Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

Sleutjes, Julia; Kleimeier, Lotte E. R.; Leenders, Erika; Klein, Willemijn M.; Draaisma, J. M. T.

doi:10.1159/000517605

Cited by 30 publications

(24 citation statements)

References 70 publications

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“…RIT1 patients had severe lymphatic anomalies during several stages of life. Previous studies reported a genotype-phenotype correlation of lymphatic anomalies in patients with a pathogenic variant in RIT1 (Kouz et al, 2016;Sleutjes et al, 2022). One of the included patients had a pathogenic variant in RRAS2.…”

Section: Discussionmentioning

confidence: 99%

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Swarts¹,

Kleimeier²,

Leenders

et al. 2022

American J of Med Genetics Pt A

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Noonan syndrome (NS) has been associated with an increased risk of lymphatic anomalies, with an estimated prevalence of 20%. The prevalence of lymphatic anomalies seems to differ between pathogenic variants. Therefore, this study aims to describe the clinical presentation, prevalence and genotype-phenotype correlations of lymphatic anomalies during life in patients with NS. This retrospective cohort study included patients (n = 115) who were clinically and genetically diagnosed with NS and visited the Noonan expertise Center of the Radboud University Medical Center between January 2015 and March 2021. Data on lymphatic anomalies during lifetime were obtained from medical records. Lymphatic anomalies most often presented as an increased nuchal translucency, chylothorax and/or lymphedema. Prenatal lymphatic anomalies increased the risk of lymphatic anomalies during infancy (OR 4.9, 95% CI 1.7-14.6). The lifetime prevalence of lymphatic anomalies was 37%.Genotype-phenotype correlations showed an especially high prevalence of lymphatic anomalies during infancy and childhood in patients with a pathogenic SOS2 variant (p = 0.03 and p < 0.01, respectively). This study shows that patients with NS have a high predisposition for developing lymphatic anomalies during life. Especially patients with prenatal lymphatic anomalies have an increased risk of lymphatic anomalies during infancy. Genotype-phenotype correlations were found in pathogenic variants in SOS2.

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Section: Discussionmentioning

confidence: 99%

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Swarts¹,

Kleimeier²,

Leenders

et al. 2022

American J of Med Genetics Pt A

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“…Binding of VEGF-C to VEGFR3 results in tyrosine phosphorylation, which in turn activates Ras/Raf/extracellular signal regulated kinase (ERK) signaling and eventually promotes LEC migration and sprouting ( Mäkinen et al, 2021 ). In humans, gain-of-function mutations in Ras pathway-related genes including HRAS , RAF1 , PTPN11 , KRAS , SOS1 and RIT1 are actually identified in Noonan syndrome and related disorder (Costello syndrome) patients associated with increased NT ( Croonen et al, 2013 ; Sleutjes et al, 2022 ). Noonan syndrome is a multiple malformation syndrome with characteristic facies, congenital heart disease, and short stature, and presents with prenatal and postnatal lymphedema ( Noonan, 2006 ; Sleutjes et al, 2022 ).…”

Section: Defective Lymphatic Vascular Developmentmentioning

confidence: 99%

“…In humans, gain-of-function mutations in Ras pathway-related genes including HRAS , RAF1 , PTPN11 , KRAS , SOS1 and RIT1 are actually identified in Noonan syndrome and related disorder (Costello syndrome) patients associated with increased NT ( Croonen et al, 2013 ; Sleutjes et al, 2022 ). Noonan syndrome is a multiple malformation syndrome with characteristic facies, congenital heart disease, and short stature, and presents with prenatal and postnatal lymphedema ( Noonan, 2006 ; Sleutjes et al, 2022 ). Some of these gene mutations have been shown to cause fetal nuchal edema in mouse models.…”

Section: Defective Lymphatic Vascular Developmentmentioning

confidence: 99%

Fetal nuchal edema and developmental anomalies caused by gene mutations in mice

Sugiyama

Hirashima²

2022

Front. Cell Dev. Biol.

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Fetal nuchal edema, a subcutaneous accumulation of extracellular fluid in the fetal neck, is detected as increased nuchal translucency (NT) by ultrasonography in the first trimester of pregnancy. It has been demonstrated that increased NT is associated with chromosomal anomalies and genetic syndromes accompanied with fetal malformations such as defective lymphatic vascular development, cardiac anomalies, anemia, and a wide range of other fetal anomalies. However, in many clinical cases of increased NT, causative genes, pathogenesis and prognosis have not been elucidated in humans. On the other hand, a large number of gene mutations have been reported to induce fetal nuchal edema in mouse models. Here, we review the relationship between the gene mutants causing fetal nuchal edema with defective lymphatic vascular development, cardiac anomalies, anemia and blood vascular endothelial barrier anomalies in mice. Moreover, we discuss how studies using gene mutant mouse models will be useful in developing diagnostic method and predicting prognosis.

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“…[ 10 ]. Genotype-phenotype studies in patients with NS found that lymphatic disease is more prevalent in patients with NS due to pathogenic variants in SOS2 and RIT1 [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Lymphatic Phenotype of Noonan Syndrome: Innovative Diagnosis and Possible Implications for Therapy

Kleimeier

Schaik

Leenders

et al. 2022

JCM

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Dysregulation of the Ras/Mitogen-activated protein kinase (MAPK) signaling pathway is suggested to play a pivotal role in the development of the lymphatic system in patients with Noonan Syndrome (NS). Pathogenic gene variants in the Ras/MAPK pathway can therefore lead to various lymphatic diseases such as lymphedema, chylo-thorax and protein losing enteropathy. Diagnosis and treatment of the lymphatic phenotype in patients with NS remain difficult due to the variability of clinical presentation, severity and, probably, underlying unknown pathophysiologic mechanism. The objective of this article is to give an overview of the clinical presentation of lymphatic disease in relation to central conducting lymphatic anomalies (CCLA) in NS, including new diagnostic and therapeutic options. We visualized the central conducting lymphatic system using heavily T2-weighted MR imaging (T2 imaging) and Dynamic Contrast-enhanced MR Lymphangiography (DCMRL) and compared these results with the lymphatic clinical presentation in seven patients with NS. Our results show that most patients with NS and lymphatic disease have CCLA. Therefore, it is probable that CCLA is present in all patient with NS, presenting merely with lymphedema, or without sensing lymphatic symptoms at all. T2 imaging and DCMRL can be indicated when CCLA is suspected and this can help to adjust therapeutic interventions.

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Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

Cited by 30 publications

References 70 publications

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Fetal nuchal edema and developmental anomalies caused by gene mutations in mice

Lymphatic Phenotype of Noonan Syndrome: Innovative Diagnosis and Possible Implications for Therapy

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