Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?


      Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas.


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        • Otten P
        • Pizzolato GP
        • Rilliet B
        • Berney J
        131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies.
        Neurochirurgie. 1989; 35 (82-83, 128-131)
      1. Moriarity JL, Wetzel M, Clatterbuck RE, Javedan S, Sheppard JM, Hoenig-Rigamonti K, et al. The natural history of cavernous malformations: a prospective study of 68 patients Neurosurgery. 1999;44(6):1166-1171; discussion 1172-1173.

        • Draheim KM
        • Fisher OS
        • Boggon TJ
        • Calderwood DA
        Cerebral cavernous malformation proteins at a glance.
        J Cell Sci. 2014; 127: 701-707
        • Laberge-le Couteulx S
        • Jung HH
        • Labauge P
        • Houtteville JP
        • Lescoat C
        • Cecillon M
        • Marechal E
        • Joutel A
        • Bach JF
        • Tournier-Lasserve E
        Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.
        Nat Genet. 1999; 23: 189-193
        • Pajtler KW
        • Witt H
        • Sill M
        • Jones DT
        • Hovestadt V
        • Kratochwil F
        • et al.
        Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups.
        Cancer Cell. 2015; 27: 728-743
        • Panwalkar P
        • Clark J
        • Ramaswamy V
        • Hawes D
        • Yang F
        • Dunham C
        • et al.
        Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome.
        Acta Neuropathol. 2017; 134: 705-714
        • Zapotocky M
        • Beera K
        • Adamski J
        • Laperierre N
        • Guger S
        • Janzen L
        • et al.
        Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: cure at a cost.
        Cancer. 2019; 125: 1867-1876
        • Marto JP
        • Gil I
        • Calado S
        • Viana-Baptista M
        Cerebral cavernous malformation: a Portuguese family with a novel CCM1 mutation.
        Case Rep Neurol. 2016; 8: 193-198
        • Yang C
        • Wu B
        • Zhong H
        • Li Y
        • Zheng X
        • Xu Y
        A novel CCM1/KRIT1 heterozygous deletion mutation (c.1919delT) in a Chinese family with familial cerebral cavernous malformation.
        Clin Neurol Neurosurg. 2018; 164: 44-46
        • Yang C
        • Zhao J
        • Wu B
        • Zhong H
        • Li Y
        • Xu Y
        Identification of a novel deletion mutation (c.1780delG) and a novel splice-site mutation (c.1412-1G>A) in the CCM1/KRIT1 gene associated with familial cerebral cavernous malformation in the Chinese population.
        J Mol Neurosci. 2017; 61: 8-15
        • Yang C
        • Nicholas VH
        • Zhao J
        • Wu B
        • Zhong H
        • Li Y
        • et al.
        A novel CCM1/KRIT1 heterozygous nonsense mutation (c.1864C>T) associated with familial cerebral cavernous malformation: a genetic insight from an 8-year continuous observational study.
        J Mol Neurosci. 2017; 61: 511-523
        • Mao CY
        • Yang J
        • Zhang SY
        • Luo HY
        • Song B
        • Liu YT
        • et al.
        Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations.
        Int J Neurosci. 2016; 126: 1071-1076
        • Zhu H
        • Guo Y
        • Feng X
        • Zhang R
        • Zhou C
        • Li G
        • et al.
        Familial cerebral cavernous angiomas: clinical and genetic features in a Chinese family with a frame-shift mutation in the CCM1 gene (krit1).
        J Mol Neurosci. 2014; 54: 790-795
        • Fisher OS
        • Boggon TJ.
        Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology.
        Cell Mol Life Sci. 2014; 71: 1881-1892
        • Orso F
        • Balzac F
        • Marino M
        • Lembo A
        • Retta SF
        • Taverna D
        miR-21 coordinates tumor growth and modulates KRIT1 levels.
        Biochem Biophys Res Commun. 2013; 438: 90-96
        • Levine B
        • Kroemer G.
        Autophagy in the pathogenesis of disease.
        Cell. 2008; 132: 27-42
        • Miracco C
        • Cosci E
        • Oliveri G
        • Luzi P
        • Pacenti L
        • Monciatti I
        • et al.
        Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours.
        Int J Oncol. 2007; 30: 429-436
        • Kilday JP
        • Rahman R
        • Dyer S
        • Ridley L
        • Lowe J
        • Coyle B
        • et al.
        Pediatric ependymoma: biological perspectives.
        Mol Cancer Res. 2009; 7: 765-786
        • Hirose Y
        • Aldape K
        • Bollen A
        • James CD
        • Brat D
        • Lamborn K
        • et al.
        Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups.
        Am J Pathol. 2001; 158: 1137-1143
        • DiStefano PV
        • Kuebel JM
        • Sarelius IH
        • Glading AJ
        KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling.
        J Biol Chem. 2014; 289: 33054-33065
        • Shenkar R
        • Sarin H
        • Awadallah NA
        • Gault J
        • Kleinschmidt-DeMasters BK
        • Awad IA
        Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations.
        Neurosurgery. 2005; 56: 343-354
        • Russo A
        • Neu MA
        • Theruvath J
        • Kron B
        • Wingerter A
        • Hey-Koch S
        • et al.
        Novel loss of function mutation in KRIT1/CCM1 is associated with distinctly progressive cerebral and spinal cavernous malformations after radiochemotherapy for intracranial malignant germ cell tumor.
        Childs Nerv Syst. 2017; 33: 1275-1283
        • Lee CH
        • Chung CK
        • Kim CH
        Genetic differences on intracranial versus spinal cord ependymal tumors: a meta-analysis of genetic researches.
        Eur Spine J. 2016; 25: 3942-3951
        • Yao Y
        • Mack SC
        • Taylor MD
        Molecular genetics of ependymoma.
        Chin J Cancer. 2011; 30: 669-681
        • Mohankumar KM
        • Currle DS
        • White E
        • Boulos N
        • Dapper J
        • Eden C
        • et al.
        An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes.
        Nat Genet. 2015; 47: 878-887
        • Bayliss J
        • Mukherjee P
        • Lu C
        • Jain SU
        • Chung C
        • Martinez D
        • et al.
        Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.
        Sci Transl Med. 2016 Nov 23; 8 (366ra161)