Are there any genetic variants other than PIK3CA (phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) associated with Klippel-Trenaunay syndrome (KTS)?

Genetic Variants in Klippel-Trenaunay Syndrome Beyond PIK3CA

While PIK3CA mutations are the predominant genetic cause of Klippel-Trenaunay syndrome (KTS), accounting for approximately 85-90% of cases, no other specific genetic variants have been definitively established as causative for KTS. 1, 2, 3, 4

Primary Genetic Etiology

• PIK3CA somatic mutations are identified in 85.7% of KTS patients using targeted next-generation sequencing with high coverage (mean 119,000x), demonstrating this is the primary genetic driver 4
• The most common PIK3CA variants are hotspot mutations E542K, E545K, H1047R, and H1047L in exons 9 and 20, though non-hotspot variants (C420R, Q546K, Q546R) also occur 4
• These mutations occur as low-level mosaicism with variant allele frequencies ranging from 1.6-17.4% (mean 6.9%), explaining why standard genetic testing may miss them 4

KTS Classification Within PROS Disorders

• KTS is now classified within the PIK3CA-Related Overgrowth Spectrum (PROS) disorders, a group of conditions all caused by activating PIK3CA mutations 1, 2, 3
• The PIK3CA gene encodes p110α, the catalytic subunit of phosphatidylinositol 3-kinase, which activates the PI3K/AKT/mTOR signaling pathway 4
• Histopathological examination demonstrates phosphorylation of pathway proteins (p-AKT, p-mTOR, p-4EBP1) in affected vascular and adipose tissues, confirming pathway activation 4

Evidence Against Other Genetic Variants

• No other genes have been reproducibly associated with KTS in the available literature, despite comprehensive genetic analysis 1, 2, 3, 4
• The 14-15% of KTS cases without identified PIK3CA mutations likely represent technical limitations in detecting very low-level mosaicism rather than alternative genetic causes 4
• Unlike other vascular malformation syndromes, KTS does not show mutations in genes like RASA1, TEK, or GNAQ that cause phenotypically distinct conditions 2, 3

Clinical Implications for Genetic Testing

• Amplicon-based targeted next-generation sequencing with ultra-high coverage (>100,000x) is required to detect the low-level PIK3CA mosaicism characteristic of KTS 4
• Testing can be performed on formalin-fixed paraffin-embedded (FFPE) tissues from resected lesions, even after archival periods of 3-7 years 4
• Clinical diagnosis remains based on the presence of at least two of three features: capillary malformation (port-wine stain), venous/lymphatic malformations, and limb overgrowth 2, 3

Therapeutic Relevance

• Identification of PIK3CA mutations enables targeted therapy with PI3K inhibitors (alpelisib) or mTOR inhibitors (sirolimus), which have shown promise in preventing abnormal growth and complications 1, 3
• The direct PI3K inhibitor alpelisib has demonstrated efficacy in PROS disorders and represents a personalized medicine approach for PIK3CA-mutated KTS 1

Critical Diagnostic Pitfall

• Standard Sanger sequencing or low-coverage NGS panels will miss most KTS-associated PIK3CA mutations due to their low variant allele frequencies, leading to false-negative results 4
• Specialized testing with variant allele frequency detection thresholds below 2% is essential for diagnostic confirmation 4