Foot or hand malformations related to deep venous system anomalies of the lower limb in Klippel-Trenaunay syndrome

Pedro Redondo, MD, PhD,a Gorka Bastarrika, MD, PhD,b Leyre Aguado, MD,a Antonio Martnez-Cuesta, MD, MSc, FRCR,b Alejandro Sierra, MD, PhD,b Juan Cabrera, MD, PhD,b and Alberto Alonso-Burgos, MDb Pamplona, Spain
Background: Klippel-Trenaunay syndrome (KTS) is a capillary-lymphatic-venous malformation associated with soft tissue and skeletal hypertrophy of one or more limbs. Deep venous system (DVS) anomalies are reported to be present in 8% to 18% of patients with KTS; approximately 25% of patients with KTS have hand or foot malformations. Objective: We sought to assess whether the presence of hand or foot malformations in KTS is a predictor of DVS anomalies. Methods: Retrospective data were collected from 51 consecutive patients with KTS seen in a university hospital between January 2000 and February 2008. Patients with possible Proteus syndrome were not included. The presence and patency of the DVS was studied using conventional venography, multidetector computed tomography, or fast 3-dimensional magnetic resonance imaging venography. Results: Seventeen hand or foot malformations were present in 9 patients, consisting of: toe macrodactyly in 5 patients (two bilateral and one with plantar expansion); toe microdactyly in one patient; nger macrodactyly in one patient; nger macrodactyly and ectrodactyly in one patient; syndactyly in 4 patients; and clinodactyly with camptodactyly of the hand of one patient with lower limb KTS. Eleven patients had DVS anomalies (one with aplasia of entire DVS; one with duplication of the supercial femoral vein; 7 with hypoplasia of femoral vein; and 7 with aplasia of the popliteal vein). All patients with hand or foot malformations also had DVS anomalies (P \ .001). Limitations: Small sample size was a limitation. Conclusion: The presence of hand or foot malformations in KTS may predict the presence of DVS anomalies. ( J Am Acad Dermatol 2009;61:621-8.) Key words: deep venous system; hand/foot overgrowth; hand or foot malformations; Klippel-Trenaunay syndrome; macrodactyly.

lippel-Trenaunay syndrome (KTS) is a congenital vascular anomaly, dened as a triad including a port-wine stain, underlying bony

Abbreviations used: DVS: deep venous system KTS: Klippel-Trenaunay syndrome PS: Proteus syndrome

From the Departments of Dermatologya and Radiology,b Unit of Vascular Malformations, University Clinic of Navarra. Partially supported by a grant from Gobierno de Navarra (proyecto 45/2004). Conflicts of interest: None declared. Accepted for publication April 2, 2009. Reprint requests: Pedro Redondo, MD, PhD, Department of Dermatology, University Clinic of Navarra, 31080 Pamplona, Spain. E-mail: predondo@unav.es. Published online July 6, 2009. 0190-9622/$36.00 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.04.027

and soft tissue hypertrophy, and varicose veins and/or venous malformations. Port-wine stains are reported to be present in 98% of patients with KTS, varicosities or venous malformations in 72%, and some form of limb hypertrophy in 67%.1 Up to 10% of these patients present with hypotrophy of the affected limb.2 KTS may be unilateral in 85% of patients, bilateral in 12.5%, and crossed-bilateral in 621

