Sinrom Bureau Barriere

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SINDROMUL BUREAU-BARRIRE: STUDIU PE 11 CAZURI

BUREAU-BARRIRE SYNDROME: A STUDY OF 11 CASES

V. PTRACU

* Universitatea de Medicin i Farmacie din Craiova, Clinica de Dermatologie.University of Medicine and Farmacy Craiova Craiova, Dermatology Clinic

Rezumat

Sindromul Bureau-Barrire (acropatia ulceromuti-lant sporadic) este o polinevrit de origine etanolic,nsoit de leziuni cutanate i osteoarticulare.

Prezentm observaiile epidemiologice, clinico-evolutive i terapeutice n urma unui studiu retrospectivpe 11 cazuri de sindrom Bureau-Barrire.

Bolnavi i metod: Lotul de bolnavi a cuprins 10 M,1 F, cu vrsta medie de 59,5 ani i un istoric al bolii deaproximativ 2,6 ani. Diagnosticul a fost stabilit pe bazaexamenului dermatologic, neurologic i a investigaiilorimagistice.

Tratamentul a constat n vitamine din grupul B,vitamina E, hemoreologice, hepatotrope, antibioterapiegeneral (la cazurile cu suprainfecie), corectarea dezechi-librelor nutriionale i ngrijiri locale cu soluii antiseptice,plus topice epitelizante.

Rezultate: Toi bolnavii consumau cronic alcool, iar 9erau fumtori. apte bolnavi afirmau expunereandelungat la frig i umiditate, n context profesional. Auprezentat urmtoarele comorbiditi: hepatit cronic toxicetanolic (6 bolnavi); hepatit cronic mixt (1 bolnav);sindrom anemic (5 bolnavi); afeciuni gastrointestinale (3bolnavi); dislipidemie (3 bolnavi); rozacee, eritem pelagroidi lipomatoza Launois-Bensaude (cte un bolnav).

La nou bolnavi am obinut ameliorarea leziunilor, maievident la cazurile cu istoric recent de sindrom Bureau-Barrire, fr leziuni osoase severe. La doi pacieni, datoritleziunilor osoase grave i suprainfeciei, s-a ajuns laamputaii (un caz cu amputaie de haluce i alt caz cuamputaie de degete la un picior).

Concluzii: Tratamentul complex precoce i renunareala consumul de alcool pot opri evoluia sindromului

Summary

Bureau-Barrire syndrome (sporadic ulcero-mutilating acropathy) is a peripheral neuropathy ofethanolic origin, accompanied by cutaneous andosteoarticular lesions.

Epidemiological, clinical, evolutive and therapeuticalobservations are shown from a retrospective study on 11cases of Bureau-Barrire syndrome.

Patients and method: The group of patientsconsisted of 10M and 1F with the average age of 59,5 and ahistory of disease of about 2,6 years. The diagnosis wasestablished on dermatological, neurological and imagisticexaminations .

Treatment consisted of group B vitamins, Vitamin E,hemorheologics, hepatotropics, general antibiotics (insuperinfection cases), correcting nutritional imbalancesand local treatment with antiseptic solutions and topical re-epithelization.

Results: All the patients were chronically consumingalcohol 9 of which were smokers. Seven patients claimedthey have been subjected to prolonged exposure to cold andhumidity due to their professions. They showed thefollowing comoborbidities: toxic ethanolic chronic hepatitis(6 patients) mixt chronic hepatitis (1 patient), anemicsyndrome (5 patients) gastrointestinal disorders (3patients), dyslipidemia (3 patients), rosacea (1 patient),pelagroid erythema (1 patient) and Launois- Bensaudelipomatosis (1 patient).

Nine patients showed an improvement on the state oftheir lesions, most obvious in cases with a recent history ofBureau-Barrire syndrome without severe bonelesions. Two patients due to severe bone injuries andsuperinfection required amputation (hallux amputation inone case and toe amputation in the other).

Conclusions: Complex and early treatment andquitting alcohol consumption can stop the evolution of

STUDII CLINICE I EXPERIMENTALEEXPERIMENTAL AND CLINICAL STUDY

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DermatoVenerol. (Buc.), 57: 205-219

Sindromul Bureau-Barrire, denumit iacropatia ulcero-mutilant dobndit, nsu-meaz leziuni cutanate (ulceraii mutilante alepiciorului), osoase (osteoliz) i neurologice(disociaie termo-algezic de tip siringomielic).

Acest sindrom a fost descris pentru primadat n Frana, n 1957, de autorii al cror numel poart. Suferina se instaleaz insidios iintereseaz cu precdere alcoolicii cronici [1].

Prezentm observaiile epidemiologice,clinico-evolutive i terapeutice pe un lot de 11bolnavi cu sindrom Bureau-Barrire.

Bolnavi i metodAm efectuat un studiu retrospectiv pe o

perioad de doi ani, cuprinznd bolnavii cusindrom Bureau-Barrire, spitalizai n ClinicaDermatologie Craiova. Este vorba de 11 cazuri(10 M, 1 F), cu vrsta medie de 59,5 ani i unistoric al bolii de aproximativ 2,6 ani, doar 3bolnavi fiind la prima internare.

Diagnosticul a fost stabilit pe baza exame-nului dermatologic, neurologic i a investigaiilorimagistice pentru evidenierea interesrii osoase.La fiecare caz am reinut factorii de risc(consumul cronic de alcool, fumatul, expunereaprelungit la frig i umiditate) i am efectuatexplorri paraclinice pentru diagnosticareacomorbiditilor.

Rezultate

Toi cei 11 bolnavi consumau cronic alcool, iar9 erau fumtori. apte bolnavi afirmau expunereandelungat la frig i umiditate, n contextprofesional (muncitori la reele electrice,activitate n zootehnie, mecanici de utilaje grele).

Ulcerele plantare au fost bilaterale la 4 cazurii unilaterale la celelalte 7 cazuri, media fiind de

Bureau-Barrire syndrome, also calledacquired ulcer-mutilant acropathy, sums up

cutaneous lesions (mutilant ulceration of thefoot), bone lesions (osteolysis) and neuro-logical lesions (thermoalgesic dissociation ofsyringomyelic type).

This syndrome was first described in Francein 1957 by the authors whose name it bears.Suffering starts insidiously and primarily affectschronic alcoholics [1].

Epidemiological, clinical, evolutive andtherapeutical observations are shown from astudy on 11 cases of Bureau-Barrire syndrome.

