Foot or Hand Malformations Related

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Foot or hand malformations related to deep venoussystem anomalies of the lower limb in

Klippel-Trenaunay syndromePedro Redondo, MD, PhD,a Gorka Bastarrika, MD, PhD,b Leyre Aguado, MD,a Antonio Martınez-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 arereported to be present in 8% to 18% of patients with KTS; approximately 25% of patients with KTS havehand 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 notincluded. The presence and patency of the DVS was studied using conventional venography, multidetectorcomputed 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; fingermacrodactyly in one patient; finger 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 hadDVS anomalies (one with aplasia of entire DVS; one with duplication of the superficial femoral vein; 7 withhypoplasia 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 DVSanomalies. ( J Am Acad Dermatol 2009;61:621-8.)

Key words: deep venous system; hand/foot overgrowth; hand or foot malformations; Klippel-Trenaunay syndrome; macrodactyly.

K

lippel-Trenaunay syndrome (KTS) is a con-genital vascular anomaly, defined as a triadincluding a port-wine stain, underlying bony

and soft tissue hypertrophy, and varicose veinsand/or venous malformations. Port-wine stains arereported to be present in 98% of patients with KTS, varicosities or venous malformations in 72%, andsome form of limb hypertrophy in 67%.1 Upto10%of these patients present with hypotrophy of theaffected limb.2 KTS may be unilateral in 85% of

patients, bilateral in 12.5%, and crossed-bilateral in

Abbreviations used:

DVS: deep venous system

KTS: Klippel-Trenaunay syndromePS: 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: [email protected].

Published online July 6, 2009.

0190-9622/$36.00

ª 2009 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2009.04.027

621

mailto:[email protected]





2.5%, with both upper and lower limb involvementin 10% of patients.3,4 Superficial venous anomaliesinclude ectasia of small veins, varicosities, venousmalformations, and persistent embryologic veins.2

Deep venous system (DVS) abnormalities may include aplasia, hypoplasia, aneurysmal dilatation,avalvulia, and duplication of the affected veins.Because these anomaliesmay preclude surgery orsclerotherapy of sympto-matic venous malforma-tions,5 the presence andpatency of the DVS shouldfirst be demonstrated by venography or noninvasiveimaging procedures.6

The limb hypertrophy inKTS is usually uniform and

generally produces an asym-metry with respect to thecontralateral limb. Around25% of patients with KTShave hand or foot malforma-tions,7 although these arealso classically associated inthe literature with theProteus syndrome (PS).8,9

In this study, we found anassociation between hand orfoot malformations and the

existence of DVS anomaliesof the lower limb in patients with KTS.

METHODSIn all, 51 consecutive patients with KTS referred

between January 2000 and February 2008 to our vascular malformation clinic were retrospectively included. Their median age was 26 years (range9-44 years). DVS patency was evaluated in allpatients by means of either conventional ascending venography, multidetector computed tomography,or fast 3-dimensional magnetic resonance imaging

venography. The study was approved by the insti-tutional review board and written informed consent was obtained from all participants.

Differential diagnosis with PSThe diagnosis of KTS was made independently by

at least 3 expert vascular specialists. Followingpreviously published recommendations,10 we usedthe scoring systems of Hotamisligil11 and Bieseckeret al8 to avoid a possible misdiagnosis of PS as KTS.The Hotamisligil11 rating scale assesses the presenceof: macrodactyly and/or hemihypertrophy (5

points); plantar or palmar cerebriform hyperplasia

(4 points); lipoma/subcutaneous tumor (4 points);epidermal nevus (3 points); macrocephaly and/orskull exostoses (2.5 points); and other minor abnor-malities (1 point). The maximum score is 19.5 points, with scores below 10 ruling out the diagnosis of PS.The scoring system described by Biesecker et al8

defines 3 mandatory general criteria (mosaic distri-bution of lesions, progress-ive course, and sporadicoccurrence) for the diagnosisof PS. It requires as welleither the presence of aconnective tissue nevus (cat-egory A) or at least two‘‘category B’’ signs (epider-mal nevus, overgrowth, early manifestation of specifictumors) or 3 ‘‘category C’’

signs (lipoma/lipodystrophy, vascular malformation, facialdysmorphism).

