SG07 When blood isn’t enough: tissue sequencing unlocks the diagnosis of blue rubber bleb naevus syndrome

Abstract

Blue rubber bleb naevus syndrome (BRBNS) is a rare venous malformation disorder characterized by cutaneous and gastrointestinal vascular lesions, often presenting with chronic gastrointestinal bleeding and iron-deficiency anaemia. Somatic mosaic variants in the TEK gene are now recognized as the main genetic mechanism; however, these may be undetectable on conventional blood-based genetic testing, delaying diagnosis and treatment. We report a male infant who presented at 8 weeks of age with a solitary vascular swelling of the right foot, diagnosed as a lymphovenous malformation. He underwent sclerotherapy and surgical debulking in infancy with good initial outcome. From 5 years of age, he developed recurrent iron-deficiency anaemia requiring repeated oral supplementation. At 10 years, he presented with severe symptomatic anaemia (haemoglobin 59 g L−1, positive quantitative faecal immunochemical test and melaena) requiring hospital admission. Extensive gastrointestinal investigations, including upper and lower endoscopy and capsule endoscopy, revealed multiple vascular malformations within the stomach and large bowel. Given clinical suspicion of a syndromic vascular malformation, blood-based genetic testing (GLMN, TEK, PIK3CA) was performed but was negative. Following multidisciplinary discussion at a tertiary vascular anomalies centre, next-generation sequencing was performed on skin tissue excised in infancy. This identified two pathogenic somatic TEK variants (encoding p.Tyr897Cys and p.Arg918Ser), confirming a diagnosis of BRBNS. The patient subsequently commenced oral sirolimus, with stabilization of haemoglobin levels and early clinical improvement. This case highlights the importance of considering BRBNS in children with cutaneous venous lesions and unexplained recurrent anaemia. Negative blood-based testing does not exclude mosaic vascular malformation syndromes; analysis of affected tissue may be essential for diagnosis. Achieving a unifying diagnosis not only clarifies skin and gastrointestinal findings but also directs management and treatment. Increased awareness of tissue-based genetic testing can improve diagnostic accuracy in rare vascular disorders, informing prognosis and facilitating access to targeted treatments.