A new case of Smith‐Kingsmore syndrome with somatic MTOR pathogenic variant expands the phenotypic spectrum to lateralized overgrowth

Abstract

Smith‐Kingsmore syndrome (SKS) is a rare autosomal dominant disorder caused by heterozygous germline activating pathogenic variants in mammalian target of rapamycin (MTOR) on chromosome 1p36. A few patients with disseminated mosaicism have been described so far and they seem to display a different phenotype when compared to germline cases. Here we report the sixth case with a disseminated mosaic MTOR pathogenic variant, a 7‐year‐old boy with hemimegalencephaly, epilepsy, developmental delay, hypomelanosis of Ito, and lateralized overgrowth. Genetic testing revealed a pathogenic variant (c.4448G > A, p.Cys1483Tyr) in MTOR with a frequency of 32% in the DNA extracted from a skin sample, 3% in saliva and 0.46% in blood. The clinical features observed in our patient further corroborate the existence of differences in phenotypic presentation of germline and mosaic SKS cases. Moreover, lateralized overgrowth, a finding never described so far in SKS, further expands the phenotypic spectrum of SKS and allows the inclusion of MTOR pathogenic variants among the several causes of asymmetric body overgrowth.

The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth

“…Therefore, in our case, the patient exhibited HME, capillary malformation, and length discrepancy of the feet, revealing an unexpected phenotypic feature that expands the known phenotype associated with AKT3-related conditions. Additionally, this underscores the phenotypic overlap among syndromes associated with the PI3K-AKT-mTOR pathway, as evidenced by the similarity to the clinical case described by Carli et al 40…”

“…Finally, Alcantara et al 8 showed that vascular malformations are common features of AKT3-related disorders, but, unlike PIK3CArelated disorders, they are rarely associated with somatic overgrowth or tissue hypertrophy. For example, the clinical case described by Carli et al, 40 involving a 7-year-old boy with HME, generalized tonic seizures, mild developmental delay, lateralized overgrowth, and Ito hypomelanosis, and a mosaic variant in MTOR, confirmed the presence of these features not only in PTENopathies but also in the spectrum of mTOR-related conditions. Notably, this characteristic had not been previously reported in AKT3-related cases.…”

Detailed Clinical and Functional Studies of New MTOR Variants in Smith-Kingsmore Syndrome Reveal Deficits of Circadian and Sleep Homeostasis

“…Heterozygous de novo or inherited gain-of-function (GOF) pathogenic variants of the MTOR gene underlie SKS. SKS was first described a decade ago 1,2 , and since then over 70 patients representing 26 unique alleles have been reported, with the p.Glu1799Lys allele comprising nearly half of all reported cases [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] . While the majority of them are germline mutations, several somatic cases have recently been reported.…”