and ampicillin with or without sulbactam. No significant correlation was found with the remaining studied antibiotics. No significant correlation was found between leukoesterase and the resistance patterns in all of the studied antibiotics, except cefazolin. CONCLUSION: Urinary nitrite results are not helpful in choosing an initial antibiotic to treat a UTI. Leukocytosis in the blood or urine or the presence of a fever cannot be used to predict bacterial resistance. The use of nitrofurantoin or cephalexin for the treatment of cystitis was optimum, and in the presence of negative leukoesterase, nitrofurantoin was preferable to cephalexin.