Postmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue.

We report a case of a somatic overgrowth syndrome diagnosed at forensic autopsy with the aid of next generation sequencing as Proteus syndrome. Somatic overgrowth syndromes result from spontaneous somatic mutations that arise early in development and display a mosaic pattern of expression in patient tissues. Due to the temporal and anatomic heterogeneity of these syndromes, phenotypes vary widely, resulting in clinical overlap. Furthermore, the variable ratio of mutated to nonmutated cells in patient tissue can result in low-level mutations that could be missed using Sanger sequencing. Due to these factors, recent literature points to next generation sequencing (NGS) as an adjunct to diagnosis of these rare entities. A male in his fourth decade of life presented to our forensic autopsy service with physical features suggestive of a somatic overgrowth syndrome. Due to the paucity of clinical information accompanying the individual, a definitive diagnosis based on physical characteristics, alone, was not possible. Next generation sequencing of affected formalin-fixed and paraffin-embedded brain tissue confirmed the presence of the variant in AKT1 (c.49G>A, p.Glu17Lys, in 14.13% of reads) found in Proteus syndrome. To our knowledge, this is the first report of the mosaic variant of AKT1 detected in brain tissue and the first reported case of a postmortem diagnosis of Proteus syndrome with the aid of NGS. We conclude that NGS can be used as an adjunctive method to support a specific diagnosis among the somatic overgrowth syndromes postmortem in the absence of sufficient clinical history.

Giant cell myocarditis causing sudden death in a patient with sarcoidosis.

Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

Giant cell myocarditis causing sudden death in a patient with sarcoidosis

Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

First Report of Prenatal Ascertainment of a Fetus With Homozygous Loss of the SOX10 Gene and Phenotypic Correlation by Autopsy Examination.

The SOX10 gene plays a vital role in neural crest cell development and migration. Abnormalities in SOX10 are associated with Waardenburg syndrome Types II and IV, and these patients have recognizable clinical features. This case report highlights the first ever reported homozygous loss of function of the SOX10 gene in a human. This deletion is correlated using family history, prenatal ultrasound, microarray analysis of amniotic fluid, and ultimately, a medical autopsy examination to further elucidate phenotypic effects of this genetic variation. Incorporating the use of molecular pathology into the autopsy examination of fetuses with suspected congenital anomalies is vital for appropriate family counseling, and with the ability to use formalin-fixed and paraffin-embedded tissues, has become a practical approach in autopsy pathology.

Differential Diagnosis of Hepatic Necrosis Encountered at Autopsy.

The liver is subject to a variety of extrinsic and intrinsic insults that manifest with both specific and nonspecific patterns of necrosis. In the autopsy setting, these patterns are often encountered as incidental findings or even causes of death. There are several etiologies of hepatic necrosis, including toxins, drug injuries, viral infections, ischemic injuries, and metabolic disease, all of which possess overlapping gross and histologic presentations. Nonetheless, patterned necrosis in the context of clinical and demographic history allows for the forensic pathologist to develop a differential diagnosis, which may then be pruned into a specific or likely cause. The aim of the following review is to elucidate these patterns in the context of the liver diseases from which they arise with the goal developing a differential diagnosis and ultimate determination of etiology. Acad Forensic Pathol. 2018 8(2): 256-295.

Success in Implementation of a Resident In-Service Examination Review Series.

OBJECTIVES: Primary pathology board certification has been correlated with senior resident in-service examination (RISE) performance. We describe our success with an annual, month-long review series. METHODS: Aggregate program RISE performance data were gathered for 3 years prior to and 3 years following initiation of the review series. In addition, mean United States Medical Licensing Examination Step 1 and 2 Clinical Knowledge scores for residents participating in each RISE examination were obtained to control for incoming knowledge and test-taking ability. Linear models were used to evaluate differences in average RISE performance prior to and following the initiation of the review series in addition to controlling for relevant covariates. RESULTS: Significant improvement was noted in the grand total, anatomic pathology section average, clinical pathology section average, and transfusion medicine section. Although not statistically significant, improvement was noted on the cytopathology and clinical chemistry sections. There was no significant difference in scores in hematopathology, molecular pathology, and the special topics section average. In addition, improvement in primary pathology board certification rates was also noted. CONCLUSIONS: Institution of a month-long RISE review series demonstrated improved overall performance within our training program. The success could easily be replicated in any training program without significant disruption to an annual didactic series.

Opioid-Associated Deaths in South Carolina, 2013-2016: A Retrospective Review.

