Cardiac Involvement Research Articles

Echocardiographic Documentation of Dilated Cardiomyopathy Development in Dogs Naturally Infected with Trypanosoma cruzi.

We aimed to characterize the echocardiographic alterations in dogs from an endemic region that were naturally infected with T. cruzi. Dogs (n = 130) seropositive for antibodies against T. cruzi and/or with acute parasitemia were enrolled in the study. Indicators of changes in the structure and systolic and diastolic functions of the left ventricle (LV) and blood flow patterns were evaluated by echocardiography. The frequency and extent of alterations in these indicators were associated with the severity of the disease. Briefly, 15 (11.54%) dogs were diagnosed with dilated cardiomyopathy (DCM), and 115 (88.46%) dogs were diagnosed as being without DCM. Infected dogs with DCM exhibited structural features of LV dysfunction, e.g., a significant (p < 0.05) increase in the LV internal diameter at systole and diastole (LVID-s, LVID-d) and a decline in the LV posterior wall (LVPW-d) thickness at diastole. Despite an increase in stroke volume and cardiac output indicating contraction force, DCM resulted in a decreased ejection fraction, affecting systolic function. Dogs that were diagnosed as DCM-negative but were positive for T. cruzi by PCR exhibited a high frequency of an increase in the thickness of the interventricular septum in systole (IVS-s) and the LV posterior wall in diastole (LVPW-d), a decline in the LV inner diameter (LVID-d, LVID-s), and fractional shortening (FS). The thinning of the LVPW at systole was the most defining feature observed in chronically infected dogs. In summary, this is the first study reporting the echocardiographic changes occurring in dogs naturally infected with T. cruzi and developing DCM. Our data suggest that changes in LVID are a major indicator of risk of cardiac involvement, and the observation of changes in the IVS, LVPW, and FS have predictive value in determining the risk of DCM development in infected dogs.

Systemic Complications of an Exceptional Case of Ruptured Left Intra-Ventricular Hydatid Cyst in a Child

Cardiac involvement in hydatid disease is exceptional but has a formidable prognosis. Cardiac localization of hydatidosis exposes to the dissemination of vesicles in the systemic circulation, especially when it is located on the left side. Its treatment is essentially surgical, which helps to avoid complications and the spread of the disease. We report the case of a 13-year-old patient with no particular pathological history, hospitalized for an ischemic stroke and limb ischemia, who was found to have a mass at the apex of the left ventricle on transthoracic cardiac ultrasound. The diagnosis of hydatid cyst was strongly suggested by the discovery of hydatid cyst membranes during the anatomopathological examination of the operative samples from the surgical thrombectomy of the left lower limb. Cardiac magnetic resonance imaging showed a mycotic aneurysm, while serology for hydatid disease was negative. A medical treatment based on albendazole was initiated, but the patient died in a context of multi-visceral failure postoperatively after the cardiac mass excision performed under extracorporeal circulation.

Hydroxychloroquine-azithromycin, doubase C, and QTc prolongation in congolese patients with COVID-19: Myth or reality?

BACKGROUND QTc interval prolongation with an increased risk of torsade de pointes (Tsd) has been described in coronavirus disease 2019 (COVID-19) patients treated with hydroxychloroquine (HCQ) and azithromycin (AZI) in Western countries. In the DR Congo, few studies have evaluated the safety of this association or proposed new molecules. AIM To determine the incidence of QTc prolongation and Tsd in COVID-19 patients treated with HCQ-AZIs vs doubase C (new molecule). METHODS In present randomized clinical trial, we have included patients with mild or moderate COVID-19 treated with either HCQ-AZI or doubase C. Electrocardiogram (ECG) changes on day 14 of randomization were determined based on pretreatment tracing. Prolonged QTc was defined as ≥ 500 ms on day 14 or an increase of ≥ 80 ms compared to pretreatment tracing. Patients with cardiac disease, those undergoing other treatments likely to prolong QTc, and those with disturbed ECG tracings were excluded from the study. RESULTS The study included 258 patients (mean age 41 ± 15 years; 52% men; 3.4% diabetics, 11.1% hypertensive). Mild and moderate COVID-19 were found in 93.5% and 6.5% of patients, respectively. At baseline, all patients had normal sinus rhythm, a mean heart rate 78 ± 13/min, mean PR space 170 ± 28 ms, mean QRS 76 ± 13 ms, and mean QTc 405 ± 30 ms. No complaints suggesting cardiac involvement were reported during or after treatment. Only four patients (1.5%) experienced QTc interval prolongation beyond 500 ms. Similarly, only five patients (1.9%) had an increase in the QTc interval of more than 80 ms. QTc prolongation was more significant in younger patients, those with high viral load at baseline, and those receiving HCQ-AZI (P &lt; 0.05). None of the patients developed Tsd. CONCLUSION QTc prolongation without Tsd was observed at a lower frequency in patients treated with HCQ-AZI vs doubase C. The absence of comorbidities and concurrent use of other products that are likely to cause arrhythmia may explain our results.