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2.5%, with both upper and lower limb involvement (4 points); lipoma/subcutaneous tumor (4 points); in 10% of patients.3,4 Superficial venous anomalies epidermal nevus (3 points); macrocephaly and/or include ectasia of small veins, varicosities, venous skull exostoses (2.5 points); and other minor abnormalformations, and persistent embryologic veins.2 malities (1 point). The maximum score is 19.5 points, Deep venous system (DVS) abnormalities may with scores below 10 ruling out the diagnosis of PS. include aplasia, hypoplasia, aneurysmal dilatation, The scoring system described by Biesecker et al8 defines 3 mandatory general criteria (mosaic distriavalvulia, and duplication of the affected veins. bution of lesions, progressBecause these anomalies ive course, and sporadic may preclude surgery or CAPSULE SUMMARY occurrence) for the diagnosis sclerotherapy of symptoof PS. It requires as well matic venous malformaA relationship between Klippeleither the presence of a tions,5 the presence and naunay syndromeeassociated Tre patency of the DVS should connective tissue nevus (cathand/foot malformations and first be demonstrated by egory A) or at least two involvement of the deep venous system venography or noninvasive category B signs (epiderof the lower extremities has not been imaging procedures.6 mal nevus, overgrowth, early previously described. The limb hypertrophy in manifestation of specific KTS is usually uniform and In our series all patients with hand or tumors) or 3 category C generally produces an asymfoot malformations had deep venous signs (lipoma/lipodystrophy, metry with respect to the system abnormalities (P \.001). vascular malformation, facial contralateral limb. Around dysmorphism). The presence of hand or foot 25% of patients with KTS malformations in patients with Klippelhave hand or foot malformanaunay syndrome may be a predictor Tre RESULTS tions,7 although these are of deep venous system abnormalities. The diagnosis of KTS was also classically associated in conrmed in all patients The presence at birth of hand and foot the literature with the evaluated. A port-wine stain malformations can help identify infants Proteus syndrome (PS).8,9 was present in 100% of panaunay syndrome who with Klippel-Tre In this study, we found an tients, varicosities and a veare at greatest risk of complications and association between hand or nous malformation in 94% need closer follow-up. foot malformations and the (48 of 51), and limb hyperexistence of DVS anomalies trophy in 58% (31 of 51). KTS of the lower limb in patients with KTS. was unilateral in 66% (34 of 51) of patients, bilateral in 18% (9 of 51) (Fig 1), crossed-bilateral in 4% (2 of METHODS 51) (Fig 2), and hemicorporal in 12% (6 of 51) (Fig 3). In all, 51 consecutive patients with KTS referred between January 2000 and February 2008 to our vascular malformation clinic were retrospectively Hand or foot malformations included. Their median age was 26 years (range Nine of the patients had malformations of hands 9-44 years). DVS patency was evaluated in all or feet. The port-wine stain was localized (limited to patients by means of either conventional ascending one limb) in 3 patients, involved both limbs in two venography, multidetector computed tomography, patients (in one of which there was extension to the or fast 3-dimensional magnetic resonance imaging trunk), was hemicorporal in two patients, and venography. The study was approved by the insticrossed-bilateral in another two (one of them with tutional review board and written informed consent involvement of both lower limbs). Seventeen hand was obtained from all participants. or foot malformations were found in 9 patients (7 toe macrodactyly [Fig 1], two finger macrodactyly [Figs 2 Differential diagnosis with PS and 3], one ectrodactyly [Fig 3], 4 syndactyly [Figs 1, The diagnosis of KTS was made independently by 3, and 4], one clinodactyly, one toe microdactyly [Fig at least 3 expert vascular specialists. Following 5], and one camptodactyly). This last case correpreviously published recommendations,10 we used sponds to a patient with KTS that mainly involved the the scoring systems of Hotamisligil11 and Biesecker lower limbs. According to the Hotamisligil11 scale 8 et al to avoid a possible misdiagnosis of PS as KTS. score and classification of Biesecker et al,8 a diag11 The Hotamisligil rating scale assesses the presence nosis of PS was ruled out in all patients. The demoof: macrodactyly and/or hemihypertrophy (5 graphic and clinical data of the 9 patients with hand points); plantar or palmar cerebriform hyperplasia and foot malformations are shown in Table I. In all
d d d d

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Fig 1. Left, Anteroposterior view showing extent of port-wine stain, distal hypertrophy (in black), and involvement of deep venous system ( framed in blue). Middle, Magnetic resonance phlebography with maximum intensity projection reconstruction, demonstrating bilateral popliteal vein aplasia (arrows) and left femoral vein hypoplasia (open arrow). Right, Toe macrodactyly associated with syndactyly of right foot.

