Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-06 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonyms: Klippel-Trenaunay syndrome, Angioosteohypertrophy syndrome

Definition: In 1990, Klippel and Trenaunay originally described the entity of limb overgrowth, multiple cutaneous angiomata and varicose veins, which was confirmed by Parkes-Weber in 1918 and extended by the infrequent finding of arteriovenous fistulae. This syndrome is a rare congenital soft tissue anomaly, with sporadic occurrence, characterized by a triad of multiple hemangiomas, arteriovenous fistulas and unilateral limb hypertrophy, due to bony and soft tissue overgrowth.

Incidence:  Rare.

Etiology: Happle suggested a paradominant inheritance most satisfactorily explains the findings. Heterozygous individuals for a single gene defect are phenotypically normal. The trait is only expressed when a somatic mutation occurs in the normal allele at an early stage of embryogenesis. The embryo is then a mosaic of homozygous or heterozygous cell lines for the mutation. This explains the patchy distribution of the defect[3].

Recurrence risk: Probably none, although some cases have raised the possibility of autosomal dominance[4][5].

Diagnosis: These may include hydrops fetalis (from high output cardiac failure) with limbs edema and hypertrophy (fig. 3) (more girth then length), ascites, abnormal abdominal hemangiomatous masses (figs 1-2), and hepatomegaly[6],[7]. A beautiful 3D diagnosis was made recently[8].

Figure 1: Cross-section at the level of the lower abdomen. Note the multicystic irregular and ill-defined masses.

Figure 2: Cross-section at the level of the lower abdomen. Note the multicystic irregular and ill-defined masses.

Figure 3: A large shell of soft-tissue encompasses the thigh. The contra-lateral thigh was normal.

Pathogenesis: The exact mechanism causing Klippel-Trenaunay-Weber syndrome is not known. A mesodermal defects affecting angiogenesis and associated with persistent of the embryonic vascular network might explain the vascular anomalies. Others have suggested that a disturbance in the regulation of tissue growth factors is the underlying mechanism.

Genetic anomaly: This may be due to a single gene defect on either chromosome 5q or p11[9].

Associated anomalies: Kasabach-Merritt syndrome of thrombocytopenia due to platelet consumption within the hemangioma and high output cardiac failure may complicate the outcome.

Differential diagnosis: Lymphangioma, Proteus syndrome and fetal thoracic mass (even if color flow Doppler studies of the mass are negative).

Prognosis: When detected prenatally the disorder is usually more severe and the prognosis poor when associated with cardiac insufficiency.

Management: Termination of pregnancy can be offered in the severe forms; otherwise, no alteration of management is expected. Given the rarity of the disease, there isn't enough information available to counsel patients regarding obstetric outcome.

References:

[1] Berry SA, Peterson C, Mize W, Bloom K, Zachary C, Blasco P, Hunter D Klippel-Trenaunay syndrome. Am J Med Genet 1998 Oct 2;79(4):319-26

[2] Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P Klippel-Trenaunay syndrome: spectrum and management. Mayo Clin Proc 1998 Jan;73(1):28-36

[3] Happle R Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol 1993 Nov;129(11):1460-70

[4] Lorda-Sanchez I, Prieto L, Rodriguez-Pinilla E, Martinez-Frias ML Increased parental age and number of pregnancies in Klippel-Trenaunay-Weber syndrome. Ann Hum Genet 1998 May;62 ( Pt 3):235-9

[5] Ceballos-Quintal JM, Pinto-Escalante D, Castillo-Zapata I A new case of Klippel-Trenaunay-Weber (KTW) syndrome: evidence of autosomal dominant inheritance. Am J Med Genet 1996 Jun 14;63(3):426-7

[6] Christenson, L., Yankowitz, J., Robinson, R. : Prenatal diagnosis of Klippel-Trenaunay-Weber syndrome as a cause for in utero heart failure and severe postnatal sequelae. Prenatal Diag. 17: 1176-1180, 1997.

[7] Paladini D, Lamberti A, Teodoro A, Liguori M, D"Armiento M, Capuano P, Martinelli P Prenatal diagnosis and hemodynamic evaluation of Klippel-Trenaunay-Weber syndrome. Ultrasound Obstet Gynecol 1998 Sep;12(3):215-7

[8] Shih JC, Shyu MK, Chang CY, Lee CN, Lin GJ, Chen WH, Fan YT, Hsieh FJ Application of the surface rendering technique of three-dimensional ultrasound in prenatal diagnosis and counseling of Klippel-Trenaunay-Weber syndrome. Prenat Diagn 1998 Mar;18(3):298-302

[9] Whelan, A. J., Watson, M. S., Porter, F. D., Steiner, R. D. : Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation. Am. J. Med. Genet. 59: 492-494, 1995.