Three-dimensional speckle tracking echocardiography for evaluation of ventricular function in patients with systemic lupus erythematosus: relationship between duration of lupus erythematosus and left ventricular dysfunction by using global longitudinal strain

BackgroundCardiovascular diseases are leading causes of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Cardiac involvement in SLE can often go undetected. Three-dimensional (3D) speckle tracking echocardiography (STE) is a noninvasive imaging technique that can assess the function of the heart’s ventricles in an accurate and reproducible way. This makes it an attractive option for detecting early signs of heart disease in SLE patients. By identifying these subclinical cardiac abnormalities, 3D-STE may help reduce the negative impact of cardiovascular diseases in SLE population. Therefore, this study aimed to compare the left ventricular (LV) function between patients with SLE compared to age- and gender-matched controls using two-dimensional (2D) and 3D-STE.ResultsThe current study found no significant differences in left ventricle ejection fraction, left ventricle end-diastolic volume, left ventricle end-systolic volume, left ventricle end-diastolic mass, and left ventricle end-systolic mass between the two groups. However, the SLE group exhibited a significantly lower LV global longitudinal strain (GLS) compared to the control group according to all types of echocardiographic assessments, including 3D and 2D long-axis strain, apical 2-chamber, and apical 4-chamber assessments (all P values < 0.05). Furthermore, a good inter-rater reliability and intra-rater reliability were observed regarding the LVGLS measurement with 3D-STE. Additionally, the study identified a significant correlation between LVGLS and SLE duration (r (50) = 0.46, P < 0.001). The use of prednisolone and nephrology disorders was also found to impact LVGLS measurements.ConclusionsDespite a normal LVEF in patients with SLE, LVGLS measurements indicated that LV systolic dysfunction was observed more frequently in SLE patients compared to their healthy counterparts. Therefore, advanced 3D-STE techniques may be useful in identifying subtle abnormalities in LV function in SLE patients.

Cardiac evaluation of patients with juvenile dermatomyositis.

The present study aims to evaluate possible cardiac involvement in juvenile dermatomyositis (JDM) patients by conventional methods and cardiac magnetic resonance imaging (MRI) along with a systematic review of the literature on cardiac features in JDM. The study group consisted of JDM patients who underwent cardiac MRI. We conducted a systematic review of the published literature involving JDM patients with cardiac involvement. In the present study, although baseline cardiologic evaluations including electrocardiography and echocardiography were within normal limits, we showed late gadolinium enhancement on cardiac MRI in 3 of 11 JDM patients. In the literature review, we identified 25 articles related to cardiac involvement in JDM. However, none of them, except one case report, included cardiac MRI of JDM patients. Cardiac abnormalities have been reported among the less frequent findings in patients with JDM. Cardiovascular complications during the long-term disease course are a leading cause of morbidity and mortality in these patients. Early detection of cardiac involvement by cardiac MRI in patients with JDM and aggressive treatment of them may improve the clinical course of these patients. The myocardium in patients with JDM may be involved by inflammation. Myocardial involvement may be evaluated by using contrast-enhanced cardiac MRI. This is the first study evaluating cardiac involvement by cardiac MRI in JDM patients. MRI may show early cardiac involvement in patients whose baseline cardiologic evaluations are within normal limits. Early detection of cardiac involvement by cardiac MRI may improve the long-term prognosis of patients with JDM.

