Developmental Disorders of the Lymphatics

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Saturday, November 26, 2005

Klippel-Trenaunay-Weber Syndrome

Klippel-Trenaunay-Weber Syndrome

Parkes Weber Syndrome

Related Terms:

angioosteohypertrophy syndrome, klippel trenaunay parkes weber syndrome

Related Terms: Parkes Weber syndrome, PWS, Klippel-Trenaunay syndrome, KTS, Kasabach-Merritt syndrome, angioosteohypertrophy syndrome, cutaneous capillary malformation, congential vascular nevus, capillary hemangioma, port-wine stain, lymphedema


Clinical Features:

irst described by French physicians Klippel and Trenaunay in 1900, this syndrome is characterized by port-wine stain (capillary hemangioma), varicose veins and bony and soft tissue hypertrophy involving an extremity.Other features involve lymphedema or lymphatic obstruction, cellulitis, chronic venous insufficiency, stasis dermatitis, poor wound healing, ulceration, thrombosis, and emboli.


Capillary hemangiomas (port-wine stain), stasis dermatitis, thrombophlebitis, cellulitis, limb disparity, and more serious sequelae such as thrombosis, coagulopathy, bleeding, pulmonary embolism, and congestive heart failure. (1), lymphedema is also a consistent complication.
Other indications may include asymmetric face, facial haemangiomas, advanced tooth eruption, macrocephaly, heterotopia, glaucoma, cutaneous pustules/ulcers


Klippel Trenaunay appears to be a non-hereditary syndrome although there is still an ongoing discussion involving this.


Simple diagnosis can be made by observation and examination. Venous and lymphatic complications are diagnosed using radiological tests such as lymphoscintigrahy, ultra-sounds, and MRI. Venograms, and arteriograms may also be used.


Treatment is varied for the different symptoms present. Compression garments are used to control the lymphedema, prophylactic antibiotics are of course, used to treat the cellulitis and lymphangitis spells. Orthopedic procedures are available for the limb hypertrophy and wound treatment is sometimes necessary for ulcerations.Other treatments for the symptoms or complications include lasers for the hemangiomas, and surgical intervention for the vascular anomalies may be called for.


University of Minnesota



Alternative titles; symbols




Gene map locus 5q13.3


A number sign (#) is used with this entry because at least some cases of Klippel-Trenaunay syndrome are caused by mutation in or gain-of-function translocation involving the VG5Q gene (608464).

The features of Klippel-Trenaunay-Weber syndrome are large cutaneous hemangiomata with hypertrophy of the related bones and soft tissues. The disorder resembles, clinically and in its lack of definite genetic basis, Sturge-Weber syndrome (185300), and indeed the 2 have been associated in some cases (Harper, 1971). Suggestions of a genetic 'cause' are meager (Waardenburg, 1963). See 116860. Lindenauer (1965) described brother and sister. He suggested that when arteriovenous fistula is also present, the disorder is distinct from the KTW syndrome and might be called Parkes Weber syndrome, since Weber (1907) described cases of this type as well as cases seemingly identical to those of Klippel and Trenaunay (1900). Lindenauer (1965) also suggested that the deep venous system is atretic in KTW syndrome and, as a corollary, that stripping of varicose veins is unwise. Campistol et al. (1988) described an affected 19-year-old woman who had multiple renal pelvic hemangiomas and renal artery aneurysm. Viljoen (1988) reviewed the clinical features of the syndrome. Lawlor and Charles-Holmes (1988) described a 25-year-old woman with KTW syndrome who had life-threatening menorrhagia due to uterine hemangioma. In an infant with this syndrome, Mor et al. (1988) observed hydrops fetalis (gross edema of the limbs, ascites, and palpable liver). The infant lost 520 gm of weight in the first 6 days of life without medication.

