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

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.

Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor

“…In a recently published study, Carmignac et al detected pathogenic mosaic MTOR variants in the DNA samples from hypopigmented skin only, absent from blood-derived DNA in half of their cohort. Their findings are also consistent with upregulation of mTORC1, resulting in hypopigmentation due to partial suppression of melanogenesis, similar to hypochromic patches in TSC [11]. The clinical history of our patient supports this second-hit hypothesis.…”

Pigmentary mosaicism as a recurrent clinical manifestation in three new patients with mosaic trisomy 12 diagnosed postnatally: cases report and literature review

“…Cutaneous manifestations are commonly caused by somatic mosaicism, and it is known that the presence of differential skin pigmentation is related with the presence of two distinct genotypes in each type of skin [ 15 , 35 – 37 ]. Genomic mosaicism represented by multiple non-recurring mosaic chromosomal abnormalities, and recently with mosaic single-gene variants, have been widely reported in patients with pigmentary mosaicism [ 30 , 35 , 38 – 42 ]. Chromosome 12 has at least 6 genes that are related with melanosome biogenesis: KRT2A , ADAMTS20 , WNT1 , SILV , VPS33A and KITLG .…”

mTORC1 activity negatively regulates human hair follicle growth and pigmentation

“…TS is typically associated with hypopigmentation of skin (hypomelanotic macules; also referred to as “ash leaf spots”) and hair (poliosis), which is often used as an early diagnostic sign of TS (Cartron et al , 2021; Islam, 2021; Takahashi et al , 2022). Other manifestations of TS are the formation of various tumors and severe neurodevelopmental and renal abnormalities (Carmignac et al , 2021; Girodengo et al , 2022; Luo et al , 2022). Given the poliosis phenotype associated with TS, we hypothesized that mTORC1 activity may regulate human hair follicle (HF) pigmentation and hair graying (canities)—a complex, temporarily reversible, and stressor‐sensitive process that ultimately shuts off melanin production (melanogenesis) in the HF pigmentary unit (HFPU), typically long before it becomes irreversible due to a depletion of HF melanocyte stem cells (O'Sullivan et al , 2021; Rosenberg et al , 2021).…”