A patient with pulmonary hypertension: a rare case of AL amyloidosis involving the heart and external auditory canal

The article presents a case of immunoglobulin light chain amyloidosis with cardiac involvement without typical noncardiac manifestations. A complex diagnostic search for the cause of newly diagnosed pulmonary hypertension is described. Aspects of differential diagnosis in invasive hemodynamic assessment of pulmonary circulation and echocardiographic data are discussed. A special case feature is involvement of the hearing organ, which is very rare.

Deciphering the Cardiovascular Conundrum of COVID-19: An In-depth Review

Abstract: The coronavirus disease pandemic raised a notable deal of discussion among scientists and the public, in addition to necessitating the adaptation of healthcare staff for nearly two years. COVID-19 caused various respiratory symptoms and lung damage. In addition, it also played a major role in insulting the circulatory system. The frequency of heart-lung involvement with its inverse relationship with prognosis is highlighted in the review. Direct cardiac involvement (COVID-19 myocarditis) was followed by subsequent cardiac involvement (myocardial damage, myocardial infarction, and arrhythmias). The coronavirus disease vaccination's continual effects, cardiovascular problems, and the way the virus aggravated preexisting cardiovascular illness were ultimately studied in this review.

Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis.

The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%. Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.

Exploring Periodontal Conditions, Salivary Markers, and Systemic Inflammation in Patients with Cardiovascular Diseases

(1) Background: This cross-sectional investigation appreciated the role of serum C-reactive protein (CRP), several hematologic-cell markers, and salivary inflammation-related molecules [calprotectin (S100A8/A9), interleukin-1β (IL-1β), kallikrein] to predict periodontitis in patients with atherosclerotic cardiovascular disease (ACVD), arrhythmia, or both. Also, we appreciated the relationship between the inflammatory burden and periodontal destruction with the type of cardiac pathology. (2) Methods: Demographic, behavioral characteristics, periodontal indicators, blood parameters, and saliva samples were collected. (3) Results: All 148 patients exhibited stage II or III/IV periodontitis. Stage III/IV cases exhibited significantly increased S100A8/A9 levels (p = 0.004). A positive correlation between S100A8/A9 and IL-1β [0.35 (&lt;0.001)], kallikrein [0.55 (&lt;0.001)], and CRP [0.28 (&lt;0.001)] was observed. Patients with complex cardiac involvement had a significantly higher number of sites with attachment loss ≥ 5 mm [19 (3–30)] compared to individuals with only arrhythmia [9 (3.25–18)] or ACVD [5 (1–12)] [0.048♦ {0.162/0.496/0.14}]. (4) Conclusions: Severe, extensive attachment loss may be indicative of patients with complex cardiac conditions, which underscores the essential role of periodontal status in relation to systemic diseases. The correlations between the rising trends of the inflammatory parameters suggest a potential interconnection between oral and systemic inflammation.

Eosinophilic Granulomatosis with Polyangiitis with ophthalmic involvement: A Case report and Literature Review

Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a systemic necrotizing vasculitis primarily affecting small blood vessels. It is characterized by extravascular eosinophilic granulomas, peripheral eosinophilia, and often coexists with asthma. This rare condition can affect individuals of any gender and age, presenting with a variety of multisystemic symptoms. Prognosis is largely influenced by cardiac involvement, evaluated using the Five-Factor Score (FFS) to guide treatment decisions. Respiratory manifestations, particularly severe and corticosteroid-dependent asthma, are common in EGPA and may aid in its early diagnosis. In this case report, we describe a patient with an uncontrolled asthma admitted for moderate asthma exacerbation. Clinical examination revealed ocular redness and skin lesions, along with hypereosinophilia on assessment and reticulo-micronodular infiltrates on chest CT scan. EGPA diagnosis was confirmed based on the ACR 1990 criteria, wich have been updated and substituted with more objective criteria in 2022. According to the FFS score, the patient underwent systemic corticosteroid therapy in conjunction with azathioprine, leading to an overall favorable outcome over a 3-year follow-up period.

