Pediatric Cardiology

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension. View Article Haarman MG, Kerstjens-Frederikse WS, Vissia-Kazemier TR, Breeman KTN, Timens W, Vos YJ, Roofthooft MTR, Hillege HL, Berger RMF. J Pediatr. 2020 Jun 2:S0022-3476(20)30689-2. doi: 10.1016/j.jpeds.2020.05.051. Online ahead of print. PMID: 32502478 Take Home Points: Prevalence of pulmonary arterial hypertension (PAH)-associated gene disorders and other genetic disorder was high in pediatric patients with PAH. In this study, 27% had a PAH-associated gene mutation/variant, 17% had a genetic disorder with an established association with PAH and in 23% genetic disorders without an established association with PAH were identified. Underlying genetic mutation impact survival and can be useful in risk stratification. Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric Cardiology Journal Watch:   This study describes the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry. The study also explores genotype-phenotype associations and outcomes. Of the 70 subjects in the study 19 (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beal’s syndrome, and various copy number variations). Of the 70 children tested, 40 children were diagnosed with isolated PAH. Transplant-free survival, unadjusted for clinical variables, varied significantly between groups of children with different genetic disorders. Children with CbIC deficiency and children with PVOD had the worst unadjusted outcome with a median transplant-free survival of <1 year, whereas pediatric TBX4 variant carriers showed the most favorable outcome.

Multi-System Inflammatory Syndrome in Children in Association with COVID-19. View Article Simpson JM, Newburger JW. Circulation. 2020 Jun 11. doi: 10.1161/CIRCULATIONAHA.120.048726. Online ahead of print. PMID: 32525700 Take Home Points: Multisystem inflammation in children (MIS-C) is a newly recognized syndrome mimicking Kawasaki disease in some aspects of clinical presentation and clinical course temporally associated with COVID-19 infection. Multisystem inflammatory syndrome in children shares similarities with atypical Kawasaki disease, however, clinical criteria of diagnosis of Kawasaki disease was not fulfilled. Coronary dilation including giant aneurysm can happen. Markers of inflammation and cardiac involvement—including troponin I, brain natriuretic peptide, D-dimer, C-reactive protein, and interleukin 6—were all elevated. Left ventricular systolic dysfunction requiring ionotropic support is common. Additional studies are needed to determine the longer-term impact of MIS-C on myocardial function and coronary arteries. The optimal treatment for MIS-C is uncertain. Patients are often treated with immunomodulatory therapy including intravenous immunoglobulin and steroids. In more severe cases e anakinra, infliximab, or tocilizumab has been used. Comment from Dr. Shaji Menon (Salt Lake City, Utah), section editor of Pediatric Cardiology Journal Watch:  This article is an excellent commentary on the above discussed original article by Simpson and Newburger.

Quiat D, Witkowski L, Zouk H, Daly KP, Roberts AE.J Am Heart Assoc. 2020 Jun 2;9(11):e016195. doi: 10.1161/JAHA.120.016195. Epub 2020 May 27.PMID: 32458740   Take Home Points:   Clinical genetic testing identifies about ⅓ of patients with a primary dilated cardiomyopathy (DCM) with many variants of unknown significance (VUS). Reevaluation/reclassification of prior genetic testing decreased the number of VUS but a large number still remained. Familial genetic testing may help with interpretation of the results.   Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch:  Only ~ 30-50% of DCM cases have an identifiable etiology, with neuromuscular and myocarditis being the most common. With the improvement in genetic testing, many of the “idiopathic” cases have shown pathogenic variants. However, the amount of VUS has been quite high, and in some regards, this could be considered almost as a “worst case scenario” since it remains unclear if this is the pathogenic etiology or a benign variant. This can markedly affect future family planning or determine prognosis in genotypic carriers. In 2015, the American College of Medical Genetics and Genomics established a 5-tier classification system for VUS (pathogenic, likely pathogenic, uncertain significance, likely benign, benign). This, along with an increase in testing panel content and availability of allele databases, people with a VUS on testing in the past may be able to be reclassified, allowing for improved diagnosis, prognosis, and family counseling.   In this paper, a cohort of 63 patients over a 10 year period (2008-2018) with DCM was evaluated. 18% had a family history of cardiomyopathy or sudden death. 30% had a disease causing variant identified with nearly half occurring de novo. 116 variants were found on initial gene testing, 8 classified as pathogenic, 11 likely pathogenic, 90 VUS, 3 likely benign, and 2 benign (and an additional 2 as unclassified). Reclassification was performed which resulted in the downgrading of 29% (26/90) of VUS to either likely benign or benign and an absolute decrease in the number of BUS from 60% to 52% and an increase in likely benign/benign from 14% to 24%. See table 2. In those with a positive family history (9), 3 variants were inherited and 6 were de novo mutations. In 6 patients with potentially disease causing VUS, familial testing showed 3 occurring de novo and 3 inherited. Interestingly though, they did not find a difference in rates of positive cardiomyopathy genetic testing in patients with (27%) or without (33%) a family history cardiomyopathy or sudden death. With regards to testing, larger gene panels (> 50) found 27% with pathogenic variants vs. 20% in smaller panels (< 50). Of their cohort, 29/63 (46%) underwent heart transplantation or died during the follow up period.   This study shows that periodic reclassification and familial cascade genetic testing can reduce the number of VUS to allow for better diagnosis and future screening for DCM. Unfortunately, the percentage of VUS remains high, so hopefully with further reevaluation as larger panels and other advances are made (or use of whole genome testing is done), this can be improved. Since there are no clear guidelines for how to undergo this process, the authors recommend a review of genetic testing any time there is a VUS, more than a year has passed, and the parents are planning to have more children.