Patients and methodWe have conducted a retrospective study

over a period of two years, containing patientswith Bureau-Barrire syndrome, hospitalized inDermatology Clinic Craiova. The group ofpatients consisted of 10M and 1F with theaverage age of 59,5 and a history of disease ofabout 2,6 years only 3 patients being at their firsthospitalization.

The diagnosis was established ondermatological, neurological and imagisticexamainations highlighting bone condition. Ineach case we took into account the risk factors(chronic alcohol consumption, smoking, pro-longed exposure to cold and humidity) and weperformed paraclinical examination for thediagnosis of comorbidities.

ResultsAll the patients were chronically consuming

alcohol 9 of which were smokers. Seven patientsclaimed they have been subjected to prolongedexposure to cold and humidity due to theirprofessions (workers in electrical networking,

Bureau-Barrire i preveni complicaiile osoase, carenecesit uneori amputaii mutilante.

Sindromul Bureau-Barrire este considerat o afeciunerar, ns procentul mare al consumatorilor cronici dealcool impune realizarea unor studii pentru cunoatereaincidenei reale.

Cuvinte cheie: sindromul Bureau-Barrire, alcool,comorbiditi, lipomatoza Launois-Bensaude.

Bureau-Barrire syndrome and can help prevent bonedisorders that sometimes require amputation.

Bureau-Barrire syndrome is considered a rare diseasebut a large percentage of chronic alcohol consumers enforcesthe conduct of studies to know its true incidence.

Key words: Bureau-Barrire syndrome, alcohol,comorbidities, Launois-Bensaude lipomatosis.

Intrat n redacie: 3.07.2012Acceptat: 20.08.2012

Received: 3.07.2012Accepted: 20.08.2012

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aproximativ dou ulcere / bolnav. Au prezentatcte trei ulcere, 2 bolnavi, cte dou ulcere, 3bolnavi i cte un ulcer, 5 bolnavi. Un singurpacient a avut 4 ulcere plantare.

Polineuropatia senzitiv periferic a fostprezent la toi bolnavii din lotul studiat.

Radiografia picioarelor a evideniat:osteoporoz i osteoliz (11 cazuri); osteonecrozi osteofitoze (4 cazuri); modificri artrozice (3cazuri); fractur veche consolidat (un caz).

Patru cazuri prezentau limitarea mobilitiiarticulaiilor metatarso-falangiene prin deformriarticulare.

Comorbiditile la bolnavii notri au fost: hepatit cronic toxic etanolic - 6 bolnavi; hepatit cronic mixt (etanolic i infecie

cu VHB) - 1 bolnav; sindrom anemic - 5 bolnavi; afeciuni gastrointestinale - 3 bolnavi; dislipidemie 3 bolnavi; rozacee, eritem pelagroid i lipomatoza

Launois- Bensaude - cte un bolnav. Tratamentul a constat n administrarea de

vitamine din grupul B, vitamina E, hemoreo-logice (pentoxifilin), hepatotrope (lagosa, liv52),antibioterapie general (la cazurile cu supra-infecie), corectarea dezechilibrelor nutriionale ingrijiri locale cu soluii antiseptice, plus topiceepitelizante. La externare am recomandat oprireaconsumului de alcool i a fumatului, igienriguroas la nivelul picioarelor, folosirea denclminte adecvat, evitarea ortostatismuluiprelungit i a expunerii picioarelor la frig iumezeal.

La nou bolnavi am obinut ameliorarealeziunilor. Ameliorarea a fost mai evident lacazurile cu istoric recent de sindrom Bureau-Barrire, fr leziuni osoase severe.

Discuii

Sindromul Bureau-Barrire aparine acropa-tiilor ulcero mutilante, izolate de Thvenard n1942, care se refer la afeciunile ce au n comunurmtoarele manifestri:

tulburri trofice cutanate, exprimate prinulceraii cronice i recidivante, culocalizare preferenial plantar (malperforant plantar);

leziuni osoase de tip osteolitic cu formarea degeode i distrugeri osoase urmate de

activity in zootechnics, heavy machinerymechanics).

Plantar ulcers were bilateral in 4 cases andunilateral in the other 7, the average beingaround 2 ulcers / patient. Two patients had 3ulcers, 3 patients had 2 ulcers, and 5 patients had1 ulcer. Only one patient had 4 plantar ulcers.

Peripheral sensory polyneuropathy waspresent at all patients from the studied group.

Foot X-ray showed: osteoporosis and osteo-lysis (11 cases); osteonecrosis and osteophytosis(4 cases); arthritic disorders (3 cases); oldconsolidated fracture (one case).

Four cases showed limited limited metatarso-phalangeal joint mobility through articulardeformation.

Comorbidities at our patients were: toxic ethanolic chronic hepatitis (6

patients); mixt chronic hepatitis (ethanolic and

infection with HBV) - 1 patient; anemic syndrome - 5 patients; gastrointestinal disorders 3 patients; dyslipidemia 3 patients; rosacea, pelagroid erythema and Launois-

Bensaude lipomatosis each patient.Treatment consisted of group B vitamins,

Vitamin E, hemorheologics (pentoxifylline),hepatotropics (Silymarin, Liv.52), general anti-biotics (in superinfection cases), correctingnutritional imbalances and local treatment withantiseptic solutions, and topical re-epithelization.When we discharged the patients, we recomend-ed quiting alcohol consumption and smoking,rigurous hygiene at the foot region, use of propershoes, avoiding prolonged orthostatism andexposure of feet to cold and humidity.

Nine patients showed an improvement onthe state of their lesions. The improvement wasmost obvious to the cases with recent history ofBureau-Barrire syndrome without severe bonelesions.

Discussion

The Bureau-Barrire syndrome belongs to theulcero-mutilating acropathies isolated byThvenard in 1942, which refer to diseases thathave in common the following manifestations:

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amputaii spontane de degete ideformarea piciorului (picior cubic);

leziuni neurologice complexe, nelipsindtulburrile de sensibilitate de tipsiringomielic (dispariia sensibilitiitermice i dureroase, cu pstrareasensibilitii tactile).

Acest grup cuprinde: sindromul Bureau-Barrire; sindromul Thvenard; sindromulHajdu-Cheney; sindroame mielodisplazicensoite de tulburri trofice cutanate; piciorulneuropat diabetic [2].