RESULTSThe diagnosis of KTS was

confirmed in all patientsevaluated. A port-wine stain was present in 100% of pa-tients, varicosities and a ve-nous malformation in 94%

(48 of 51), and limb hyper-trophy in 58% (31 of 51). KTS was unilateral in 66% (34 of 51) of patients, bilateralin 18% (9 of 51) (Fig 1), crossed-bilateral in 4% (2 of 51) (Fig 2), and hemicorporal in 12% (6 of 51) (Fig 3).

Hand or foot malformationsNine of the patients had malformations of hands

or feet. The port-wine stain was localized (limited toone limb) in 3 patients, involved both limbs in twopatients (in one of which there was extension to thetrunk), was hemicorporal in two patients, and

crossed-bilateral in another two (one of them withinvolvement of both lower limbs). Seventeen handor foot malformations were found in 9 patients (7 toemacrodactyly [Fig 1], two finger macrodactyly [Figs 2and 3], one ectrodactyly [Fig 3], 4 syndactyly [Figs 1,3, and 4], one clinodactyly, one toe microdactyly [Fig5], and one camptodactyly). This last case corre-sponds to a patient with KTS that mainly involved thelower limbs. According to the Hotamisligil11 scalescore and classification of Biesecker et al,8 a diag-nosis of PS was ruled out in all patients. The demo-graphic and clinical data of the 9 patients with hand

and foot malformations are shown in Table I. In all

CAPSULE SUMMARY

d A relationship between Klippel-

Trenaunay syndromeeassociated

hand/foot malformations and

involvement of the deep venous system

of the lower extremities has not beenpreviously described.

d In our series all patients with hand or

foot malformations had deep venoussystem abnormalities (P \ .001).

d The presence of hand or foot

malformations in patients with Klippel-

Trenaunay syndrome may be a predictor

of deep venous system abnormalities.

d The presence at birth of hand and foot

malformations can help identify infants

with Klippel-Trenaunay syndrome who

are at greatest risk of complications and

need closer follow-up.

J A M A CAD DERMATOL

OCTOBER 2009622 Redondo et al



cases the malformations were present during the firstmonths of life.

DVS anomaliesEleven (22%) of 51 patients with KTS had DVS

anomalies (one aplasia of the whole DVS, one dupli-cation of the superficial femoral vein, 7 hypoplasia/aplasia of thefemoral vein [Figs1to4],and7aplasiaof the popliteal vein [Figs 2 to 5]) (Table II). None of thestudied patients had arteriovenous fistulae, and adiagnosis of Parkes Weber syndrome was ruled out.

Statistical analysisThe statistical analysis was performed using the

Fisher exact test (2-sided). All patients with hand orfoot malformations had DVS anomalies ( P \ .001).Only two patients with KTS but without macrodac-tyly or hemihypertrophy or atrophy had DVS anom-alies. With the exception of one patient with atrophy of one hand, all other asymmetries (hypertrophy oratrophy) were in the limb affected by themalformation.

DISCUSSIONMacrodactyly is an uncommon congenital malfor-

mation characterized by the enlargement of soft

tissue and bony elements of fingers and toes but

not of metacarpals or metatarsals. Clinodactyly (abnormal deviation of fifth finger in coronal or

radioulnar plane), ectrodactyly (absence of digits),camptodactyly (flexion contracture of proximalinterphalangeal joint of finger), and syndactyly (abnormal connection between adjacent digits) arealso rare. In a study by McGrory et al,7 29 of 108patients with KTS had a malformation, includingmacrodactyly, syndactyly, clinodactyly, metatarsusprimus varus, polydactyly, camptodactyly, orcongenital trigger finger. An atypical h ypotrophic variant of KTS has also been described.2,12 Two of the patients with KTS included in the current serieshad hypotrophy of the upper limb with bone

involvement; one of these had hemicorporal distri-bution of port-wine stains and hand involvement with macrodactyly, ectrodactyly, and syndactyly, whereas the other patient showed port-wine stainsthat mainly affected the lower limbs and had upperlimb and hand hypotrophy, with clinodactyly andcamptodactyly.

