The Klippel-Trénaunay Syndrome in 2022: Unravelling Its Genetic and Molecular Profile and Its Link to the Limb Overgrowth Syndromes

Abstract

The Klippel-Trénaunay syndrome is an unusual syndrome of vascular and dermatologic manifestation in which patients demonstrate hemihypertrophy of the soft tissue and bones of one limb, cutaneous haemangiomas and varicosities in anatomically abnormal positions. Described in 1900 by two French physicians, the etiology remained unclear until recently, when evidence emerged that there was a genetic basis for this sporadic disorder. Genes that encoded pathological angiogenic factors and caused vascular dysmorphogenesis, explaining the molecular bases of this syndrome, were identified. Several angiogenic genes were identified but one gene, the AGGF1 (formerly VG5Q ) gene, was seen in mutations involving patients diagnosed with Klippel-Trénaunay syndrome. Furthermore, this syndrome was also noted to have overlapping clinical features linked with the “overgrowth syndromes,” in which genetic mutations along somatic lines were identified. These involved The PI3K enzyme which forms part of the phosphoinositide 3–kinase pathway which is encoded by the PIK3CA-gene. This enzyme mediates embryonic cellular growth in-utero and diseases involved in this pathway are classified as members of the PIK3CA-related overgrowth syndrome. This paper reviews the status of what is now known about the molecular genetics of this unusual, but clinically challenging disorder and its differentiation from similar diseases, linked with the PIK3CA-gene and the related overgrowth syndromes.

A rare case of Klippel-Trenaunay syndrome presenting with chronic myeloid leukemia

“…4,11,12 Additionally, the PIK3CA gene has also been reported to be responsible from the genotype of some of the patients with CVLM. 1,13 Somatic mutations in PIK3CA cause many overgrowth syndromes (particularly Cloves, fibro adipose hyperplasia and megalencephaly-capillary malformation) that have recently been identified as the PIK3CA-related overgrowth syndromes. 14,15 Many types of cancer have been reported in individuals with CVLM.…”

A Rare Case of Klippel-Trénaunay Syndrome

“…Two French doctors, Maurice Klippel and Paul Trénaunay, demonstrated that three children suffered from cutaneous hemangiomatous lesions along with asymmetrical hypertrophy of soft tissues and bony components in the early 19th century, coining the term "nevus variquece osteohypertrophique" [5]. KTS is a rare syndrome characterized by capillary microvascular malformations and abnormal venous development, resulting in varicosities and hypertrophy of the bone and soft tissue [1,2].…”

“…There are several genetic defects that contribute to KTS, including overexpression of the angiogenic factor VG5Q and a de novo supernumerary ring chromosome 18 [5,6]. Most cases are sporadic [6].…”

“…Most cases are sporadic [6]. It has been postulated that there is a primary occlusion of the venous system, resulting in increased intravenous tension, which causes venous varicosities and soft-tissue involvement [5]. Numerous genes overlook the alteration in the balance between angiogenesis and vasculogenesis that results in microvascular abnormality [2,5].…”

“…There have also been reports of deep venous anomalies such as aplasia, aneurysmal dilation, and duplications. Patients are at risk of significant morbidities, including bleeding, deep vein thrombosis, and embolism [5].…”