Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation

Abstract

Familial cerebral cavernous malformations due to the common Hispanic mutation (FCCM1-CHM) is an endemic condition among the Hispanic population of the Southwestern United States associated with significant morbidity and mortality. Cutaneous vascular malformations (CVMs) can be found in individuals with FCCM1-CHM, but their morphology, prevalence, and association with cerebral cavernous malformations (CCMs) has not been well characterized. A cross-sectional study of 140 individuals with confirmed FCCM1-CHM was performed with statistical analyses of CVM, CCM, and patient characteristics. We then compared these findings to other cohorts with Familial cerebral cavernous malformations (FCCM) due to other mutations. We observed a higher overall prevalence and a different predominant morphological subtype of CVM compared to previous FCCM cohorts. While the number of CVMs was not a reliable indicator of the number of CCMs present, each person with one or more CVMs had evidence of central nervous system (CNS) disease. Awareness of the morphology of these cutaneous lesions can aid in the diagnosis of individuals with FCCM-CHM in Hispanic patients or those with family history of CCM.

Cerebral cavernous malformations do not fall in the spectrum of PIK3CA-related overgrowth

“…It has been well defined that at least one of three known CCM genes, KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3), is disrupted in most human familial CCM cases. Subsequent experiments have validated that CCM lesions can be caused by germ-line mutations in familial cases,48–51 and somatic mutations in sporadic cases in various ethnic groups,52–54 while one study reported 36% of sporadic CCM lesion samples contained novel somatic mutations among all three CCM genes 53. Furthermore, somatic second-hit CCM mutations, although a very rare event, have been reported in both familial55 and sporadic cases53 and have been further validated through in vitro cultured EC models56 as well as in vivo animal models 57.…”

Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cerebral cavernous malformation

“…Familial CCM cases also display cavernous malformations outside the brain, including in the bone, spine, adrenal glands, and skin (Campione et al, 2013 ; Haghighi et al, 2013 ; Manole et al, 2020 ; Sirvente et al, 2009 ; Strickland et al, 2017 ; Tandberg et al, 2020 ; Toll et al, 2009 ). Specifically, among familial cases with CCM1 / KRIT1 , cutaneous lesions reported include congenital hyperkeratotic capillary‐venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs) (Manole et al, 2020 ; Sirvente et al, 2009 ).…”

“…Familial CCM cases also display cavernous malformations outside the brain, including in the bone, spine, adrenal glands, and skin (Campione et al, 2013 ; Haghighi et al, 2013 ; Manole et al, 2020 ; Sirvente et al, 2009 ; Strickland et al, 2017 ; Tandberg et al, 2020 ; Toll et al, 2009 ). Specifically, among familial cases with CCM1 / KRIT1 , cutaneous lesions reported include congenital hyperkeratotic capillary‐venous malformations (HCCVMs), punctate capillary malformations (PCMs), and deep blue nodules (DBNs) (Manole et al, 2020 ; Sirvente et al, 2009 ). Interestingly, similar appearing cutaneous lesions have been reported in another inherited vascular disease called capillary malformation‐arteriovenous malformation (CM‐AVM) caused by mutations in RASA1 (CM‐AVM1) and EPHB4 (CM‐AVM2) (Amyere et al, 2017 ; Eerola et al, 2003 ).…”

KRIT1‐positive hyperkeratotic cutaneous capillary venous malformation

“…In the United States, most familial cases of CCM1 are found in the Hispanic population in the Southwest region due to a founder effect from Spanish settlers 4 . Cutaneous manifestations of familial CCM include deep blue nodules, capillary malformations, and hyperkeratotic cutaneous capillary venous malformations (HCCVM) 4 . HCCVM have been associated most commonly with CCM1, and less commonly with variants in PDCD10 (CCM3) 2,5 .…”

“…capillary venous malformations (HCCVM). 4 HCCVM have been associated most commonly with CCM1, and less commonly with variants in PDCD10 (CCM3). 2,5 We present the case of an infant with KRIT1positive HCCVM associated with familial CCM, highlighting the importance of genetic testing in patients with vascular anomalies.…”