CORRESPONDENCE
539 ActaDV ActaDV
Advances in dermatology and venereology Acta Dermato-Venereologica
RASA1 Variants in Capillary Malformations of Children : A Comment to Maruani A et al .
Rudolf HAPPLE Department of Dermatology , University of Freiburg , Hauptstr . 7 , DE-79104 Freiburg , Germany . E-mail : rudolf . happle @ uniklinik-freiburg . de
Maruani et al . ( 1 ) present the results of an extensive multicentre study including a cohort of 113 children whose legs were affected by one or more capillary malformations ( CMs ). These individuals were examined for the presence of germline RASA1 variants . The authors avoid the term “ mutations ” because they are not sure whether the documented alleles are pathogenic . In 7 children they found heterozygosity for a RASA1 variant . Maruani et al . ( 1 ) use the presently prevailing classification of the International Society for the Study of Vascular Anomalies ( ISSVA ) ( 2 , 3 ). However , this nomenclature does not discriminate between CMs that have specifically different dermatological criteria ( 4 ).
Fig . 2 of the study presents 6 “ examples of clinical characteristics ”. However , Fig . 2a – c shows neither naevus flammeus nor rhodoid naevi ( capillary malformation-arteriovenous malformation ; CM-AVM ). In my opinion , the most likely diagnosis is naevus roseus . This clinical entity is now well-established in Europe ( 4 – 6 ), but is still disregarded in other regions of the world ( 2 , 3 ). Its molecular cause is unknown , but mutations in GNAQ , GNA11 , AKT1 or PIK3CA have been excluded ( personal communication : Veronica Kinsler , London , UK , 20 October 2017 ). Fig . 2d shows a “ geographictype CM ” ( 3 ) that may represent a port-wine naevus of the Proteus type or the CLOVES type ( 4 ), or a port-wine naevus of a still unknown type . Hence , the authors are correct to doubt that the RASA1 variant pL116V is a pathogenic mutation . Fig . 2e suggests a diagnosis of rhodoid naevi ( CM-AVM ) ( 4 ) because a faint anaemic halo surrounds the pink macule on the left thigh , whereas the large segmentally arranged macule on the right lower leg may be taken as an example of type 2 segmental mosaicism ( 7 ). Finally , the bilateral vascular stains shown in Fig . 2f can , in my opinion , not be classified , but a diagnosis of rhodoid naevi ( CM-AVM ) can be excluded .
From a genetic point of view , when the underlying gene causing naevus roseus is determined , the children in Fig . 2a-c should be tested for a mutation in this gene .
The underlying gene will almost certainly be elucidated in 2018 . The girl in Fig . 2d should be tested for the presence of a PIK3CA or AKT1 mutation . Moreover , the girl in Fig . 2e should be tested for an EPHB4 mutation ( 8 , 9 ), as already proposed by the authors .
In conclusion , the large-scale molecular study of CMs presented by Maruani et al . ( 1 ) shows that focusing on a single gene , such as RASA1 , will yield less specific results . As an initial step , it may be preferable to categorize CMs according to their dermatological criteria , which would simplify the search for the molecular basis of a given disorder .
REFERENCES
1 . Maruani A , Durieux-Verde M , Mazereeuw-Hautier J , Boccara O , Martin L , Chiaverini C , et al . Search for RASA1 variants in capillary malformations of the legs in 113 children : results from the French National Paediatric Cohort CONAPE . Acta Derm Venereol 2018 ; 98 : 251 – 255 .
2 . Wassef M , Vikkula M . Vascular anomalies classification : recommendations from the International Society for the Study of Vascular Anomalies . Pediatrics 2015 ; 136 : 203 – 214 .
3 . Rozas-Muñoz E , Frieden IJ , Roé E , Puig L , Baselga E . Vascular stains : proposal for a clinical classification to improve diagnosis and management . Pediatr Dermatol 2016 ; 33 : 570 – 584 .
4 . Happle R . Capillary malformations : a classification using specific names for specific skin disorders . J Eur Acad Dermatol Venereol 2015 ; 29 : 2295 – 2305 .
5 . Valdivielso-Ramos M , Mauleón C , Hernanz JM . Phacomatosis spilorosea with oligodontia , scoliosis and fibrous cortical defects . J Eur Acad Dermatol Venereol 2012 ; 26 : 260 – 262 .
6 . Fink C , Happle R , Enk A , Haenssle HA . Phacomatosis spilorosea : visual diagnosis and associated pathologies of a rare entity . J Eur Acad Dermatol Venereol 2016 ; 30 : e69 – e70 .
7 . Panzer R , Happle R , Fölster-Holst R . Rhodoid naevus syndrome : why is this name preferable to ‘ capillary malformationarteriovenous malformation ’? J Eur Acad Dermatol Venereol 2017 ; 31 : e446 – e448 .
8 . Yu J , Streicher JL , Medne L , Krantz ID , Yan AC . EPHB4 mutation implicated in capillary malformation-arteriovenous malformation syndrome : a case report . Pediatr Dermatol 2017 ; 34 : e227 – e230 .
9 . Amyere M , Revencu N , Helaers R , Pairet E , Baselga E , Cordisco M , et al . Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation ( CM-AVM2 ) deregulating RAS-MAPK signaling . Circulation 2017 ; 136 : 1037 – 1048 .
The authors of the original article ( Maruani et al .) were given the opportunity to comment in response to this Correspondence , but chose not to do so .
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2903 Acta Derm Venereol 2018 ; 98 : 539