Patients with pathogenic variants in the Ras-ERK pathway (Ras-opathies) can present with a broad array of clinical features, including features associated with inborn errors of immunity (IEI), predisposition to malignancy (JMML) and autoimmunity [2, 3]. An increased susceptibility to infection and/or hypogammaglobulinemia, however, has not been described before among NS patients aside from secondary hypogammaglobulinemia in patients with NS-related lymphangiectasia [4].

Mutations in genes (PTEN, PI3KCD, PI3KR1) associated with the PI3K/AKT/mTOR kinase pathway that lead to increased AKT phosphorylation and subsequently increased S6 kinase activity produce a clinical phenotype (activated PI3-kinase delta syndrome– APDS) that includes increased susceptibility to viral infection, lymphoma, hypogammaglobulinemia, and lymphoproliferation [5,6,7,8]. Increased pAKT has been demonstrated in activated T cells of patients with APDS [5,6,7]. Increased pAKT has also been demonstrated in unstimulated B cells from patients with APDS, allowing discrimination from patients with antibody deficiency of alternative aetiology [9]. Other IEI’s known to dysregulate the mTOR-S6 kinase pathway include LRBA deficiency and IEI’s related to mutations in genes associated with the CARD11-BCL10-MALT1 (CBM) signalosome [8]. These conditions together are sometimes referred to as “immune-TOR-opathies”.

The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase- protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signalling pathways are central to the control of cell survival, proliferation, metabolism, and response to extracellular cues [10]. There is evidence of intersection and cross regulation between these pathways (Fig. 2). The Ras-ERK pathway cross-activates PI3K-mTORC1 signalling by regulating PI3K, TSC2, and mTORC1, and increased activation of the RAS-ERK pathway can also lead to mTORC1 activity through ERK and ribosome S6 kinase signalling via the TSC complex [10]. Pathway convergence is also evident through the action of both pathways on S6 kinases, leading to increased cell survival and proliferation.

Pathway interaction. This figure. (adapted from Mendoza et al.[10]) illustrates how the Ras-ERK and PI3K-AKT-mTOR signalling pathways influence each other by cross inhibition (red lines) and cross-activation (green lines). Positive regulation is denoted as an arrow; negative regulation as a blunt-ended line. The MAPK1 gene encodes ERK2 which positively regulates the PI3K-AKT-mTOR pathway but also acts to negatively regulate the pathway upstream by phosphorylation of GAB

P1 had a combination of clinical and immunological features reminiscent of both Ras-opathy and immune-TOR-opathy patients. We hypothesise that the mutation in MAPK1 leads to increased pS6 in T-cells, possibly due to an effect on both the Ras-ERK and PI3K-ATK-mTOR pathway caused by convergence between the two signalling pathways. In an analogy of the phenotype of patients with other immune-TOR-opathies, this may explain P1’s increased susceptibility to infection, hypogammaglobulinemia and immune dysregulation. While P1’s most prominent finding on initial clinical laboratory testing was hypogammaglobulinemia, the relative reduction in the proportion of class-switched memory B cells, the relative increase in transitional-B cells, and the relative sparing of serum IgM levels suggest a defect in T-cell help rather than an intrinsic B-cell compartment disorder. Evaluation of the immunological phenotype in other patients with Noonan Syndrome 13 is needed to clarify this more definitively.

To conclude, we suggest sequencing of MAPK1 in patients presenting with Noonan Syndrome phenotype and features of immunodeficiency/immunodysregulation, and careful evaluation of the immune system in patients with activating mutations in MAPK1 and other genes on the Ras-ERK pathway.