Fabry disease caused by the GLA p.Gly183Asp (p.G183D) variant: Clinical profile of a serious phenotype

BackgroundThe detailed clinical phenotype of patients carrying the α-galactosidase gene (GLA) c.548 G > A/p.Gly183Asp (p.G183D) variant in Fabry disease (FD) has not been thoroughly documented in the existing literature. MethodsThis paper offers a meticulous overview of the clinical phenotype and relevant auxiliary examination results of nine confirmed FD patients with the p.G183D gene variant from two families. Pedigree analysis was conducted on two male patients with the gene variant, followed by biochemical and genetic screening of all high-risk relatives. Subsequently, evaluation of multiple organ systems and comprehensive instrument assessment were performed on heterozygotes of the p.G183D gene variant. ResultsThe study revealed that all patients exhibited varying degrees of cardiac involvement, with two demonstrating left ventricular wall thickness exceeding 15 mm on echocardiography, and the remaining six exceeding 11 mm. Impaired renal function was evident in all six patients with available blood test data, two of whom underwent kidney transplantation. Eight cases reported neuropathic pain, and five experienced varying degrees of stroke or transient ischemic attack (TIA). ConclusionThis study indicates that the GLA p.G183D gene variant can induce premature organ damage, particularly affecting the heart, kidneys, and nervous system.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C

ObjectivesThe aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. Study designMulticenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1–4, 5–11, 12–16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. ResultsTime to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. ConclusionsThe stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

Exploring the Role of Genetics in Sarcoidosis and Its Impact on the Development of Cardiac Sarcoidosis

Sarcoidosis is a multifaceted and multisystemic inflammatory disorder, the etiology of which remains unknown. However, it has been suggested that an intricate interplay between genetic, environmental, and inflammatory factors may contribute to the development and progression of sarcoidosis. Although 30–50% of patients demonstrate extra-pulmonary manifestations, cardiac involvement is rare, affecting only 2–5% of cases. Diagnosis is often challenging, relying on the careful application of clinical judgment, histopathological evidence, and imaging biomarkers. In this literature review, we aim to provide a comprehensive overview of the current understanding of the genetic basis of sarcoidosis, the contribution to the pathogenesis of the disorder, and discuss the potential link between certain genetic variants and the development of cardiac sarcoidosis.

Multisystem Inflammatory Syndrome in Neonates Associated with COVID-19 in Neonatal ICU of a Tertiary Care Hospital.

Neonatal multisystem inflammatory syndrome (MIS-N) is a unique disease of neonates described in several case reports from all over the world with a myriad of presentations and the emergence of new cases. Retrospective case series. Place and Duration of the Study: Department of Paediatrics, Fazaia Medical College, Pakistan Air Force Hospital, Islamabad, Pakistan, from December 2021 to November 2022. The study was conducted on neonates who were managed as MIS-N in the neonatal ICU. Data were collected and analysed on SPSS version 24. Patients in this study ranged from newborns to 13 days of age with a mean age of 3.27 ± 4.29 days and average gestational age of 35.18 ± 3.67 weeks. Among these neonates, 7 (63.6%) had bleeding diathesis, 11 (100%) had seizures, 8 (72.2%) presented with haemodynamic instability and shock, and 7 (63.3%) had signs of heart failure. All neonates (100%) had markedly raised SARS-CoV2 IgG antibodies, CRP, ferritin, D-dimers, interleukin 6, procalcitonin, 10 (90.9%) had hypoalbuminemia, and 7 (63.3%) had deranged coagulation profile. Cardiac involvement was seen in all neonates (100%) with raised proBNP and myocardial dysfunction on echocardiography. Pulmonary hypertension was present in 6 (54.4%) neonates. High mortality was observed at 6 (54.5%) among which 4 (66.6%) were premature neonates. MIS-N is a new disease entity which is still under research. There is a high propensity for cardiovascular system involvement and higher mortality among preterm neonates. Neonatal multisystem inflammatory syndrome (MIS-N), Multisystem inflammatory syndrome in children (MIS-C), SARS-CoV2 infection, SARS-CoV2 spike protein, SARS-CoV2 IgG antibodies.

Value of SLE-DAS in assessing disease activity in patients with systemic lupus erythematosus: a single-centre retrospective study

ObjectivesThis study aimed to evaluate the clinical value of the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) for assessing disease activity in patients with SLE.MethodsClinical data were collected from patients...

