Abstract
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.
Keywords
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References
- 131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies.Neurochirurgie. 1989; 35 (82-83, 128-131)
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.
- Cerebral cavernous malformation proteins at a glance.J Cell Sci. 2014; 127: 701-707
- Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.Nat Genet. 1999; 23: 189-193
- Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups.Cancer Cell. 2015; 27: 728-743
- 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
- Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: cure at a cost.Cancer. 2019; 125: 1867-1876
- Cerebral cavernous malformation: a Portuguese family with a novel CCM1 mutation.Case Rep Neurol. 2016; 8: 193-198
- 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
- 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
- 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
- Exome capture sequencing identifies a novel CCM1 mutation in a Chinese family with multiple cerebral cavernous malformations.Int J Neurosci. 2016; 126: 1071-1076
- 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
- Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology.Cell Mol Life Sci. 2014; 71: 1881-1892
- miR-21 coordinates tumor growth and modulates KRIT1 levels.Biochem Biophys Res Commun. 2013; 438: 90-96
- Autophagy in the pathogenesis of disease.Cell. 2008; 132: 27-42
- Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours.Int J Oncol. 2007; 30: 429-436
- Pediatric ependymoma: biological perspectives.Mol Cancer Res. 2009; 7: 765-786
- Chromosomal abnormalities subdivide ependymal tumors into clinically relevant groups.Am J Pathol. 2001; 158: 1137-1143
- KRIT1 protein depletion modifies endothelial cell behavior via increased vascular endothelial growth factor (VEGF) signaling.J Biol Chem. 2014; 289: 33054-33065
- Variations in structural protein expression and endothelial cell proliferation in relation to clinical manifestations of cerebral cavernous malformations.Neurosurgery. 2005; 56: 343-354
- 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
- Genetic differences on intracranial versus spinal cord ependymal tumors: a meta-analysis of genetic researches.Eur Spine J. 2016; 25: 3942-3951
- Molecular genetics of ependymoma.Chin J Cancer. 2011; 30: 669-681
- An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes.Nat Genet. 2015; 47: 878-887
- Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas.Sci Transl Med. 2016 Nov 23; 8 (366ra161)
Article Info
Publication History
Published online: May 03, 2020
Accepted:
April 15,
2020
Received in revised form:
March 2,
2020
Received:
October 29,
2019
Identification
Copyright
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