Clinical and Cytometric Study of Immune Involvement in a Heterogeneous Cohort of Subjects With RASopathies and mTORopathies.

Erica Valencic,Prisca Da Lozzo,Flavio Faletra,Alberto Tommasini,Elena Ghirigato,Francesco Facca,Gianluca Tornese,Andrea Magnolato,Elisa Piscianz,Andrea Taddio

doi:10.3389/fped.2021.703613

Erica Valencic, Prisca Da Lozzo + Show 8 more

Open Access

https://doi.org/10.3389/fped.2021.703613

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Abstract

RASopathies and mTORopathies are groups of genetic syndromes associated with increased activation of the RAS-MAPK or the PI3K-AKT-mTOR pathway, resulting in altered cell proliferation during embryonic and postnatal development. The RAS-MAPK and the PI3K-AKT-mTOR pathways are connected to each other and play a crucial role in adaptive immunity. However, with the exception of Activated PI3K delta syndrome (APDS), immune function has not been deeply studied in these disorders. We collected clinical and immunophenotypic data of a cohort of patients with RASopathies and mTORopathies. Overall, we enrolled 47 patients (22 females, 25 males, age 2–40 years): 33 with neurofibromatosis type 1, 11 Noonan syndrome and 3 Bannayan-Riley-Ruvalcaba syndrome. 8 patients reported a history of invasive infections requiring hospitalization and intravenous antibiotic therapy. Only 3 patients reported a history of unusual, difficult-to-treat or deep-seated infection. Adenotonsillectomy was performed in 11 patients (24%). However, in most cases (83%) patients' parents did not perceive their child as more prone to infections than their peers. Lymphocyte subpopulations were analyzed in 37 of the 47 patients (16 female, 21 males, age 1–40 years). Among the studied lymphocyte subsets, the only consistent alteration regarded an increased percentage of immature B cells (recent bone marrow emigrants) in 34 out of 37 (91,9%) patients, and an increased percentage of double negative T cells in 9 patients. In conclusion, although borderline immune abnormalities were present in a significant proportion of subjects and adenotonsillectomy was performed more frequently than expected for the general population, no major immune disturbance was found in this cohort of patients.

Highlights

MATERIALS AND METHODSRASopathies are a class of genetic syndromes due to germline mutations in genes that encode protein components of the RAS-mitogen activated protein kinase (MAPK) pathway [1]
This wide group includes Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (i.e. LEOPARD syndrome), cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome and capillary malformation-arterovenous malformation (CMAVM) syndrome
The cohort comprised 33 patients affected with Neurofibromatosis type 1, 11 patients with Noonan syndrome and 3 patients with Bannayan-Riley-Ruvalcaba syndrome

Summary

Introduction

RASopathies are a class of genetic syndromes due to germline mutations in genes that encode protein components of the RAS-mitogen activated protein kinase (MAPK) pathway [1]. This wide group includes Neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (i.e. LEOPARD syndrome), cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome and capillary malformation-arterovenous malformation (CMAVM) syndrome. All the mutations found in RASopathies result in increased signaling and/or constitutive activation of the RASMAPK pathway, impacting proliferation of many cell types during embryonic and postnatal development [1]. Activating mutations of the RAS-MAPK pathway genes are associated with oncogenic transformation and carcinogenesis, with RAS found to be somatically mutated in 20% of malignancies [3, 4]

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