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Zoltan Vajo, MD; Constantine A. Stratakis, MD, DSc
From the Units of Genetics and Endocrinology, Section on Pediatric Endocrinology, Developmental Endocrinology Branch, National Institute of Child Health and Development (Dr Stratakis); and the National Human Genome Research Institute (Dr Vajo), National Institutes of Health, Bethesda, Md.

Arch Pediatr Adolesc Med. 1998;152:1149-1150.

A 14-YEAR-OLD adolescent boy has had body asymmetry since birth (Figure 1). His left extremities, particularly the leg, are larger than the right extremities, but the discrepancy became more noticeable during puberty (Figure 2). An extensive nevus flammeus is present on the left side of his chest (Figure 3), back, and right posterior aspect of the neck extending to the shoulder (Figure 4). Both feet and the left hand demonstrate asymmetric toe (Figure 5) and finger growth.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Denouement and Discussion: Klippel-Trenaunay Syndrome

Figure 1. Asymmetric growth of the left side of the body is apparent. The left thorax is larger than the right, resulting in scoliosis.

Figure 2. The circumference of the left leg is greater than the right. A previous osteotomy has corrected leg length discrepancy.

Figure 3. A large nevus flammeus covers the left side of the chest without crossing the midline.

Figure 4. A large nevus flammeus covers the back with a similar lesion on the right posterior aspect of the neck and shoulder without crossing the midline.

Figure 5. The feet show disproportionate growth of toes and partial syndactyly of the second and third toes, bilaterally.

Klippel-Trenaunay syndrome (KTS), angio-osteohypertophy syndrome, is characterized by asymmetric overgrowth of a limb and soft tissue associated with vascular malformations, nevus flammeus, and varicosities. Originally described by Klippel and Trenaunay¹ in 1900, in 1907 Parkes Weber² added the infrequent finding of arteriovenous fistula, resulting in the more commonly used name Klippel-Trenaunay-Weber syndrome. Since the first reports, additional patients with KTS, internal hemangiomas, and other life-threatening vascular anomalies, including renal pelvic hemangiomas, renal artery aneurysm, and varicose veins, have been reported.^3-5

CLINICAL PRESENTATION
Overgrowth of one or more limbs is present at birth or develops in early childhood. The asymmetric growth is not necessarily ipsilateral with the nevus flammeus. The nevus flammeus is associated with underlying venous and lymphatic malformations and their associated skeletal overgrowth. In addition to the nevus flammeus, other vascular lesions may be present, including superficial and deep hemangiomas, phlebectasia, and varicosities. These vascular lesions rarely present internally or cover an extensive area.

Additional anomalies have been described in patients with KTS, including heart defects, abnormalities of the digits, and various skin lesions.^6-8 In rare cases, the complications of extensive vascular malformations may lead to life-threatening situations such as disseminated intravascular coagulation, congestive heart failure, progressive pulmonary insufficiency secondary to repeated pulmonary emboli, thrombophlebitis, and infections.^{3, 9}

PATHOGENESIS
Although several hundred patients with KTS have been described, the true frequency of the syndrome is not known.¹⁰ Most cases seem to be sporadic, although a familial occurrence is evident.^4-5 Most patients have normal karyotypes, but a patient with a chromosomal abnormality [t(5;11)(q13.3;p15.1)] has been reported.⁷ This case supports the suggestion that KTS may be due to a single gene defect, perhaps localized to 5q or 11p.

The most likely mode of inheritance of KTS is multifactorial, but the paradominant mechanism has also been suggested.¹¹ According to this theory, KTS is caused by a single gene defect, which is expressed when the normal allele is either lost or silenced in a mosaic pattern early in development through the processes of clonal expansion of homozygous or hemizygous cells and/or through tissue specific imprinting. Carriers of this mutation would be phenotypically normal and the defect would be clinically detectable in their heterozygote offspring only if somatic homozygosity or hemizygosity occurred during early embryogenesis. Homozygote embryos would not survive and, accordingly, diffuse involvement of many tissues, even in a heterozygote embryo, would not be compatible with life.

TREATMENT AND PROGNOSIS
Most patients with KTS do relatively well, although many will require osteotomies or other orthopedic procedures for limb asymmetry correction.¹⁰ Scoliosis caused by extremity or, less frequently, chest abnormalities should be recognized early and treated appropriately. Older patients may present with arthritic symptoms and other joint problems related to their skeletal anomalies.^{4, 10} Surgical procedures on the extremities may lead to complications of ulcers, gangrene, and lymphedema, but these rarely lead to amputation.¹⁰

The presence of arteriovenous fistulae, which distinguish Klippel-Trenaunay-Weber syndrome from KTS, portends a poorer prognosis because of progressive hypertrophy of bone and soft tissue. The fistulae may also lead to congestive heart failure as a result of increased cardiac output.

Supportive care includes compression bandages for varicosities and lymphedema. Cutaneous infections must be treated aggressively to prevent systemic complications.

AUTHOR INFORMATION
Accepted for publication June 13, 1997.

Reprints: Constantine A. Stratakis, MD, DSc, Section on Pediatric Endocrinology, National Institutes of Health, 10 Center Dr, MSC 1862, Bldg 10, Room 10 N 262, Bethesda, MD 20892-1862.

REFERENCES
1. Klippel M, Trenaunay P. Du naevus variquex osteo-hypertrophique. Arch Gen Med. 1900;185;641-672. 2. Parkes Weber F. Angioma formation in connection with hypertrophy of limbs and hemihypertrophy. Br J Dermatol. 1907;19:231-235. ISI 3. Samuel M, Spitz L. Klippel-Trenaunay syndrome. Br J Surg. 1995;82:757-761. FULL TEXT | PUBMED 4. Aelvoet GE, Jorens PG, Roelen LM. Genetic aspects of Klippel-Trenaunay syndrome. Br J Dermatol. 1992;126:603-607. ISI | PUBMED 5. Lindauer SM. The Klippel-Trenaunay syndrome: varicosity, hypertrophy and hemangioma with no arterio-venous fistula. Ann Surg. 1965;162:303-314. ISI | PUBMED 6. Ceballos-Quintal JM, Pinto-Escalante D, Castillo-Zapata I. A new case of Klippel-Trenaunay-Weber syndrome. Am J Med Genet. 1996;63:426-427. FULL TEXT | ISI | PUBMED 7. Whelan M, Watson MS, Porter FD, Steiner RD. Klippel-Trenaunay-Weber syndrome associated with a 5:11 balanced translocation. Am J Med Genet. 1995;59:492-494. FULL TEXT | ISI | PUBMED 8. Furukawa T, Igata A, Toyokura Y, Ikeda S. Sturge-Weber and Klippel-Trenaunay syndrome with nevus of Ota and Ito. Arch Dermatol. 1970;102:640-645. FULL TEXT | PUBMED 9. Muluk SC, Ginns LC, Semigran MJ, Kaufman JA, Gertler JP. Klippel-Trenaunay syndrome with multiple pulmonary emboli. J Vasc Surg. 1995;21:686-690. PUBMED 10. Servelle M. Klippel and Trenaunay's syndrome. Ann Surg. 1985;201:365-373. ISI | PUBMED 11. Happle R. Klippel-Trenaunay syndrome: is it a paradominant trait? [letter]. Br J Dermatol. 1993;128:465.

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