Early onset LGMDR19 with unusual features related to GMPPB gene in South Indian siblings with variable phenotype

Guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) is a cytoplasmic enzyme that catalyzes the synthesis of GDP-mannose, a crucial substrate for several glycosylation pathways. Reports of pathogenic variants in the GMPPB gene are infrequent. As of April 2023, 109 cases with pathogenic variants in the GMPPB gene have been reported worldwide. Here, we present two siblings born of consanguineous parentage from Southern India. This is a retrospective study on genetically confirmed siblings with GMPPB pathogenic variants. The siblings, a 15-year-old girl, and a 13-year-old boy, presented with progressive limb-girdle weakness and cataracts from early childhood. The girl had exertion-induced breathlessness and mental subnormality. Creatine kinase levels were 5750 and 4320 IU/L. An echocardiogram of the heart revealed global hypokinesia, moderate left ventricular dysfunction, and mild mitral regurgitation with dilation of the left atrium and left ventricle in the girl child. Exome sequencing showed a homozygous pathogenic variant (NM_021971.4 (GMPPB): c.358A&gt;G (p.Met120Val) in Exon 4 of GMPPB gene in both the siblings. Thus, we report an unusual early onset LGMD phenotype of GMPPB-related disorder with cardiac involvement and cataracts from a single family.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.

A Rare Case of Cardiac Amyloidosis Secondary to Multiple Myeloma in A Young Male Presenting with Shortness of Breath

Introduction: Multiple myeloma (MM) is a haematological malignancy associated with various systemic manifestations, including AL amyloidosis.AL amyloidosis is a systemic condition arising from abnormal protein misfolding and deposition, leading to organ dysfunction. Cardiorenal involvement is characteristic. Cardiac amyloidosis causes significant morbidity and mortality, particularly in MM patients. Case Report: A 40-year-old previously well male presented with exertional dyspnoea, lower limb swelling, and frothy urine. Clinical examination and investigations were consistent with an MM complicated by AL amyloidosis affecting the heart and kidneys. The diagnosis of amyloidosis was confirmed through renal biopsies revealing Congo red positivity, along with cardiac imaging showing typical amyloidosis findings. The presence of bone marrow plasma cells 72% confirmed myeloma. Conclusion: This case highlights the challenges in managing MM-associated AL amyloidosis with cardiac and renal involvement. It underscores the importance of comprehensive diagnostic approaches, multidisciplinary collaboration, and tailored treatment strategies. Despite the poor prognosis, diligent management can lead to favourable outcomes and improved quality of life for affected individuals.

LMNA p.Arg624His missense variant reduces lamin expression at mRNA level: elucidating molecular pathways toward cardiac involvement in laminopathies

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Innovation LMNA is a gene encoding lamin A/C proteins of the cell nuclear lamina. Pathogenic variants in LMNA cause a group of diseases known as laminopathies, a common cause of dilated cardiomyopathy (DCM). LMNA is the second most frequently mutated gene in DCM. Although molecular mechanisms underlying the cardiac involvement are unclear, previous studies have shown a reduction of the lamin expression in LMNA heterozygous mutation carriers. We identified a missense variant in LMNA, c.1871G&amp;gt;A (p.Arg624His), in a family affected with DCM. In this study, we analysed the impact of the p.Arg624His variant on the mRNA expression through quantitative PCR (qPCR) to demonstrate its pathogenicity. RNA was isolated from patient’s peripheral blood lymphocytes. Quantitative reverse transcription PCR (RT-qPCR) with LMNA specific primers was performed to measure lamin RNA levels. Whole-exome sequencing (WES) through next-generation sequencing (NGS) yielded an heterozygous missense variant in the LMNA gene (NM_170707.4(LMNA): c.1871G&amp;gt;A; p.Arg624His; ClinVar ID 66870) classified as variant of uncertain significance (VUS) in five members of a family affected with DCM. Computational (In-Silico) programs predict a damaging effect and variant is absent from controls in population databases. RT-qPCR demonstrated a significant reduction in the LMNA mRNA expression between the control (II.1) and affected family members (II.3, III.1) (Figure 2). According to evidence of co-segregation, variant frequency, results of in-silico predictors and mRNA reduction, LMNA p.Arg624His variant has been reclassified as pathogenic. In this study we reclassified to pathogenic a variant of uncertain significance in LMNA which reduces mRNA expression and leads to cardiac laminopathy. Further investigations are needed to determine the effect on the protein.