Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities
Virginie Carmignac, Cyril Mignot, Emmanuelle Blanchard, Paul Kuentz, Marie‐Hélène Aubriot‐Lorton, Victoria Parker, Arthur Sorlin, Sylvie Fraitag, Jean‐Benoît Courcet, Yannis Duffourd, Diana Rodriguez, Rachel Knox, Satyamaanasa Polubothu, Anne Boland, Robert Olaso, Marc Délepine, Véronique Darmency, Melissa Riachi, Chloé Quēlin, Paul Rollier, Louise Goujon, Sarah Grotto, Yline Capri, Marie‐Line Jacquemont, Sylvie Odent, Daniel Amram, Martin Chevarin, Catherine Vincent‐Delorme, B. Catteau, Laurent Guibaud, Alexis Arzimanoglou, Malika Keddar, Catherine Sarret, Patrick Callier, D. Bessis, David Geneviève, Jean‐François Deleuze, Christel Thauvin, Robert K. Semple, Christophe Philippe, Jean‐Baptiste Rivière, Veronica A. Kinsler, Laurence Faivre, P. Vabres
Abstract
PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.