Sindromul Bureau-Barrire apare ndeosebila brbaii de 48-50 de ani, mari consumatori dealcool, care triesc n condiii de mizerie, frig iumiditate. Nu are caracter familial [3].

Cel mai frecvent, primele leziuni dermato-logice din sindromul Bureau-Barrire apar dup7 10 ani de la instalarea strii de dependenalcoolic. Incidena acestui sindrom este ncretere i se afl n strns corelaie cu incidenaalcoolismului cronic.

Etiopatogenie

S-au emis urmtoarele teorii patogenice alesindromului Bureau- Barrire:

Teoria mecanic (Wolkmann) - acord oimportan fundamental microtrauma-tismelor la care sunt supuse articulaiilecele mai expuse (punctele de sprijinfiziologice ale piciorului). Factori favo-rizani sunt analgezia i hipotoniamuscular periarticular;

Teoria simpatic (Leriche) - pune accent pedisfunciile de reglare a vasomotricitii, cudeschiderea unturilor arteriovenoase,hiperemie i hiperhidroza;

Teoria integrativ, care afirm c factorulmecanic este cauza determinant a afec-iunii, iar factorul simpatic are rol favo-rizant.

Factorul etiologic principal al sindromuluiBureau- Barrire este alcoolul, consumat cronicn cantiti mari.

n ultima perioad, exist urmtoarele ten-dine privind consumul de alcool:

expansiunea consumului de alcool nAfrica, Oceania, Extremul Orient;

coborrea vrstei butorilor;

trophic skin disorders expressed by chronicaland recurrent ulcerations, preferentiallylocalized plantar (plantar perforating mal);

osteolytic type bone lesions with theformation of geodes and bone destructionfollowed by spontaneous amputation offingers and foot deformity (cubic foot );

complex neurological damage, accompaniedby sensitivity disorders of syringomielitictype (loss of thermal and pain sensitivity,while maintaining tactile sensitivity).

This group contains: Bureau-Barrire syn-drome, Thvenard syndrome, Hajdu-Cheneysyndrome, myelodysplastic disorders accom-panied by trophic skin disorders, diabeticneuropathic foot [2].

The Bureau-Barrire syndrome occursmainly in men of 48-50 years, heavy alcoholdrinkers, living in misery, cold and humidity. Ithas not a familial character [3].

Usually, the first skin lesions in the Bureau-Barrire syndrome occur after 7 up to 10 yearsafter becoming an alcoholic. The incidence of thissyndrome is increasing and is closely related withthe incidence of chronic alcoholism.

Etiopathogenesis

They issued the following theories patho-genic Bureau-Barrire syndrome:

Mechanical theory (Wolkmann) - gives afundamental importance to the microtraumatisms faced by the most vulnerablejoints (physiological support points of thefoot). Predisposing factors are analgesiaand periarticular muscle weakness;

Sympathetic theory (Leriche) - focuses onthe adjustment of vasomotility dys-functions, with the opening of thearteriovenous shunts, hyperaemia andhyperhidrosis;

Integrative theory- states that themechanical factor is the root cause of thecondition and the sympathetic factor has aleading role.

The main etiological factor of the Bureau-Barrire syndrome is the alcohol, consumedchronically in large amounts.

Lately, there have been the following trendsin the alcohol consumption:

Alcohol consumption growth in Africa,Oceania, Far East;

Younger and younger drinkers; The increasing number of distilled drinks

over those obtained by natural fer-mentation;

There are registered more cases ofalcoholism in women.

We are talking about high alcohol con-sumption in the following situations:

For men: exceeding 3-7 units of alcoholconsumed daily or more than 7 unitsconsumed at least 3 times a week.

For women: exceeding 2-5 units of alcoholconsumed over 5 units daily or at least 3times a week.

Moderate drinking is defined as daily use of1-2 units. One unit of alcohol represents 13.5 galcohol , the equivalent of a 0.5 liter bottle of beer,a glass of 125 ml of wine or 40 g of alcoholicbeverages (40 degrees).

All 11 patients from our study consumedalcohol chronically, in large amounts. In addition,at the chronic etylics we often discoverinsufficient and unbalanced intake of nutrients,plus minerals and vitamin deficiencies andprotein enteropathy caused by alcohol.

Alcohol, vitamin deficienciency and hypo-proteinaemia cause damage to the sensitive nerveposterior roots and posterior cords of the spinalcord. Because of them, trophic tissue distur-bances occur (with little resistance to injury andlow regeneration capacity) and disturbances ofperipheral circulation [4].

Microscopy studies highlight: the reductionof the number of myelinated fibers; chronic andprogressive degenerative changes of nerve fibers;proliferation of connective tissue (predominantendoneural); schwannian minor injuries; normalmicrovascularisation (vasa vasorum).

Electronic microscopy studies highlight:retracted neurons, axoplasm clarification due todisappearance of microtubules, axonal takeoffscaused by the appearance of edema betweenaxon and schwannian sheath.

Reographic, oximetry, capilaroscopic andangiographic researches revealed in the Bureau-Barrire syndrome the reduction of the vasculartone in the affected area with the opening ofarteriolo-venous shunts and the acceleration of

ponderea din ce n ce mai mare abuturilor distilate n detrimentul celorobinute prin fermentaie natural;

se nregistreaz tot mai multe cazuri dealcoolism la femei.

vorbim despre consumul ridicat de alcooln urmtoarele situaii:

pentru brbai: depirea a 3-7 uniti dealcool consumate zilnic sau peste 7 uniticonsumate cel puin de 3 ori pe sptmn;

pentru femei: depirea a 2-5 uniti alcoolconsumate zilnic sau peste 5 uniti de celpuin 3 ori pe sptmn.

Consumul moderat de alcool este definit prinfolosirea zilnic a 1-2 uniti. O unitate alcoolreprezint 13,5 g alcool, echivalentul unei sticlede bere de 0,5 l, un pahar de vin de 125 ml sau 40 g buturi spirtoase (40 grade trie).

Toi cei 11 bolnavi din lotul nostru consumaucronic alcool n cantitate mare. n plus, la etiliciicronici ntlnim de cele mai multe ori un aportinsuficient i dezechilibrat de principii nutritive,la care se adaug carene mineralo-vitaminice iproteice cauzate de enteropatia alcoolic.