cases the malformations were present during the first months of life. DVS anomalies Eleven (22%) of 51 patients with KTS had DVS anomalies (one aplasia of the whole DVS, one duplication of the supercial femoral vein, 7 hypoplasia/ aplasia of the femoral vein [Figs 1 to 4], and 7 aplasia of the popliteal vein [Figs 2 to 5]) (Table II). None of the studied patients had arteriovenous fistulae, and a diagnosis of Parkes Weber syndrome was ruled out. Statistical analysis The statistical analysis was performed using the Fisher exact test (2-sided). All patients with hand or foot malformations had DVS anomalies (P \ .001). Only two patients with KTS but without macrodactyly or hemihypertrophy or atrophy had DVS anomalies. With the exception of one patient with atrophy of one hand, all other asymmetries (hypertrophy or atrophy) were in the limb affected by the malformation.

DISCUSSION
Macrodactyly is an uncommon congenital malformation characterized by the enlargement of soft tissue and bony elements of ngers and toes but

not of metacarpals or metatarsals. Clinodactyly (abnormal deviation of fth nger in coronal or radioulnar plane), ectrodactyly (absence of digits), camptodactyly (exion contracture of proximal interphalangeal joint of nger), and syndactyly (abnormal connection between adjacent digits) are also rare. In a study by McGrory et al,7 29 of 108 patients with KTS had a malformation, including macrodactyly, syndactyly, clinodactyly, metatarsus primus varus, polydactyly, camptodactyly, or congenital trigger finger. An atypical hypotrophic variant of KTS has also been described.2,12 Two of the patients with KTS included in the current series had hypotrophy of the upper limb with bone involvement; one of these had hemicorporal distribution of port-wine stains and hand involvement with macrodactyly, ectrodactyly, and syndactyly, whereas the other patient showed port-wine stains that mainly affected the lower limbs and had upper limb and hand hypotrophy, with clinodactyly and camptodactyly. Few studies have been published on the DVS anomalies present in patients with KTS. Aplasia or hypoplasia of the deep venous trunks was observed among 8% of patients with a vascular malformation of venous predominance.13 Other reported disorders, with fewer physiologic repercussions, are

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Fig 2. Left, Anteroposterior view showing extent of port-wine stain, distal hypertrophy (in black), and involvement of deep venous system ( framed in blue). Middle, Magnetic resonance phlebography with curved maximum intensity projection, demonstrating femoral vein hypoplasia (open arrow) and popliteal vein aplasia (arrow). Note communication of entire venous drainage of leg with huge lateral thigh vein (arrowheads). Right, Enlarged thumb and second and third fingers of right hand.

phlebectasias, aneurysms, avalvulia, and duplication or malposition of the deep venous trunks.13 In one series consisting of 49 patients with KTS, 9 (18%) presented with aplasia/hypoplasia of the deep venous trunks,14 a very similar percentage to that found in the current series (22%). To our knowledge, a relationship between hand/foot malformations and involvement of the DVS of the lower limb has not previously been described in patients with KTS. In addition to KTS, the differential diagnosis of diseases associated with macrodactyly, megalodactyly, or digital gigantism includes brolipomatosis, idiopathic localized gigantism, neurobromatosis, Milroy disease, tuberous sclerosis, and other overgrowth syndromes with complex vascular anomalies (PS, Parkes Weber syndrome, Sturge-Weber syndrome, macrocephaly-cutis marmorata, and Bannayan-Riley-Ruvalcaba syndrome). PS is a rare disorder characterized by overgrowth of multiple tissues, vascular malformations, and connective tissue or epidermal nevi. PS, rst dened in 1979 by Cohen and Hayden,15 was characterized

