title: Mixed vascular nevus syndrome: a report of four new cases and a literature review.
abstract: BACKGROUND
  Mixed vascular nevus (or nevus vascularis mixtus) represents an admixture of cutaneous vascular malformations of the telangiectatic type and angiospastic spots of nevus anemicus. It can occur as an purely cutaneous trait or as a hallmark of a neurocutaneous phenotype (mixed vascular nevus syndrome) characterised by the combination of: (I) paired vascular (telangiectatic and anemic) twin nevi and brain abnormalities of the Dyke-Davidoff-Masson type (i.e., crossed cerebral/cerebellar hemiatrophy with hypoplasia of the ipsilateral cerebral vessels and homolateral hypertrophy of the skull and sinuses (hyperpneumatisation) with contralateral hemispheric hypertrophy); or (II) paired vascular twin nevi and brain malformations of the Dyke-Davidoff-Masson type in association with systemic abnormalities consisting in facial asymmetry, skeletal anomalies (i.e., Legg-Calvé-Perthes-like disease) and disorders of autoimmunity (i.e., diabetes, thyroiditis). In 2014, Happle proposed to name the syndrome with the eponym Ruggieri-Leech syndrome.
  
  
  METHODS
  Review of the existing literature on nevus vascularis mixtus and information on our personal experience on new cases and follow-up of previously reported cases by some of us.
  
  
  RESULTS
  The existing literature revealed 4 previous studies including 33 cases with an inferred purely cutaneous trait and 3 cases with a combination of paired vascular twin nevi and brain malformation of the Dyke-Davidoff-Masson type. Our personal experience includes 4 unpublished patients (1 female and 3 males; currently aged 2 to 34 years) seen and followed-up at our Institutions in Italy who had: paired vascular nevi involving either the face (n=2) or the face and parts of the body (n=2); facial asymmetry (n=4); mild to moderate facial dysmorphic features (n=2); developmental delay (n=3); seizures/stroke-like episodes and associated hemiplegia (n=4); muscular hypotrophy (n=2); mild to moderate hemispheric atrophy (n=4); skull osseous hypertrophy (n=4); hyperpneumatisation of the sinuses (n=2); hypoplastic brain vessels (n=4); colpocephaly and malformation of cortical development (n=2). Follow-up data on our previous 2 cases revealed that the vascular abnormalities in the skin and nervous system were stable over years without neurological progression or deterioration.
  
  
  CONCLUSIONS
  Pathogenically, this complex phenotype suggests that embryonic pairing and somatic recombination of recessive (didymotic) alleles controlling the balance between constriction (i.e., nevus anemicus) and dilatation (i.e., nevus telangiectaticus) of blood vessels could be the primary event causing the phenomena of cutaneous and brain vascular twin spotting and the paired phenomena of skull hyperpneumatisationvs. hypertrophy and brain megalencephaly/colpocephalyvs. cortical dysplasia. This association is likely more frequent than previously thought and should be investigated by means of: (I) brain and spinal cord imaging (combination of CT and MRI studies); (II) skeletal X-ray studies (when dictated by clinical findings); (III) systemic ultrasound studies; (IV) neurophysiologic studies (EEG); (V) psychomotor testing; (VI) and laboratory investigation (including immune-mediated dysfunction).
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Ruggieri
authors.affiliation: National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy;; Institute of Neurological Sciences, National Research Council, Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Polizzi
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Strano
authors.affiliation: Unit of Dermatology, IRCCS Oasi M. Santissima, Troina, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Schepis
authors.affiliation: Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Morano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Belfiore
authors.forename: Stefano
authors.initials: S
authors.lastname: Palmucci
authors.forename: Pietro Valerio
authors.initials: PV
authors.lastname: Foti
authors.affiliation: Department of Educational Sciences, Section of Psychology, Section of Neurology, University of Catania, Catania, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Pirrone
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Neurology, University of Catania, Catania, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Sofia
authors.affiliation: Department of Biomedical Sciences and Morphologic and Functional Imaging, Policlinico "G. Martino", University of Messina, Messina, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: David
authors.affiliation: Department of Molecular Neurosciences, University College of London, London, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Salpietro
authors.affiliation: Unit of Pediatric Neuroradiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Mankad
authors.affiliation: Department of Medical and Surgical Sciences and Advanced Technologies "G. F. Ingrassia", Section of Radiology, University of Catania, Catania, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Milone
keywords: Dyke-Davidoff-Masson syndrome; EEG; Mixed vascular nevus; computerised tomography (CT); magnetic resonance imaging (MRI); mixed vascular nevus syndrome; nevus anemicus; nevus vascularis mixtus; telangiectatic nevus; ultrasound