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)

1 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
2 CHU Trousseau [APHP]
3 CHU Pitié-Salpêtrière [AP-HP]
4 CHRU Tours - Centre Hospitalier Régional Universitaire de Tours
5 MAVIVHe - Morphogénèse et antigénicité du VIH, des Virus des Hépatites et Emergents
6 FHU TRANSLAD (CHU de Dijon)
7 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
8 CAM - University of Cambridge [UK]
9 Hôpital Necker - Enfants Malades [AP-HP]
10 GOSH - Great Ormond Street Hospital for Children [London]
11 UCL - University College of London [London]
12 IG - Institut de Génomique d'Evry
13 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
14 AP-HP Hôpital universitaire Robert-Debré [Paris]
15 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
16 CHI Créteil
17 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
18 HCL - Hospices Civils de Lyon
19 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
20 IP - Institut Pascal
21 CHU Clermont-Ferrand
22 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
23 PCCEI - Pathogenesis and Control of Chronic and Emerging Infections
24 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
25 Hôpital d'Enfants [CHU Dijon]
26 Edin. - University of Edinburgh

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.

Domaines: Neurosciences [q-bio.NC]; Génétique humaine

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, 2021, 23 (8), pp.1484-1491. ⟨10.1038/s41436-021-01161-6⟩. ⟨hal-03602359⟩