in 1983 by Wiedeman et al16 as a rare hamartomatous disorder with a wide range of abnormalities. Despite the availability of established criteria for the diagnosis of PS, diagnosis remains difficult in the absence of molecular markers or other diagnostic laboratory tests, as it is an intrinsically variable disorder. KTS is the most difcult entity to distinguish from PS, particularly with respect to vascular anomalies. Hoeger et al10 reported 35 vascular anomalies in all 22 (100%) patients with PS, among whom vascular tumors, port-wine stains, and venous malformations were equally common. Vascular tumors were more prevalent and port-wine stains and venous malformations slightly less common than in other published series. Previously, a total of 118 vascular anomalies had been described in 70 of 100 (70%) patients with PS. There is only one published study on the prevalence of DVS anomalies in patients with PS.17 In fact, there appears to be considerable ambiguity between KTS and PS as shown in two studies where 7 of 22 (28%)9 and 6 of 18 (33%)8 patients with PS had been given the diagnosis of KTS. There have

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Fig 3. Left, Posteroanterior view showing extent of port-wine stain, distal hypertrophy (in black), and involvement of deep venous system ( framed in blue). Middle, Direct magnetic resonance phlebography with curved maximum intensity projection, demonstrating femoral vein hypoplasia (open arrow) and popliteal vein aplasia (arrow). Note communication of entire venous drainage of leg with huge lateral thigh vein (arrowheads). Right, Left hand atrophy with enlarged thumb, syndactyly, and ectrodactyly.

also been case reports illustrating an overlap between PS and KTS18 and describing the management in both syndromes.19 Whereas hypertrophy is usually conned to sites of vascular anomalies in KTS, vascular malformations are only rarely observed on the hypertrophied side in PS, with the exception of varicosities related to an associated patchy dermal hypoplasia. The subset of patients with KTS and the crossed-bilateral form has also been described to have hypertrophy and vascular malformations in different quadrants. However, this entity is not universally accepted as a KTS subset, and some of these patients may in fact have PS.7 Clinical scoring systems can be useful to define classic PS and to rule out this overgrowth syndrome9,11 but they are not yet adequate to assess the so-called regional PS.20 Therefore, for several authors an isolated macrodactyly may represent an incomplete manifestation of PS. Servelle21 proposed that obstruction or atresia of the deep veins in the leg produce chronic venous hypertension, which is in turn responsible for the

development of port-wine stains, varicose veins, and limb hypertrophy. Other authors have hypothesized that KTS is a generalized mesodermal abnormality and that the deep vein abnormalities are part of the syndrome but not its cause.22 Recent findings in KTS and PS suggest the presence of an underlying somatic mutation. Although this mutation is thought to involve growth factor receptors of mesodermal and ectodermal tissues in PS,23,24 it is likely to specifically affect the regulation of vascular growth during embryogenesis in KTS. Two genetic defects of the angiogenic factor VG5Q,25 RASA1 mutations,26 and de novo supernumerary ring chromosome 18 were recently detected in patients with KTS.27 According to the recent classication of portwine stains into geographic and metameric morphology, geographic stains are associated with a more pronounced lymphatic involvement and more complications.28 In a recent study of 16 patients, our group proposed a possible relationship between the presence of geographic stains and DVS anomalies.6 In the current article, we

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Fig 4. Left, Anteroposterior view showing extent of port-wine stain, distal hypertrophy (in black), and involvement of deep venous system ( framed in blue). Middle, Direct multidetector computed tomography phlebography with maximum intensity projection and volumerendering reconstructions, demonstrating femoral vein hypoplasia (open arrows) and popliteal vein aplasia (arrows). Right, Toe macrodactyly associated with syndactyly of left foot.

report another anatomic relationship, demonstrating that the presence of hand and foot malformations has significant correlation with the occurrence of DVS anomalies of the lower limbs in this group of patients with KTS.