Alcoolul, hipoproteinemia i carenele vita-minice determin leziuni la nivelul rdcinilorposterioare ale nervilor senzitivi i cordoanelorposterioare din mduva spinrii. Datorit lor,apar tulburri trofice ale esuturilor (cu micrezisten la traumatisme i capacitate deregenerare sczut) i perturbri ale circulaieiperiferice [4].

Studiile de microscopie optic evideniaz:reducerea numrului de fibre mielinizate; modi-ficri degenerative cronice i evolutive alefibrelor nervoase; proliferri de esut conjunctiv(predominant endoneural); leziuni schwannieneminore; microvascularizaie (vasa vasorum)normal.

Studiile de microscopie electronic eviden-iaz: neuroni retractai, clarificarea axoplasmeidatorat dispariiei microtubulilor, decolriaxonale prin apariia unui edem ntre axon iteaca schwannian.

Cercetrile reografice, oximetrice, capilaro-scopice i angiografice au evideniat n cadrulsindromului Bureau-Barrire reducerea tonu-sului vascular n zona afectat, cu deschidereaunturilor arteriolo-venoase i accelerarea circu-laiei terminale. Astfel, se poate vorbi de o


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situaie aparent paradoxal, hipervascularizaieprin deschiderea acestor unturi, dar cu ischemieperiferic tisular. Rezult de aici scdereatroficitii esuturilor, care sub aciunea trauma-tismelor minore i infeciilor dezvolt ulceretrofice.

Modificrile circulaiei sanguine au rolpreponderent i n producerea leziunilor osoase,care sunt constante i precoce n sindromulBureau-Barrire.

La toate acestea, adugm c alcoolul, ncantitate mare, este aterogen prin inducereadislipidemiei, prezent la 3 dintre bolnavii notri.Cum peste 90% dintre alcoolici sunt i fumtori,nu trebuie neglijat nici rolul aterogen alfumatului. n plus, nicotina determin eliberareamasiv de catecolamine, care conduc la scdereacantitii de oxigen la nivelul esuturilor.Concentraia ridicat de carboxihemoglobin icreterea activitii plachetare sunt de asemeneacauze ale hipoxiei tisulare. Adesea, bolnavii cusindrom Bureau-Barrire au i anemie, ntlnitde noi la 5 bolnavi.

Aspecte clinice

De cele mai multe ori, bolnavul se prezint lamedic trziu, cu ulcer plantar cronic nedureros ihiperkeratoz accentuat periulceroas (fig.1).Iniial zonele plantare de presiune maxim devinhiperkeratozice. Pe una dintre acestea, la unmoment dat, apare o flicten sau o mic ulceraienedureroas, care neglijat evolueaz spre ulcercrateriform.

Examenul clinic evideniaz, de asemenea, laaceti bolnavi aspectul violaceu al tegumentului,hiperhidroz (picior suculent), lirea iinfiltrarea halucelor (mega haluce), deformarea idevierea degetelor (fig. 2), clavusuri, distrofiiunghiale, eventual o micoz interdigital.

Deformarea i devierea degetelor, sub-luxaiile metatarso-falangiene i scurtareapiciorului conduc la tulburri de static, la rndullor agravnd simptomatologia sindromuluiBureau-Barrire. Examinarea atent a picioarelorpoate evidenia la anumii bolnavi o fals grifproximal, secundar procesului sever deosteoliz metarso- falangian. n grifa proximalreal este vorba de hiperextensia articulaieimetatarso-falangiene i flexia articulaieiinterfalangiene proximale [5].

the terminal venous circulation. Therefore, wecan speak of a seemingly paradoxical situation,hypervascularization by opening these shunts,with peripheral tissue ischemia. This leads to thedecrease of tissue trophicity, that under theaction of minor injuries and infections developtrophic ulcers.

Blood flow changes have an important role inproducing bone lesions, which are constant andappear early in the Bureau-Barrire syndrome.

To all this, we add that alcohol in largequantities is atherogenic because it inducesdyslipidemia, present in 3 of our patients.Because over 90% of alcoholics are also smokerswe should not neglect the atherogenic role of thesmoking. In addition, nicotine causes the massiverelease of catecholamines, leading to a decreasedamount of oxygen into the tissue level. Highconcentration of carboxyhemoglobin andincreased platelets activity are also causes of thetissue hypoxia. Often, patients with Bureau-Barrire syndrome also have anemia,encountered by us in 5 patients.

Clinical aspectsMost of the times, the patients go late to the

doctor already with chronic painless plantar ulcerand pronounced periulcerous hyperkeratosis(fig. 1). Originally peak pressure plantar areasbecome hyperkeratotic ones. On one of them, atsome point, blistering occurs or a small painlessulcer that progresses to crateriform ulcer, ifneglected.

Clinical examination also reveals in thesepatients the purple appearance of the skin,hyperhidrosis (juicy leg), the widening andinfiltration of the toes (dactylomegalic big toe),the deformation and deflection of the fingers(fig.2), clavuses, nail dystrophy, possibly aninterdigital mycosis.

The deformation and the deviation of thefingers, the metatarso phalangeal subluxationstogether with the foot shortening lead to staticposition troubles and in turn they aggravate theBureau-Barrire syndrome symptoms. Thecareful examination of the feet can show in somepatients a false proximal claw, which issecondary to the severe process of metatarsophalangeal osteolysis. In the real proxi-mal claw we have the hyperextension of the

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Aa cum am subliniat la etiopatogeniasindromului Bureau-Barrire, aceti bolnavi decele mai multe ori consum cronic alcool. Deaceea un examen dermatologic minuios poateevidenia multiplele semne cutaneo-mucoasentlnite n alcoolism: facies rozat, eritem palmar,hipersudaie, telangiectazii, echimoze, con-junctive subicterice, arcul senil cornean,deformarea firului de pr (fir de pr ntirbuon) etc.

De asemenea, alcoolul poate induce urm-toarele afeciuni: eritemul pelagroid, porfiriacutanat tardiv, lipomatoza Launois Bensaude, contractura Dupuytren. Alte derma-toze sunt agravate de alcool: psoriazis, dermatitaseboreic, rozaceea, eczema numular,carcinoamele spinocelulare orale, infeciilecutanate.

Un bolnav din lotul nostru n momentulspitalizrii a prezentat i eritem pelagroid, iaraltul avea tabloul clinic complet al lipomatozeiLaunois Bensaude. n ambele comorbiditi seia n consideraie rolul consumului cronic dealcool [6].

