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

Kleimeier, Lotte E. R.; Schaik, C. van; Leenders, Erika; Itkin, Maxim; Klein, Willemijn M.; Draaisma, J. M. T.

doi:10.3390/jcm11113128

Cited by 7 publications

(12 citation statements)

References 34 publications

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“…They include neonatal presentations with congenital lymphedema, chylothorax, or ascites, but may also occur at any age postnatally in patients without a perinatal history of lymphatic abnormalities. They likely result from a primary maldevelopment of central conducting lymphatic vessels (Kleimeier et al, 2022; Pieper et al, 2022). Notably, lymphatic abnormalities also represent the most frequent fetal manifestation of RASopathies.…”

Section: Shared Patterns Of Organ Involvement In Ns‐like Rasopathiesmentioning

confidence: 99%

Clinical overview on RASopathies

Zenker

2022

American J of Med Genetics Pt C

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RASopathies comprise a group of clinically overlapping developmental disorders caused by genetic variations affecting components or modulators of the RAS-MAPK signaling cascade, which lead to dysregulation of signal flow through this pathway. Noonan syndrome and the less frequent, clinically related disorders, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, and Noonan syndrome-like disorder with loose anagen hair are part of the RASopathy spectrum and share a recognizable pattern of multisystem involvement. This review describes the "Noonan syndrome-like" phenotype as a common phenotypic signature of generalized developmental RAS pathway dysregulation. Distinctive features of the different entities are revisited against the background of the understanding of underlying genetic alterations and genotype correlations, which has evolved rapidly during the past 20 years, thereby leading to suggestions regarding the nosology of RASopathies. K E Y W O R D S cardiofaciocutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair 1 | INTRODUCTION The term "RASopathies" was coined in 2009 (Tidyman & Rauen, 2009). It denotes a group of clinically overlapping multisystem disorders that share a common molecular pathogenesis in that the underlying genetic variations affect components or modulators of the RAS-MAPK signaling cascade and lead to dysregulation of signal flow through this pathway. No generally accepted definition and definitive delineation of RASopathies exist, so far. The major classes of disorders that have been grouped under this umbrella term are summarized in Table 1. This clinical overview is focused on Noonan syndrome (NS; MIM #PS163950) and the less frequent, clinically related disorders, Costello syndrome (CS; MIM #218040), cardiofaciocutaneous syndrome (CFCS: MIM #PS115150), Noonan syndrome with multiple lentigines (NSML; MIM #151100), Noonan syndrome-like disorder with loose anagen hair (NSLH; MIM #PS607721), collectively referred to in the following as "Noonan syndrome-like RASopathies (NS-like RASopathies)." They represent disorders that are caused by a mild to moderate and generalized constitutional RAS pathway dysregulation (Figure 1a) and have a multisystem phenotype. Based on the current pathogenetic concepts and understanding it can be concluded that the "NS-like" clinical picture represents the common phenotypic signature of a systemic RAS pathway dysregulation that starts in the embryonic period. This notion is supported by the fact that all genes known to cause NS-like RASopathies encode for components or modulators of the RAS-MAPK signaling cascade. However, this does not mean that disturbed signaling through MAPKs as the sole effectors can explain all the organ-specific pathophysiology. In fact, cellular pathways are interconnected and abnormal signaling in one of them

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Section: Shared Patterns Of Organ Involvement In Ns‐like Rasopathiesmentioning

confidence: 99%

Clinical overview on RASopathies

Zenker

2022

American J of Med Genetics Pt C

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“…These techniques have allowed researchers to identify single-gene disorders causing CCLA ( Table 1 ). Mosaic and germline RASopathies due to pathogenic variants that result in upregulation of the RAS/MAPK signaling pathway are the most common causes of CCLA ( Figure 1B ) ( 48 , 61 , 80 – 88 ). Specifically, somatic pathogenic variants in ARAF , BRAF , KRAS , and MAP2K1 resulting in isolated lymphatic as well as syndromic presentations have been identified ( 48 , 61 , 82 , 85 ).…”

