Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype.

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.

Anti-IL12p40 autoantibodies in a teenage girl with multiple recurrent abscesses.

More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.

A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT).

There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present that case of a boy who underwent HSCT for Haemophagocytic Lymphohistiocytosis (HLH) aged 2 years. Following Intervention with HSCT this boy's growth has severely decelerated (stature less than 1st centile matched for age) and he has developed a spondyloepiphyseal dysplasia.

Social cognition differentiates phenocopy syndrome of behavioural variant frontotemporal dementia from behavioural variant frontotemporal dementia.

BACKGROUND: Patients displaying clinical features of behavioural variant of frontotemporal dementia (bvFTD) but lacking both neuroimaging abnormalities and clinical progression are considered to represent the phenocopy syndrome of bvFTD (phFTD). Extensive clinical overlap between early phase bvFTD and phFTD hampers diagnostic distinction. We aimed to assess the diagnostic value of clinician-rated, self-reported and caregiver-reported symptoms for clinical distinction between phFTD and bvFTD. METHODS: There were 33 phFTD and 95 probable bvFTD patients included in the study (total N = 128). Clinician-rated, self-reported tests and caregiver-reported symptoms were compared between phFTD and bvFTD on social cognition, behaviour, mood and activities of daily living (ADL). Scores were compared between groups, followed by multiple logistic regression analysis, adjusted for age and sex. Receiver operating characteristic curves were plotted to assess diagnostic value. RESULTS: Using clinician-rated and self-reported tests, phFTD patients performed better on facial emotion recognition and reported more depressive symptoms. Caregiver-reported behavioural symptoms indicated higher behavioural and ADL impairment in phFTD compared to bvFTD. Facial emotion recognition provided highest diagnostic accuracy for distinction of phFTD from bvFTD (area under the curve (AUC) 0.813 95% CI 0.735-0.892, P < 0.001, sensitivity 81%, specificity 74%) followed by depressive symptoms (AUC 0.769 95% 0.674-0.864, P < 0.001 sensitivity 81%, specificity of 63%). CONCLUSION: Social cognition tests are most suitable for distinction of phFTD from bvFTD. Caregiver-reported questionnaires and phFTD diagnosis seemed inversely correlated, showing more symptoms in phFTD. Further research is needed on phFTD aetiology and in caregivers taking into account disease burden to assess what explains this discrepancy between clinician-rated and caregiver-based tools.

Captagon-induced Brugada phenocopy: A report of two cases.

Brugada phenocopies (BrP) represent electrocardiogram changes identical to those of true congenital Brugada syndrome but are induced by reversible clinical conditions. Previous cases have been reported in patients following recreational drug use. This report presents two cases of type 1B BrP associated with Fenethylline abuse, a recreational drug known by its trade name, Captagon.

Brugada ECG phenocopy in hypertrophic cardiomyopathy: The time matter.

An Implantable Cardioverter-Defibrillator was implanted in an asymptomatic 56-year-old man, with type 2 Brugada pattern on ECG, inducible ventricular fibrillation at elective electrophysiological study, and a family history of sudden cardiac death. Seventeen years later, the patient was admitted to the hospital due to palpitations related to a typical atrial flutter. A transthoracic echocardiogram unexpectedly revealed a clinically manifest hypertrophic cardiomyopathy.

Brugada phenocopy associated with multiple psychotic drugs.

Brugada phenocopy (BrP) is a clinical condition characterized by transient ECG changes of Brugada syndrome (BrS), which can be due to various clinical conditions. We describe a case report of BrP due to psychotic drugs.

A case of Brugada phenocopy alteration induced by immune checkpoint inhibitors.

Immunotherapy has shown remarkable efficacy in various cancer treatments. However, enhanced T-cell immune surveillance can lead to aberrant immune responses, resulting in severe immune checkpoint inhibitor-related adverse events. This is a case report of a patient previously treated with immune checkpoint inhibitors who presented with ST-segment elevation without abnormal troponin and cardiac enzyme spectrum test results. Cardiac toxicity of immune checkpoint inhibitors mainly manifests as acute immune-mediated myocarditis. While Brugada phenocopy is commonly caused by fever, electrolyte abnormalities, tricyclic/tetracyclic antidepressants, and marijuana use, we suspect that it was induced by immune checkpoint inhibitors in the current case.

Diagnostic and therapeutic dilemmas in a patient with myocarditis, Brugada syndrome and arrhythmic syncope.

