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

Am J Med Genet A. 2015 Apr;167A(4):744-51. doi: 10.1002/ajmg.a.36982. Epub 2015 Feb 23.


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 malignant HCM. In the boy, progressive HCM was diagnosed during the first week of life and a diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in PTPN11. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated enhanced Akt/mTOR pathway activity. 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 9,600 to <1,000 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 principally be feasible for infantile NSML. The preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling.

Keywords: NSML; Noonan syndrome with multiple lentigines; PTPN11; RASopathy; hypertrophic cardiomyopathy; mTOR.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Cardiomyopathy, Hypertrophic / diagnosis*
  • Cardiomyopathy, Hypertrophic / surgery
  • DNA Mutational Analysis
  • Disease Progression
  • Everolimus / therapeutic use*
  • Genetic Association Studies
  • Heart Transplantation
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • LEOPARD Syndrome / diagnosis*
  • LEOPARD Syndrome / surgery
  • Male
  • Mutation, Missense
  • Myocardium / pathology
  • Palliative Care
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics


  • Immunosuppressive Agents
  • Everolimus
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11