We present the case of a child with RASA1-negative CM-AVM syndrome with a de novo missense mutation in EPHB4, a transmembrane tyrosine kinase receptor essential for vasculogenesis.
Haploinsufficiency of RASA1, located on chromosome 5q14.3, has been identified as the etiology underlying the disorder capillary malformation-arteriovenous malformation (CM-AVM).
The objective of the study was to identify somatic RASA1 "second hits" from vascular malformations associated with CM-AVM syndrome, and describe phenotypic variability.
These three individuals had epistaxis and dermal lesions that were described as telangiectases but whose location and appearance resembled lesions described in some individuals with RASA1-related disorders (capillary malformation-arteriovenous malformation syndrome).
Gene mutations have been identified in 2 Mendelian syndromes of which VOGM is an infrequent but associated phenotype: capillary malformation-arteriovenous malformation syndrome ( RASA1) and hereditary hemorrhagic telangiectasia ( ENG and ACVRL1).
These RASA1-associated cutaneous capillary malformations (CMs) can accompany internal or cutaneous arteriovenous malformation (AVM) or arteriovenous fistula to constitute CM-AVM syndrome.
Mutations in gene RASA1 have been historically associated with capillary malformation-arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail.
Maternal and fetal capillary malformation-arteriovenous malformation (CM-AVM) due to a novel RASA1 mutation presenting with prenatal non-immune hydrops fetalis.
A germline mutation was identified in 23 probands (53.5 ± 14.9%): 8 in ENG (34.8 ± 14.2%), 1 in ACVRL1 (4.3 ± 6%) leading to a diagnosis of HHT, and 14 in RASA1 (60.9 ± 14.4%) leading to a diagnosis of capillary malformation/arteriovenous malformation type 1.No EphB4 gene mutation was identified.
In humans, RASA1 mutations cause capillary malformation-arteriovenous malformation (CM-AVM); whether it also functions as a regulator of the lymphatic vasculature is unknown.