Aelvoet et al. (1992) provided evidence that Klippel-Trenaunay syndrome occasionally shows familial aggregation. In addition, they found isolated vascular nevi to be overrepresented in relatives of KTS patients. Happle (1993) suggested that what he referred to as paradominant inheritance most satisfactorily explains the findings. According to this concept, KTS would be caused by a single gene defect. Heterozygous individuals would be, as a rule, phenotypically normal, and therefore the allele would be transmitted imperceptibly through many generations. The trait would only be expressed when a somatic mutation occurred in the normal allele at an early stage of embryogenesis, giving rise to a clonal population of cells either homozygous or hemizygous for the KTS mutation. One example of a genetic mechanism that might cause homozygosity of a cell population arranged in a mosaic pattern is somatic recombination. Presumably, diffuse involvement of the entire body would not be possible because of nonviability of embryos developing from a homozygous zygote.

Muluk et al. (1995) described the case of a 32-year-old man in whom progressive pulmonary insufficiency was found to be due to repeated pulmonary emboli from the deep venous malformations associated with KTS. Samuel and Spitz (1995) reviewed the clinical features and management of 47 children with KTS treated since 1970. Hemangiomas and soft tissue and/or skeletal hypertrophy were present in all 47 patients; venous varicosities developed in 37 (79%). None had clinical evidence of macrofistulous arteriovenous communications. Thromboembolic episodes occurred in 5 children (11%), and 25 (53%) experienced thrombophlebitis. The Kasabach-Merritt syndrome (141000) was observed in 21 (45%), and 6 (13%) presented with high-output heart failure. Other manifestations included hematuria in 5 (11%), rectal or colonic hemorrhage in 6 (13%), and vaginal, vulval, or penile bleeding in 6 (13%) children with visceral and pelvic hemangiomas. In 26 patients (55%), symptomatic treatment only was required. Surgery was undertaken in selected cases for complications of the hemangioma, for cosmetic reasons, and for chronic venous insufficiency. Only 1 of the 4 children who underwent resection of varicose veins improved.

Whelan et al. (1995) reported the case of a girl with KTW syndrome associated with a reciprocal translocation: t(5;11)(q13.3;p15.1). This raised the possibility that this disorder is due to a single gene defect and that the gene is located on 5q or p11. At birth a capillary hemangioma of the right arm and a vascular anomaly of the left trunk with extension onto the left thigh was noted. At age 3 months, the patient's mother noted that the right second toe was larger than corresponding left toe. Subsequent progression to right leg hypertrophy was noted in the first 5 years of life.

Ceballos-Quintal et al. (1996) reported a family in which a child had large skin hemangiomata, overgrowth of the right leg, and severe heart defects (patent ductus arteriosus (see 607411), atrial septal defect, prolapsed tricuspid valve, and pulmonic stenosis). Her mother had a large capillary hemangioma on the left side of the back and developed severe varicosities in both legs. The maternal grandmother developed severe varicosities of the legs at a young age. The clinical signs in the mother and maternal grandmother were interpreted as mild expression of the KTW syndrome and the family tree was thought to support autosomal dominant inheritance.

By ultrasound examination, Christenson et al. (1997) made the prenatal diagnosis of KTW syndrome complicated by early fetal congestive heart failure. The postnatal course was complicated by Kasabach-Merritt syndrome of thrombocytopenia due to platelet consumption within the hemangioma. Neonatal cardiopulmonary resuscitation and limb amputation were required.

Berry et al. (1998) reviewed 49 cases of KTS. All were sporadic. They speculated that the disorder may be due to a somatic mutation for a factor critical to vasculogenesis and angiogenesis in embryonic development.

Lorda-Sanchez et al. (1998) presented an epidemiologic analysis of a consecutive series of cases of KTW syndrome identified in the Spanish Collaborative Study of Congenital Malformations. They found an increase in parental age and in the number of pregnancies, as well as familial occurrence of hemangiomas. These observations suggested a genetic contribution to the occurrence of KTW syndrome. Although the effect of increased paternal age on the origin of spontaneous germline mutations is well documented for dominant conditions, sporadic conditions that are presumably caused by somatic mosaicism are not supposed to show advanced parental age. The increased parental age would be consistent with the model of paradominant inheritance. Epidemiologic studies of retinoblastoma, a classic example of the 2-hit model of Knudson, have shown an association of older parental age with the first mutation event in germinal cells in sporadic hereditary retinoblastoma (DerKinderen et al., 1990) but no evidence for risk factors related to the second somatic mutation (Matsunaga et al., 1990).