Lipomatoza Launois-Bensaude este sinonimcu Adenolipomatoza cervical, Boala luiMadelung, Lipomatoza simetric benign,Lipomatoza cervical, Lipomul inelar al gtului.

Lipomatoza Launois-Bensaude a fostmenionat pentru prima dat de Brodie n 1846,apoi de Madelung n 1888, pentru ca n 1898

metatarso phalangeal articulation and the flexionof the proximal inter- phalangeal articulation [5].

As we have already underlined in theetiopathogeny of the Bureau-Barrire syndromethese patients are chronic consumers of alcohol.Thats why a thorough dermatologic examinationcan show multiple cutaneo-mucous signs met inalcoholism: pink facies, palmar erythema, hyper-sudation, telangiectasia, ecchymosis, subictericsclera, the cornean senile arch, the deformation ofthe hair ( corkscrew like hair) etc.

Alcohol can also induce the followingdiseases: pelagroid erythema, late cutaneousporphyria, Launois Bensaude lipomatosis,Dupuytren contracture. Some other dermatosisare aggravated by alcohol: psoriasis, seborrheicdermatosis, rosacea, nummular eczema, oralspinocellular carcinomas , cutaneous infections.

One patient of our group, during hishospitalisation, presented also pelagroiderythema and another one had the full clinicpicture of the Launois Bensaude lipomatosis. Inboth the two comorbidities they are taken intoconsideration the role of the chronic alcoholconsumption [6].

The Launois-Bensaude lipomatosis is syno-nymous to: the cervical adenolipomatosis,Madelung disease, the symetric benignlipomatosis, the cervical lipomatosis, the ringlipoma of the neck. The Launois-Bensaudelipomatosis was mentioned for the first time byBrodie in 1846, then by Madelung in 1888, and

Fig. 1 Sindrom Bureau-Barrire, ulcere crateriformeFig. 1. Bureau-Barrire syndrome, craterous ulcers

Fig. 2 Sindrom Bureau-Barrire, hiperhidroz (picioaresuculente), deformarea i devierea degetelorFig. 2. Bureau-Barrire syndrome, hyperhidrosis (juicy leg),fingers deformities and deviation

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Launois i Bensaude s raporteze o serie de 65cazuri.

Etiopatogenia este incomplet elucidat. Sediscut despre un deficit enzimatic local privindmetabolismul esutului adipos i de asemenea, seia n calcul un deficit al AMP-ului ciclic.

Se asociaz cu alcoolismul, artrita, guta,tumori endocrine, hipotiroidismul, diabetul,hipertrigli-ceridemia, sindromul mediastinal,tulburri hepatice (alcoolice), anemia microcitar.Boala apare n special la brbaii cu alcoolismcronic.

La bolnavul nostru, n vrst de 50 ani,consumator cronic de alcool, lipomatozaLaunois-Bensaude (fig. 3, 4) a precedat cu 11 anidebutul sindromului Bureau-Barrire (fig. 5).

then in 1898 Launois and Bensaude reported aseries of 65 cases.

The etiopathogeny is not completely clearedup. There are discussions about a local enzymedeficiency concerning the adipose tissue meta-bolism and it is also taken into consideration anAMP cyclic deficiency .

It is associated with the alcoholism, arthritis,gout, endocrine tumours, hypotiroidism, dia-betes, hypertrigliceridemia, mediastinal syn-drome, hepatic troubles (alcoholic ones),microcitary anaemia. The disease appears mostlyin men with chronic alcoholism.

Our patient, aged 50 a chronic alcoholconsumer suffered from Launois-Bensaude lipo-matosis (fig. 3, 4) 11 years before the beginning ofthe Bureau-Barrire syndrome (fig. 5).

Fig. 3. Lipomatoza Launois-BensaudeFig. 3. Launois-Bensaude lipomatosis

Fig. 4. Launois-Bensaude lipomatosisFig. 4. Lipomatoza Launois-Bensaude

Fig. 5. Sindrom Bureau-Barrire la bolnavul cu lipomatozLaunois-BensaudeFig. 5. Patient with Launois-Bensaude lipomatosis andBureau-Barrire syndrome

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Tabloul clinic const n mase lipomatoasevoluminoase, dispuse simetric pe prile latero-cervicale, sub brbie, ceaf (ceafa de bizon),ulterior i la rdcina membrelor superioare saun zonele pectorale.

La bolnavii cu lipomatoz Launois-Bensaudes-au raportat leziuni vertebrale i neurologice:mielopatie cervical, compresiuni radiculare,degenerescen de tip maladie Charcot,neuropatie senzitiv [7].

n ceea ce privete evoluia lipomatozeiLaunois-Bensaude, masele lipomatoase cresc lentn dimensiuni, produc deformri inestetice careafecteaz calitatea vieii. Pot aprea tulburrifuncionale de compresie laringian [8], [9],uneori disfagie [10]. Degenerescena malign(liposarcom) este rarisim.

Tratamentul lipomatozei Launois-Bensaudepresupune ntreruperea consumului de alcool.Ct privete masele lipomatoase, s-au obinutunele rezultate prin liposucie. Rezultate multmai bune au fost obinute prin abordarechirurgical [11], [12]. Bolnavii trebuie supra-vegheai pentru depistarea eventualelor com-plicaii.

Revenind asupra principalei manifestridermatologice din sindromul Bureau-Barrire,anume ulcerul cronic plantar, acesta este denumitde clinicieni mal perforant plantar, termen lansatde Nelaton n 1852. Subliniem faptul c, alturide sindromul Bureau-Barrire, exist numeroaseafeciuni care se pot exprima clinic prin malperforant plantar: piciorul diabetic; afeciuni neurologice:

stri disrafice (mielodisplazia cu spinabifid lombar);

siringomielia; traumatisme medulare sau ale nervilor

spinali; boli degenerative ale sistemului nervos

(scleroza n plci, boala Charcot-MarieThot, boala Friedrich, scleroza lateralamiotrofic etc.);

compresii medulare sau radiculare; polinevrite (saturnin, arsenical etc.); acropatia ulcero-mutilant forma

familial; tabes;

The clinic picture shows lipomatous massesof great volume symmetrically positioned on thelatero cervical parts under the chin, nape (bisonnape), then at the roots of the superiormembers or in the pectoral area.

At the patiens with Launois-Bensaude lipo-matosis there were reported vertebral and neuro-logical lesions: cervical mielopathy, radicularcompressions, degenerescence of the type ofthe Charcot disease, sensitive neuropathy [7].