Few studies have been published on the DVSanomalies present in patients with KTS. Aplasia orhypoplasia of the deep venous trunks was observedamong 8% of patients with a vascular malformationof venous predominance.13 Other reported disor-

ders, with fewer physiologic repercussions, are

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 resonancephlebography with maximum intensity projection reconstruction, demonstrating bilateralpopliteal vein aplasia (arrows ) and left femoral vein hypoplasia (open arrow ). Right , Toemacrodactyly associated with syndactyly of right foot.


V OLUME 61, NUMBER 4 Redondo et al 623



phlebectasias, aneurysms, avalvulia, and duplicationor malposition of the deep venous trunks.13 In oneseries consisting of 49 patients with KTS, 9 (18%)presented with aplasia/hypoplasia of the deep venous trunks,14 a very similar percentage to thatfound in the current series (22%). To our knowledge,a relationship between hand/foot malformations andinvolvement of the DVS of the lower limb has notpreviously been described in patients with KTS.

In addition to KTS, the differential diagnosis of diseases associated with macrodactyly, megalodac-tyly, or digital gigantism includes fibrolipomatosis,idiopathic localized gigantism, neurofibromatosis,Milroy disease, tuberous sclerosis, and other over-growth syndromes with complex vascular anomalies(PS, Parkes Weber syndrome, Sturge-Weber syn-drome, macrocephaly-cutis marmorata, andBannayan-Riley-Ruvalcaba syndrome).

PS is a rare disorder characterized by overgrowthof multiple tissues, vascular malformations, andconnective tissue or epidermal ne vi. PS, first defined

in 1979 by Cohen and Hayden,

15

was characterized

in 1983 by Wiedeman et al16 as a rare hamartomatousdisorder with a wide range of abnormalities. Despitethe availability of established criteria for the diagno-sis 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 difficult entity to distinguish fromPS, particularl y with respect to vascular anomalies.Hoeger et al10 reported 35 vascular anomalies in all

22 (100%) patients with PS, among whom vasculartumors, port-wine stains, and venous malformations were equally common. Vascular tumors were moreprevalent and port-wine stains and venous malfor-mations slightly less common than in other pub-lished series. Previously, a total of 118 vascularanomalies 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 withPS.17 In fact, there appears to be considerable ambi-guity 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


black ), and involvement of deep venous system ( framed in blue ). Middle , Magnetic resonancephlebography with curved maximum intensity projection, demonstrating femoral vein hypo-plasia (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 secondand third fingers of right hand.





also been case reports illustrating an overlapbetween PS and KTS18 and describing the manage-ment in both syndromes.19

Whereas hypertrophy is usually confined to sitesof vascular anomalies in KTS, vascular malforma-tions are only rarely observed on the hypertrophiedside in PS, with the exception of varicosities relatedto an associated patchy dermal hypoplasia. Thesubset 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 aKTS subset, and some of these patients may in facthave PS.7 Clinical scoring systems can be useful todefine classic PS and to rule out this overgrowthsyndrome9,11 but they are not yet adequate to assessthe so-called regional PS.20 Therefore, for severalauthors an isolated macrodactyly may represent anincomplete 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, andlimb hypertrophy. Other authors have hypothesizedthat KTS is a generalized mesodermal abnormality and that the deep vein abnormalities are part of thesyndrome but not its cause.22 Recent findings in KTSand PS suggest the presence of an underlyingsomatic mutation. Although this mutation is thoughtto involve growth factor receptors of mesodermaland ectodermal tissues in PS,23,24 it is likely to

specifically affect the regulation of vascular growthduring embryogenesis in KTS. T wo genetic defectsof 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 classification of port- wine stains into geographic and metameric mor-phology, geographic stains are associated with amore pronounced ly mphatic involvement andmore complications.28 In a recent study of 16patients, our group proposed a possible relation-ship between the presence of geographic stains

and DVS anomalies.

6

In the current article, we

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 magneticresonance 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.





report another anatomic relationship, demonstrat-

ing that the presence of hand and foot malforma-tions has significant correlation with the occurrenceof DVS anomalies of the lower limbs in this groupof patients with KTS.

