Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis

Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.

440 Assessing cardiac output by echocardiography: is contrast always better?

Aims Contrast echocardiography is very useful in clinical cardiology. It is mainly performed for the assessment of global left ventricular (LV) function, left ventricular ejection fraction (LVEF), and stroke volume (SV), thanks to improved visualization of endocardial LV borders. Contrast echocardiography, however, is not always easily available, it is more expensive than an ordinary echocardiography and it can be contraindicated in some situations (e.g. in the presence of egg allergy). This study aimed to compare the estimation of cardiac output during traditional transthoracic echocardiography and after the injection of (Sonovue) contrast. Methods and results Patients who underwent an echocardiography with and without injection of (Sonovue) contrast between April 2019 and September 2021 were enrolled in the study. A complete transthoracic echocardiography was performed and Sonovue contrast was then injected. End-diastolic and end-systolic left ventricular volume in apex 4 and 2 chamber views, biplane LVEF with Simpson’s formula, end-diastolic and end-systolic left ventricular diameters in parasternal long axis were measured prior and after injecting contrast. Left ventricular outflow tract diameter (LVOTd) was measured and LV outflow tract velocity time integral was traced in order to calculate LVOT VTI SV, as the product of LVOT cross sectional area (assuming that LVOT is circular) to the LVOT VTI. LVOT VTI SV obtained during traditional echocardiography was compared to LVEF SV, calculated as the difference between end-diastolic and end-systolic volume traced after injecting Sonovue contrast. Seventy-eight patients were enrolled in the study. Forty-two had history of CAD, 22 presented dilatative cardiomyopathy, 2 hypertrophic cardiomyopathy (HMC), 1 arrhythmogenic right ventricular dysplasia; 16 had atrial fibrillation, 66 arterial hypertension, and 20 diabetes. The main indications for contrast echocardiography were measurement of EF (39 cases) and exclusion of thrombi in LV apex (18 cases). Other indications were suspect of HCM, atrial myxoma or LV non-compaction. LVOT VTI stroke volume was calculated in 64 patients (LVOT diameter was not well visualized in 8 patients and LVOT VTI could not be measured in 14 patients due to poor acoustic windows). In the same patients LVEF Stroke Volume was also calculated. A strong correlation (P-value < 0.0001) between LVOT stroke volume and LVEF Stroke Volume was found (Figure 1). Conclusions Contrast echocardiography is very useful in clinical practice, however, requires trained physicians and its use is not widespread. This study demonstrates that estimating cardiac output through LVOT VTI SV, in patients with suboptimal echo images can be equally accurate as measuring LVEF SV with contrast echocardiography. This could be particularly useful in the acute settings when contrast echocardiography isn’t always feasible and knowing cardiac output can be important for therapeutic implications.

Analysis of Selected Cardiovascular Biomarkers in Takotsubo Cardiomyopathy and the Most Frequent Cardiomyopathies

Introduction: Among the causes of de novo diagnosed cardiomyopathy, Takotsubo cardiomyopathy (TTC) plays a minor role, with an occurrence of 50,000–100,000 cases per annum in the United States. In clinical practice, a differentiation of a TTC toward an ischemic cardiomyopathy (ICMP) or a dilatative cardiomyopathy (DCMP) appears to be challenging, especially in a subacute setting or in atypical types of TTC.Methods: To investigate this issue, we analyzed serum levels of sST2, GDF-15, suPAR, HFABP, and clinical parameters including echocardiography in 51 patients with TTC, 52 patients with ischemic cardiomyopathy (ICMP) and 65 patients with dilated cardiomyopathy (DCMP).Results: sST-2 seemed to be the most promising biomarker for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.879, p = < 0.001, Cut off values: 12,140.5 pg/ml) or to a DCMP (AUC: 0.881, p = < 0.001, cut off value: 14521.9 pg/ml). GDF-15 evidenced a slightly lower AUC for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.626, p = 0.028) and to a DCMP (AUC: 0.653, p = 0.007). A differential diagnostic value was found for H-FABP in the prediction of a DCMP compared to TTC patients (AUC: 0.686, p = < 0.001). In propensity score matching for left ventricular ejection fraction, sex, and cardiovascular risk factors, differences in the plasma levels of sST2 and H-FABP in the matched cohort of TTC vs. DCMP remained statistically significant. In the matched cohort of TTC vs. ICMP, differences in sST2 also remained statistically significantConclusion: As medical therapy, long term prognosis, interval of follow-ups, rehabilitation program and recommendations differ completely between TTC and ICMP/DCMP, biomarkers for differential diagnosis, or rather for confirmation of diagnosis, are warranted in cases of cardiomyopathies with unsure origin. sST-2, GDF-15 and H-FABP might facilitate the classification.

