title: Cutis tricolor: a literature review and report of five new cases.
abstract: BACKGROUND
  Cutis tricoloris a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e.g., cutis marmorata telangectasica congenita (phacomatosis achromico-melano-marmorata)] or in the context of other skin (e.g., ataxia-telangiectasia and phacomatosis pigmentovascularis, PPV) or complex malformation phenotypes (e.g., microcephaly and dwarfism).
  
  
  METHODS
  (I) Review of the existing literature; and (II) information on our personal experience (clinical, laboratory and imaging data) on new cases withcutis tricolorseen and followed-up at our institutions during years 2010-2016.
  
  
  RESULTS
  The existing literature revealed 19 previous studies (35 cases) with pure cutaneous or syndromic cutis tricolor phenomena. Our personal experience included 5 unpublished patients (3 boys; 2 girls; currently aged 2 to 14 years) seen and followed-up at our Institutions in Italy who had: (I) skin manifestations of the cutis tricolor type (N=5); (II) skeletal abnormalities including small skull (n=2), obtuse angle of mandible (n=3), mild to moderate scoliosis (n=3), vertebral defects (n=3), and long bones bowing (n=3); mild psychomotor delay (n=3); epilepsy (n=2); anomalies of the corpus callosum (n=3); and cavum vergae (n =2).
  
  
  CONCLUSIONS
  This study further confirms and expands the overall phenotype of cutis tricolor. By literature review and personal experience we conclude that the skin abnormalities of the cutis tricolor type are stable over time; the skeletal defects are mild to moderate and do not progress or cause relevant orthopaedic complications; the neurological/behavioural phenotype does not progress and the paroxysmal events (when present) tend to decrease over time; there is a typical facial phenotype in some patients (long, elongated face, thick and brushy eyebrows, hypertelorism, deep nasal bridge with large bulbous nose and anteverted nostrils), which characterizes a somewhat distinct syndromic phenotype; some patients may develop early onset cataracts. The allelic dydymotic hypothesis of post-zygotic mutations likely involving the same gene loci could well explain the overall skin, bone, lens and nervous system phenomena of migration of different streaks of clones in the different tissues.
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 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.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.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, University of Catania, Catania, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Pirrone
authors.affiliation: Department of Pediatrics and Child Neuropsychiatry, Section of Pediatric Radiology, La Sapienza University, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Roggini
authors.affiliation: Department of Biomedical Sciences and Morphologic and Functional Imaging, Policlinico "G. Martino", University of Messina, Messina, Italy.
authors.forename: Emanule
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: 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: Cutis tricolor; Ruggieri-Happle syndrome (RHS); imaging; magnetic resonance imaging (MRI); mosaicism; mosic; neurological; skin