CONCLUSION
Varicose veins or venous malformations in KTS are not always evident at birth and may become more apparent with increasing age. The presence at birth of macrodactyly or other hand and foot malformations can help identify infants and children with KTS who are at greatest risk of complications and need closer follow-up. Thus, the presence of hand or foot malformations in patients with KTS may be a predictor of DVS anomalies.
REFERENCES 1. Jacob AG, Driscoll DJ, Shaughnessy WJ, Stanson AW, Clay RP, Gloviczki P. Klippel-Trenaunay syndrome spectrum and management. Mayo Clin Proc 1998;73:28-36. 2. Beals RK, Lovrien EW. Diffuse capillary hemangiomas associated with skeletal hypotrophy. J Pediatr Orthop 1992;12: 401-2. 3. Gloviczki P, Hollier LH, Telander RL, Kaufman B, Bianco AJ, naunay synStickler GB. Surgical implications of Klippel-Tre drome. Ann Surg 1983;197:353-62.

4. Mulliken J, Young A. Combined vascular malformations. In: Mulliken J, editor. Vascular birthmarks: hemangiomas and malformations. Philadelphia: Saunders; 1988. pp. 159-72. 5. Baskerville PA, Ackroyd JS, Thomas ML, Browse NL. The Klippel-Trenaunay syndrome: clinical, radiological and hemodynamic features and management. Br J Surg 1985;72: 232-6. 6. Bastarrika G, Redondo P, Sierra A, Cano D, Martnez-Cuesta A, Lopez-Gutierrez JC, Cabrera J. New techniques for the evaluation and therapeutic planning of patients with Klippelnaunay syndrome. J Am Acad Dermatol 2007;56:242-9. Tre 7. McGrory BJ, Amadio PC, Dobyns JH, Stickler GB, Unni KK. Anomalies of the fingers and toes associated with Klippel Trenaunay syndrome. J Bone Joint Surg Am 1991;73:1537-46. 8. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, et al. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 1999;84:389-95. 9. Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA 2001;285:2240-3. 10. Hoeger PH, Martinez A, Maerker J, Harper JI. Vascular anomalies in Proteus syndrome. Clin Exp Dermatol 2004;29:222-30. 11. Hotamisligil GS. Proteus syndrome and hamartomas with overgrowth. Dysmorphol Clin Genet 1990;4:87-102. 12. Bircher AJ, Koo JY, Frieden IJ, Berger TG. Angiodysplastic syndrome with capillary and venous malformation associated with soft tissue hypotrophy. Dermatology 1994;189:292-6. 13. Eifert S, Villavicencio JL, Kao TC, Taute BM, Rich NM. Prevalence of deep venous anomalies in congenital vascular malformations of venous predominance. J Vasc Surg 2000; 31:462-71.

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Fig 5. Left, Anteroposterior view showing extent of port-wine stain, distal hypertrophy (in black), and involvement of deep venous system ( framed in blue). Middle, Magnetic resonance phlebography with maximum intensity projection reconstruction, demonstrating popliteal vein aplasia (open arrow). Note connection of entire venous drainage of leg with huge lateral thigh vein (arrows and arrowheads). Gluteal (open arrows) and lumbar (*) veins can also be seen. Right, Fourth toe microdactyly of right foot.

naunay syndrome Table I. Clinical features of patients with Klippel-Tre

Patient No. Age, y Sex Location Vascular stain Hypertrophy

1 (Fig 1) 2 3 4 5 (Fig 2) 6 (Fig 3)

28 31 9 22 24 34

M F F M M M

Lower limbs Hemicorporal Right lower limb Lower limbs and trunk Left lower limb, upper right limb Hemicorporal

Blotchy/segmental Geographic Geographic Geographic Blotchy Geographic

Soft Soft Soft Soft Soft

tissue tissue tissue and bone tissue and bone tissue

7 8 (Fig 4) 9 (Fig 5)

39 24 35

M M F

Lower limbs, left side of back Left lower limb Right lower limb

Blotchy Blotchy Geographic

Soft tissue (lower limb) and upper limb hypotrophy (soft tissue and bone) Left upper limb hypotrophy Soft tissue and bone Soft tissue

F, Female; M, male.

