Klippel-trénaunay syndrome Q87.2

Rare, mostly sporadically occurring, syndromal vascular + mesenchymal (capillary/vernous/lymphatic/cohesive/osteogenic) malformation (for an overview, see Vascular malformations below), characterized by the triad:

1. unilateral capillary malformation(nevus flammeus) of an extremity (usually lower extremity)
2. primary varicosis
3. Giant growth of the lesional limb (more rarely, <10%, is hypotrophy) of the affected limb(s).

Note: hemodynamically relevant AV fistulas are not included. However, the transitions to Parkes Weber syndrome are fluid.

Worldwide occurrence, panethnic.

The etiopathogenesis has not yet been clarified.

Genes have been identified that code for pathological angiogenic factors and cause vascular dysmorphogenesis. Of importance are mutations in the AGGF1 gene (formerly VG5Q) which are detectable in lesional tissue. AGGF1 codes for an angiogenic factor.

In addition, this syndrome has been found to have clinical overlap with the "overgrowth syndromes", in which genetic mutations along somatic lineages have been identified. These affected the PI3K enzyme, which is part of the phosphoinositide 3-kinase metabolism and is encoded by the gene of the same name. Diseases related to the PI3K signaling pathway are classified as PIK3CA-associated overgrowth syndromes (Harnarayan P et al. 2022).

VG5Q codes for an angiogenic factor. At least some PIK3CA mutations can apparently also be detected in the mosaic (see PTEN gene below).

The capillary malformation of the skin (nevus flammeus) is already present at birth and increases noticeably from the 2nd decade of life.

In the physical growth phase, syndromic vascular malformations, giant stature and orthopedic problems (pelvic obliquity) come into clinical focus.

Thus, Klippel-Trénaunay syndrome appears in childhood and early adolescence as an (apparently) monoorganic vascular malformation (port-wine stain) of the skin.

There is no firm evidence that the extent of the capillary malformation of the skin is associated with the extent of the systemic involvement (lymphedema, overgrowth phenomena with hypertrophy of skeleton and soft tissues).

Dermatologically little known are the cases of vascular malformations of the extremities without any skin involvement.

Mostly asymmetrical infestation of a limb or the face. Less frequent are oligosymptomatic, bilateral, alternating and cross-dissociated manifestations.

Skin changes in the affected extremity:

• extensive capillary malformation(nevus flammeus - usually entire extremity) with large, bizarrely circumscribed bright red, saturated red or blue-red, completely asymptomatic patches. The spots do not follow the Blaschko line system.
• Lymphedema
• Hemangiomas
• absent sweat and sebaceous glands
• Ulcerations
• livedo reticularis
• pronounced varicosis. In about 17% of cases, a persistent marginal vein can be detected.

Extracutaneous manifestations:

• Overgrowth phenomena with dysproportionate giant growth and soft tissue and bone hypertrophy of the affected limb. Anomalies of the deep leg veins, angiomatous enforcement of the limb muscles. Skeletal changes (pelvic obliquity, spinal deformity).
• Less common are rectal bleeding or hematuria with colonic, rectal or bladder involvement.

Parkes Weber syndrome; Cobb syndrome; Servelle-Martorell syndrome; Maffucci syndrome; neurofibromatosis type I; Beckwith-Wiedemann syndrome.

Integument: Symptomatic treatment of bacterial and mycotic secondary infections arising from lymphedema. Preventive regular skin care (e.g. with Ungt. emulsif. aq.). Immediate sanitation of possible entry sites. Treatment of the oedemas by means of complex extended decongestive therapy. It is also important to treat the varices with surgical repair, sclerotherapy or ligation. If necessary, laser therapy of the nevus flammeus with argon laser or dye laser.

Extracutaneous manifestations: Vascular anomalies should be repaired at an early stage, if possible, in order to avoid secondary damage (e.g. cardiac volume load due to arterio-venous shunt) and to reduce the risk of bleeding and embolism. Radiological-interventional procedures (e.g. microembolisation) as well as vascular surgical measures can be considered.

In addition, regular monitoring (MRI) of the bone sections in the area of giant growth and bone hypertrophy (in addition to orthopaedic changes (e.g. pelvic obliquity), patients are prone to microbial colonisation due to trophic disorders of the skin and lymphoedema, which can lead to osteomyelitis).

Due to the increased blood volume of the altered extremity, the extremity sweats more. This is perceived as unpleasant by some patients. On the foot, the patient may be bothered by an increased smell of sweat.

1. Aggarwal K et al. (2003) Klippel-Trenaunay syndrome with a life-threatening thromboembolic event. J Dermatol 30: 236-240
2. Geoffroy Saint-Hilaire I (1832) Histoire générale et particulière des anomalies de l'organization chez l'homme et les animaux. Ouvrage comprenant des recherches sur les caractères, la classification, l'influence physiologique et pathologique, les rapports généraux, les lois et les causes des monstruosités, des variétés et vices de conformation ou traité de tératologie. Baillière (Paris) 1832-1837
3. Gianlupi A et al. (1999) Recurrent pulmonary embolism associated with Klippel-Trenaunay-Weber syndrome. Chest 115: 1199-1201
4. Happle R et al. (1993) Klippel-Trenaunay syndrome: is it a paradominant trait? Br J Dermatol 128: 465.

5. Harnarayan P et al. (2022) The Klippel-Trénaunay Syndrome in 2022: Unravelling Its Genetic and Molecular Profile and Its Link to the Limb Overgrowth Syndromes. Vasc Health Risk Manag 18:201-209.

6. Helmbold P et al. (1994) Klippel-Trenaunay syndrome with intestinal involvement and mammary carcinoma in a man. Act Dermatol 20: 288-291
7. Klippel M, Trenaunay P (1900) Du naevus variqueux osteohypertrophique. Arch Gen Med (Paris) 3: 641-642
8. Larralde M et al. (2014) Capillary malformation-arteriovenous malformation: a clinical review of 45 patients. Int J Dermatol 53:458-461.
9. Lee BB et al. (2014) Diagnosis and treatment of venous malformations. consensus document of the international union of phlebology (iup): updated-2013. Int Angiol PubMed PMID: 24961611.
10. Macmurdo CF et al. (2016) RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome. Am J Med Genet doi: 10.1002/ajmg.a.37613
11. Sahinoglu Z et al (2003) Prenatal sonographic diagnosis of Klippel-Trenaunay-Weber syndrome associated with umbilical cord hemangioma. Am J Perinatol 20: 1-6
12. Oduber CE et al. (2013) The persistent embryonic vein in Klippel-Trenaunay syndrome. Vasc Med 18:185-191.
13. Samuel M et al. (1995) Klippel-Trenaunay syndrome - Clinical features, complications and management in children. Br J Surg 82: 757-761
14. Tian XLet al. (2009 Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature 427:640-645
15. Weber FP (1907) Angioma-formation in connection with hypertrophy of limbs and hemi-hypertrophy. Br J Dermatology (Oxford) 19: 231-235
16. Weber FP (1918) Hemangiectatic hypertrophy of limbs - congenital phlebarteriectasis and so-called congenital varicose veins. Brit J Child Dis 25: 13.