Neurological manifestations in individuals with isolated or syndromic (Ruggieri-Happle syndrome) phenotypes with “cutis tricolor”: a study of 14 cases

Background: The term cutis tricolor describes the combination of congenital hyper- and hypo-pigmented skin lesions in close proximity to each other in a background of normal complexion. This phenomenon has been reported so far: (i) as pure cutaneous trait, (ii) as a part of a complex malformation syndrome (Ruggieri-Happle syndrome RHS), (iii) as a distinct type (cutis tricolor parvimaculata); (iv) in association with other (e.g., vascular) skin disturbances. Aim: The aim of this study was to define the spectrum of neurological abnormalities in cutis tricolor. Methods: A retrospective and prospective 14-year study of clinical, electroencephalographic (EEG), neuroradiological (MRI), cytogenetic and ZFHX1B gene studies of 14 individuals (8 M, 6 F; aged 228 years) with cutis tricolor (4 pure cutaneous; 10 syndromic) was undertaken. Results: Neurological involvement was recorded in 71.4% (10/14) of the patients [100% (10/10) in RHS and null (0/4) in cases with isolated skin manifestations] and included psychomotor delay (n=8), seizures (n=9), EEG abnormalities (n=6), a behavioural phenotype (n=4), non-specific brain abnormalities (n=6). Genetic analyses excluded ZFHX1B mutations and revealed a 19qter deletion (n=1). Conclusions: Even though we could not exclude the ascertainment and referral biases, we concluded that cutis tricolor may be a marker of underlying neurological involvement particularly in subjects with a syndromic (RHS) phenotype