Lymphatic Malformation Responsive to Sirolimus in Keratinocytic Epidermal Nevus Syndrome with KRAS Mutation: A Case and Brief Literature Discussion

Sideris, Emily; Tng, Er Tsing Vivian; Chee, Paul

doi:10.1159/000515247

Cited by 7 publications

(8 citation statements)

References 15 publications

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“…Mutations in RAS isoforms are also known to be implicated in lymphatic malformation 3 . There are rare case reports of KEN with an underlying KRAS mutation, and reports of an associated lymphatic malformation are rarer still 4–6 . In the present patient, the KEN extends across the entire trunk, suggesting the KRAS mutation likely occurred early in development and affected multiple tissues.…”

Section: Discussionmentioning

confidence: 63%

“…3 There are rare case reports of KEN with an underlying KRAS mutation, and reports of an associated lymphatic malformation are rarer still. [4][5][6] In the present patient, the KEN extends across the entire trunk, suggesting the KRAS mutation likely occurred early in development and affected multiple tissues. The epidermal nevus and pericardial effusion were considered unrelated for several years.…”

mentioning

confidence: 65%

“…Epidermal nevi frequently recur following superficial destructive therapies, so an asymptomatic nevus without significant complications is often managed conservatively 2 . However, increased understanding of the pathogenesis has enabled the implementation of targeted therapies 3,6 . An MEK inhibitor was offered to the patient but declined due to the presently tolerable symptom state.…”

Section: Discussionmentioning

confidence: 99%

“…2 However, increased understanding of the pathogenesis has enabled the implementation of targeted therapies. 3,6 An MEK inhibitor was offered to the patient but declined due to the presently tolerable symptom state. This case is presented as a possible expansion of the epidermal nevus syndrome spectrum to include the association of an extensive KEN with a mediastinal lymphatic malformation resulting in a chronic chylous pericardial effusion.…”

mentioning

confidence: 99%

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Widespread keratinocytic epidermal nevus with an associated chylous pericardial effusion

Rowe

Snyder

Treat

2023

Pediatric Dermatology

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A 17‐year‐old male presented for review of a widespread keratinocytic epidermal nevus (KEN) in the setting of a chronic pericardial effusion. Biopsy of the epidermal nevus revealed a KRAS mutation. Pericardiocentesis revealed a chylous effusion and magnetic resonance lymphangiogram demonstrated an underlying lymphatic malformation. There are rare case reports of KEN with an associated KRAS mutation. This case highlights the importance of being alert to epidermal nevus syndrome, particularly in patients with a widespread nevus and seemingly unrelated pathology.

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Section: Discussionmentioning

confidence: 63%

mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Widespread keratinocytic epidermal nevus with an associated chylous pericardial effusion

Rowe

Snyder

Treat

2023

Pediatric Dermatology

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“…Lymphatic anomalies have rarely been reported with ECCL ( 34 ), though the association with lymphatic anomalies and germline RASopathies is well established ( 4 , 39 – 41 ). Additionally, activating KRAS pathogenic variants have also recently been described as a cause of aberrant vascular development, vascular malformation, and lymphatic anomalies including lymphedema, chylothorax, macrocystic lymphatic malformation, lymphangiectasia, and Gorham-Stout disease ( 10 – 13 , 34 , 40 , 42 – 44 ).…”

Section: Discussionmentioning

confidence: 99%

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

Sheppard¹,

March²,

Seiler³

et al. 2023

JCI Insight

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Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS . To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

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New prospectives on treatment opportunities in RASopathies

Gelb

Yohe

Wolf

et al. 2022

American J of Med Genetics Pt C

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The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.

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Lymphatic Malformation Responsive to Sirolimus in Keratinocytic Epidermal Nevus Syndrome with KRAS Mutation: A Case and Brief Literature Discussion

Cited by 7 publications

References 15 publications

Widespread keratinocytic epidermal nevus with an associated chylous pericardial effusion

Widespread keratinocytic epidermal nevus with an associated chylous pericardial effusion

Lymphatic disorders caused by mosaic, activating KRAS variants respond to MEK inhibition

New prospectives on treatment opportunities in RASopathies

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