We present a case of a previously healthy 23-year-old male who presented with chest pain, palpitations and spontaneous type 1 Brugada electrocardiographic (ECG) pattern. Positive family history for sudden cardiac death (SCD) was remarkable. Initially, clinical symptoms in combination with myocardial enzymes elevation, regional myocardial oedema with late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and inflammatory lymphocytoid-cell infiltrates in the endomyocardial biopsy (EMB) suggested the diagnosis of a myocarditis-induced Brugada phenocopy (BrP). Under immunosuppressive therapy with methylprednisolone and azathioprine, a complete remission of both symptoms and biomarkers was accomplished. However, the Brugada pattern did not resolve. The eventually spontaneous Brugada pattern type 1 established the diagnosis of Brugada syndrome (BrS). Due to his previous history of syncope, the patient was offered an ICD that he declined. After his discharge he experienced a new episode of arrhythmic syncope. He was readmitted and received an ICD.

Brugada pattern as part of the electrocardiographic abnormalities in hyperkalemia.

A 78-year-old man presented to the emergency department with a 10-day history of diarrhea and presyncope. His electrocardiogram showed a type-1 Brugada pattern but also a first-degree atrioventricular block, right bundle branch block, and peaked and symmetrical hyperacute T waves. A blood test revealed a potassium level of 9.3 mEq/L. After hemodialysis with normalization of serum potassium, the electrocardiographic abnormalities disappeared. An ajmaline challenge excluded the possibility of Brugada syndrome.

True Brugada syndrome ECG or Brugada phenocopy ECG? Can the ECG itself tell us the diagnosis?

We described a type 1 Brugada electrocardiogram and discussed about the potential diagnostic electrocardiographic indicators to differentiate true Brugada syndrome and Brugada phenocopy.

A dynamic Brugada sign due to left anterior descending coronary artery occlusion.

Brugada phenocopies (BrP) include several conditions with a common electrocardiographic (ECG) pattern that are indistinguishable from classical Brugada syndrome (BrS). In this report, we describe two cases of acute myocardial infarction (AMI) presenting as BrP. The majority of cases of BrP in AMI have been reported due to right coronary artery (RCA) occlusion. Rarely, the left anterior descending artery (LAD) is incriminated as the cause. In both our cases of BrP, LAD was the culprit vessel.

A case of cardiac sarcoidosis mimicking Brugada syndrome.

A 17-year-old boy was admitted for management of ventricular fibrillation (VF) with intermittent Brugada pattern on ECG. On evaluation, cardiac MRI revealed myocardial scar and mediastinal lymphadenopathy. 18-Fluorodeoxyglucose positron emission tomography scan showed inflammation in the heart, lungs, and lymph nodes. He was diagnosed as a case of cardiac sarcoidosis (CS) and treated with steroids. However, there was a reactivation of cardiac inflammation and the development of a second VF storm. Following catheter ablation, the patient's arrhythmia improved. This report highlights the inflammation due to CS mimicking channelopathic features.

Brugada phenocopy in pulmonary embolism - clinicopathological case study and literature review.

Brugada syndrome (BrS) is an inherited channelopathy characterized on ECG by coved (type 1) or saddle-back (type 2) ST-segment elevation (STE) of 2 or more mm in the right precordial leads and is associated with an increased risk of malignant ventricular arrhythmias. The term Brugada phenocopy (BrPh) indicates conditions that may reversibly induce Brugada-like ECG pattern in patients without true BrS; e.g.: metabolic abnormalities, mechanical heart compression, ischemia, myocarditis/pericarditis, and pulmonary embolism (PE). Only 9 cases of BPh associated with PE have been described so far. The authors present another case of a 41-year-old-male and analyze the clinical data of all 10 subjects (7 males and 3 females). Type 1 of ECG Brugada pattern was present in 7 patients (including ours), type 2 was found in 2 persons; in 1 case ECG pattern was not defined. In 7 patients STE was prominent (5 mm or more in at least 1 lead). STE was limited to V1-V2 leads in 4 persons, extended to V3 in 3 patients and even to V4 in 3 other patients, which correlated with the significant right ventricular (RV) dilatation. Concomitant left ventricular (LV) systolic dysfunction was reported only in 1 patient, which suggested that paradoxical embolization of coronary artery was not the mechanism of BrS-like STE. Clinical course of PE was usually severe (5 individuals were treated with thrombolysis) and in 3 cases it ended with death. The autopsy was only performed on our patient. It showed diffuse (ischemic) injury of RV and LV secondary to RV overload, decreased cardiac output and severe oxygen deficiency in myocardium, which could have led to BrS pattern in ECG.

