Cardiac transplantation in children with Noonan syndrome

Abstract

NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS‐specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post‐discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.

Variants of significance: medical genetics and surgical outcomes in congenital heart disease

“…Approximately 40-65% of patients with Noonan Syndrome can have significant bleeding diathesis because of a number of anomalies in the clotting cascade including deficiency of multiple clotting factors, von Willebrand deficiency, platelet dysfunction, and thrombocytopenia in isolation or combination which can change over time [54][55][56][57]. This makes evaluation complex as a significant number of labs need to be drawn for a comprehensive coagulation evaluation and sometimes the blood volume is limiting in infants [58].…”

“…Outcomes from cardiac transplantation in Noonan Syndrome demonstrate issues with bleeding in three of the 18 patients. One patient had known von Willebrand disease, another had severe thrombocytopenia which was associated with extramedullary hematopoiesis requiring splenectomy, and one patient ultimately died posttransplant with a portal vein thrombosis and ischemic bowel [55]. It is recommended that patients with Noonan Syndrome with known coagulopathy be treated as high-risk transplant candidates with surveillance for both bleeding and thrombosis [55].…”

“…One patient had known von Willebrand disease, another had severe thrombocytopenia which was associated with extramedullary hematopoiesis requiring splenectomy, and one patient ultimately died posttransplant with a portal vein thrombosis and ischemic bowel [55]. It is recommended that patients with Noonan Syndrome with known coagulopathy be treated as high-risk transplant candidates with surveillance for both bleeding and thrombosis [55]. Underlying all of this is the fact that Noonan Syndrome is underdiagnosed in CHD as it molecularly requires specific suspicion and specific molecular testing [57].…”

“…RASopathies, the most common of which is being Noonan Syndrome, have significant risk for cardiomyopathy, but thankfully cardiac transplantation seems to be rare and generally not due to congenital structural cardiac concerns [55]. 1p36 deletion is a known cause of both CHD and left ventricular noncompaction cardiomyopathy [64,65].…”

Mary Ella Mascia Pierpont: Geneticist, scientist, mentor, friend (1945–2020)

“…During the past 10 plus years, her major research interest involved studies of the RASopathies, especially Noonan and cardiofaciocutaneous (CFC) syndromes. She wrote several expert studies focused on cardiac complications in the RASopathies (McCallen et al, 2019; Menon, Pierpont, & Driscoll, 2008; Pierpont et al, 2014; Pierpont & Digilio, 2018; Romano et al, 2010). She was also a clinical expert in aortopathies, a site investigator for the National Heart, Lung, and Blood Institute (NHLBI)‐funded Trial of Beta Blocker Therapy (Atenolol) versus Angiotensin II Receptor Blocker Therapy (Losartan) in Individuals with Marfan Syndrome and an influential participant in the resulting study (Lacro et al, 2014).…”