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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

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Abstract

Purpose

Cerebrospinal cavernous malformations (CCMs) are vascular lesions characterized by dilated and leaky capillary caverns. CCMs can cause seizures, focal neurological deficits or acute intracranial hemorrhage; however, most patients are asymptomatic. CCMs occur either sporadically or as a familial autosomal-dominant disorder. We present a clinical and molecular study of a patient with distinctive cerebral and spinal cavernous malformations following radiochemotherapy for a malignant brain tumor.

Methods

The patient had multiple magnet resonance imaging (MRI) examinations of his brain and spine following radiochemotherapy for a primary intracranial germ cell tumor (GCT), as part of his oncologic follow-up. The MRI sequences included susceptibility-weighted imaging (SWI). The coding exons and their flanking intronic regions of KRIT1/CCM1 gene were analyzed for mutations by polymerase chain reaction (PCR) and direct sequencing.

Results

MRI revealed numerous cerebral and spinal microhemorrhages and pronounced cavernous malformations that progressed with subsequent follow-up imaging. Genetic analysis demonstrated a novel heterozygous KRIT1/CCM1 two base pair deletion (c.1535_1536delTG) in exon 14. This deletion leads to a frameshift with a premature stop codon at nucleotide position 1553 and a highly likely loss of function of the KRIT1 protein.

Conclusion

We describe a patient with a novel heterozygous germ line loss of function mutation in KRIT1, which is associated with rapid-onset and highly progressive CCMs after radiochemotherapy for a malignant brain tumor.

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Acknowledgements

We sincerely thank the patient and his family for participating in this study.

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Author notes

  1. Alexandra Russo and Marie Astrid Neu contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology/Hemostaseology, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Alexandra Russo, Marie Astrid Neu, Johanna Theruvath, Bettina Kron, Arthur Wingerter & Joerg Faber

  2. Department of Radiation Oncology and Radiation Therapy, University Medical Center Mainz, Mainz, Germany

    Silla Hey-Koch

  3. Department of Neuroradiology, University Medical Center Mainz, Mainz, Germany

    Yasemin Tanyildizi

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  1. Alexandra Russo
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Correspondence to Joerg Faber.

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Electronic supplementary material

Fig. 6

CCM presentation in different MRI sequences. Seven years and 4 months after completion of initial radiotherapy, MRI scans through a similar axial level of the brain show various appearances of the CCMs. Comparison of T1-weighted (a), T2-weighted (b, c) and T2*-weighted (d) images highlight the sensitivity of the different signal sequences in detection of CCMs. (GIF 109 kb)

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Russo, A., Neu, M.A., Theruvath, J. 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 33, 1275–1283 (2017). https://doi.org/10.1007/s00381-017-3434-x

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