Severe neuroimaging anomalies are usually associated with random X inactivation in leucocytes circulating DNA in X-linked dominant Incontinentia Pigmenti Volodia Dangouloff-Ros a,b,c,d, ⁎, Smail Hadj-Rabia d,e,1 , Judite Oliveira Santos c,f,1 , Elodie Bal c,f,1 , Isabelle Desguerre c,d,g , Manoelle Kossorotoff d,g , Isabelle An h,i , Asma Smahi c,f , Christine Bodemer d,e , Arnold Munnich c,d,f , Julie Steffann c,d,f , Nathalie Boddaert a,b,c,d a Department of Pediatric Radiology, Hôpital Necker Enfants Malades, AP-HP, 149 rue de Sèvres, 75105 Paris, France b INSERM U1000, 149 rue de Sèvres, 75015 Paris, France c UMR 1163, Institut Imagine, 24 boulevard du Montparnasse, 75015 Paris, France d University René Descartes, PRES Sorbonne Paris Cité, 12 rue de l'Ecole de Médecine, Paris, France e Department of Pediatric Dermatology, Hôpital Necker Enfants Malades, AP-HP, 149 rue de Sèvres, 75105 Paris, France f Genetic unit, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France g Department of Pediatric Neurology, Hôpital Necker Enfants Malades, AP-HP, 149 rue de Sèvres, 75105 Paris, France h Department of Neurology, Hôpital de la Pitié-Salpêtrière, AP-HP, 47-83 boulevard de l'hôpital, 75013 Paris, France i University Pierre et Marie Curie, Sorbonne Universités, 4 place Jussieu, 75005 Paris, France abstract article info Article history: Received 1 May 2017 Received in revised form 2 July 2017 Accepted 3 July 2017 Available online xxxx Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes cir- culating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI (n = 5), mild white matter abnormalities with cortical and corpus callosum atrophy (n = 6), and severe cortical abnormalities suggesting a vascular disease (n = 7). Most patients with severe abnormalities had random X-inactivation (6/7,86%), while 80% (4/5) of patients with normal MRI and 100% (6/6) of patients with mild white matter abnormalities had skewed inactivation. These results suggest that skewed chromosome X-inactivation may protect brain from damage, while in case of random inactivation, expression of the mutated IKBKG gene may lead to severe brain lesions. © 2017 Elsevier Inc. All rights reserved. Keywords: Incontinentia Pigmenti Brain IKBKG protein, human X chromosome inactivation Magnetic Resonance Imaging 1. Introduction Incontinentia pigmenti (IP, OMIM#308300) is an X-linked dominant skin disorder characterized by a four stage skin eruption in heterozygote females, followed by Blaschko lines. IP is usually lethal in male fetuses. Tooth anomalies and ophthalmologic manifestations might be severe [1] and central nervous system manifestations occur in approximately 30% of cases [2]. The most frequent neurological anomalies include seizures, motor impairment and mental retardation [2,3]. In 2000, the International Incontinentia Pigmenti Consortium has ascribed IP to mu- tations of the inhibitor of the kappa B kinase gamma gene (IKBKG, NEMO), located on chromosome Xq28 [4–6]. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene located on chromosome Xq28 [4,5,7]. This mutation is associated with skewed X chromosome inactivation in females, but few cases of random X inac- tivation have been also reported [8]. Various patterns of brain MRI anomalies have been reported, including white matter T2-weighted hypersignal, corpus callosum and cortical atrophy, and rarely ischemic and hemorrhagic lesions [2,9]. To date, why some but not all IP patients develop neurological anomalies remains poorly understood. We have questioned whether brain anomalies in IP could be associ- ated with either particular IKBKG mutations or a specific pattern of X- chromosome inactivation. Molecular Genetics and Metabolism xxx (2017) xxx–xxx Abbreviations: IP, Incontinentia Pigmenti; IKBKG, Inhibitor of the Kappa B Kinase Gamma gene. ⁎ Corresponding author at: Service de Radiologie pédiatrique, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75015 Paris, France. E-mail address: volodia.dangouloff-ros@aphp.fr (V. Dangouloff-Ros). 1 These authors contributed equally to this work. YMGME-06215; No. of pages: 5; 4C: http://dx.doi.org/10.1016/j.ymgme.2017.07.001 1096-7192/© 2017 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Please cite this article as: V. Dangouloff-Ros, et al., Severe neuroimaging anomalies are usually associated with random X inactivation in leucocytes circulating DNA in X-linked dominant..., Mol. Genet. Metab. (2017), http://dx.doi.org/10.1016/j.ymgme.2017.07.001