While speaking about the evolution of theLaunois-Bensaude lipomatosis, the dimensionsof the lipomatous masses are slowly growing,they produce non aesthetic deformations that canaffect the life quality. They may appear functionaltroubles as the larinx compression [8], [9],sometimes disphagia [10]. Malign degene-rescence (liposarcoma) is very rare.

The treatment of the Launois-Bensaudelipomatosis supposes to cut the alcoholconsumption. While speaking about thelipomatosic masses there have been obtainedsome results by liposucction. Better results wereobtained by surgical procedures [11], [12]. Thepatients must be observed in order to trace outthe possible complications.

Speaking about the main dermatologicmanifestation of the Bureau-Barrire syndrome,namely the plantar chronic ulcer, this has beencalled by the specialists perforating plantar mal,name proposed by Nelaton in 1852. We underlinethe fact that besides the Bureau-Barriresyndrome there are several diseases that couldbe clinically expressed by perforating plantarmal: the diabetic leg; neurologic diseases:

disraphic conditions (mielodisplasiawith lombar spina bifida);

syringomyelia; medular or spinal nerves trauma; degenerative diseases of the nervous

system (cerebro spinal sclerosis ,Charcot-Marie Thot disease, Friedrichdisease, lateral amiotrophic sclerosis,etc.);

medular or radicular compressions; polyneuritis (saturnin one, arsenic one

etc.); familial ulcero-mutilating acropathy;

tabes;

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lepra; amiloza ereditar cu neuropatie (tipul I sau

portughez); radiodermita cronic plantar ulcerat; arteriopatii cronice periferice; tratamente neadecvate (cauterizri, apli-

caii de azot lichid etc.) pentru uneleafeciuni cu localizare plantar.

Mal-ul perforant plantar din sindromulBureau-Barrire trebuie difereniat n primulrnd de piciorul diabetic, care reprezint unadintre cele mai importante complicaii alediabetului zaharat. Leziunile din piciorul diabeticintereseaz concomitent pielea, esutul sub-cutanat, nervii, vasele i esutul osos [13].

Diagnosticul de picior diabetic cuprinde celpuin trei din urmtoarele leziuni:

mal perforant plantar - apare la 15-25% dinpacienii cu diabet zaharat. Debuteaz cuhiperkeratoz, care ulcereaz central i nuare tendin la vindecare spontan.Afecteaz zonele de presiune maxim:halucele, la nivelul articulaiilor metatarso-falangiene I i II;

neuropatia diabetic sindrom polinevritic,pseudosiringomielic sau pseudotabetic;

micro i /sau macroangiopatia diabetic; osteoartropatia diabetic picior scurtat i

lit. Radiologic se observ osteoporoz,osteoliz, ngustarea corticalei, scurtareafalangelor, fracturi spontane;

Una dintre complicaiile severe ale diabetuluizaharat este gangrena diabetic, urmat frecventde amputaii.

Tulburri neurologice

Acestea sunt consecina n primul rnd alconsumului cronic de alcool. Efectele etanoluluipredomin la nivelul sistemului nervos periferic, unde afectarea este frecvent dubl: toxic nprincipal i carenial n mod secundar.

Aciunea etanolului determin o axonopatiedistal care este element patogenic esenial nsindromul Bureau-Barrire. Degenereaz cape-tele distale ale axonilor, cu evoluie proximalspre corpul neural.

Atingerea carenial este cauzat de deficitulprotidic, vitaminic (grupul B, vitamina E) ienzimatic (prin disfuncii hepatice).

leprosy; hereditary amylosis with neuropathy (type

I or portugese); chronic plantar ulcerated radiodermitis; peripheric chronic arteriopathies; not adequate treatments (cauteriza-

tions, liquid nitrogen aplications, etc.) forsome diseases with plantar localization.

The perforating plantar mal in the Bureau-Barrire syndrome firstly must be differenciatedfrom the diabetic leg, which represents one of themost important complications of the diabetesmellitus. The lesions in the diabetic leg concern inthe same time the skin , the sub cutaneous tissue,the nerves, the vessels and the bone tissue [13].

The diabetic leg diagnosis has at least three ofthe following lesions:

The perforating plantar mal - it appears in 15-25% of the patients with diabetes mellitus.It begins with a hyperkeratosis, whichulcers in the central part and has not thetendency to heal spontaneously. It affectsthe zones of maximum pression: thehallux, in the metatarso-phalangealarticulations I and II;

The diabetic neuropathy the polyneuriticsyndrome, pseudosyringomyelic orpseudotabetic;

The micro and /or diabetic macroangiopathy; The diabetic osteoartropathy shortened and

widened leg. By radiological means it isobserved osteoporosis, osteolisis, thenarrowing of the cortical, the phalangsshortening, spontaneous fractures;

One of the severe complications of thediabetes mellitus is the diabetic gangrenefrequently followed by amputations.

Neurologic disordersThese are in the first place, the consequence

of the chronic alcohol consumption. Theconsequences of the ethanol are dominant at thelevel of the peripheric nervous system, where theaffectation is frequently double: mainly a toxicone and secondly one creating deficits.

The action of ethanol causes a distalaxonopathy, which is a crucial pathogenicelement in the Bureau-Barrire syndrome. Itdegenerates the distal ends of the axons, with aproximal evolution towards the neural body.

Reaching of the deficiency gap is caused byprotidic deficiency, vitamin deficiency (B group,

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Etilismul cronic este implicat att n etiologiapolineuropatiei cu predominana afectrii axo-nale, ct i a polineuropatiei cu predominanademielinizrii. Totui el este cauza major apolineuropatiei toxice senzitive axonale, ntlnitn sindromul Bureau-Barrire.

Polineuropatia cu predominan axonal areurmtoarele caracteristici:

sunt prezente tulburri neurologice de tipsiringomielic;

reflexele sunt mult timp conservate,exceptnd reflexul ahilian care poate fidiminuat sau abolit;

tulburrile simpatice sunt mai frecventedatorit atingerii fibrelor mici ne-mielinizate;

osteoartropatia predomin la antepicior icru tarsul;

examenele electrofiziologice evideniazconservarea relativ a vitezei conduceriinervoase i alterarea predominant aamplitudinii rspunsului nervului lastimulare;

anatomic, atingerea predomin la nivelulfibrelor amielinice C, vectoare ale cilorsimpatice i termoanalgezice.