Section: State-of-the-art Genetic Advances Facilitate Identification ...mentioning

confidence: 99%

“…Specifically, somatic pathogenic variants in ARAF , BRAF , KRAS , and MAP2K1 resulting in isolated lymphatic as well as syndromic presentations have been identified ( 48 , 61 , 82 , 85 ). Germline monoallelic pathogenic variants in PTPN11 , KRAS , HRAS , BRAF , RAF1 , RIT1 , SOS1 , SOS2 , and RASA1 have been identified in individuals with CCLA and Noonan syndrome, CCLA and Costello syndrome, CCLA and cardiofaciocutaneous syndrome, or CCLA and capillary malformation-arteriovenous malformation syndrome ( 48 , 61 , 80 – 88 ). Interestingly, the phenotypic heterogeneity may be due to second hits, as has been demonstrated in RASA1 disorders ( 89 – 93 ).…”

Section: State-of-the-art Genetic Advances Facilitate Identification ...mentioning

confidence: 99%

Central conducting lymphatic anomaly: from bench to bedside

Garlisi Torales,

Sempowski,

Krikorian

et al. 2024

Journal of Clinical Investigation

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Central conducting lymphatic anomaly (CCLA) is a complex lymphatic anomaly characterized by abnormalities of the central lymphatics and may present with nonimmune fetal hydrops, chylothorax, chylous ascites, or lymphedema. CCLA has historically been difficult to diagnose and treat; however, recent advances in imaging, such as dynamic contrast magnetic resonance lymphangiography, and in genomics, such as deep sequencing and utilization of cell-free DNA, have improved diagnosis and refined both genotype and phenotype. Furthermore, in vitro and in vivo models have confirmed genetic causes of CCLA, defined the underlying pathogenesis, and facilitated personalized medicine to improve outcomes. Basic, translational, and clinical science are essential for a bedside-to-bench and back approach for CCLA.

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“…168,231 These complex flow disorders often have a syndromatic background (eg, Noonan syndrome, Turner syndrome). 234,235 To plan adequate treatment in these cases, it is imperative to perform dynamic lymphatic imaging to understand central lymphatic flow alterations. To this end, DC-MRL and XRL may not be sufficient, and transabdominal thoracic duct cannulation can be necessary to differentiate hypoplasia of the thoracic duct from obstruction (Fig.…”

Section: Neonatal Lymphatic Flow Disordersmentioning

confidence: 99%

“…More complex central lymphatic flow disorders also demonstrate a more complex flow pattern, typically involving dysplasia or hypoplasia/aplasia of central lymphatics (eg, the thoracic duct) with effusions in more than 1 compartment accompanied by edema/anasarca 168,231 . These complex flow disorders often have a syndromatic background (eg, Noonan syndrome, Turner syndrome) 234,235 . To plan adequate treatment in these cases, it is imperative to perform dynamic lymphatic imaging to understand central lymphatic flow alterations.…”

Section: Therapeutic Approaches To Lymphatic Diseasesmentioning

confidence: 99%

Back to the Future II—A Comprehensive Update on the Rapidly Evolving Field of Lymphatic Imaging and Interventions

Pieper

2023

Invest Radiol

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Lymphatic imaging and interventional therapies of disorders affecting the lymphatic vascular system have evolved rapidly in recent years. Although x-ray lymphangiography had been all but replaced by the advent of cross-sectional imaging and the scientific focus shifted to lymph node imaging (eg, for detection of metastatic disease), interest in lymph vessel imaging was rekindled by the introduction of lymphatic interventional treatments in the late 1990s. Although x-ray lymphangiography is still the mainstay imaging technique to guide interventional procedures, several other, often less invasive, techniques have been developed more recently to evaluate the lymphatic vascular system and associated pathologies. Especially the introduction of magnetic resonance, and even more recently computed tomography, lymphangiography with water-soluble iodinated contrast agent has furthered our understanding of complex pathophysiological backgrounds of lymphatic diseases. This has led to an improvement of treatment approaches, especially of nontraumatic disorders caused by lymphatic flow abnormalities including plastic bronchitis, protein-losing enteropathy, and nontraumatic chylolymphatic leakages. The therapeutic armamentarium has also constantly grown and diversified in recent years with the introduction of more complex catheter-based and interstitial embolization techniques, lymph vessel stenting, lymphovenous anastomoses, as well as (targeted) medical treatment options. The aim of this article is to review the relevant spectrum of lymphatic disorders with currently available radiological imaging and interventional techniques, as well as the application of these methods in specific, individual clinical situations.

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

Cited by 7 publications

References 34 publications

Clinical overview on RASopathies

Clinical overview on RASopathies

Central conducting lymphatic anomaly: from bench to bedside

Back to the Future II—A Comprehensive Update on the Rapidly Evolving Field of Lymphatic Imaging and Interventions

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