Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord. They are formed by closely clustered, enlarged capillary channels (so called “caverns”) consituted by a single layer of endothelium, which is abnrormally thin. The vessels are filled with slow-moving or stagnant blood that is usually clotted or in a state of decomposition. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase in number over time. Hundreds of lesions may be identified, depending on the person’s age and the imaging technique used. Infants and children may already have CCMs, although the majority become evident between the second and fifth decades. Symptoms may vary significantly, even within the same family. Some patients (around 50%) may even be asymptomatic for their entire life, whereas others may develop seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. 9% of patients develop cutaneous vascular lesions, whereas 5% develop retinal vascular lesions.
Detailed clinical description
Clinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32%).
Cerebral hemorrhages may remain intralesional (within the cavernoma) or extend beyond the borders of the lesion. A more aggressive presentation of cerebral hemorrhages have been originally noted in children rather than adults, although more recent studies suggest that the hemorrhage risk is comparable in these two groups.
Familial CCMs occur predominantly in the brain, but have also been reported in the spinal cord, retina (5% CCM patients) and skin (9% of CCM patients).
Generally, signs and symptoms of CCMs may include weakness, numbness, difficulty speaking, difficulty understanding others, unsteadiness, vision changes or severe headache. Seizures also can occur, and neurological issues can progressively worsen over time with recurrent bleeding (hemorrhage). Repeat bleeding can occur soon after an initial bleed or much later, or a repeat bleed may never occur.
The primary treatment option for a CCM is surgical removal. Radiation therapy has not been shown to be effective. The decision to operate is made based upon the risk of approaching the lesion.
Autpsies show that approximately 0.4%-0.5% of the general population have either sporadic CCM or familial CCM. The common occurrence of asymptomatic vascular lesions in individuals with familial CCM (up to 40-50%) suggests that the population incidence of FCCM is probably underestimated.
CCMs are a monogenic disease, that is caused by a heterozygous mutation in one of few different genes. So, far, 4 genes are known to be associated to CCMs: KRIT1, CCM2, PDCD10, and PIK3CA. The exact mechanisms that leads to the formation of CCM lesions remains unknown.
In KRIT1 there are no specific mutational hotspots and pathogenic variants are scattered acrross the entire gene sequence, being mainly loss-of-function mutations such as nonsense, frameshift and splice mutations (notably, even some missense mutations in the KRIT1 gene have been found to actually alter not the aminoacid sequence, but the splicing process).
CCM2 variants usually leads to gene inactivation. Several point mutations and small indels have been described, although a large common deletion of 77.6 Kbp (comprising exons 2 to 10) exists as a founder mutation in the US.
Also PDCD10 variants, whether they are point mutations or large deletions, are predicted to be loss-of-function.
Notably, also large deletions have been described in the KRIT1, CCM2, and PCDC10 genes, with different frequencies in different populations: exonic or multiexonic deletions account for 5% of the cases in US, 4% of the cases in France and as much as 40% of cases in Italy.
CCMs represent 5%-15% of all cerebral vascular malformations. Other vascular malformations of the brain that should be distinguishable from CCM by neuroimaging and clinical manifestations are the following
– Arteriovenous malformations (KRAS mutations, ENG, ACVRL1, and GDF2 mutations in hemorrhagic telangectasia type 1)
Capillary malformation-arteriovenous malformations (RASA1 and EPHB4 genes)
Capillary malformations, congenital 1 (somatic mutations in GNAQ)
– Venous malformations
– Telangiectases (ATM gene mutations)
– Vascular tumors such as hemangioblastomas (including those seen in Von Hippel-Lindau syndrome – VHL gene mutations)
Vascular malformations associated in Sturge-Weber syndrome (GNAQ gene)
In addition, it’s woth to remember that even some non genetic conditions may lead to brain imaging findings similar to those seen in individuals with CCM: hypertensive angiopathy, trauma, multiple hemorrhagic metastases, myloid angiopathy (with lacunar stroke), pneumocephalus, cysticercosis.
Genetic testing strategy
Doing a multigene panel including the CCMs genes and the genes of the differential diagnosis may be the fastest approach to the genetic diagnosis. However, it is highly recommended that the panel is based on either whole exome sequencing or whole genome sequencing, so to warrant to analysis of further genes if the panel is negative. All Breda Genetics’ panels are based on wither whole exome sequencing or whole genome sequencing.