Polineuropatia cu predominan demie-linizant se caracterizeaz prin:

hipoestezie sau anestezie plus atingerenotabil a sensibilitii profunde;

reflexele sunt afectate global; osteoartropatie frecvent la nivelul

tarsului; examenele electrofiziologice evideniaz

diminuarea predominant a vitezei deconducere i reducerea mai puin impor-tant a amplitudinii potenialelor;

anatomic predomin fenomenul dedemielinizare.

Sintetiznd, la bolnavul cu sindromulBureau-Barrire, examenul neurologic evi-deniaz dispariia sensibilitii termice idureroase, ncepnd cu extremitatea distal (noset) i urcnd apoi spre gamb (n ciorap),cu pstrarea sensibilitii tactile (disociaie termo-algezic de tip siringomielic). Reflexul ahiliandispare progresiv. Tulburrile de sensibilitate,iniial asimetrice, ating dup mai multe lunideopotriv ambele membre inferioare.

vitamin E) an enzymatic deficiency (in hepaticdysfunctions).

Chronic ethilism (alcoholism) is involvedboth in the etiology of polyneuropathy withpredominant axonal damage and in poly-neuropathy with predominant demyelization.However, it is considered the major cause ofaxonal toxic sensitive polyneuropathy encoun-tered in the Bureau-Barrire syndrome.

Features of polyneuropathy with axonalpredominance:

the presence of syringomyelic neurologicaldisorders

reflexes are conserved for a long period,except for the achilian reflex, which can bediminished or abolished;

sympathic disorders are more commonbecause of the interaction between smalldemyelized fibers;

ostheoartropathy is more common inforeleg and spares the tarsus;

electrophysiological tests highlights therelative conservation of speed in neuronaltransmissions and it alters predominantlythe response of the nerve when stimulated;

anatomically, the interference of amielinicC fibers, vectors for the sympathic tractand thermo analgesis.

Predominant demyelization neuropathy ischaracterized by:

hypoesthesia or anesthesia and notablechange on profound sensitivity;

global modification of reflexes; frequent tarsian ostheoartropathy; electrophysiological examinations high-

light the predominant diminish ofconductive speed and less importantreduction for the amplitude of thepotentials;

demyelization process is anatomicallypredominant.

All in all, at the patient suffering from theBureau-Barrire syndrome, the neurologicalexamination highlights the disappearance ofthermic and pain sensitivity, starting with thedistal extremity and going up along the leg butconserving the tactile sensitivity (a syringo-myelic thermoalgesic dissociation). The achilianreflex can progressively disappear. Initialasymmetric sensitivity disorders can affect bothinferior members after several months.

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Leziuni osoase

Radiografia picioarelor evideniaz, nfuncie de vechimea bolii, osteoporoz, osteoliz(fig. 6) i resorbia la nivelul metatarsienelor ifalangelor. Apar geode, distrugerea falangelor,fracturi parcelare, subierea metatarsienelor(aspect de acadea pe jumtate supt), sub-luxaii metatarso-falangiene. n fig. 7 sunt evi-deniate leziunile osoase severe prezente la unuldin bolnavii studiai.

Subliniem faptul c leziunile osoase nu suntspecifice sindromului Bureau-Barrire. Aspecteasemntoare pot fi ntlnite n oricare dintresindroamele acroosteolitice. Sindroamele acro-osteolitice sunt afeciuni care au n comunfenomenul de liz a oaselor situate la extre-mitatea membrelor, la care se adaug o serie desemne specifice pentru fiecare afeciune. Acestgrup cuprinde:

sindromul Bureau-Barrire; acropatia ulcero-mutilant forma familial; lepra; tabes; diabetul zaharat cu piciorul diabetic; algodistrofia Sudeck-Leriche; sclerodermia sistemic; sindromul Raynaud; afeciuni neurologice (spina bifida, siringo-

mielia, traumatisme ale nervilor periferici); boli endocrine hiperparatiroidism;

Bone injury

Leg radiography highlights, depending onthe duration of the disease, osteoporosis (fig. 6)and resorption at the level of metatarsals andphalanges. There can appear geodes, destructionof the phalanges, parcelar fractures, thinning ofthe metatarsal bones, phalangeal-metatarsalsubluxations. In fig. 7, severe bone injuries arehighlighted on one of the patients.

We emphasize that bone injuries are notspecific for the Bureau-Barrire syndrome.Similar disorders can be encountered in any ofthe achro- osteolytic syndromes. Achro-osteolytic syndromes are affections that have acommon phenomenon of lysis of the bones of theextremity of the member, with a series of specificsigns for each disorder. It includes:

Bureau-Barrire syndrome; Familial ulcero- mutilating acropathy; Leprosy; Tabes; Diabetes mellitus with diabetic foot; Sudeck-Leriche algodystrophy; Systemic scleroderma; Raynaud syndrome; Neurological affections (spina bifida,

syringomyelia, trauma of the perifericnerves);

Endocrine diseases- hiperparathyroidism;

Fig. 6. Sindrom Bureau-Barrire, leziuni osoase (osteoliz ntreimea proximal a diafizei falangei proximale haluce stng)Fig. 6. Bureau-Barrire syndrome, bone lesions (osteolysis ofproximal phalangeal diaphysis of left hallux )

Fig. 7. Leziuni osoase severe n cadrul sindromuluiBureau-BarrireFig. 7. Bureau-Barrire syndrome: severe bone lesions

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boli profesionale (expunerea la clorura devinil, la siliciu, la vibraii etc.);

boli genetice (sindromul Ehlers-Danlos,boala Farber, pahidermoperiostoza, sin-dromul Winchester, sindromul Hurler).

Tratament

Conduita terapeutic presupune : suprimarea alcoolului i fumatului; alimentaie echilibrat, cu aport vitaminic; medicaie hepatotrop; pentru tulburrile circulatorii se admi-

nistreaz hydergin (regleaz circulaia lanivelul unturilor arteriolo-venoase),pentoxifilin;

tratamentul ulcerului plantar necesitclinostatism prelungit i cooperare deplinntre pacieni i personalul medical. Tre-buie stpnit suprainfecia cu anti-bioterapie general. Se nltur hiper-keratoza periulceroas, iar pe ulcer se voraplica epitelizante. Factorii de cretere suntbenefici [14];

uneori este nevoie de intervenii chirur-gicale (nlturarea sechestrelor osoase,amputaii de necesitate). Dezarterializarea,prin ligatura arterei pedioase, poate creterata de vindecarea a ulcerelor;

bolnavul trebuie s evite frigul, umezeala,ortostatismul prelungit. nclmintea tre-buie s fie comod, flexibil i clduroas(n anotimpurile reci). Pacientul trebuie sse obinuiasc cu autocontrolul sistematical picioarelor.

