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Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Virginie Carmignac 1 Cyril Mignot 2, 3 Emmanuelle Blanchard 4, 5 Paul Kuentz 1, 6 Marie-Hélène Aubriot-Lorton 7 Victoria E.R. Parker 8 Arthur Sorlin 1, 6, 7 Sylvie Fraitag 9 Jean-Benoît Courcet 1, 6, 7 yannis Duffourd 1, 6 Diana Rodriguez 3 Rachel G. Knox 8 Satyamaanasa Polubothu 10, 11 Anne Boland 12 Robert Olaso 12 Marc Delepine 12 Véronique Darmency 7 Melissa Riachi 11 Chloé Quelin 13 Paul Rollier 13 Louise Goujon 13 Sarah Grotto 14 yline Capri 14 Marie-Line Jacquemont 15 Sylvie Odent 13 Daniel Amram 16 Martin Chevarin 1, 6 Catherine Vincent-Delorme 17 Benoît Catteau 17 Laurent Guibaud 18 Alexis Arzimanoglou 18, 19 Malika Keddar 7 Catherine Sarret 20, 21 Patrick Callier 1, 6, 7 Didier Bessis 22, 23 David Geneviève 22, 24 Jean-François Deleuze 12 Christel Thauvin 1, 6, 25 Robert Semple 8, 26 Christophe Philippe 1 Jean-Baptiste Rivière 1, 6 Veronica Kinsler 10, 11 Laurence Faivre 1, 6, 25 Pierre Vabres 1, 6 
23 PCCEI - Pathogenesis and Control of Chronic and Emerging Infections
INSERM - Institut National de la Santé et de la Recherche Médicale : U 1058, UM - Université de Montpellier, UA - Université des Antilles, Etablissement français du don du sang [Montpellier]
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.
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Submitted on : Tuesday, May 10, 2022 - 10:29:08 AM
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Virginie Carmignac, Cyril Mignot, Emmanuelle Blanchard, Paul Kuentz, Marie-Hélène Aubriot-Lorton, et al.. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities. Genetics in Medicine, Nature Publishing Group, 2021, 23 (8), pp.1484-1491. ⟨10.1038/s41436-021-01161-6⟩. ⟨hal-03602359⟩



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