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Molecular and clinical profile of patients referred as Noonan or Noonan-like syndrome in Greece: a cohort of 86 patients

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Abstract

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease’s recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype–phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p < 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes.

Conclusion: Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis.

What is Known:

• Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway.

• Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring.

What is New:

• NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes.

• The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.

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Data availability

Raw data are available upon request.

Code availability

Not applicable.

Abbreviations

CFC:

Cardiofacio-cutaneous syndrome

HCM:

Hypertrophic cardiomyopathy

NS:

Noonan syndrome

PS:

Pulmonary valve stenosis

NGS:

Next-generation sequencing

SNPs:

Single-nucleotide polymorphisms

VUS:

Variants of unknown clinical significance

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Acknowledgements

We cordially thank the families for their cooperation.

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Author notes

  1. George Papadopoulos and Anna Papadopoulou contributed equally to this work.

Authors and Affiliations

  1. 3rd Department of Pediatrics, University of Athens, Medical School, University General Hospital “ATTIKON”, Chaidari, Greece

    George Papadopoulos, Anna Papadopoulou, Anastasios Papadimitriou, Vassiliki Papaevangelou & Evangelia Bountouvi

  2. Department of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Konstantina Kosma

  3. Division of Endocrinology, Diabetes and Metabolism, Center for Rare Paediatric Endocrine Diseases, First Department of Paediatrics, Medical School, National and Kapodistrian University of Athens, Agia Sophia Children’s Hospital, Athens, Greece

    Christina Kanaka-Gantenbein

  4. Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Sophia Kitsiou-Tzeli

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Contributions

GP, AP and EB conducted material preparation, and wrote of the manuscript. Patient’s stratification was performed by SK-TZ, KK, AP, CK-G and VP. AP wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Anna Papadopoulou.

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Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki and its later amendments. Medical ethical approval was granted by the local medical ethics committee of Attikon University general hospital with the file number (4492/16.07.2019).

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Written informed consent was obtained from the participants or/and the parents of the participating children, as well as patients’ assess where applicable.

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Not applicable.

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The authors declare no competing interests.

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Papadopoulos, G., Papadopoulou, A., Kosma, K. et al. Molecular and clinical profile of patients referred as Noonan or Noonan-like syndrome in Greece: a cohort of 86 patients. Eur J Pediatr 181, 3691–3700 (2022). https://doi.org/10.1007/s00431-022-04574-w

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