La nou bolnavi din lotul studiat am obinutreducerea dimensiunii ulcerelor plantare. Dinnefericire la doi pacieni, datorit leziunilorosoase grave i suprainfeciei, s-a ajuns laamputaii (un caz cu amputaie de haluce fig. 8;alt caz cu amputaie de degete la un picior fig. 9).

Concluzii

Tratamentul complex (dermatologic, neuro-logic, ortopedic) precoce i renunarea la con-sumul de alcool pot opri evoluia sindromuluiBureau-Barrire i preveni complicaiile osoase,care necesit uneori amputaii mutilante.

Professional diseases (exposure to vinylclorure, silicium);

Genetic diseases (Ehlers-Danlos syndrome,Farber disease, pachydermoperiostosis,Winchester syndrome, Hurler syndrome).

Treatment

Therapeutic behavior includes: giving up alcohol and smoking; balanced diet with vitamin consumption; hepatotropic medication; for circulatory disorders hydergin is

administrated (it adjusts the circulation atthe arterial-venous shunt level), pentoxi-fylline;

plantar ulcer treatment requests prolongedclinostatism and full cooperation betweenpatients and medical personnel. Superinfection must be suppresses by generalantibiotic therapy. The periulceros hyper-keratosis is removed and epithelizationfactors will be applied on the ulcer.Growing factors are benefic [14];

sometimes it requires surgical inter-ventions (removal of the bone attachment,necessity amputation). Dearterialization,with ligature of the pedios artery, canincrease the ulcer cure rate;

the patient must avoid cold, humidity,prolonged orthostatism. Shoes must becomfortable, flexible and warm (in the coldseason). Patients must get used to syste-matic self-control of his legs.

Nine patients out of those included in thesurvey have presented a drawback of the plantarulcers. Unfortunately, in the case of two of thepatients, because of the severe bone injuries andinfection, it all came down to amputation (ahallux amputation fig. 8; another patient withtoe fingers amputation fig. 9).

Conclusions

Precocious complex treatment (dermato-logical, neurological, orthopedic) and giving updrinking can stop the evolution of the Bureau-Barrire syndrome and can prevent the bonedisorders that sometimes require mutilantamputations.

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Sindromul Bureau-Barrire este considerat oafeciune rar, ns procentul mare al consu-matorilor cronici de alcool impune realizareaunor studii pentru cunoaterea incidenei reale.

The Bureau-Barrire syndrome is considereda rare disorder, but the great number of chronicconsumers of alcohol request for researchesconcerning the real incidence.

Fig. 8 Amputaie haluce drept dup complicaia sindro-mului Bureau-BarrireFig. 8. Right hallux amputation as a complication ofBureau-Barrire syndrome

Fig. 9. Sindrom Burreau-Barrire, ulcere crateriforme, lipsdegete prin amputaie de necesitateFig. 9. Bureau-Barrire syndrome: craterous ulcers, absenceof fingers by necessity amputation

Bibliografie/Bibliography

1. E. Thoma , T. Ruzicka , G. Donhauser, T. Albrecht, O. Braun-Falco Clinical aspects and therapy of Bureau Barrire syndrome. Observations of 17 cases with review of the literature, Der Hautarzt 44(1)/1993: 5-13

2. V. Ptracu Sindromul Bureau-Barrire, Medical UPDATE, 1(28)/2001: 36-39; 423. Gh.Bucur, Dana Angela Opri Boli dermatovenerice, enciclopedie, ed. a II-a, Editura Medical Naional,

Bucureti 2002: 47-48; 715-716;4. J. Dissemond, J. Knab, M. Goos Bureau-Barrire-Syndrom der Hand: Ein Fallbericht ber eine ungewhnliche

Lokalisation, Der Hautarzt, 55(4)/2014:371-3755. F. Bonnel, F. Canovas, L. Olie et. al. Les pathologies du pied, Impact Mdecin 498/23 Juin 2000: 1-166. K. Preisz, S. Krpati. A. Horvth Launois-Bensaude syndrome and Bureau-Barrire syndrome in a psoriatic

patient: successful treatment with carbamazepine, Eur J Dermatol, 12(3)/2002: 267-2697. J. Kanitakis Autres tumeurs cutanes, J-H Saurat, J-M Lachapelle, D. Lipsker, L. Thomas Dermatologie et

infections sexuellement transmissibles, 5e ditions, edit. Masson, Paris 2009:6868. R. Ostrowski and A. D. Rubin Benign symmetric lipomatosis involving the supraglottic larynx: a rare cause of

dysphonia, Otolaryngology, vol. 145/2011: 3603619. D. Milisavljevic, M. Zivic, Z. Radovanovi, P. Stankovic Severe dyspnea as atypical presenting symptom of

Madelung's disease, Hippokratia, vol. 14, no. 2/2010:13313510. N. Catenacci, F. Moschella, G. Cascini A case of Launois- Bensaude lipomatosis associated with dysphagia,

Minerva chirurgica 39(5)/1984: 341-34511. W. J. Zhang, H. Jiang, J. L. Zhang et al. Surgical treatment of multiple symmetric lipomatosis (Madelung's

disease): a single-center experience, Journal of Oral and Maxillofacial Surgery, vol. 69/2011:2448245112. D. Goglniceanu, Daniela Trandafir, Violeta Trandafir Lipomatoza simetric benign - sindromul Launois-

Bensaude sau boala Madelung, Jurnalul de Chirurgie, Iasi, 2005, Vol. 1, Nr. 2: 190-195

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13. Ariela Hafner, Eli Sprecher Ulcers, section seventeen (105), J. L. Bolognia, J.L. Jorizzo, J. V. Schaffer, Dermatology,Third Edition, Elsevier, 2012: 1740-1741

14. A. A. Ramelet Manifestations cutanes des alterations vasculaires et neurologiques des members infrieurs, J-HSaurat, J-M Lachapelle, D. Lipsker, L. Thomas Dermatologie et infections sexuellement transmissibles, 5editions, edit. Masson, Paris 2009:755-756

Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresa de coresponden: [email protected] address: [email protected]

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