Sperandeo et al. (2000) described a family in which 1 first cousin had KTW syndrome and the other had Beckwith-Wiedemann syndrome (BWS; 130650). The probands, sons of 2 sisters, showed relaxation of the maternal IGF2 (147470) imprinting, although they inherited different 11p15.5 alleles from their mothers and did not show any chromosome rearrangement. The patient with BWS also displayed hypomethylation of KvDMR1, a maternally methylated CpG island within an intron of the KvLQT1 gene (607542). The unaffected brother of the BWS proband shared the same maternal and paternal 11p15.5 haplotype with his brother, but the KvDMR1 locus was normally methylated. Methylation of the H19 gene (103280) was normal in both the BWS and KTW syndrome probands. Linkage between the IGF2 receptor gene (IGF2R; 147280) and the tissue overgrowth was excluded. These results raised the possibility that a defective modifier or regulatory gene unlinked to 11p15.5 caused a spectrum of epigenetic alterations in the germline or early development of both cousins, ranging from the relaxation of IGF2 imprinting in the KTW syndrome proband to disruption of both the imprinted expression of IGF2 and the imprinted methylation of KvDMR1 in the BWS proband. The data indicated that loss of IGF2 imprinting is not necessarily linked to alteration of methylation at the KvDMR1 or H19 loci and supports the notion that IGF2 overexpression is involved in the etiology of tissue hypertrophy observed in different overgrowth disorders, including KTW syndrome.

Cohen (2000) defined Klippel-Trenaunay syndrome and challenged 4 conceptions frequently found in the literature on this disorder. He considered it improper to add arteriovenous fistulas to the syndrome and on that basis to rename the disorder Klippel-Trenaunay-Weber syndrome. Although Parkes Weber syndrome (as Cohen called it) and Klippel-Trenaunay syndrome are similar, slow flow venous malformations are predominant in KTS, whereas arteriovenous fistulas are always found in Parkes Weber syndrome. Large series of patients with Parkes Weber syndrome were reported by Robertson (1956) and Young (1988). The involved limb is warm. The color of the cutaneous vascular malformation is usually more diffuse and pinker than that observed in KTS. Lymphatic malformations found in KTS do not occur in Parkes Weber syndrome. Cohen (2000) questioned that Sturge-Weber syndrome and KTS are the same disorder. Cohen (2000) considered the affected brother and sister described by Lindenauer (1965) as the only well-documented examples of KTS in a family.

The de novo translocation t(8;14)(q22.3;q13), reported by Timur et al. (2000) and Wang et al. (2001), points to a pair of chromosomes different from those focused on by Whelan et al. (1995) as the possible site of the Klippel-Trenaunay gene. Wang et al. (2001) used FISH to define the breakpoints on 8q22.3 and 14q13 in relation to specific markers and suggested that their study provided the basis for the fine mapping and ultimate cloning of a novel vascular gene at 8q22.3 or 14q13.

Tian et al. (2004) characterized the breakpoint of the translocation in a patient with Klippel-Trenaunay syndrome described by Whelan et al. (1995) and identified the VG5Q gene (608464). The chromosomal translocation results in increased expression of VG5Q in the translocation patient. They also identified 5 of 130 patients with Klippel-Trenaunay syndrome who were heterozygous for an E133K mutation (608464.0001), which also results in a gain of function. Tian et al. (2004) suggested that patients with the VG5Q E133K mutation may carry a second mutational hit in VG5Q or another gene within the affected tissues.

Timur et al. (2004) identified a de novo supernumerary ring chromosome in a patient with mild mental retardation, long tapering fingers, elongated and thin feet, and KTS. The ring marker chromosome was found to be mosaic, present in 24% of cells, and was shown to be derived from chromosome 18, r(18). FISH was used to define the breakpoints involved in formation of the r(18). The 18p breakpoint was located less than 10 cM from the centromere; the 18q breakpoint was located between the centromere and BAC clone 666n19 (GenBank AC036178), representing a region of less than 40 kb. The data suggested that the r(18) mostly originated from 18p, with an estimated size of less than 10 cM.


