CM-AVM syndrome in a neonate: case report and treatment with a novel flow reduction strategy

Behr, Gerald; Liberman, Leonardo; Compton, Jocelyn; Garzon, María C.; Morel, Kimberly D.; Lauren, Christine T.; Starc, Thomas J.; Kovacs, Stephen J.; Beltroni, Vincent; Landres, Rachel; Anyane‐Yeboa, Kwame; Meyers, Philip M.; Bacha, Emile A.; Kandel, Jessica J.

doi:10.1186/2045-824x-4-19

Cited by 10 publications

(10 citation statements)

References 12 publications

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“…PKWS caused by RASA1 mutation typically presents with symmetrical overgrowth of the involved extremity with large cutaneous CM and diffuse microshunting causing cardiac volume overload. Recent reports of upper-and lower-extremity lymphedema (6,7), together with the finding that a small number of CM-AVM patients develop chylothorax and chylous ascites (5), indicate that lymphatic malformation may be an additional phenotype associated with mutations in RASA1. In mice, deletion of Rasa1 causes embryonic lethality, as a result of abnormal blood vessel development.…”

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confidence: 99%

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Burrows

Gonzalez-Garay

Rasmussen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

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Mutations in gene RASA1 have been historically associated with capillary malformation-arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes-Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.CM-AVM | lymphatics | near-infrared fluorescence imaging | indocyanine green imaging T he gene RASA1 encodes for protein p120 Ras GTPaseactivating protein (p120 RasGAP or RASA1) that regulates Ras activation and blood vessel growth in humans. Germ-line mutations in RASA1 cause the autosomal dominant vascular disorder capillary malformation-arteriovenous malformation (CM-AVM), with high penetrance and variable expressivity [Online Mendelian Inheritance in Man (OMIM) no. 608354] (1-5). CMs are observed in all patients with RASA1 mutations and present as single or multiple small pink cutaneous lesions. Fast-flow lesions that include AVMs, arteriovenous fistulas, and Parkes-Weber syndrome (PKWS) (OMIM no. 608355) are observed in one-third of cases. PKWS caused by RASA1 mutation typically presents with symmetrical overgrowth of the involved extremity with large cutaneous CM and diffuse microshunting causing cardiac volume overload. Recent reports of upper-and lower-extremity lymphedema (6, 7), together with the finding that a small number of CM-AVM patients develop chylothorax and chylous ascites (5), indicate that lymphatic malformation may be an additional phenotype associated with mutations in RASA1. In mice, deletion of ...

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mentioning

confidence: 99%

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Burrows

Gonzalez-Garay

Rasmussen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

116

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“…Another had only two CMs and a family history of large, atypical CMs and AVMs; she has not undergone genetic testing. Two cases had PKWS; one had upper extremity involvement and three large CMs . The other had a congenital pink patch on the thigh that became warm at 5 years of age, as the patient also developed leg asymmetry.…”

Section: Discussionmentioning

confidence: 99%

Clinical Spectrum of Capillary Malformation–Arteriovenous Malformation Syndrome Presenting to a Pediatric Dermatology Practice: A Retrospective Study

Weitz

Lauren

Behr

et al. 2014

Pediatric Dermatology

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Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by RASA1 mutations. The prevalence and phenotypic spectrum are unknown. Evaluation of patients with multiple CMs is challenging because associated AVMs can be life threatening. The objective of this study was to describe the clinical characteristics of children presenting with features of CM-AVM to an academic pediatric dermatology practice. After institutional review board approval was received, a retrospective chart review was performed of patients presenting between 2009 and 2012 with features of CM-AVM. We report nine cases. Presenting symptoms ranged from extensive vascular stains and cardiac failure to CMs noted incidentally during routine skin examination. All demonstrated multiple CMs, two had Parkes Weber syndrome, and two had multiple infantile hemangiomas. Seven patients had family histories of multiple CMs; three had family histories of large, atypical CMs. Six had personal or family histories of AVMs. Genetic evaluation was recommended for all and was pursued by six families; four RASA1 mutations were identified, including one de novo. Consultations with neurology, cardiology, and orthopedics were recommended. Most patients (89%) have not required treatment to date. CM-AVM is an underrecognized condition with a wide clinical spectrum that often presents in childhood. Further evaluation may be indicated in patients with multiple CMs. This study is limited by its small and retrospective nature.

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“…3 In our area, we have found a similar prevalence, with seven cases in a population of 820 000 people (0Á85 per 100 000). Capillary malformation-arteriovenous malformation is a clinically and genetically heterogeneous syndrome, [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and its clinical diagnosis is based on the identification of the characteristic small, multifocal CMs. As large CMs (up to 15 cm in diameter) can appear, and the reported number of CMs in individual cases can range from one to 60 lesions, evidence of RASA1 mutation or familial history of CMs or AVMs allows the diagnosis of doubtful cases.…”

Section: Discussionmentioning

confidence: 99%

Hypotrichosis associated with capillary malformation-arteriovenous malformation syndrome

et al. 2014

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CM-AVM syndrome in a neonate: case report and treatment with a novel flow reduction strategy

Cited by 10 publications

References 12 publications

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Clinical Spectrum of Capillary Malformation–Arteriovenous Malformation Syndrome Presenting to a Pediatric Dermatology Practice: A Retrospective Study

Hypotrichosis associated with capillary malformation-arteriovenous malformation syndrome

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