Allelic heterogeneity of Proteus syndrome

Abstract

Proteus syndrome is mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G>A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7 ½ years of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in AKT1.

Lateralized and Segmental Overgrowth in Children

“…A clinical criteria scoring system and specific molecular test lead to the diagnoses of classic Proteus syndrome or AKT1-related overgrowth spectrum when a variant is found in a patient with few of the typical features [ 63 ]. Proteus syndrome has been almost exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic gain-of-function variant in AKT1 [ 64 ], also observed in cancers [ 51 , 65 ].…”

Phenotype and Surgical Treatment in a Case of Proteus Syndrome With Craniofacial and Oral Findings

“…However, it has not been yet possible to establish a correlation between the mutation status of the tissue and the lesions in the syndrome (45). Recent studies show allelic heterogeneity of Proteus syndrome in AKT1 mutations, so lack of evidence of the characteristic mutation should no longer be interpreted as an exclusion diagnosis in a potential case of Proteus syndrome (46). The patient's genetic status was not examined because the patient had been treated before the characteristic mutation was identified.…”

“…The patient developed type I diabetic mellitus. The association of Proteus syndrome and diabetes is not listed in reviews on the syndrome (16), nor in more recent papers based on the genetic characterization of AKT1 mutation in the disease (46). Syndromal associations with diabetes mellitus have been described for mutations of the AKT2 gene (62).…”

A rare gynecologic presentation of proteus syndrome: A case report

“…The condition is caused by a somatic activating mutation in a gene called AKT1, located on chromosome 14q, associated with mosaicism, and has a sporadic occurrence and progressive course [ 2 , 5 ]. Different allelic mutations can lead to the phenotypic presentation of Proteus syndrome [ 1 ].…”

“…Systemic associations include pulmonary, dermatologic, hematologic, gynecologic, neurologic and osseous [ 4 ]. The mutation involves a kinase specific to serine threonine that signals an activation of AKT/mMTOR [ 5 ]. This mutation activates growth and slows down apoptosis.…”