Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

Abstract

Background Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL. Results Eighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities. Conclusions The abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.

Clinical characteristics and surgical management of facial infiltrating lipomatosis: a single center experience

“…Twenty-one patients underwent genetic testing, with the genotypes of 18 patients previously described in our prior investigation [ 13 ]. The remaining three patients carried PIK3CA p.Asn345Lys, p.Cys420Arg, and p.Glu453Lys mutations.…”

“…Nineteen specimens were found to harbor somatic PIK3CA mutations. Furthermore, our previous analysis [ 13 ], revealed that hotspot mutations were associated with more severe FIL phenotypes, further enriching our understanding of FIL's molecular pathogenesis.…”

“…Genomic DNA was extracted from epidermal nevus ( n = 3) and subcutaneous adipose tissue ( n = 18). The sequencing method has been described in a previous article [ 13 ]. Briefly, the Qiagen DNA Extraction Kit (#13,323) was utilized to extrate DNA from the tissue samples.…”

Single-cell sequencing of facial adipose tissue unveils FKBP5 as a therapeutic target for facial infiltrating lipomatosis

“…Histologically, it is marked by mature, non-encapsulated adipocytes that can diffusely infiltrate the adjacent soft tissues [ 1 ]. The condition is visible at birth, with patients exhibiting hemifacial swelling and myriad phenotypic features such as macrodontia, hemimacroglossia, lip hypertrophy, epidermal nevi, and mucosal neuromas [ 2 ]. These abnormalities can significantly impact facial appearance.…”

“…PIK3CA variants can result in a structural alteration in p110α, leading to its release from the inhibitory effects of the p85α regulatory subunit, thereby continuously stimulating downstream signaling molecules and causing overactivation of the PI3K-AKT-mTOR pathway [ 9 ]. Our previous work found that PIK3CA hotspot variants (E542K, E545K, H1047R) can lead to more severe FIL phenotypes, characterized by an increased number and severity of affected soft tissues [ 2 ]. However, although PIK3CA variants may be the primary cause of FIL, it is still unclear how they initiate these pathological processes by impacting downstream molecules.…”