Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: Palliative treatment with a rapamycin analog

Abstract

Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and a malignant form of HCM. In the boy, progressive HCM was diagnosed during the first week of life and diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in the PTPN11 gene. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated reduced RAS/MAPK and enhanced Akt/mTOR pathway activities. Because of the patient’s critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9600 to <1000 pg/ml, but no reversal of cardiac hypertrophy was observed. Examination of the explanted heart revealed severe hypertrophy and myofiber disarray with extensive perivascular fibrosis. These findings provide evidence that Akt/mTOR activity is enhanced in NSML with HCM and suggest that rapamycin treatment could be principally feasible for infantile NSML. But the preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling.

Low-dose dasatinib rescues cardiac function in Noonan syndrome

“…Similarly, NSML mouse models that present with HCM have been reported to respond to inhibition of the mTOR pathway using rapamycin (25). Clinical studies also have reported that treatment with a rapamycin analog in a NSML patient improved cardiomyopathy and decreased brain natriuretic peptide levels in serum (26). Whereas treating the cardiac defects for NS or NSML might require distinct therapeutic regimens, our data suggest that in conditions in which either NS-or NSML-related cardiac dysfunction is suspected, a single therapeutic such as dasatinib might provide a novel strategy to improve cardiac functionality.…”

“…Given the clinical importance there has been significant interest in developing pharmacological treatments for cardiomyopathies in NS and NSML (24). It has been shown that inhibitors of the Akt/mTOR pathway can ameliorate HCM in the NSML model (25,26), whereas, genetic interference with, or pharmacologic inhibition of, MEK/ERK in a NS mouse model suppresses the development of CHD (27)(28)(29)(30). Uncovering targets and subsequently viable pharmacological therapies that encompass the overlapping clinical spectra between NS and NSML should fulfill a significant unmet clinical need.…”

Heart Failure in Pediatric Patients With Congenital Heart Disease

“…44 Recently, the first trial of a mTOR inhibitor was reported in an infant with NSML and rapidly progressive HCM with a goal of halting progression of hypertrophy and outflow tract obstruction until the time of transplant. 45 An understanding of the genetic basis of HF in this case led to trial of a pathway specific inhibitor for treatment.…”

Recent advances in RASopathies

“…An inhibitor of mammalian target of rapamycin has been shown to reverse heart defects in both a mouse model of 74 and in an individual with NSML. 75 Histone demethylase inhibitors that might not be directly associated with the RAS/ERK pathway have also been shown to ameliorate the phenotype of a mouse model of CFC syndrome. 73 Further studies will explore the pathogenetic mechanisms behind and therapeutic approaches for RASopathies.…”