Characteristics of Li-Fraumeni Syndrome in Japan; A Review Study by the Special Committee of JSHT.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, and the majority of patients with LFS have been identified with germline variants in the p53 tumor suppressor (TP53) gene. In the past three decades, considerable case reports of TP53 germline variants have been published in Japan. To the best of our knowledge, there have been no large-scale studies of Japanese patients with LFS. In this study, we aimed to identify Japanese patients with TP53 germline variants and to reveal the characteristics of LFS in Japan. We collected reported cases by reviewing the medical literature and cases diagnosed at the institutions of the authors. We identified 68 individuals from 48 families with TP53 germline pathogenic or likely pathogenic variants. Of the 48 families, 35 (72.9%) had missense variants, most of which were located within the DNA-binding loop. A total of 128 tumors were identified in the 68 affected individuals. The 128 tumor sites were as follows: breast, 25; bones, 16; brain, 12; hematological, 11; soft tissues, 10; stomach, 10; lung, 10; colorectum, 10; adrenal gland, 9; liver, 4; and others, 11. Unique phenotype patterns of LFS were shown in Japan in comparison to those in a large national LFS cohort study in France. Above all, a higher frequency of patients with stomach cancer was observed in Japanese TP53 germline variant carriers. These results may provide useful information for the clinical management of LFS in Japan.

Brugada phenocopy in a patient with unstable angina and three-vessel coronary artery disease.

A 52-year-old male was admitted with unstable angina and three-vessel coronary artery disease. Electrocardiography (ECG) changes consistent with type-1 Brugada ECG pattern were noted during admission. The patient was asymptomatic for syncope and had no family history of sudden cardiac death, ICD implantation, and Brugada syndrome. After coronary by-pass graft the Brugada ECG pattern resolved, and ajmaline test did not elicit type-1 ECG pattern, confirming the suspicion of Brugada phenocopy.

A case of anomalous aortic origin of coronary artery associated with a coved-type electrocardiogram.

Brugada syndrome (BrS) is a sudden cardiac death syndrome characterized by a coved-type electrocardiogram (ECG). Different disorders, such as ischemia, can emulate a Brugada-pattern ECG (Brugada phenocopy). We report herein, the first case of surgical epicardial electrophysiological mapping in a successfully resuscitated patient with an anomalous aortic origin of the coronary artery (AAOCA) associated with a coved-type ECG. It was debatable whether the coved-type ECG and the abnormal arrhythmogenic substrate in the epicardial right ventricular outflow tract were derived from BrS or from repetitive ischemia due to AAOCA; however, the epicardial electrophysiological mapping helped in deciding the treatment strategy.

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.

The Behavioral Variant Frontotemporal Dementia Phenocopy Syndrome: A Review.

OBJECTIVES: The relatively recent identification of a subgroup of patients with apparent behavioral variant frontotemporal dementia (bvFTD) that fails to progress with time has led to a reevaluation of our understanding of bvFTD, and a growing body of research that attempts to characterize the mimic or "phenocopy" syndrome. In this article, we review the literature relating to the phenocopy syndrome, focusing in particular on distinguishing characteristics and potential etiologies. METHODS: Published articles were identified via a systematic search of PubMed and Embase. Observational and interventional studies, case reports, and case series were sought for inclusion. RESULTS: While bvFTD and the phenocopy syndrome are clinically indistinguishable at initial presentation, the presence or absence of characteristic changes on neuroimaging predicts 2 very different illness trajectories. The etiology for the phenocopy presentation remains uncertain. It is likely that the syndrome represents a heterogenous assortment of clinical frontal syndromes encompassing atypical neurodegenerative, psychiatric, psychological, and as yet unknown neuropsychiatric causes. CONCLUSIONS: Although the prognosis of the phenocopy syndrome is generally held to be more favorable than that of bvFTD, patients and families are subject to major disruption in their relationships and social and occupational functioning. Early recognition is crucial to facilitate timely interventions aimed at maintaining relationships, roles, and quality of life of those affected.

Underlying pathology identified after 20 years of disease course in two cases of slowly progressive frontotemporal dementia syndromes.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed a benign course over 26 years, his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated slowly over 22 years, his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.