Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis. CASE PRESENTATION: The male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby's parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child. CONCLUSIONS: CPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

Case report: A rare combination of aldosterone-secreting adrenocortical carcinoma and papillary thyroid carcinoma with Graves' disease.

Adrenocortical carcinoma (ACC) is a rare malignancy originating in the adrenal glands, aldosterone-producing ACC, even rarer. Papillary thyroid carcinoma (PTC), by contrast, accounts for the majority of thyroid carcinomas. We herein describe the first reported case of a female with comorbidities of aldosterone-producing ACC, PTC, and Graves' Disease(GD). The patient achieved transient clinical remission following adrenalectomy. However, three months later, aldosterone-producing ACC lung metastases emerged. Subsequently, within another three-month interval, she developed thyroid eye disease(TED). The patient died roughly one year after the adrenal operation. Exome sequencing did not reveal associations between aldosterone-producing ACC, PTC, and GD, and the underlying concurrence mechanism has yet to be elucidated. Further research of similar cases are needed to confirm potential links between the three pathologies.

Case report: Novel compound heterozygous IL1RN mutations as the likely cause of a lethal form of deficiency of interleukin-1 receptor antagonist.

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.

Very Long-term Survivorship in Pediatric DIPG: Case Report and Review of the Literature.

Diffuse intrinsic pontine gliomas are lethal tumors with a prognosis generally less than 1 year. Few cases of survivors of 5 years or more have been reported. This case report highlights the journey of a 9.5-year survivor who underwent 3 rounds of focal radiotherapy; she experienced 6 years of progression-free survival following the first round but ultimately succumbed to her disease. An autopsy revealed a favorable IDH1 mutation and the absence of H3K27M. This case reiterates the importance of extensive molecular analyses in diffuse intrinsic pontine gliomas and explores the potential benefit of re-irradiation in patients with positive responses and long periods of remission.

Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments.

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro. We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.

Granulomatous myocarditis arising from intravesical Bacillus Calmette-Guérin therapy leading to death diagnosed by postmortem examination: a case report.

BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) is used as a standard adjuvant therapy for non-muscle invasive urothelial cancer. Most patients tolerate the treatment well, with mild side effects. Systemic complications are extremely rare, occur due to BCG dissemination and are associated with immunocompromised state and urothelial breach. CASE PRESENTATION: We present a case of a 78-year-old male, a former smoker, with history of non-muscle invasive urothelial carcinoma status post partial resection followed by intravesical BCG therapy. An autopsy was performed due to the sudden nature of his death. Autopsy showed multiple necrotizing granulomas in the brain, atrium, ventricles, lungs, kidneys, and urinary bladder. Stains for acid-fast bacilli and fungi were negative. In addition, bilateral lungs showed evidence of bronchopneumonia secondary to cytomegalovirus. CONCLUSION: Granulomatous myocarditis arising from BCG therapy is extremely rare. Our patient with urothelial cancer treated with BCG developed multiorgan granulomas, most likely due to a hypersensitivity reaction to intravesical BCG. Arrhythmia induced by granulomatous myocarditis was the cause of his death. Although there have been few cases of systemic BCG-osis causing fatal sepsis leading to death, a cardiac cause of death is unique.

A case of fatal monkeypox infection: necropsy and molecular findings, with some considerations related to clinical management.

OBJECTIVE: Human monkeypox (mpox) is usually self-limited infection; however, rising data show a worse outcome in patients with impaired immune status, particularly those co-infected with HIV [Mitjà O, Alemany A, Marks M, Lezama Mora JI, Rodríguez-Aldama JC, Torres Silva MS et al. Mpox in people with advanced HIV infection: A global case series. Lancet. 2023; 401:939-49. DOI:https://doi.org/10.1016/S0140-6736(23)00273-8] [Govind A, Lazarte SM, Kitchell E, Chow JY, Estelle CD, Fixsen E et al. Severe mpox infections in people with uncontrolled human immunodeficiency virus (HIV). Clin Infect Dis. 2023; 76:1843-6. DOI:https://doi.org/10.1093/cid/ciad052]. METHODS: We report the clinical, pathological, and molecular study of a patient with mpox infection and a late HIV diagnosis, with fatal outcome. RESULTS: Necropsy revealed visceral spread of mpox. Mpox virus was sequenced twice during the admission, uncovering an emerging mutation near a genomic region where mutations associated with tecovirimat resistance have been documented. DISCUSSION: Monkeypox can manifest as an opportunistic infection in individuals with advanced HIV-associated immunosuppression.

Hydroa Vacciniforme Lymphoproliferative Disorder in a Young Spanish Woman: An Infrequent Case With Fatal Outcome.

