Kinsler VA, Thomas AC, Ishida M, et al. 2016;34:155163. (hi) Photomicrographs of skin biopsy with (h) dilated dermal lymphatic channels (asterisk) and small cellular clusters (circle). Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Thin sections were scraped from diagnostic formalin-fixed paraffin-embedded (FFPE) tissue blocks, which had been obtained either at biopsy (2/5 cases), or at autopsy (3/5 cases). Figure 2. Correspondence to 2014;164:383388. Variants at each of these three sites result in a constitutively active NRAS protein and therefore, constitutive activation of downstream signaling pathways, resulting in unchecked cell proliferation.21. 31,32,33). Mutation analysis for the KLA, Figure 2. Adams DM, Trenor CC 3rd, Hammill AM, et al. 1989;49:46824689. Before Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations. Results The median age at onset was 6.5 years (range, birth to 44 years). Expert Rev Anticancer Ther. 2012;49:249253. Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. This condition usually affects multiple areas of your child's body, including their bone, spleen, liver, lungs and mediastinum (the soft tissue of their chest). In addition to the prevalence of these variants in human cancers, somatic activating RAS variants have been identified in several benign cutaneous, skeletal, and vascular disorders (TableS4). Epub 2019 May 2. Adv Wound Care (New Rochelle). Interestingly, in preliminary functional analyses by Manevitz-Mendelson et al., artificial overexpression of the NRAS p.Q61R variant allele in zebrafish actually impaired lymphatic development.7 This raises the possibility that a mosaic microenvironment with wild-type lymphatic endothelial cells may be necessary to cause a proliferative phenotype in vivo. We searched the exome data of KLA2 for other somatic hotspot variants,16 and for rare (i.e., frequency <0.001 in gnomAD database), nonsynonymous variants in other genes that have previously been implicated in vascular anomalies (TableS1). ISSN 1530-0366 (online) Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions, and systemic involvement. We thank all who participated in this study, and their families. Kaposiform lymphangiomatosis (KLA) is a more recently characterized systemic and frequently aggressive lymphatic anomaly, typically presenting in childhood or early adulthood (Fig. All rights reserved. overall survival rate with limited effective treatments.1-4 In recent years, molecular studies identied somatic muta- . We thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. Online ahead of print. 2015;135:16981700. We have also potentially identified (though not validated) a novel missense (p.V66L) and a novel nonsense (p.R114X) variant in TEK, in the lone NRAS p.Q61R-negative patient in our cohort, which represents a candidate for consideration if additional p.Q61R-negative patients are found. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. 2006;441:424430. This variant was also present on 20/105 reads (19%) from the KLA5 RNA sequencing data. lymphatic malformation, kaposiform, lymphangiomatosis, NRAS. 1993;17:321328. ), the Wilkes Tumor Foundation (K.C.K. [14273] The lymphatic system is part of the immune system made up of vessels that help to protect the body from infection and foreign substances. Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy. Unable to load your collection due to an error, Unable to load your delegates due to an error. We identified a somatic activating NRAS variant (c.182 A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1% to 28%, that was absent from the tested control tissues. -, Boscolo E, Pastura P, Glaser K, Goines J, Hammill AM, Adams DM, Dickie P, Hsi Dickie B, Le Cras TD (2019) Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis. As RAS activation also activates PI3K/mTOR signaling, it is not surprising that patients would have some benefit from sirolimus therapy. HHS Vulnerability Disclosure, Help Even with multimodal treatments,. (bd) Magnetic resonance imaging. J Pediatr. 2019 Aug;66(8):e27790. 2003;3:1122. Pediatrics. ), and the Alberta Childrens Hospital Research Institute (K.C.K.). J Pediatr 164: 383388 2015;526:6874. National Library of Medicine KLA is typically diagnosed in childhood and results in significant risk of respiratory compromise, infections, coagulopathy, and early death (Croteau et al, 2014 ). Boespflug A, Caramel J, Dalle S, Thomas L. Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date. The University of Calgary Institutional Review Board and the Committee on Clinical Investigation of Boston Childrens Hospital approved this study. For each exome, 7999% of target bases were covered at least 15-fold, and 4292% of target bases were covered at least 50-fold, by unique reads with a minimum base quality score of 20 (TableS2). However, TEK is likely to be haploinsufficient,13 and inherited heterozygous loss-of-function TEK variants cause primary congenital glaucoma (MIM 617272) by disrupting vascular development in the anterior chamber.34 It cannot be excluded that a very low-level somatic nonsense variant could have pathogenic effects on lymphatic endothelial organization, causing a spindled/kaposiform phenotype. Ther Adv Med Oncol. Herein, we document the pathology in 43. J Investig Med High Impact Case Rep. 2023. 2). For the two unpaired tumor samples (KLA4 and KLA5), we ran Mutect2 in tumor-only mode, and ignored the germline_risk filter, including in our analysis any calls in which that was the only filter applied. patients with KLA suffer from high morbidity and mortality with 51% survival after 5 years21 and overall survival rate of 34%.3 Poor prognosis is due to progressive pulmonary disease and serosal haemorrhage. (e) Thoracoscopic image with extensive visceral pleural involvement. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects. Ann Am Thorac Soc 2014;11: 92 . A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. Abstract Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. is a scientific advisor to Aevi Genomic Medicine Inc., and he and CHOP own shares in the company. In KLA, the lymphatic system vessels expand and can spread and cause damage. and JavaScript. MeSH The NRAS p.Q61R variant has recently been reported in a single case of generalized lymphatic anomaly (GLA), formerly known as diffuse lymphangiomatosis.7 The distinction of KLA from GLA has only recently been made.3,4 While both are characterized by a generalized lymphatic anomaly of soft tissue that often includes viscera and bone, KLA is more commonly marked by significant coagulopathy, a more aggressive clinical course, and is pathologically distinct as defined by the presence of a spindled lymphatic endothelial component.3,4 It is of interest that the case of GLA with an NRAS p.Q61R variant reported by Manevitz-Mendelson et al. Please enable scripts and reload this page. Codon 61 NRAS variants, specifically, have been identified in epidermal nevi (MIM 162900) (ref. We thank the members of the Vascular Anomalies Center at Boston Childrens Hospital, for their ongoing support for patients and families affected by KLA, and the many benefactors who make this research possible. Outlook for KLA Long-term outcomes for children with KLA vary depending on the extent of the lymphatic leaks, which part of the body is affected and whether the child is treated and monitored by a facility that has experience working with individuals with lymphatic disorders. . We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. Kaposiform lymphangiomatosis (KLA) is a rare type of tumor and vascular malformation that results from the abnormal development of the lymphatic system . Boscolo E, Pastura P, Glaser K, Goines J, Hammill AM, Adams DM, Dickie P, Hsi Dickie B, Le Cras TD. Search for Similar Articles (b) dPCR results from lesional tissue of participant KLA4, demonstrating amplification of variant allele (14%). Downward J. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Bethesda, MD 20894, Web Policies government site. 23), multiple congenital melanocytic nevi (CMNS [MIM 137550]) and neurocutaneous melanosis (NCMS [MIM 249400]) (ref. Pediatr Radiol. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. Droplet digital polymerase chain reaction (ddPCR) result with five mutant positive droplets (circle) from a low concentration leftover sample which resulted in 0.005% fractional abundance. We analyzed the exome sequences based on the Genome Analysis Toolkit (GATK) Best Practices for Somatic Short Variant Discovery.10 Briefly, sequence reads were aligned to the reference human genome (GRCh37) using the BurrowsWheeler Aligner MEM algorithm (BWA-MEM),11 duplicates were marked using Picard, and base quality scores were recalibrated using GATK (see Supplementary Methods for all commands and arguments used). Cancer. 2018;138:933945. 2016;136:481486. The resulting somatic variant calls were then annotated using ANNOVAR.14 See Supplementary Methods for all commands used. Digital chips were run on a ProFlex 2 Flat PCR thermocycler (Applied Biosystems by Thermo Fisher Scientific) with the following cycling conditions: 96C 10minutes, then 39 cycles of 60C for 2minutes, followed by 98C 30seconds, then a final elongation step at 60C 2minutes and 10C hold. CAS Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. NRAS is a proto-oncogene that encodes a small GTPase that normally functions to regulate cell proliferation via the MAPK and PI3K/AKT signaling pathways19,20,21consistent with the pathways in which somatic variants in other vascular anomalies have so far been identified (TableS1). Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Although similar spindled endothelial cells are also found in kaposiform hemangioendothelioma (KHE), KHE is a localized vascular tumor with a distinct histopathology commonly seen in infants and toddlers and often associated with coagulopathy (KasabachMerritt phenomenon).6 A genetic cause for these complex lymphatic anomalies has not yet been identified, although a somatic activating NRAS variant (p.Q61R) was recently identified in a single case of GLA, and shown to have a pathogenic effect on the lymphatic endothelium.7 Despite multimodal therapy, the overall prognosis of KLA remains poor, with an overall survival of 34% (refs. Coronal CT image of the chest at baseline with pleural fluid and intralobular septal thickening (arrow) (A), and 3months after starting trametinib (B). Nature. In the meantime, to ensure continued support, we are displaying the site without styles volume21,pages 15171524 (2019)Cite this article. Aoki Y, Niihori T, Inoue S, Matsubara Y. Additional work, particularly in model organisms, will be needed to further explore these possibilities. Nat Rev Cancer. Kaposiform lymphangiomatosis (KLA) is a subtype of generalized . 2015;166:10481054.e510. KLA is clinically heterogeneous. -. We tested six KHE tumor samples for the NRAS p.Q61R variant, and all were negative (TableS3). J Invest Dermatol. Identification of a causative variant would enable more efficacious targeted therapies for this aggressive disease. Kaposiform lymphangiomatosis: unifying features of a heterogeneous disorder. 2014;92:107122. In addition, the variant was identified in all six new KLA tumor samples, at levels ranging from 1% to 8% (Table1, Fig. Slider with three articles shown per slide. Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Departments of Pathology & Laboratory Medicine and Medical Genetics, Alberta Childrens Hospital Research Institute and Cumming School of Medicine, University of Calgary, Calgary, AB, Canada, Sarah F. Barclay PhD&Kyle C. Kurek MD, MMSc, Department of Pathology, Boston Childrens Hospital, Boston, MA, USA, Kyle W. Inman MD,Valerie L. Luks MD,Alyaa Al-Ibraheemi MD,Alanna J. Additionally, for this search, we looked at germline variants in the lesional tissue sample, called using the HaplotypeCaller from GATK4, following their recommended best practices.10. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%. Correspondence: Harry P.W. It does not have a current standard treatment and presents poor overall prognosis. Nevertheless, TEK represents a potential candidate for screening if additional NRAS p.Q61R-negative individuals with KLA are identified. Curr Protoc Bioinformatics. 1996;87:11811190. Thoracic involvement in KLA is more extensive than in GLA, and includes mediastinal, pleural, and parenchymal pulmonary disease, often with recurrent pleural and/or pericardial effusions. Variant is on 26/188 reads (14%). Patients with KLA suffer from high morbidity and mortality with 51% survival after 5 years 2 and overall survival rate of 34% 1. Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis. 2017;17:985990. ISSN 1098-3600 (print), https://doi.org/10.1038/s41436-018-0390-0, A somatic activating KRAS variant identified in an affected lesion of a patient with GorhamStout disease, Genomic profiling informs diagnoses and treatment in vascular anomalies, Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition, The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy, High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms, Novel GATA6-FOXO1 fusions in a subset of epithelioid hemangioma, Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations, Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotypephenotype relationships, Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome, NRASQ61R mutation in human endothelial cells causes vascular malformations, Sirolimus in the treatment of kaposiform lymphangiomatosis, A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations, Cancel doi: 10.1038/s41390-022-01986-0. (ad) Participant KLA2. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. Using Lumpy,15 we also excluded large structural variants, copy-number variations (100bp10kbp in size), or loss of heterozygosity in the exome data of this individual (FigureS1; commands in Supplementary Methods). Most common organs involved are the lung, heart, bone, and spleen. -, Hammill AM, Wentzel M, Gupta A, Nelson S, Lucky A, Elluru R, Dasgupta R, Azizkhan RG, Adams DM (2011) Sirolimus for the treatment of complicated vascular anomalies in children. Careers. 