Klippel-Trenaunay Syndrome

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580 Klippel-Trenaunay syndrome is primarily a rare congenital capillary-venous vascular malformation associated with altered limb bulk and/or length. In 1900, Klippel and Trenaunay first reviewed systematically a condition consist- ing of capillary nevus, early onset of varicosities, and hypertrophy of tissues and bones of the affected limb. These three features constitutes the primary diagnostic criteria of the syndrome today. The additional name Weber is sometimes added to describe those individuals who also have clinically significant arteriovenous malformations as a component of the syndrome, an association noted by Weber in 1918. More than 1000 cases of Klippel-Trenaunay syndrome have now been reported in the literature.

GENETICS/BASIC DEFECTS

1. Etiology unknown a. Sporadic occurrence

b. Somatic mutation of an as-yet-unknown gene c. Multifactorial inheritance

d. Autosomal dominant inheritance with variable expression

2. One potential site of localization of gene: either chromo- some arm 5q or 11p based on the report of an affected child with KT syndrome and a balanced reciprocal chro- mosome translocation, t(5;11)(q13.3;p15.1)

3. Possible mechanisms/pathogenesis leading to overgrowth of the affected limb: poorly defined

a. Two phases of manifestations i. Increased bulk or girth

ii. Increased length accompanied by bone enlargement

b. Increased girth and size of bone due to venous hyper- tension, based on observations following hindleg deep vein ligation in dogs

c. Atresia of the venous system leading to stasis, edema, varicosities and ultimately to limb elongation and hypertrophy

d. Limb enlargement seen in children following thrombosis or ligation of a deep vein postnatally

e. Overgrowth in fetal life promoted by increased blood flow through the abnormal capillary network and cutaneous venous channels

f. A mesodermal defect acting on angiogenesis leading to the formation of the hemangiomata and varicose veins

g. A defect in the process of vessel remodeling during embryogenesis

CLINICAL FEATURES

1. Triad

a. Combined vascular malformations of the capillary, venous, and lymphatic types

b. Varicosities of unusual distribution, in particular the lateral venous anomaly observed during infancy or childhood

c. Limb enlargement 2. Cutaneous manifestations

a. Primarily a diffuse capillary malformation b. Typically present on an affected limb c. May be present on any body part

d. Often presenting as an irregular but relatively linear border

e. Rarely crossing the midline when present on the trunk, sometimes exhibiting a sharp demarcation 3. Vascular malformations

a. Typically combined with cutaneous capillary malformation

b. Persistence of abnormal superficial veins associated with deep venous hypoplasia/duplications and abnormal venous valve formation

c. Presence of mixed vascular malformations including capillary, venous, arterial, and lymphatic systems d. Classification of vascular malformations by Mulliken

and Glowacki (1982)

i. Capillary-venous malformation (CVM): typical finding

ii. CVLM (CVM + lymphatic malformation): common finding

iii. CLAVM (including arterial malformation):

uncommon e. Congenital in nature

f. Not responding to agents used in the treatment of hemangiomas such as prednisone or interferon-α 4. Limb hypertrophy

a. Due to an increase in bulk of the subcutaneous tissues b. Bony hypertrophy

5. Sites of involvement

a. Lower limb most common (about 95%) b. Upper limb (about 5%)

c. Trunk only: uncommon d. Orofacial involvement

i. Jaw enlargement ii. Facial asymmetry iii. Malocclusions

iv. Premature tooth eruption

v. Hemangioma of the lips, tongue and oral mucosa 6. Sex ratio: males and females affected equally

