I ask: I just saw a 2 yo asymptomatic boy who shares a KRIT1 mutation for familial cerebral cavernous malformations with his father. The father had presented with seizures in adulthood and was then found to have cerebral cavernous malformations. The father was treated surgically for the symptomatic malformation. To date the boy has had no cerebral imaging. His parents would prefer to defer this until he would not require sedation for the study. Is this reasonable?
A neurosurgeon responds: You could get a nonsedated quick brain MRI just to get a quick look under the hood. More data points to be able see if any are growing at an unreasonable rate.
A neurologist responds: Should be reasonable to wait. You know he is at risk because of the mutation. Bleeding from these low pressure sinusoidal lesions, should it occur, would be low pressure and likely to result in bad HA or seizures rather than the often devastating bleeds that result from AVMs or aneurysms, so there is less urgency in identifying a cavernous malformation than an AVM or aneurysm. Cavernous malformations are often indolent, sitting there for years without bleeding, so would you recommend surgery in an asymptomatic 2 year old even if an MRI identified one or more lesions? I doubt it, and if not, what is the therapeutic yield of the MRI? Finally, even with MRI cavernous malformations are difficult to recognize unless they have had some amount of prior bleeding (yielding the hemosiderin that makes the characteristic bulls-eye lesion on MRI), although one could infer a Dx given the family history and the mutation. There is a possibility that the scan would be more informative in a couple of years.
A couple of things I would do now. If not done already, I would arrange for an ophthalmology consultation. These lesions can occur in the retina, and a small bleed there would be likely to cause permanent visual loss or even blindness, so identifying this lesion might in fact trigger more aggressive Rx. I would educate the family about possible manifestations of malformation bleeding. I have seen these manifest as new seizures, headaches, unexplained isolated vomiting, weakness, and clumsiness. Add visual disturbance, which I have not seen but should be on the list. Any of these things should lead to the MRI.
Asymptomatic family members (including parents and offspring of a proband) who have been identified by MRI as having lesions consistent with CCM or by molecular genetic testing as having the family-specific mutation may be evaluated with repeat MRI in special circumstances.
Note: Although it has been recommended that asymptomatic adults and children who are known to have the family-specific disease-causing mutation or who are at risk for CCM based on family history undergo surveillance with MRI examination at regular intervals based on the observation that new lesions form over time [Kattapong et al 1995], asymptomatic lesions are rarely treated. Therefore, the clinical utility of such routine screening has yet to be determined.
From reference below: After identification of a mutation in a seemingly sporadic case, genetic counseling and testing can be offered to the parents and further relatives. While screening CCM1, CCM2, and CCM3 genes for mutations in the index patient may occasionally be laborious, genetic confirmation or exclusion of a previously detected mutation within the same family is quick and cost-effective when compared to MRI. Furthermore, genetic testing identifies mutation carriers even in the absence of clinical symptoms and neuroradiologically visible cavernomas. In the event that a parental mutation is confirmed, presymptomatic genetic testing of further family members selects those relatives who are at risk and truly require clinical and neuroradiological surveillance as described before. Hence, we suggest to perform gradient-echo MR scans for asymptomatic family members with a confirmed CCM mutation to assess their current CNS involvement. Serial MR scans may be undertaken once per year. Depending on the findings and patient interests, even asymptomatic cavernomas can be removed surgically with a good outcome for prevention of consecutive bleeding and neurological deficits .
Sürücü O, Sure U, Gaetzner S, Stahl S, Benes L, Bertalanffy H, Felbor U. Clinical impact of CCM mutation detection in familial cavernous angioma. Childs Nerv Syst. 2006;22:1461–4.
INTRODUCTION AND BACKGROUND:
A 3-year-old Bosnian girl with a large symptomatic brainstem and multiple supratentorial cavernous angiomas, who underwent neurosurgical treatment, is presented. As multiple cavernomas are more common in familial cases, genetic analyses and neuroradiological imaging were performed in the patient and her parents to see whether there was any evidence for inheritance. This information is important for genetic counseling and provision of medical care for at-risk relatives. Currently, no recommendation is available on how to manage these cases.
Genetic analyses demonstrated a novel CCM1 frameshift mutation (c.1683_1684insA; p.V562SfsX6) in the child and the asymptomatic 27-year-old mother. Sensitive gradient-echo magnetic resonance imaging of the mother revealed multiple supratentorial lesions, whereas analogous imaging of the father showed no pathological findings.
This case exemplifies that seemingly sporadic cases with multiple lesions might well be hereditary and that presymptomatic genetic testing of family members may identify relatives for whom clinical and neuroradiological monitoring is indicated.
Riant F, Odent S, Cecillon M, Pasquier L, de Baracé C, Carney MP, Tournier-Lasserve E. Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations. Clin Genet. 2014 Dec;86(6):585-8.
Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.