2016;61:3339. We did not identify the NRAS p.Q61R variant in one individual, KLA2, despite testing two independent lesional tissue samples. The four types of CLAs include: Generalized lymphatic anomaly (GLA). Alternatively, the observed effects may be the result of artificial expression under a pan-vascular promoter, such as fli-1, and/or a dosage effect from NRAS overexpression.29 It is also unclear how this NRAS variant is associated with such divergent biologic behavior as seen in metastatic melanoma, KLA, and more banal anomalies. Bioinformatics. 2023 Apr;70(4):e30219. 2016;46:12821290. Hemostatic anomalies, marked by coagulopathy and intralesional hemorrhage, are common and can be rapidly progressive and lethal. Characterization of kaposiform lymphangiomatosis tissue-derived cells. Kaposiform lymphangiomatosis: Diagnosis, pathogenesis, and treatment. The most common presentations were respiratory symptoms (50%), hemostatic abnormalities (50%), and an enlarging, palpable mass (35%). Kozakewich, MD, Department of Pathology, Boston Childrens Hospital, 300 Longwood Avenue, Boston, MA 02115 (e-mail: [emailprotected]u). Nature. Croteau SE, Kozakewich HP, Perez-Atayde AR, et al. Germline alterations in components of the RAS/MAPK pathway, including NRAS, cause a group of syndromes known as RASopathies, including neurofibromatosis type 1, Noonan syndrome, Costello syndrome, capillary malformationarteriovenous malformation syndrome, and others.28 The NRAS p.Q61R variant has not been identified in any of these syndromes. 2016;536:285291. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Though the GNAQ variant (c.175 A>C, p.M59L) was also reported in a study of acral melanoma,18 we showed that, in our data, it was likely a false positive variant call, representing the mismapping of a small number of reads spanning a polymorphism on chromosome 2 (see Results, Additional analyses in KLA2). We hypothesized that this might also be the case for KLA. Wouters V, Limaye N, Uebelhoer M, et al. may email you for journal alerts and information, but is committed Genomic profiling informs diagnoses and treatment in vascular anomalies. A somatic activating NRAS variant associated with kaposiform lymphangiomatosis. Recently, several vascular anomalies have been shown to be caused by somatic activating variants in the MAPK and PI3K/AKT pathways (TableS1). This highlights the importance of secondary validation of high-throughput sequencing results, especially for somatic variant calls that may be present on a low number of sequencing reads. Finally, we have highlighted a potentially recurrent false positive GNAQ variant (c.175 A>C, p.M59L) that should be carefully evaluated whenever it appears as a candidate in high-throughput sequencing studies. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2015;3:288295. Please try after some time. 2016;99:443450. The 5-year survival rate is 50% (1 . Groesser L, Peterhof E, Evert M, Landthaler M, Berneburg M, Hafner C. BRAF and RAS mutations in sporadic and secondary pyogenic granuloma. Abstract Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). Pediatr Blood Cancer. Similar soft tissue abnormalities axillae. Keywords: Some error has occurred while processing your request. 2017;18:435445. Lim YH, Ovejero D, Sugarman JS, et al. ras oncogenes in human cancer: a review. TL1 TR001880/TR/NCATS NIH HHS/United States, Children's Hospital of Philadelphia (CHOP), Adams DM, Trenor CC 3rd, Hammill AM, Vinks AA, Patel MN, Chaudry G, Wentzel MS, MobberleySchuman PS, Campbell LM, Brookbank C et al (2016) Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Epub 2023 Jan 22. Kaposiform lymphangiomatosis (KLA) is a recently identified 1 rare LM that may be a subtype and/or more severe form of generalized lymphatic anomaly (GLA). Lim YH, Douglas SR, Ko CJ, et al. 2015;136:e203e214. Moon KR, Choi YD, Kim JM, et al. Analysis of protein-coding genetic variation in 60,706 humans. MD*, Division of Interventional Radiology, Boston Childrens Hospital and Harvard Medical School, Division of Hematology/Oncology, Boston Childrens Hospital and Dana-Farber Cancer Institute, Department of Medicine, Boston Childrens Hospital, Dana-Farber/Boston Childrens Hospital Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, Departments of Pathology & Laboratory Medicine, Medical Genetics, Alberta Childrens Hospital Research Institute and Cumming School of Medicine, University of Calgary, Calgary, AB, Canada, ##Division of Oncology, Department of Pediatrics, Comprehensive Vascular Anomalies Program, Childrens Hospital of Philadelphia, University of Pennsylvania Medical Center, Philadelphia, PA. K.C.K. ) their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy journal alerts information! 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