There is no certainty about the complete tumor spectrum of this tumor syndrome as of yet. We know from other autosomal dominant hereditary cancer predisposition syndromes that tumors can arise in different and distinct tissue types, for example, in Lynch syndrome and Von Hippel Lindau syndrome [
17,
18]. In those diseases, the problem is bi-allelic shutdown of a tumor suppressor gene within the tumor tissue. It apparently depends on the nature of the exact tumor suppressor gene, which types of tissues will be at risk for tumor formation. The evidence of the few cases of
SMARCE1-related CCMs that have been published so far, together with the evidence of the patient reported here, shows that the
SMARCE1 gene also acts as a tumor suppressor gene [
13]. In the clear cell meningiomas, there is a second hit causing inactivation of the wild-type allele [
14]. So far, no other tumor types than spinal and intracranial CCMs have been described in
SMARCE1-positive patients. Strategic gathering of patient and family data can help determine if we need to be on the lookout for other types of tumors in carriers, and further knowledge is needed to better understand why loss of SMARCE1 expression specifically leads to CCMs. For now, we propose to screen for spinal and intracranial CCMs only. Raffalli-Ebezant et al. reported on a carrier female who appeared to have multiple, asymptomatic spinal lesions in keeping with intradural meningiomas [
11]. This suggests that multiple tumors can be present and screening of the whole brain and spine is advisable.
All mutations in the
SMARCE1 gene found so far in CCM patients are loss-of-function mutations, including frameshift and nonsense mutations, an inversion and two large deletions [
11,
13,
14,
19]. Missense mutations in the
SMARCE1 gene cause a clinically very different syndrome called Coffin-Siris syndrome (OMIM 135900) with congenital mental retardation and dysmorphisms as main features [
20,
21]. The so far known CCM patients with a loss-of-function
SMARCE1 mutation have no clinical signs of Coffin-Siris syndrome, and screening for developmental delay or dysmorphisms is therefore not necessary.
It is currently unclear if missense mutations in the
SMARCE1 gene causing Coffin-Siris syndrome predispose to CCMs later in life. This combination has actually been described very recently for a related gene causing Coffin-Siris syndrome, the
SMARCB1 gene. A patient with Coffin-Siris syndrome phenotype and a constitutional missense
SMARCB1 gene mutation developed schwannomatosis [
22].