Brooksaler (1966); Furukawa et al. (1970); Koch (1956); Servelle (1985); Viljoen et al. (1987)
1. Aelvoet, G. E.; Jorens, P. G.; Roelen, L. M. :
Genetic aspects of the Klippel-Trenaunay syndrome. Brit. J. Derm. 126: 603-607, 1992.PubMed ID :
2. Berry, S. A.; Peterson, C.; Mize, W.; Bloom, K.; Zachary, C.; Blasco, P.; Hunter, D. :
Klippel-Trenaunay syndrome. Am. J. Med. Genet. 79: 319-326, 1998.PubMed ID :
3. Brooksaler, F. :
The angioosteohypertrophy syndrome (Klippel-Trenaunay-Weber syndrome). Am. J. Dis. Child. 112: 161-164, 1966.PubMed ID :
4. Campistol, J. M.; Agusti, C.; Torras, A.; Campo, E.; Abad, C.; Revert, L. :
Renal hemangioma and renal artery aneurysm in the Klippel-Trenaunay syndrome. J. Urol. 140: 134-136, 1988.PubMed ID :
5. Ceballos-Quintal, J. M.; Pinto-Escalante, D.; Castillo-Zapata, I. :
A new case of Klippel-Trenaunay-Weber (KTW) syndrome: evidence of autosomal dominant inheritance. Am. J. Med. Genet. 63: 426-427, 1996.PubMed ID :
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.PubMed ID :
7. Cohen, M. M., Jr. :
Klippel-Trenaunay syndrome. (Editorial) Am. J. Med. Genet. 93: 171-175, 2000.PubMed ID :
8. DerKinderen, D. J.; Koten, J. W.; Tan, K. E. W. P.; Beemer, F. A.; Van Romunde, L. K. J.; Den Otter, W. :
Parental age in sporadic hereditary retinoblastoma. Am. J. Ophthal. 110: 605-609, 1990.PubMed ID :
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Sturge-Weber and Klippel-Trenaunay syndrome with nevus of Ota and Ito. Arch. Derm. 102: 640-645, 1970.PubMed ID :
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Klippel-Trenaunay syndrome: is it a paradominant trait? (Letter) Brit. J. Derm. 128: 465 only, 1993.PubMed ID :
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Sturge-Weber syndrome with Klippel-Trenaunay-Weber syndrome. Birth Defects Orig. Art. Ser. VII(8): 314-317, 1971.
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Du naevus variqueux osteo-hypertrophique. Arch. Gen. Med. 185: 641-672, 1900.
13. Koch, G. :
Zur Klinik, Symptomatologie, Pathogenese und Erbpathologie des Klippel-Trenaunay-Weberschen syndroms. Acta Genet. Med. Gemellol. 5: 326-370, 1956.
14. Lawlor, F.; Charles-Holmes, S. :
Uterine haemangioma in Klippel-Trenaunay-Weber syndrome. J. Roy. Soc. Med. 81: 665-666, 1988.
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The Klippel-Trenaunay syndrome: varicosity, hypertrophy and hemangioma with no arteriovenous fistula. Ann. Surg. 162: 303-314, 1965.PubMed ID :
16. Lindenauer, S. M. :
The Klippel-Trenaunay-Weber syndrome: varicosity, hypertrophy and hemangioma with no arteriovenous fistula. Ann. Surg. 162: 303-314, 1965.PubMed ID :
17. Lorda-Sanchez, I.; Prieto, L.; Rodriguez-Pinilla, E.; Martinez-Frias, M. L. :
Increased parental age and number of pregnancies in Klippel-Trenaunay-Weber syndrome. Ann. Hum. Genet. 62: 235-239, 1998.PubMed ID :
18. Matsunaga, E.; Minoda, K.; Sasaki, M. S. :
Parental age and seasonal variation in the births of children with sporadic retinoblastoma: a mutation-epidemiologic study. Hum. Genet. 84: 155-158, 1990.PubMed ID :