ABSTRACT: Hydroa vacciniforme (HV) lymphoproliferative disorder is a rare NK/T-cell lymphoma mainly affecting children and with a clinical resemblance to HV, which is mostly reported in Latin American and some Asian countries. Overall, the mature T cell and NK-cell neoplasms are now grouped into 9 families based on diverse concepts: cell of origin/differentiation state, clinical scenario, disease localization, and cytomorphology. HV lymphoproliferative disorder is listed within the group of Ebstein Barr Virus-positive T-cell and NK-cell lymphoid proliferations and lymphomas of childhood according to the fifth edition of the World Health Organization Classification of mature lymphoid neoplasms. We report the extraordinary case of a 22-year-old white woman, native of Spain, first presented in 2016 when she started suffering from recurrent facial edema. Four years later, the disease progressed with lymph node spreading and a fatal outcome. Here, we describe the clinical and histological presentation of the lymphoma throughout its evolution. Cases like this can be difficult to classify posing a real challenge to clinicians and pathologists. So, it is vital to be aware of the rare presentation of this disease to be able to identify the clinical and histological picture to make a correct diagnosis and establish an early treatment.

[Asymptomatic SARS-CoV-2 Infection and "in situ split" Liver Resection with Fatal Outcome - A Case Report]. / SARS-CoV-2-Infektion und "In-situ-Split"-Leberresektion mit tödlichem Verlauf.

We report the perioperative course of a 47-year-old patient who underwent a two-stage liver resection for bilobar metastatic colorectal carcinoma. The respiratory asymptomatic patient was tested positive for SARS-CoV-2 by PCR detection one day before the second surgical procedure. Postoperatively, the patient suffered cardiovascular arrest on postoperative day 8 and died despite immediately initiated resuscitative measures. With an initial clinical suspicion of vascular liver failure, postmortem pathologic examination revealed the underlying cause of death to be COVID-19-related myocarditis with acute right heart failure. Individual multidisciplinary risk assessment should be considered very critically when deviating from the "7-week rule" because the benefit is difficult to objectify, even in oncologic patients.

Cerebral haemorrhage with fatal outcome after ECT.

ECT is generally regarded as a safe and efficient treatment. In this case report, a 76-year-old female patient did not wake up as expected after ECT. The patient was transferred to the emergency department, and a CT-scan showed an intracerebral haemorrhage. She died within two days of the event, and an autopsy confirmed the diagnosis and did not reveal any underlying cerebral pathology.

First Swedish case of fatal equine parasitic encephalitis by Halicephalobus gingivalis.

BACKGROUND: Halicephalobus gingivalis is a nematode with zoonotic potential which can cause fatal opportunistic infections in various mammals. The parasite has never been diagnosed in Sweden, in any species, prior to the presented case. CASE PRESENTATION: An imported 21-year-old Icelandic mare developed severe neurological signs. The horse was eventually euthanized and submitted for post-mortem examination where severe lesions in the kidneys were noted. Histopathology revealed the presence of H. gingivalis in both kidneys and the brain. Phylogenetic analysis of the parasite determined it to belong to Lineage 1. CONCLUSIONS: With the occurrence of H. gingivalis in Sweden, the disease should be added to the list of differential diagnoses in cases with acute onset of neurological disease in both horses and other mammals including humans.

Spurious Presentation of Pulmonary Kaposi Sarcoma as Unresolved Pneumonia Led to Fatal Outcome.

Acquired immunodeficiency syndrome (AIDS)-associated Kaposi sarcoma (KS) is an angioproliferative neoplasia caused by infection with human herpesvirus 8 (HHV-8). It typically presents with mucocutaneous involvement, but it can be disseminated. Initial presentation with primarily pulmonary KS is rare. We present a case of a 32-year-old male with untreated human immunodeficiency virus (HIV) diagnosed 1 year before presentation who developed progressively worsening cough and shortness of breath for 6 months. He was hospitalized twice and treated for unresolved pneumonia in an outside hospital. The patient concomitantly developed purplish nodules on his face, then the upper trunk, back, chest, and thighs bilaterally that gradually increased in size and number. Histopathology findings from skin lesions were consistent for KS. Bronchoscopy found multiple erythematous plaques throughout the tracheobronchial tree with telangiectasias and inflammation suggestive of pulmonary KS. His imaging findings and positive serum HHV-8 polymerase chain reaction (PCR) were consistent with disseminated KS. He started antiretroviral therapy (ART) to treat his HIV infection, followed by liposomal doxorubicin chemotherapy. But both ART and chemotherapy were interrupted due to adherence and insurance issues. The patient was readmitted with acute respiratory failure requiring mechanical ventilation with multiple vasopressors that led to the patient's demise. The late recognition of KS diagnosis and delayed treatment can lead to worse outcomes.

[Clinical case report of acute dinitrophenol poisoning with a fatal outcome of Udmurt Republic]. / Klinicheskii sluchai ostrogo otravleniya dinitrofenolom s letal'nym iskhodom v Udmurtskoi Respublike.

