Chronic leg ulcers in Werner’s syndrome

E.K. Yeonga,*, C.C. Yangb

aDepartment of Surgery, Plastic Division, National Taiwan University Hospital, No. 1 Sec. 1, Jen-Ai Road,100, Taipei, TaiwanbDepartment of Neurology, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, 100, Taipei, Taiwan

Received 8 July 2003; accepted 21 October 2003

KEYWORDSWerner’s syndrome;

Chronic leg ulcers

Summary We report two siblings suffered from Werner’s syndrome, which is a rarepremature aging disorder caused by genetic mutations. They developed prematureaging during adolescence with loss and graying of hair, short stature, baldness,atrophic skin, thin extremities, flat feet, ‘bird’ face and cataracts. Multiple chroniculcers were noted over the feet in both patients. Healing was prolonged because ofatrophic subcutaneous tissue, poor perfusion, impaired fibroblast activity and the lossof normal foot architecture. Treatment of the ulcers was challenging, as flap optionswere limited over the lower third of the leg and skin grafting was not easy as there wasa lack of healthy granulations. However, we have successfully closed the ulcers withIntegra artificial skin and ultra-thin split thickness skin grafting with the scalp as donorsite. The main purpose of this paper is to alert physicians to this syndrome whentreatments are being planned for patients with chronic leg ulcers.Q 2003 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rightsreserved.

Werner’s syndrome is an unusual cause of chronicleg ulcer. The syndrome is a very rare autosomalrecessive disorder1 caused by WRN gene whoseprotein resembles DNA helicase. The precise mol-ecular mechanisms remain unknown. Its clinicalfindings include aged appearance, loss and grayingof hair, short stature, baldness, atrophic skin, thinextremities, flat feet, ‘bird’ face, cataracts, skinulcers, osteoporosis and type 2 diabetes mellitus.2

Fifteen percent of the patients with Werner’ssyndrome develop chronic leg ulcers.

In 2000, we encountered two siblings sufferedfrom Werner’s syndrome with multiple leg ulcers.Both of them developed clinical picture of Werner’s

syndrome during adolescence. Their family tree isshown in Fig. 1.

Case 1

A 26-year-old female who suffered from Werner’ssyndrome with multiple intractable ulcers over theright ankle (Fig. 2), lateral border and the heel ofthe right foot was admitted to hospital. She hadmultiple ulcers for months. The ulcers were6 £ 3 cm, 2 £ 3 cm and 2 £ 2 cm, respectively.Tender peripheral erythematous and tendonexposure were noted. Previous skin grafting hadfailed. Her haemoglobin was 9.6 gm/dl, RBC was3.37 £ 104/mm3; WBC, platelet, GOT, GPT, bloodsugar and total protein were normal. Serologicaltesting was negative for vascular collagen disease

The British Association of Plastic Surgeons (2004) 57, 86–88

S0007-1226/$ - see front matter Q 2003 The British Association of Plastic Surgeons. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.bjps.2003.10.011

*Corresponding author. Tel.: þ886-2-23123456 ext 5648; fax:þ886-2-23934358.

E-mail address: eky18287@mc.ntu.edu.tw

and autoimmune disorders. There was no history ofdeep vein thrombosis but Doppler ultrasound studydisclosed moderate arteriosclerosis in the majorlower leg vessels. Bone X-ray was normal. Electro-cardiogram disclosed left ventricular hypertrophyand borderline ST elevation. Physical examinationdisclosed short stature, senile appearance, loss andgraying of hair, alopecia, atrophic skin, ’bird’ face,subcutaneous tissue atrophy, hoarseness, thinextremities and flat feet. She also suffered fromneurogenic bladder and cataract. The confirmatorydiagnosis of Werner’s syndrome was by genetictesting, which revealed nucleotide 3264-5 AGdeletion of WRN gene. After admission, the patientwas treated with systemic antibiotic and localdressings. The ulcers received multiple surgicaldebridements and were finally closed with theapplication of Integra artificial skin implantation(Fig. 3) followed by ultra-thin split thickness skingrafting (4/1000 in) from the scalp as donor (Fig. 4).

Case 2

A 28-year-old female who is the elder sister of thefirst case suffered from Werner’s syndrome withmultiple intractable ulcers over the fourth and fifth

toes, the heel and the ankle. Gangrenous changesover the toes were noted. She suffers also from type2 diabetes mellitus. Serological testing was nega-tive for vascular collagen disease and autoimmunedisorders. There was no history of deep veinthrombosis but Doppler ultrasound study disclosedsevere arteriosclerosis in the major lower legvessels. Systemic antibiotic and local antibioticdressings were given. Surgical debridements wereperformed. Toes were amputated and the stumpswere covered with Integra. The heel and the ankleulcers were also covered with Integra followingsurgical debridements. Ultra-thin split thicknessskin graft was performed 3 weeks later and theulcers healed finally.

