ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

  title={ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor},
  author={Dong Li and Michael E. March and {\'A}lvaro Gutierrez-Uzquiza and Charlly Kao and Christoph Seiler and Erin Pinto and Leticia S Matsuoka and Mark R. Battig and Elizabeth Joyce Bhoj and Tara L. Wenger and Lifeng Tian and Nora K. Robinson and Tiancheng Wang and Yichuan Liu and Brant M. Weinstein and Matthew R. Swift and Hyungjn Jung and Courtney N Kaminski and Rosetta Chiavacci and Jonathan A Perkins and Michael A Levine and Patrick M A Sleiman and Patricia J Hicks and Janet T Strausbaugh and Jean Bello Belasco and Yoav Dori and Hakon H. Hakonarson},
  journal={Nature Medicine},
The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult… 

Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition

An in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis is devised and a first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation is presented.

Case Report: Progressive central conducting lymphatic abnormalities in the RASopathies. Two case reports, including successful treatment by MEK inhibition

Two adult males with Noonan syndrome with a severe and progressive CCLA are described and the therapeutic role of targeted molecular therapy with the MEK inhibitor ‘Trametinib’ is reported, which has resulted in dramatic, and sustained, clinical improvement.

Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation

It is demonstrated that MEK inhibition is a potential new and effective treatment of severe lymphatic abnormalities in patients with NS and inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients

Alpelisib administration in six patients refractory to previous pharmacological or surgical approaches improved symptoms and reduced the volume of LMs, suggesting that inhibiting PIK3CA could be effective in treating LMs.

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

It is demonstrated that somatic activating mutations in KRAS can be associated with GSD and revealed that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves.

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

The results show that most patients with NS and lymphatic disease have CCLA, and it is probable that CCLA is present in all patient with NS, presenting merely with lymphedema, or without sensing lymphatic symptoms at all.

Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema

It is determined that MDFIC controls collective cell migration, an important early event during the formation of lymphatic vessel valves, by regulating integrin β1 activation and the interaction between lymphatic endothelial cells and their surrounding extracellular matrix.

New and Emerging Targeted Therapies for Vascular Malformations

Vascular malformations are inborn errors of vascular morphogenesis and consist of localized networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. They have

Kaposiform lymphangiomatosis effectively treated with MEK inhibition

It is reported for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition.

Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications

It is concluded that SOS2 -related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.



Somatic NRAS mutation in patient with generalized lymphatic anomaly

This work isolated lymphangiomatosis endothelial cells from GLA tissue and identified a somatic mutation in NRAS, which is characterized by high proliferation and survival rates, but displayed impaired capacities for migration and tube formation.

Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

Additional functional evidence is provided for a causal relationship between pathogenic mutations in RIT1, increased RAS‐MAPK/MEK‐ERK signaling and the clinical phenotype and the associated phenotypic spectrum is expanded.

Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly

The pathogenicity of the identified EPHB4 mutation as a novel cause of CCLA is demonstrated and drugs that inhibit mTOR signaling or RAS-MAPK signaling effectively rescued the misbranching phenotype in a comparable manner, suggesting that ERK inhibitors may have therapeutic benefits in such patients with complex lymphatic anomalies.

Contribution of RIT1 mutations to the pathogenesis of Noonan syndrome: Four new cases and further evidence of heterogeneity

The role of RIT1 in the pathogenesis of Noonan syndrome is confirmed, and it seems that the identified mutations might alter protein function and therefore, the activity of ERK and P38 MAPK pathways, thus underlying the specific phenotype observed in NS patients.

Spectrum of mutations and genotype–phenotype analysis in Noonan syndrome patients with RIT1 mutations

Results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature

This report presents two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively.

A Somatic Activating NRAS Variant Associated with Kaposiform Lymphangiomatosis

Kaposiform lymphangiomatosis joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signaling pathways, and will expand treatment options for these high-risk patients as there is potential for use of targeted RAS pathway inhibitors.


The clinical data of one case of CFC syndrome, genetically determined by KRAS mutation, that involved chylothorax, lymphedema, sinus pericranii, craniosynostosis, and seizures is described.

Germline CBL mutation associated with a noonan‐like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23

A girl with a Noonan‐like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL is described, suggesting a specific association of CBL mutations in germ cell tumor predisposition.

Genetics of lymphatic anomalies.

Germline mutations have been identified in at least 20 genes that encode proteins acting around VEGFR-3 signaling but also downstream of other tyrosine kinase receptors that explain more than a quarter of the incidence of primary lymphedema, mostly of inherited forms.