14. Browse NL, Burnand KG, Thomas ML. The Klippel-Trenaunay syndrome. In: Browse NL, Burnand KG, Thomas ML, editors. Diseases of the veins: pathology, diagnosis and treatment. London: Edward Arnold; 1988. p. 609-25.

15. Cohen MM Jr, Hayden PW. A newly recognized hamartomatous syndrome. Birth Defects 1979;15:291-6. 16. Wiedeman HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The Proteus syndrome: partial gigantism of the

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naunay syndrome Table II. Hand or foot malformations and deep venous anomalies in patients with Klippel-Tre
Patient No. Technique Foot or hand malformations Deep venous system of lower limb

1 (Fig 1) 2 3 4 5 6 7 8 9 (Fig 2) (Fig 3) (Fig 4) (Fig 5)

3D-MR and CV MDCT 3D-MR 3D-MR and CV MDCT MDCT 3D-MR MDCT 3D-MR

Toe Toe Toe Toe

Bilateral femoral aplasia Femoral hypoplasia and popliteal aplasia Popliteal aplasia Bilateral popliteal aplasia and left femoral hypoplasia Finger macrodactyly Femoral hypoplasia and popliteal aplasia Finger macrodactyly, ectrodactyly, syndactyly Femoral hypoplasia and popliteal aplasia Finger clinodactyly and camptodactyly Left femoral aplasia Toe macrodactyly and syndactyly Femoral hypoplasia and popliteal aplasia Toe microdactyly Popliteal aplasia

macrodactyly, bilateral, and syndactyly macrodactyly with plantar expansion macrodactyly macrodactyly, bilateral, and syndactyly

CV, Conventional venography; MDCT, multidetector computed tomography; 3D-MR, fast 3-dimensional magnetic resonance imaging.

17.

18.

19.

20. 21. 22. 23.

hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 1983; 140:5-12. Havard S, Enjolras O, Lessana-Leibowitch M, Escande JP. Proteus syndrome: 8 cases. Ann Dermatol Venereol 1994; 121:303-8. Sansom JE, Jardine P, Lunt PW, Schutt WH, Kennedy CT. A case illustrating Proteus and Klippel-Trenaunay syndrome overlap. J R Soc Med 1993;86:478-9. Guidera KJ, Brinker MR, Kouseff BG, Helal AA, Pugh LI, Ganey TM, naunay-Weber et al. Overgrowth management in Klippel-Tre and Proteus syndromes. J Pediatr Orthop 1993;13:459-66. Smeets E, Fryns JP, Cohen MM Jr. Regional Proteus syndrome and somatic mosaicism. Am J Med Genet 1994;51:29-31. naunays syndrome: 768 operated Servelle M. Klippel and Tre cases. Ann Surg 1985;201:365-73. Baskerville PA, Ackroyd JS, Browse NL. The etiology of the naunay syndrome. Ann Surg 1985;202:624-7. Klippel-Tre Cohen MM. Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 1993;47: 645-52.

24. Rudolph G, Blum WF, Jenne EW, Schoning M, Enders H, Meitinger T, et al. Growth hormone (GH), insulin-like growth factors (IGFs), and IGF-binding protein-3 (IGFBP-3) in a child with Proteus syndrome. Am J Med Genet 1994;50: 204-10. 25. Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, et al. Identification of an angiogenic factor that when mutated naunay syndrome. Nature causes susceptibility to Klippel-Tre 2004;427:640-5. 26. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A, Watanabe S, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003;73:1240-9. 27. Timur AA, Sadgephour A, Graf M, Schwartz S, Libby ED, Driscoll DJ, et al. Identification and molecular characterization of a de novo supernumerary ring chromosome 18 in a patient naunay syndrome. Ann Hum Genet 2004;68: with Klippel-Tre 353-61. naunay syndrome: the im28. Maari C, Frieden IJ. KlippeleTre portance of geographic stains in identifying lymphatic disease and risk of complications. J Am Acad Dermatol 2004; 51:391-8.