Discussion

The understanding of aetiopathogenesis of chronicleg ulcer is essential, as improper treatment will

Figure 1 Family tree of the patients. ( ) Dead ( )patients suffer from Werner’s syndrome.

Figure 2 An intractable ulcer over the right ankle of apatient with Werner’s syndrome.

Figure 3 Immediate Integra artificial skin implantationafter wound debridement.

Figure 4 Nine months after Integra implantation andskin grafting.

Chronic leg ulcers in Werner’s syndrome 87

lead to amputations. Common causes of chronic legulcers include venous valve insufficiency, lowerextremity arterial disease and diabetes. This paperreports two cases of Werner’s syndrome as anunusual cause of chronic leg ulcers.

Werner’s syndrome is a rare cause of chroniculcer. The contributory causes in the pathogenesisof ulcerations in these patients are atrophicsubcutaneous tissue, poor perfusion, impairedfibroblast activity and the lost of normal footarchitecture. It is the combination of these riskfactors that ultimately results in multiple footulcers. Lok stated that the ulcers in Werner’ssyndrome have been related to the combination ofmechanical factors on atrophic subcutaneous tissueand skin of feet and leg associated with earlyarteriosclerosis and diabetes mellitus.3 Besides,studies have shown that there is defective DNAmetabolism and diminished replicative capacity offibroblasts4 in patients with Werner’s syndrome.

Treatment remains a challenging problem, asspontaneous wound closure is often difficult.Although local or free flaps have been reported inthe closure of intractable elbow5 or knee6 ulcers inWerner’s syndrome, their applications are notextended to the ankles and feet, as flaps arelimited in these regions. The situation is exacer-bated by the presence of subcutaneous tissueatrophy. Skin grafting is usually not successful dueto the exposure of tendons and bony structure orthe lacking of supporting granulations tissue.

Leg ulcer in Werner’s syndrome is usuallymultiple as in our cases. They are usually locatedon the heel, around the ankle, the dorso-lateralborder of the foot and the toes. Ulcers are usuallydeep with tendons or bony structure exposure andare susceptible to infections. Healing is alwaysslow. Different treatment modalities such ashyperbaric oxygen therapy, suction assistedtherapy, growth factor; phototherapy may be usedto promote wound healing besides traditionalwound dressings. However, they are usually noteffective. The ulcers in our cases were finally closedwith the use of Integra artificial skin. Integra is amembrane composed of bovine collagen withglycoaminoglycan and a layer of silicone. It func-tions as a template for cellular and vascular

infiltration during wound healing process andinduces the formation of neodermis.

Integra promotes wound closure. In our cases,the outer cortex of the bone and the exposedtendons were removed before applying the artificialskin onto the base of the ulcer. These allow cellularand vascular infiltration from the bone marrow tothe Integra which functions as the template for theformation of neodermis. Three weeks later, ultra-thin split thickness skin grafts were harvested fromthe scalps, which have higher density of skinappendages than other anatomical regions, andwere grafted onto the ulcers.

The characteristic flat foot structure and thelack of adequate thickness of soft tissue under bonyprominences in Werner’s syndrome predisposepatients to elevated foot pressure7 and, ultimately,ulcerations. Proper footwear should be consideredto avoid mechanical insults.

In conclusion, we reported two cases of patientswith Werner’s syndrome as a rare cause of chronicleg ulcer. The ulcer profile is deep, multiple andintractable. Atrophic subcutaneous tissue, poorperfusion, impaired fibroblast activity and the lostof normal foot architecture are the contributorycauses. The use of Integral artificial skin may beconsidered if conventional treatment plan is notsuccessful.

References

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Werner’s syndrome. Report of one case. J Mal Vasc 1991;16(4):381—2.

4. Goldstein S, Niewiarowski S, Singal DP. Pathological impli-cations of cell aging in vitro. Fed Proc 1975;34(1):56—63.

5. Koshima I, Shozima M, Soeda S. Repair of elbow defects andthe biochemical characteristics of Werner’s syndrome. AnnPlast Surg 1989;23(4):357—62.

6. Taniguchi Y, Tamaki T. Reconstruction of intractable ulcer ofthe knee joint in Werner’s syndrome with free latissimus dorsimyocutaneous flap. J Reconstr Microsurg 1998;14(8):555—8.

7. Morag E, Cavanagh PR. Structural and functional predictors ofregional peak pressure under the foot during walking.J Biomech 1999;32(4):359—70.

E.K. Yeong, C.C. Yang88