Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

Abstract

PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles. K E Y W O R D Saccessory, cell fate, ectopic, muscle hypertrophy, muscular hypertrophy, PIK3CA, PROS Tobias Laurell and Ann Nordgren contributed equally.

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants

“…Seven variants of PIK3CA and one variant of AKT1 that were identified in this study were previously described [ 13 , 28 ]. However, we observed a significant heterogeneity in phenotypic presentations even for the same variant, which might be a consequence of the different times during development at which mutations were acquired [ 29 ]. The exact sites of variant-induced affliction in the human body might also play a role.…”

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants

“…Seven variants in PIK3CA and one variant in AKT1 identified in this study have previously been described [11,21]. However, we observed a significant heterogeneity in phenotypic presentations even for the same variant, which might be a consequence of the different times at which variants were acquired [22]. The exact site of variant-induced affection in the human body might also have an impact on the phenotypic presentations.…”

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants

“…Seven variants of PIK3CA and one variant of AKT1 that were identi ed in this study were previously described [13,28]. However, we observed a signi cant heterogeneity in phenotypic presentations even for the same variant, which might be a consequence of the different times during development at which mutations were acquired [29]. The exact sites of variant-induced a iction in the human body might also play a role.…”