Development of renal and iliac aneurysms in a child with generalized infantile myofibromatosis

Brasseur, Benoit; Chantrain, Christophe; Godefroid, Nathalie; Sluysmans, Thierry; Anslot, Christine; Menten, Renaud; Clapuyt, Philippe; Dupont, Sophie; Vermylen, Christiane; Brichard, Bénédicte

doi:10.1007/s00467-009-1393-5

Cited by 12 publications

(15 citation statements)

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“…The second was a man with segmental overgrowth, thin, discolored skin, and multiple intra-and extracranial fusiform aneurysms with a different GOF variant (Karasozen et al, 2019). Notably, fusiform cerebral, coronary, and renal aneurysms have all been reported in individuals with constitutional PDGFRB GOF phenotypes (Brasseur et al, 2010;Frezin, Fusaro, Reding, & Godefroid, 2015;Zarate et al, 2019;Zufferey et al, 2013).…”

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confidence: 99%

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

Wenger

Bly

et al. 2020

American J of Med Genetics Pt A

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More than 50 individuals with activating variants in the receptor tyrosine kinase PDGFRB have been reported, separated based on clinical features into solitary myofibromas, infantile myofibromatosis, Penttinen syndrome with premature aging and osteopenia, Kosaki overgrowth syndrome, and fusiform aneurysms. Despite their descriptions as distinct clinical entities, review of previous reports demonstrates substantial phenotypic overlap. We present a case series of 12 patients with activating variants in PDGFRB and review of the literature. We describe five patients with PDGFRB activating variants whose clinical features overlap multiple diagnostic entities. Seven additional patients from a large family had variable expressivity and lateonset disease, including adult onset features and two individuals with sudden death. Three patients were treated with imatinib and had robust and rapid response,

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confidence: 99%

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

Wenger

Bly

et al. 2020

American J of Med Genetics Pt A

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“…When affecting a lot of vessels, FMD can be rapidly progressive, particularly in young children [ 5 ]. Renal autotransplantation is an accepted surgical treatment for FMD with involvement of renal vessels, providing good long-term results with a return to normal blood pressure [ 3 , 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…The generalized form involves multiple organs such as lung, kidney, heart, liver, adrenal glands, thyroid, gastrointestinal tract [ 1 ] and small vessels [ 2 ]. It has a poor prognosis with a mortality rate greater than 75 % [ 2 , 3 ].…”

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confidence: 99%

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Kidney transplantation in infantile myofibromatosis and fibromuscular dysplasia: a case report

et al. 2015

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IntroductionWe report what we believe to be the first case of a child affected by two rare vascular diseases complicated by kidney failure and successfully treated by kidney transplantation.Case presentationA 3-year-old Caucasian girl with fibromuscular dysplasia and infantile myofibromatosis presented with arterial hypertension and renal failure. She received a deceased donor kidney transplantation distal to an iliac graft. The technical peculiarities of this transplantation are described, as well as her favorable long-term outcome.ConclusionKidney transplantation may be considered in a patient with vascular diseases and a history of iliac surgery.

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“…Although the individuals described in this manuscript had no evidence of myofibromas, renal and iliac aneurysms have been reported in an individual with IM. 35 More research is necessary to understand the role of age-or timing-specific intracranial-aneurysm formation. PDGFRB-targeted therapy for treatment of severe IM in an individual with a heterozygous germline mutation in PDGFRB has been reported.…”

Section: Supplemental Data Ligand Binding Induces Pdgfrb Dimerizatiomentioning

confidence: 99%

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

Karasozen

Osbun

Parada

et al. 2019

The American Journal of Human Genetics

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The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor b gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent autophosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors.

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Development of renal and iliac aneurysms in a child with generalized infantile myofibromatosis

Cited by 12 publications

References 10 publications

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

Kidney transplantation in infantile myofibromatosis and fibromuscular dysplasia: a case report

Somatic PDGFRB Activating Variants in Fusiform Cerebral Aneurysms

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