Pathogenesis, Diagnosis, and Clinical Implications of Hereditary Hemochromatosis—The Cardiological Point of View

Hereditary hemochromatosis (HH) is a genetic disease leading to excessive iron absorption, its accumulation, and oxidative stress induction causing different organ damage, including the heart. The process of cardiac involvement is slow and lasts for years. Cardiac pathology manifests as an impaired diastolic function and cardiac hypertrophy at first and as dilatative cardiomyopathy and heart failure with time. From the moment of heart failure appearance, the prognosis is poor. Therefore, it is crucial to prevent those lesions by upfront therapy at the preclinical phase of the disease. The most useful diagnostic tool for detecting cardiac involvement is echocardiography. However, during an early phase of the disease, when patients do not present severe abnormalities in serum iron parameters and severe symptoms of other organ involvement, heart damage may be overlooked due to the lack of evident signs of cardiac dysfunction. Considerable advancement in echocardiography, with particular attention to speckle tracking echocardiography, allows detecting discrete myocardial abnormalities and planning strategy for further clinical management before the occurrence of substantial heart damage. The review aims to present the current state of knowledge concerning cardiac involvement in HH. In addition, it could help cardiologists and other physicians in their everyday practice with HH patients.

The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.

Abstract 15833: Immune Checkpoint Inhibitor Myocarditis Subtypes are Determined by a Cd8-dependent Transcriptional Program

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing clinical use leads to higher rates of adverse immune related events (irAEs). One of those irAEs is the ICI-induced myocarditis (ICIM) - a rare phenomenon with an estimated mortality rate of up to 50%. We aimed to characterize the molecular changes of ICIM which are not yet understood completely. Methods: Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11) and virus-induced myocarditis (VIM, n=5). Results: Clinical analysis of 19 patients with ICIM showed an inconsistent presentation, e.g. an elevation of cardiac biomarkers (hsTnT, NT-proBNP, CK), a drop in leftventricular ejection fraction or late gadolinium enhancement in cMRI. We found 3784 (FDR <0.05) upregulated genes in ICIM. Among the genes that were related to antigen presentation and processing, we mainly found an upregulation of CD8. CD8-dependent clustering of ICI-patients, on the other hand, was associated with a number of immune cell-specific genes (compared to VIM: CXCL11 (log2 fc 3.24), CXCL9 (log2 fc 4.37), GBP6 (log2 fc 5.37), GBP5 (log2 fc 3.21). Analysis of high- and low-expressing CD8 positive biopsies identified two expression patterns, suggesting different pathological mechanisms for ICIM. Conclusion: Taken together, we were able to identify CD8 and CD8-associated genes as specifically regulated transcripts in ICIM. Moreover, based on the variable clinical phenotype, we propose that analysis of CD8 and CD8-dependent genes will be important to identify ICIM patients and to potentially sub-differentiate different phenotypes.

Clinical outcome of prenatally suspected cardiac rhabdomyomas of the fetus

BackgroundThe main objective of this retrospective analysis in a large tertiary center was the clinical outcome of prenatally diagnosed cardiac rhabdomyomas as well as the identification of factors influencing fetal prognosis.MethodsA total of 45 cases of fetuses with prenatally suspected rhabdomyoma and their clinical outcome were analyzed retrospectively. A review of the literature was also performed.ResultsIn five cases, after a tuberous sclerosis complex (TSC) mutation had been confirmed, termination of pregnancy was chosen. In 30 cases postnatal data were available. In 93% TSC was confirmed clinically or by mutational analysis. Two thirds of fetuses presented with multiple tumor while one third presented with a solitary tumor. In two fetuses mild pericardial effusions were observed. Another three fetuses presented with extrasystoles prenatally. No hydrops fetalis or fetal perinatal demise were observed. After birth 41% of the children suffered from arrhythmia including supra- and ventricular tachycardia, Wolff-Parkinson-White syndrome and atrioventricular block. One child received a Fontan procedure with Glenn anastomosis. Another child with a dilatative cardiomyopathy and a left ventricular ejection fraction of 15% died. Fifty-two percent of the children with TSC suffered from epilepsy ranging from absence epilepsy and West syndrome to generalized seizures with a frequency of up to 40 per day. Two children underwent neurosurgery to remove the epileptogenic focus. One child suffered from TSC and Lesch-Nyhan disease. In another case Beckwith-Wiedemann syndrome was identified as the causative disorder.ConclusionRhabdomyoma are rare, benign tumors. There is an association with TSC. In the majority of cases rhabdomyoma are not hemodynamically relevant and do not increase in size. The quality of life of affected patients is impaired particularly due to epilepsy and psychomotor retardation.