7. Complications

a. Abnormal vasculature i. Thrombosis ii. Coagulopathy iii. Pulmonary embolism

iv. Heart failure (in the presence of significant AVM) v. Bleeding from abnormal vessels in gut, kidney,

or genitalia

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b. Gastrointestinal varicoses i. Bleeding

ii. Pain iii. Diarrhea

c. Protein-losing enteropathy secondary to intestinal lymphangiectasia

d. Infection a particular risk for patients with abnormal lymphatic drainage. Antibiotics indicated in:

i. Cellulitis ii. Surgery

iii. Injury in an affected limb

e. Pain due to venous insufficiency or lymphedema in some older children and adults

f. Venous thromboembolism

i. Chronic thromboembolic pulmonary hyperten- sion

ii. Subsequent right ventricular failure g. Occurrence of ulceration on affected leg

h. Rare occurrence of skin tumors on the affected limb i. Squamous cell carcinoma possibly secondary to

a long-standing venous ulcer ii. Basal cell carcinoma

i. Complications of pregnancy depending on location of vascular anomalies

i. Depending on the location (e.g., vulva, lower abdomen)

ii. Potential for a refractory coagulopathy presenting as Kasabach-Merritt phenomenon

8. Four commonly held conceptions about Klippel-Trenaunay syndrome challenged

a. Renaming Klippel-Trenaunay-Weber syndrome by addition of arteriovenous fistulas

i. Significant arteriovenous communications not observed in Klippel-Trenaunay syndrome in large surgical series

ii. Parkes Weber syndrome characterized by enlarged arteries and veins, capillary or venous malformations and enlargement of a limb

iii. Lymphatic malformations found in Klippel- Trenaunay syndrome not observed in Parkes Weber syndrome

b. Overlap with Sturge-Weber syndrome

i. Characteristics of Sturge-Weber syndrome: cran- iofacial angiomatosis, port-wine nevus and cere- bral calcification

ii. Overgrowth in Sturge-Weber tends to be minor and is always secondary to the vascular anomaly.

In contrast, overgrowth in Klippel-Trenaunay syndrome is striking.

c. Presence of a bleeding diathesis of the Kasabach- Merritt type

i. Kasabach-Merritt syndrome erroneously applied to patients with extensive venous or lymphati- covenous malformations who develop a local- ized intravascular coagulopathy in which the platelet count is minimally depressed (varying from 50,000 to 150,000/mm3)

ii. Profound thrombocytopenia in true Kasabach- Merritt phenomenon (varying from 3000 to 60,000/mm3)

d. Familial aggregation with various genetic interpreta- tions

i. Inadequate documentation of cases

ii. Over interpretation of minor manifestations in relatives, including “nevus flammeus”, hemangiomas, and varicosities (common manifestations in general populations)

iii. Klippel-Trenaunay syndrome defined as a capillary malformation with or without “hemihy- pertrophy” without mentioning of lymphatic malformations, lateral venous anomaly, lymphatic vesicles, or venous flares within the capillary malformation, or macrodactyly e. Klippel-Trenaunay syndrome, Parkes Weber syn-

drome, and Sturge-Weber syndrome i. Each occurring sporadically

ii. Each considered separate entity because clinical manifestations and types of complications are different

DIAGNOSTIC INVESTIGATIONS

1. Color duplex ultrasonography a. AV malformation

b. Deep venous hypoplasia (a decrease in caliber of at least 50% of a vein along its length)

c. Venous duplication d. Variable varicosities 2. Radiography

a. Enlargement of the limb bones

b. Yearly to monitor evidence of leg length discrepancy 3. Noninvasive imaging and endoscopy for severe gastroin-

testinal bleeding

4. Lymphoscintigraphy using radionuclide tracers

a. Indication: edema or a girth discrepancy more than 4 cm

b. No uptake of tracer along major lymphatics of the affected limb during repeated scans over at least a 1-hour period

5. MRI

a. Pelvis: to look for vascular malformations involving the kidneys, bladder, or intestines

b. MRI with gadolinium to distinguish lymphatic from venous malformations

c. Magnetic resonance venogram or phlebography/venog- raphy to document the lateral venous anomaly and any abnormalities that may be present in the deep veins of the leg

d. Able to demonstrate arteriovenous fistulas in Parkes Weber syndrome

GENETIC COUNSELING

1. Recurrence risk

a. Patient’s sib: not increased

b. Patient’s offspring: not increased (doubtful that autosomal dominant inheritance exists)