INTRODUCTION: Rising rates of opioid abuse in the United States have generated an overdose epidemic. Particularly in the last few years, many offices across the country have seen a shift from prescription opioid toxicity to heroin, illicitly produced fentanyl, and, more recently, various fentanyl analogs. METHODS: A retrospective review was performed to better characterize the incidence of licit opioid, heroin, fentanyl, and fentanyl analog-associated deaths in South Carolina. Three-thousand three-hundred and fifty autopsy records from the Medical University of South Carolina's forensic pathology division were reviewed to identify cases in which oxycodone, hydrocodone, heroin, fentanyl, and/or fentanyl analogs were detected. RESULTS: In 2013, the incidence of both heroin and fentanyl-associated deaths was relatively rare (2.2% and 0.4%, respectively), but increased somewhat steadily throughout the ensuing years. The incidence of fentanyl-associated death increased from 0.4% to 2.4% between 2013 and 2016. A decrease in fentanyl-associated deaths was noted between 2015 and 2016; however, 2016 saw a dramatic increase in fentanyl analogs, likely accounting for this slight dip. Heroin rose from 2.2% to 4.5% between 2013 and 2016. Combined, heroin and fentanyl accounted for 2.6% of autopsy deaths in 2013 and increased to 7.6% in 2016, with more substantial increases in 2014 and 2015. Licit opioid-associated deaths remained relatively stable throughout the study period and, when identified, were almost always polydrug comixtures. DISCUSSION: These data illustrate general increases in illicit opioid-related deaths. In contrast to larger jurisdictions, particularly in the Midwest and Northeast, heroin continues to contribute most significantly to intoxication deaths, although synthetic fentanyl and fentanyl analog-associated deaths increased dramatically beginning in 2014.

The Interplay Between Diabetes and Pancreatitis: Two Case Reports of Sudden, Natural Deaths and a Review of the Literature.

Diabetes mellitus (DM) is a common disease involving insulin resistance or deficit that, when left unchecked, may cause severe hyperglycemia and subsequent end-organ damage. Acute pancreatitis (AP) is inflammation of the pancreas that can lead to significant morbidity and mortality. AP and DM both account for a significant amount of sudden deaths, and rarely both disease processes may be present in the same decedent, causing some difficulty in wording the cause of death statement. Although much research has been directed at studying the causes and risk factors for AP and DM, there is a complex interplay between these diseases that is not fully understood. This study presents two autopsy cases of sudden, natural deaths that illustrate this interplay, along with a review of the literature. An algorithm for differentiating AP and DM is then discussed in the context of the presented cases as a proposed aid for forensic pathologists in the certification of such deaths.

Imaging coronary artery disease and the myocardial ischemic cascade: clinical principles and scope.

On a subcellular level, atherogenesis is characterized by the translocation of proatherogenic lipoproteins into the arterial wall. An inflammatory response involving complex repair mechanisms subsequently causes maladaptive vascular changes resulting in coronary stenosis or occlusion. The chronology of the underlying processes occurring from atherosclerosis to myocardial ischemia affect the selection and interpretation of diagnostic testing. An understanding of the ischemic cascade, atherosclerosis, coronary remodeling, plaque morphology, and their relationship to clinical syndromes is essential in determining which diagnostic modalities are useful in clinical practice.

The importance of microscopic examination of the lungs in decedents with sustained central intravascular catheters: a nine-case series.

Indwelling intravascular catheters provide convenient access to healthcare personnel and also recreational intravenous drug users who inject suspensions of oral medications. A nine-case series of autopsies of clinically stable decedents with indwelling catheters and sudden death is herein presented. Pulmonary histologic findings were consistent with intravenous administration of oral medications in all cases. In eight, the mechanism of death was directly attributed to occlusive vascular embolization of foreign material, with or without contribution of acute drug toxicity. In one, the mechanism of death was solely attributed to acute drug toxicity. Acute, massive embolization of foreign material may explain sudden death by vascular obstruction, whereas chronic repeated injections lead to obliteration of the pulmonary vasculature, increased pulmonary vascular resistance, and cardiac failure. Therefore, a complete autopsy with histologic examination of the lungs and toxicology testing is recommended in patients with indwelling catheters to determine the cause and mechanism of death.

Intravascular large B-cell lymphoma.

A rare type of diffuse large B-cell lymphoma, intravascular large B-cell lymphoma primarily affects the middle-aged to elderly population, with a slight predominance in men. By the time of presentation, most patients have advanced, disseminated disease, and often the diagnosis is made at autopsy. Patients may present with any of a myriad of symptoms, with any tissue potentially being infiltrated. Central nervous system and cutaneous involvement is common, as is the presence of B symptoms including fever, weight loss, and night sweats. Morphologically, growth of neoplastic cells is restricted to the lumen of small vessels. The cells are large, with 1 or more prominent nucleoli, scant cytoplasm, and frequent mitotic figures, and are commonly positive for cluster of differentiation markers 79a, 20, and 19, as well as MUM1/IRF4 and Bcl-2. Intravascular large B-cell lymphoma is aggressive, and without treatment is rapidly fatal.