Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome

Abstract

Proteus syndrome is a very rare disorder with progressive, asymmetrical, and disproportionate overgrowth of body parts with a highly variable phenotype. It is associated with mosaicism for the recurrent heterozygous somatic gain-of-function variant c.49G>A (p.Glu17Lys) in the protein kinase AKT1. We report on a girl with a progressive intraosseous lipoma of the frontal bone and additional, nonspecific features including mild developmental delay, strabism, and a limbal dermoid of the left eye. She did not fulfill the criteria for a clinical diagnosis of Proteus syndrome. However, mutation analysis of AKT1 in a lipoma biopsy revealed this specific activating variant. Several cases of progressive intraosseous lipoma of the frontal bone have been reported in the literature. Only in two of these observations, a tentative diagnosis of Proteus syndrome was made, based on additional clinical features, although without molecular-genetic verification. We conclude that oligosymptomatic Proteus syndrome should be considered in progressive intraosseous lipoma, as recognition of this diagnosis has relevant implications for genetic counseling and opens novel treatment options with AKT1 inhibitors rather than surgical procedures.

We report a case of progressive frontal intraosseous lipoma associated with the specific mosaic AKT1 variant c.49G>A (p.Glu17Lys) and expand the complex phenotypic spectrum of Proteus syndrome.

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