2. Prenatal diagnosis a. Ultrasonography

i. Asymmetric limb hypertrophy associated with cutaneous or subcutaneous cystic or multicystic lesions

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ii. Limb edema

iii. Cardiac failure ranging from isolated car- diomegaly to severe hydrops

b. MRI

i. Limb hypertrophy

ii. Multiple subcutaneous and internal hemangiomata

iii. Good definition of soft tissue lesions

iv. Identify vascular malformations and their extent

v. Presence of low signal indicating flow voids, hemosiderin deposits or calcification indicative of vascular malformations

3. Management

a. Compression garments b. Pulsed dye laser treatment

c. Reduction of significant arteriovenous malformations d. Orthopedic procedures for overgrowth

i. Significant leg length discrepancy ii. Prominent digital anomalies

REFERENCES

Berry SA, Peterson C, Mize W, et al.: Klippel-Trenaunay syndrome. Am J Med Genet 79:319–326, 1998.

Cohen MM, Jr.: Klippel-Trenaunay syndrome. Am J Med Genet 93:171–175, 2000.

De Simone C, Giampetruzzi AR, Guerriero C, et al.: Squamous cell carcinoma arising in a venous ulcer as a complication of the Klippel-Trenaunay syndrome. Clin Exp Dermatol 27:209–211, 2002.

Hale EK: Klippel-Trenaunay syndrome. Dermatol Online J 8:13, 2002.

James CA, Allison JW, Waner M: Pediatric case of the day. Klippel-Trenaunay syndrome. Radiographics 19:1093–1096, 1999.

Jih MH: Klippel-Trenaunay syndrome. Dermatol Online J 9:31, 2003.

Martin WL, Ismail KM, Brace V, et al.: Klippel-Trenaunay-Weber (KTW) syndrome: the use of in utero magnetic resonance imaging (MRI) in a prospective diagnosis. Prenat Diagn 21:311–313, 2001.

Mueller-Lessmann V, Behrendt A, Wetzel WE, et al.: Orofacial findings in the Klippel-Trenaunay syndrome. Int J Paediatr Dent 11:225–229, 2001.

Paladini D, Lamberti A, Teodoro A, et al.: Prenatal diagnosis and hemodynamic evaluation of Klippel-Trenaunay-Weber syndrome. Ultrasound Obstet Gynecol 12:215–217, 1998.

Roberts RV, Dickinson JE, Hugo PJ, et al.: Prenatal sonographic appearances of Klippel-Trenaunay-Weber syndrome. Prenat Diagn 19:369–371, 1999.

Vazquez-Sequeiros E, Sorbi D, Kamath PS, et al.: Klippel-Trenaunay-Weber syndrome: role of EUS. Gastrointest Endosc 54:660–661, 2001.

Vajo Z, Stratakis CA: Picture of the month. Klippel-Trenaunay syndrome. Arch Pediatr Adolesc Med 152:1149; discussion 1150, 1998.

Walder B, Kapelanski DP, Auger WR, et al.: Successful pulmonary thromboen- darterectomy in a patient with Klippel-Trenaunay syndrome. Chest 117:1520–1522, 2000.

Zoppi MA, Ibba RM, Floris M, et al.: Prenatal sonographic diagnosis of Klippel-Trenaunay-Weber syndrome with cardiac failure. J Clin Ultrasound 29:422–426, 2001.

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Fig. 2. A boy with Klippel-Trenaunay syndrome showing of right arm and right leg with vascular malformation

Fig. 1. A newborn with Klippel-Trenaunay syndrome showing over- growth of left leg with vascular malformation

Fig. 3. A 6-year-old boy with Klippel-Trenaunay syndrome showing overgrowth of left arm (illustrated by radiographs) associated with vascular malformation

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Fig. 4. A one-year-old infant with Klippel-Trenaunay syndrome showing asymmetric lower extremities with hypertrophic left lower extremity associated with vascular malformation (A). T1-enhanced MRI (B,C) and T2-enhanced MRI (D,E) images at thigh level show cystic and vascular lesions, indicated by high signals suggesting lymphangiomas and hemangiomas.