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Pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: the multifaceted consequences of PTPN11 mutations


The concomitant occurrence of hypertrophic cardiomyopathy and congenital heart defect in patients with RASopathies has previously been reported as associated to a worse clinical outcome, particularly closed to cardiac surgery. Different mechanisms of disease have been demonstrated to be associated with the two classes of PTPN11 mutations underlying Noonan syndrome and Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome). Although differential diagnosis between these two syndromes could be difficult, particularly in the first age of life, we underline the relevance in discriminating these two disorders in terms of affected signaling pathway to allow an effective targeted pharmacological treatment.

Dear Editor,

We read with interest a recent research by Chen and colleagues [1] reporting on the clinical and mutation profiles of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy (HCM). In this manuscript, the authors described the mutation spectrum causally linked to Noonan syndrome (NS) (MIM PS163950) and clinically related disorders, and the associated clinical outcome, based on a pediatric cohort of 47 affected subjects. An exhaustive genotype-phenotype correlation was reported. Particularly, the data allowed the authors to emphasize further the relevant contribution of the concomitant occurrence of congenital cardiac defects (CHDs) and left ventricular outflow tract obstruction (LVOTO) to the worse outcome of these patients. The authors also reported that patients with a diagnosis of NS based on clinical criteria and carrying two specific missense mutations in PTPN11 (c1417A > C, p.Q506P; c1528C > G, p.Q510E) showed an early-onset presentation of HCM and a worse clinical outcome. Indeed, out of this subgroup of eleven patients, three of them (p.Q506P, N = 1; p.Q510E, N = 2) died within 6 months from birth.

We agree with Chen and colleagues that the co-occurrence of HCM and CHDs is generally associated to a worse outcome in patients with RASopathies. Indeed, these patients may show a rapid progression of HCM and this can lead to early cardiac failure. These data are also in line with other recently published studies [2,3,4]. In particular, our experience confirms that a worse clinical outcome is strictly closed to complex cardiac surgery [2]. However, we would point out that the biochemical/functional behavior of PTPN11 mutations at codons 510 (including c.1528C > G) and 506 is drastically different from what observed for NS-causing PTPN11 mutations. Specifically, the former cause defective protein phosphatase activity and differentially affect intracellular signaling [5,6,7]. Consistent with their distinctive consequences on SHP2 function and signal transduction, these mutations do not cause NS but underlie Noonan syndrome with multiple lentigines (NSML), previously known as LEOPARD syndrome (MIM PS151100), a disorder similar but distinct from NS. NSML-associated PTPN11 mutations cluster within or close to the active site of the phosphatase, which explains their dramatic impact on phosphatase activity when compared with wild-type SHP2 and NS-causing PTPN11 mutations [5, 8, 9]. It should be noted that the presence of cutaneous manifestations as café-au-lait spots and multiple lentigines, which represent a distinctive feature of NSML, develop with age and do not generally occur in infancy. Based on this consideration, the absence of lentigines during infancy should not be used to exclude a diagnosis of NSML. HCM is an additional common complication of NSML. Differently from what reported by Chen and colleagues [1], it is now well-established, and also in line with previous reports [10], that c.1528C > G (p.Q510E) in PTPN11 is strictly associated to NSML. Review of published cases carrying the c.1528C > G missense change documents that most of the patients have a clinical diagnosis of NSML syndrome (Table 1) [11,12,13,14]. Notably, two among the three reported patients classified as having NS presented with HCM associated with deafness, a clinical feature characteristic for NSML (Table 1) [15,16,17]. In regard to c.1529A > C and c. 1530 G > C, also involving codon 510 of PTPN11, it should be noted that all of them have been reported in patients diagnosed as having NSML syndrome (Table 1) [18,19,20,21].

Table 1 Literature reports of patients carrying mutation at codon 510 of PTPN11 gene

While NS and NSML are genetic conditions with overlapping features, and clinicians experienced with these syndromes are aware of the difficulty in discriminating between these two disorders particularly in the first years of age [11, 22], we firmly believe that it is important to properly discriminate NSML from NS to allow a more effective patient management and a future personalized pharmacological treatment of the evolutive complications in these patients. Indeed, it is important to consider that different mechanisms of disease have been demonstrated to be associated with the two classes of PTPN11 mutations underlying NS and NSML. On one hand, we have hyperactive mutants promoting upregulation of MAPK signaling (NS-causing mutations), which can effectively be controlled by the use of inhibitors of signal transducers functioning in this cascade (e.g., MEK1 inhibitors) [23, 24]. On the other hand, we have hypomorphic mutants that result in enhanced signal flow through the PI3K-AKT-MTOR pathway (NSML-causing mutations). In this case, inhibitors targeting this specific cascade (e.g., AKT inhibitors, rapamycin analogs) are required to counterbalance and treat evolutive complications of NSML, including HCM [14, 25, 26]. On this argument, Wang et al. [26] reported an in vivo study suggesting that the AKT inhibitor ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients. Additionally, Hahn and colleagues [14] reported the effects of treatment with a rapamycin analog in an infant with NSML and severe HCM.

In summary, we should avoid the misleading causative association between NSML-causing PTPN11 mutations and NS, based on the diverse impact of these mutations on SHP2 function and intracellular signaling dysregulation, and their consequent significance in terms of patient management and future personalized therapeutic options.

Availability of data and materials

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Congenital cardiac defects


Hypertrophic cardiomyopathy


Left ventricular outflow tract obstruction


Noonan syndrome


Noonan Syndrome with Multiple Lentigines


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We thank Dr. Elisa Del Vecchio for her valuable collaboration in the editorial revision.


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All authors were involved in the initial conceptualization of this paper, providing critical input to the development of this manuscript. Finally, all authors were involved in the revision; they have read and approved the final manuscript. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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Correspondence to Giulio Calcagni.

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Calcagni, G., Digilio, M.C., Marino, B. et al. Pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: the multifaceted consequences of PTPN11 mutations. Orphanet J Rare Dis 14, 163 (2019).

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  • MAPK
  • Hypertrophic cardiomyopathy
  • RASopathy