THE AIM OF THE STUDY: Was to conduct the analysis of patient's clinical observation with acute dinitrophenol poisoning, admitted to a toxicological department of CCH №6 of Izhevsk, Udmurt Republic in 2021 yr. In this clinical case report, a 19 years old girl, who took 20 tablets of dinitrophenol, illegally obtained in online-shop, died. The fatal outcome was realized by the uncoupling of oxidative phosphorylation mechanism and cellular respiration, which in its turn led to serious dystrophic changes in all organs and tissues. Disorders of hemodynamics and blood rheological properties dominated in poisoning pathogenesis, led to congestion, stasis in microcirculatory vessels, hyperpermeability with multiple perivascular hemorrhages in organs, occurrence of piecemeal necrosis in kidneys and liver, nephrosis and nonspecific reactive hepatitis. Production ATP from ADP becomes impossible in these conditions, and respiratory energy chain completely disappears as heat, that explains the heat-increasing and fat-burning effects of dinitrophenol.

Gastrointestinal mucormycosis following liver transplantation: lessons learnt.

Gastrointestinal mucormycosis (GIM) is an uncommonly encountered fungal infection following solid-organ transplantation. GIM is known to be associated with immunocompromised states, remains difficult to diagnose and often results in fatal outcomes. It is plausibly the delay in initiation of appropriate treatment strategies that leads to failure of response and patient demise. We report two cases of GIM following live donor liver transplantation, presenting with bleeding and perforation, respectively, highlighting the challenges in making a timely diagnosis of mucormycosis, particularly in immunocompromised patients.

A pediatric case series of catastrophic gastrointestinal complications of posttransplant lymphoproliferative disease with increasing incidence, high association with coronavirus disease 2019, higher mortality, and a plea for early endoscopy to prevent late fatal outcome.

BACKGROUND: Posttransplant lymphoproliferative disorder is one of the most severe complications after transplantation, caused by uncontrolled proliferation of Epstein-Barr virus-positive B-cells in the setting of chronic immunosuppression. As one of the biggest transplant centers worldwide, we observed a potential increase in the number of patients with posttransplant lymphoproliferative disorder presenting with gastrointestinal symptoms in 1 year, during the coronavirus disease 2019 pandemic. There is limited information about dysregulation of the immune system following coronavirus disease 2019 infection, which may lead to Epstein-Barr virus reactivation in Epstein-Barr virus-positive B-cells and development of posttransplant lymphoproliferative disorder. Furthermore, there is no consensus in literature on a modality that can help in early diagnosis of posttransplant lymphoproliferative disorder with nonspecific gastrointestinal presentations before late and fatal complications occur. CASE PRESENTATION: Our case series includes five Iranian (Persian) patients, three female (2, 2.5, and 5 years old) and two male (2 and 2.5 years old), who developed gastrointestinal posttransplant lymphoproliferative disorder after liver transplantation. All of our patients were on a similar immunosuppressant regimen and had similar Epstein-Barr virus serologic status (seronegative at time of transplantation but seropositive at time of posttransplant lymphoproliferative disorder diagnosis). Four patients had either a positive coronavirus disease 2019 polymerase chain reaction test or exposure within the family. Although all of our patients presented with nonspecific gastrointestinal symptoms, four patients developed late posttransplant lymphoproliferative disorder complications such as bowel perforation and obstruction. All five patients with gastrointestinal posttransplant lymphoproliferative disorder received chemotherapy, but only two survived and currently are continuing the therapy. In one of the surviving patients, prompt endoscopic investigation resulted in early diagnosis of posttransplant lymphoproliferative disorder and a better outcome. CONCLUSION: Since 80% of our patients had exposure to coronavirus, a potential relationship might be suggested between the two. Furthermore, as we witnessed in one case, urgent endoscopic investigation in immunocompromised patients presenting with gastrointestinal symptoms can improve the clinical outcomes and therefore should be considered for early diagnosis of posttransplant lymphoproliferative disorder.

Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne's Muscular Dystrophy.

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., "dead" Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR-transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.).

Elderly and their companion animals, cause for pleasure or for harm, a case report of a non-bite Pasteurella multocida bacteremia in an 85-year-old woman with a fatal outcome.

We present a case of an elderly woman suffering from Pasteurella multocida (P. multocida) bacteremia, without obvious bite marks, but owning a pet dog. Although the patient was not immunocompromised, and prompt treatment with intravenous antibiotics was initiated, she developed severe septic shock with multiple organ failure and died. In healthy individuals, an infection caused by these bacteria is easy to treat and often harmless, whereas in elderly serious complications can occur. We believe this report of a fatal outcome of a P. multocida bacteremia in a non-immunocompromised, but elderly patient is important, given the growing cohort of elderly pet-owners seeking medical care. A greater awareness of this zoonosis and its potentially fatal outcome is warranted.