Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.

Ischemic Stroke in Adults With Congenital Heart Disease: A Population-Based Cohort Study.

Background Congenital heart disease (CHD) is associated with risk factors for ischemic stroke including cardiac arrhythmias and heart failure. However, few long-term follow-up data exist on ischemic stroke risk and associated mortality in adults with CHD. Methods and Results Using Danish nationwide registries, we identified individuals aged ≥18 years diagnosed with CHD, at any age, from 1963 to 2017 and a sex and birth year-matched (1:10) general population comparison cohort. We computed risks, as well as sex and birth year-adjusted hazard ratios (aHRs) for ischemic stroke and 30-day post-stroke mortality in CHD adults compared with the general population. Analyses were stratified according to age <60 years (young) and ≥60 years (older). We identified 16 836 adults with CHD. The risk of ischemic stroke at age 60 years was 7.4% in the CHD cohort and 2.9% in the general population cohort. The adjusted hazard ratios for ischemic stroke compared with the general population was 3.8 (95% CI: 3.3-4.3) in young CHD adults and 1.6 (95% CI: 1.4-1.9) in older CHD adults. The adjusted hazard ratios for post-stroke mortality compared with the general population was 2.3 (95% CI: 1.2-4.4) in young CHD adults and 1.3 (95% CI: 0.9-1.9) in older CHD adults. Conclusions Both younger and older CHD adults have an increased risk of ischemic stroke and by 60 years of age 7.4% of CHD adults will have had an ischemic stroke. Post-stroke mortality was also increased in CHD adults compared with the general population.

Adverse events rates and risk factors in adults undergoing cardiac catheterization at pediatric hospitals--results from the C3PO.

OBJECTIVE: Determine the frequency and risk factors for adverse events (AE) for adults undergoing cardiac catheterization at pediatric hospitals. BACKGROUND: Adult catheterization AE rates at pediatric hospitals are not well understood. The Congenital Cardiac Catheterization Project on Outcomes (C3PO) collects data on all catheterizations at eight pediatric institutions. METHODS: Adult (≥ 18 years) case characteristics and AE were reviewed and compared with those of pediatric (<18 years) cases. Cases were classified into procedure risk categories from 1 to 4 based on highest risk procedure/intervention performed. AE were categorized by level of severity. Using a multivariate model for high severity AE (HSAE), standardized AE rates (SAER) were calculated by dividing the observed rates of HSAE by the expected rates. RESULTS: 2,061 cases (15% of total) were performed on adults and 11,422 cases (85%) were performed on children. Adults less frequently underwent high-risk procedure category cases than children (19% vs. 30%). AE occurred in 10% of adult cases and 13% of pediatric cases (P < 0.001). HSAE occurred in 4% of adult and 5% of pediatric cases (P = 0.006). Procedure-type risk category (Category 2, 3, 4 OR = 4.8, 6.0, 12.9) and systemic ventricle end diastolic pressure ≥ 18 mm Hg (OR 3.1) were associated with HSAE, c statistic 0.751. There were no statistically significant differences in SAER among institutions. CONCLUSIONS: Adults undergoing catheterization at pediatric hospitals encountered AE less frequently than children did. The congenital heart disease adjustment for risk method for adults with congenital heart disease is a new tool for assessing procedural risk in adult patients.

Pulmonary atresia with ventricular septal defect and multifocal pulmonary blood supply: does an intensive interventional approach improve the outcome?

INTRODUCTION: Pulmonary atresia with ventricular septal defect (VSD) continues to be associated with significant morbidity and mortality, with significant institutional variation in therapeutic strategies. This study reports a single center experience utilizing an intensive transcatheter approach to promote pulmonary vascular growth. METHODS: A retrospective analysis of 20 patients undergoing surgical and transcatheter treatment for pulmonary atresia with VSD between 2002 and 2010. RESULTS: The median age at initial surgical palliation was 6.3 months (8 days to 2.5 years). Eleven patients (group 1) underwent initial surgical palliation without VSD closure and nine patients (group 2) underwent an initial complete repair with fenestrated or complete VSD closure. Group 1 had a smaller Nakata index (54 mm2/m2 vs. 134 mm2/m2 , P = .04) and a smaller absolute native pulmonary artery diameter (2.7 mm vs. 4.5 mm, P = .01) than group 2. Intraoperative angiography was performed in 10 cases to evaluate if early transcatheter intervention was warranted. The median follow-up during the study period was 2.3 years (1.6 months to 8.3 years). Of the 16 patients who survived the initial early postoperative period, 15 patients (94%) went on to receive surgical (n = 11) and/or interventional (n = 25) catheterization procedures. There was improvement in the mean Nakata index from the initial presurgical evaluation to the most recent catheterization data (38.4 mm2/m2 vs. 169.7 mm2/m2, P ≤ .05). To date, two of 11 (18%) patients in group 1 ultimately underwent surgical VSD closure. Overall mortality was six of 20 (30%) with four deaths in group 1 and two deaths in group 2. There were no procedural deaths. CONCLUSIONS: Combining surgical unifocalization procedures with subsequent early and intensive catheter-based pulmonary artery rehabilitation may improve vascular growth, ultimately rendering many patients suitable for fenestrated VSD closure. Risk stratification, including intraoperative exit angiography, is essential to determine the need for early transcatheter interventions.

Tissue Doppler measurements correlate with central venous pressure in pediatric patients after cardiac surgery.

Tissue Doppler imaging (TDI) measurements have been demonstrated to correlate with central venous pressure (CVP) in adults. We hypothesize that TDI measurements also correlate with CVP in children after cardiac surgery. Patients younger than 10 years with invasive CVP monitoring after cardiac surgery were studied. Annular tissue and atrioventricular inflow velocities were measured daily during CVP monitoring. Tissue Doppler imaging measurements were compared with CVP by univariate analyses. Subgroup analyses were performed for univentricular versus biventricular hearts. p values < or = 0.05 were considered significant. Fifty studies were performed on 28 subjects; 20 studies were performed on patients with univentricular physiology; and 30 studies were performed on patients with biventricular physiology. For all subjects, CVP correlated significantly with the right ventricular TDI measurements of e' velocity (r = -0.43), a' velocity (r = 0.35), e'/a' ratio (r = -0.42), and E/e' ratio (r = 0.44). For biventricular patients, e' velocity (r = -0.35), e'/a' ratio (r = -0.38), and E/e' ratio (r = 0.58) correlated significantly. For univentricular patients, E velocity (r = -0.62), e' velocity (r = -0.50), and a' (r = 0.61) velocity correlated significantly. Tissue Doppler imaging measurements of the right heart significantly correlated with invasively measured CVP in pediatric subjects. Different measures may correlate more strongly in those with biventricular versus univentricular physiology. With additional study, TDI may prove a valid tool for noninvasively assessing CVP in children with both bi- and univentricular physiology.

Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells.

PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens. RESULTS: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.