Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

Abstract

BACKGROUND: We aimed to examine clinical features, and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z -score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z -score (absolute regression); (3) a reduction ≥15% of the MLVWT z -score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2–12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%–100%) 1 year after presentation and 80.9% (95% CI, 70.1%–90.7%) at 5 years. Patients with MLVWT z -score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6–7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.

Lessons From a Genotype-Phenotype Study About the Clinical Spectrum of Hypertrophic Cardiomyopathy Associated With Noonan Syndrome With Multiple Lentigines and PTPN11-Mutations

“…The authors have collected the hitherto largest group of patients with specifically PTNP11-mutations in exon 7, 12, and 13 associated with NSML-HCM for a single-gene genotype-phenotype-association study. 11 The report has a similar age-spectrum to earlier reports and highlights several facts about the clinical signs useful to alert clinicians that NSML rather than NS is present. Lentigines and hypertelorism are present only in 39% and 50% of the cases with infant diagnosis, respectively, explaining why a clinical diagnosis of NSML may be missed in infancy.…”

“…Sensorineural hearing loss is helpful in the diagnosis, but it is only present in 10 out of 42 cases. 11 The long-term survival was good in patients with maximal LV wall thickness z-score <13.7 at diagnosis whereas there were 5 deaths in the first 5 years among those with a z-score >13.7. 11 Age at diagnosis was also a factor, with 4/16 of patients diagnosed <6 months of age dying or requiring a heart transplant.…”

“…10 In another study of 47 pediatric cases of RASopathy-HCM, there were three deaths in congestive heart failure in the first year of life, all associated with an exon 13 PTNP11-mutation. 2 It is therefore very welcome to have an article by Monda et al 11 in this issue, which broadens the perspective on NSML patients with HCM. The authors have collected the hitherto largest group of patients with specifically PTNP11-mutations in exon 7, 12, and 13 associated with NSML-HCM for a single-gene genotype-phenotype-association study.…”

“…However, although patients with exon 13 mutations had significantly higher initial posterior LV wall thickness than those of exon 7 and 12, they did not have a significantly higher proportion of adverse clinical outcomes in contrast to previous smaller studies. 11 Identical mutations in the same exon can be associated with diagnosis at a wide range of ages, and with a wide range of degree of hypertrophy (Table S1). The authors conclude quite rightly that "the phenotype of the patient should drive the management in NSML-HCM regardless of genetic variants. "…”

“…The authors conclude quite rightly that "the phenotype of the patient should drive the management in NSML-HCM regardless of genetic variants. " 11 The authors report 2 sudden cardiac deaths and 2 appropriate implantable cardioverter defibrillator-discharges among the 42 patients with a median followup of 3.7 years. 11 Considering that 24 of the patients were diagnosed below 4 years of age, and not likely to have reached the age at higher risk of sudden cardiac death, 4 this is a high proportion.…”