19. Mor, Z.; Schreyer, P.; Wainraub, Z.; Hayman, E.; Caspi, E. :
Nonimmune hydrops fetalis associated with angioosteohypertrophy (Klippel-Trenaunay) syndrome. Am. J. Obstet. Gynec. 159: 1185-1186, 1988.PubMed ID :
20. Muluk, S. C.; Ginns, L. C.; Semigran, M. J.; Kaufman, J. A.; Gertler, J. P. :
Klippel-Trenaunay syndrome with multiple pulmonary emboli: an unusual cause of progressive pulmonary dysfunction. J. Vasc. Surg. 21: 686-690, 1995.PubMed ID :
21. Robertson, D. J. :
Congenital arteriovenous fistulae of the extremities. Ann. Roy. Coll. Surg. Eng. 18: 73-98, 1956.PubMed ID :
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Klippel-Trenaunay syndrome: clinical features, complications and management in children. Brit. J. Surg. 82: 757-761, 1995.PubMed ID :
23. Servelle, M. :
Klippel and Trenaunay's syndrome: 768 operated cases. Ann. Surg. 201: 365-373, 1985.PubMed ID :
24. Sperandeo, M. P.; Ungaro, P.; Vernucci, M.; Pedone, P. V.; Cerrato, F.; Perone, L.; Casola, S.; Cubellis, M. V.; Bruni, C. B.; Andria, G.; Sebastio, G.; Riccio, A. :
Relaxation of insulin-like growth factor 2 imprinting and discordant methylation at KvDMR1 in two first cousins affected by Beckwith-Wiedemann and Klippel-Trenaunay-Weber syndromes. Am. J. Hum. Genet. 66: 841-847, 2000.PubMed ID :
25. Tian, X.-L.; Kadaba, R.; You, S.-A.; Liu, M.; Timur, A. A.; Yang, L.; Chen, Q.; Szafranski, P.; Rao, S.; Wu, L.; Housman, D. E.; DiCorleto, P. E.; Driscoll, D. J.; Borrow, J.; Wang, Q. :
Identification of an angiogenic factor that when mutated causes susceptibility to Klippel-Trenaunay syndrome. Nature 427: 640-645, 2004.PubMed ID :
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A de novo translocation, t(8;14)(q22.3;q13), associated with Klippel-Trenaunay syndrome (KTS). (Abstract) Am. J. Hum. Genet. 67 (Suppl. 2): A2115, 2000.
27. Timur, A. A.; Sadgephour, A.; Graf, M.; Schwartz, S.; Libby, E. D.; Driscoll, D. J.; Wang, Q. :
Identification and molecular characterization of a de novo supernumerary ring chromosome 18 in a patient with Klippel-Trenaunay syndrome. Ann. Hum. Genet. 68: 353-361, 2004.PubMed ID :
28. Viljoen, D.; Saxe, N.; Pearn, J.; Beighton, P. :
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30. Waardenburg, P. J. :
Hypertrophic haemangiectasia (Klippel-Trenaunay-Weber's syndrome).In: Genetics and Ophthalmology. Vol. 2. : :Springfield, Ill.: Charles C Thomas (pub.) 1963. Pp. 1381-1386.
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Identification and molecular characterization of de novo translocation t(8;14)(q22.3;q13) associated with a vascular and tissue overgrowth syndrome. Cytogenet. Cell Genet. 95: 183-188, 2001.PubMed ID :
32. Weber, F. P. :
Angioma formation in connection with hypertrophy of limbs and hemihypertrophy. Brit. J. Derm. 19: 231-235, 1907.
33. 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.PubMed ID :
34. Young, A. E. :
Combined vascular malformations.In: Mulliken, J. B.; Young, A. E. (eds.) : Vascular Birthmarks. Hemangiomas and Malformations. Philadelphia: W.B. Saunders 1988. Pp. 246-274.


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