CONCLUSION Varicose veins or venous malformations in KTS

are not always evident at birth and may becomemore apparent with increasing age. The presenceat birth of macrodactyly or other hand and footmalformations can help identify infants and chil-

dren with KTS who are at greatest risk of compli-cations and need closer follow-up. Thus, thepresence of hand or foot malformations in patients with KTS may be a predictor of DVS anomalies.

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black ), and involvement of deep venous system ( framed in blue ). Middle , Direct multidetectorcomputed tomography phlebography with maximum intensity projection and volume-rendering reconstructions, demonstrating femoral vein hypoplasia (open arrow s) and popliteal

vein aplasia (arrows ). Right , Toe macrodactyly associated with syndactyly of left foot.





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.

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Schirg E. The Proteus syndrome: partial gigantism of the


black ), and involvement of deep venous system ( framed in blue ). Middle , Magnetic resonancephlebography with maximum intensity projection reconstruction, demonstrating popliteal veinaplasia (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.

Table I. Clinical features of patients with Klippel-Trenaunay syndrome

Patient No. Age, y Sex Location Vascular stain Hypertrophy

1 (Fig 1) 28 M Lower limbs Blotchy/segmental Soft tissue

2 31 F Hemicorporal Geographic Soft tissue

3 9 F Right lower limb Geographic Soft tissue and bone

4 22 M Lower limbs and trunk Geographic Soft tissue and bone

5 (Fig 2) 24 M Left lower limb, upper right

limb

Blotchy Soft tissue

6 (Fig 3) 34 M Hemicorporal Geographic Soft tissue (lower limb) andupper limb hypotrophy

(soft tissue and bone)

7 39 M Lower limbs, left side of

back

Blotchy Left upper limb hypotrophy

8 (Fig 4) 24 M Left lower limb Blotchy Soft tissue and bone

9 (Fig 5) 35 F Right lower limb Geographic Soft tissue

F , Female; M, male.





hands and/or feet, nevi, hemihypertrophy, subcutaneous

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accelerated growth and visceral affections. Eur J Pediatr 1983;

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18. 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.

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et al. Overgrowth management in Klippel-Trenaunay-Weber

and Proteus syndromes. J Pediatr Orthop 1993;13:459-66.

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and somatic mosaicism. Am J Med Genet 1994;51:29-31.

21. Servelle M. Klippel and Trenaunay’s syndrome: 768 operated

cases. Ann Surg 1985;201:365-73.

22. Baskerville PA, Ackroyd JS, Browse NL. The etiology of the

Klippel-Trenaunay syndrome. Ann Surg 1985;202:624-7.23. 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

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2004;427:640-5.

26. Eerola I, Boon LM, Mulliken JB, Burrows PE, Dompmartin A,

Watanabe S, et al. Capillary malformation-arteriovenous mal-

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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

with Klippel-Trenaunay syndrome. Ann Hum Genet 2004;68:

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disease and risk of complications. J Am Acad Dermatol 2004;

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Table II. Hand or foot malformations and deep venous anomalies in patients with Klippel-Trenaunay syndrome

Patient No. Technique Foot or hand malformations Deep venous system of lower limb

1 (Fig 1) 3D-MR and CV Toe macrodactyly, bilateral, and syndactyly Bilateral femoral aplasia

2 MDCT Toe macrodactyly with plantar expansion Femoral hypoplasia and popliteal aplasia

3 3D-MR Toe macrodactyly Popliteal aplasia

4 3D-MR and CV Toe macrodactyly, bilateral, and syndactyly Bilateral popliteal aplasia and left femoralhypoplasia

5 (Fig 2) MDCT Finger macrodactyly Femoral hypoplasia and popliteal aplasia

6 (Fig 3) MDCT Finger macrodactyly, ectrodactyly, syndactyly Femoral hypoplasia and popliteal aplasia

7 3D-MR Finger clinodactyly and camptodactyly Left femoral aplasia

8 (Fig 4) MDCT Toe macrodactyly and syndactyly Femoral hypoplasia and popliteal aplasia

9 (Fig 5) 3D-MR Toe microdactyly Popliteal aplasia

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



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