P5557Cardiac autoantibodies and ventricular arrhythmias in patients with biopsy-proved myocarditis

Background Cardiac autoandibodies have been associated with dilatative cardiomyopathy in subjects with inflammatory heart disease. However, their association with ventricular arrhythmias (VA) in patients with autoimmune myocardits has never been investigated so far. Purpose To evaluate the association between cardiac autoantibodies and both baseline and FU VA in patients with a de novo diagnosis of biopsy-proved autoimmune myocarditis. Methods We enrolled 44 consecutive patients (59% males, mean age 44±13y, mean LVEF 50±10%) presenting with symptomatic VA (VF, VT, NSVT, >1ehz746.0501 PVC/24h) and a de novo diagnosis of biopsy-proved autoimmune myocarditis according to the ESC criteria. Serum anti-heart (AHA) and anti-intercalated disk (AIDA) autoantibodies were assessed at a referral center at the time of the index hospitalization. Complete baseline data, including ECG, arrhythmia telemonitoring, echocardiogram, cardiac magnetic resonance (CMR) and blood biomarkers (T-troponin, NT-proBNP) were collected. The endpoint of the study was the occurrence of major VA (VT, VF, appropriate ICD shocks) at 5y FU, as assessed by 2/y Holter ECG monitoring and (when applicable) ICD interrogation. Results At baseline evaluation, 24 (55%) and 23 patients (52%) were AHA+ and AIDA+, respectively. Clinical onset with major VA was documented in 24 patients (55%): 9 AHA+ vs. 15 AHA- (p=0.017) and 13 AIDA+ vs. 11 AIDA- (p=0.547). At presentation, no significant differences were found between AHA+ vs. AHA- and AIDA+ vs. AIDA- patients in LVEDV, LVEF, T-troponin and NT-proBNP values (all p=n.s.). Positive (2/3) Lake Louise criteria at CMR were found in 33 patients (75%; p=n.s. among different subgroups). Before discharge, 27 subjects (61%) underwent ICD implant. Optimal medical treatment was started in all of the cases, with no significant differences in betablockers, antiarrhythmic drugs and immunsuppressive therapy, among different subgroups (all p=n.s.). Overall, 10 patients (23%) experienced major VA by 5y FU: 3 AHA+ vs. 7 AHA- (p=0.147) and 9 AIDA+ vs. 1 AIDA- (p=0.013). In particular, 18 events were documented (range 1–3 episodes per patient at 2.2±1.7 y mean FU), including 3 VT episodes and 15 appropriate ICD shocks. Taking together baseline and FU data, multiple (>1) major VA episodes occurred in 8 patients: 3 AHA+ vs. 5 AHA- (p=0.436) and 8 AIDA+ vs. 0 AIDA- (p=0.005). Of note, 3/3 AHA+ patients with multiple major VA espisodes were also AIDA+ (double positivity). Conclusion In biopsy-proved autoimmune myocarditis presenting with VA, major VA occurrence by 5y FU, as well as arrhythmias recurrences, are more common among AIDA+ patients. By converse, none of the isolated AHA+ cases experienced multiple episodes of major VA. These findings may suggest distinct pathophysiological mechanisms involving the different molecular targets of cardiac autoimmunity. Acknowledgement/Funding None

Congenital Pseudohypoparathyroidism – A Late Diagnosis

The purpose of this paper is to present a case of congenital pseudohypoparathyroidism, late diagnosed in a 22-year-old patient.The patient’s history revealed hypocalcaemia, diagnosed at birth and persistent despite the treatment with calcium. At 8 years old, the patient is diagnosed with epilepsy and receives treatment with Levetiracetam and Oxcarbazepine; at 12 years old she is diagnosed with dilatative cardiomyopathy and receives treatment with Spironolactone and Glycosides. At 22 years old, she visits our Internal Medicine Department with the suspicion of polymyositis and psoriasis. Clinical examination shows armonic short stature, fourth finger hypoplasia, laboratory findings show severe hypocalcaemia, the hand X-ray - third and fourth metacarpal hypoplasia, immunological tests were negative. All data leads to the diagnosis of congenital disease, and given the history of the patient and the evolution of the clinical manifestations we presume hypoparathyroidism or pseudohypoparathyroidism, therefore PTH is dosed – with normal values, and the diagnosis of congenital pseudohypoparathyroidism is established. The patient was referred to endocrinology, where genetic tests were performed to confirm the diagnosis.In conclusion, in the absence of multiple pathology integration into a single disease, the diagnosis of the genetic disease is delayed. Therefore, it is important to have a comprehensive approach and collaboration between different specialties to establish the correct diagnosis.