forme severe de acnee ªi sindroame asociate acneei … · câteva complicaþii: carcinomul cu...

A. Severe acne variants

1. Acne conglobata (cystic acne). Acneconglobata is the most severe form of acne and isseen almost exclusively in males [1, 2]. Lesionsfirst occur at puberty and their severity increasesin time, reaching climax at the end of adolescence

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FORME SEVERE DE ACNEE ªI SINDROAME ASOCIATEACNEEI

SEVERE ACNE VARIANTS AND ACNE-ASSOCIATEDSYNDROMES

AURA VLÃDUÞI*

REFERATE GENERALEGENERAL REPORTS

Rezumat

Forme severe de acnee - Au fost luate în discuþie 8forme severe de acnee, ºi anume: 1. Acneea conglobatã(chisticã), 2. Acneea inversã, 3. Acneea cheloidianã a cefei,4. Hidradenita supurativã, 5. Pyoderma faciale, 6. Acneea(foliculita) cu germeni Gram-negativi, 7. Acneeafulminans, 8. Pyoderma gangrenosum-acne.

Sindroame asociate acneei - Acneea, una dintre celemai întâlnite afecþiuni ale pielii, este o componentã de bazãa mai multor boli sistemice sau sindroame: 1. SindromulCAH = hiperplazie adrenalã congenitalã-acnee, 2.Sindromul SAHA = alopecie androgenicã- seboree-acnee-hirsutism, 3. Sindromul PCO = ovarul polichistic-acnee, 4.Sindromul HAIR-AN = hiperandrogenism-insulinorezistenþã-akantozis nigricans-acnee, 5. Sindromul APERT= autozomal dominant-acnee-acrocefalosindactilie, 6.Sindromul SAPHO = sinovitã-acnee-pustulozã-hiper-ostozã-osteitã, 7. Sindromul PAPA = artritã piogenicã-pyoderma gangrenosum-acnee.

Cuvinte cheie: acnee, severã, fulminans, conglobatã,PG, sindroame, PCO, SAPHO, PAPA, APERT

DermatoVenerol. (Buc.), 57: 83-111

Summary

Severe acne variants – 8 severe acne variants will bediscussed in this section : 1. Acne conglobata, 2. Inverseacne, 3. Keloid acne of nape, 4. Hydradenitis suppurativa,5. Pyoderma faciale, 6. Gram-negative folliculitis acne, 7. Acne fulminans, 8. Pyoderma gangrenosum-acne.

Acne-associated syndromes - Acne, one of the mostcommon skin disorders, is also a cardinal component ofmany systemic diseases or syndromes: 1. CAH syndrome =congenital adrenal hyperplasia-acne, 2. SAHA syndrome =seborrhea-acne-hirsutism-androgenetic alopecia, 3. PCOsyndrome = polyycistic ovary-acne, 4. HAIR-ANsyndrome = hyperandrogenism-insulin resistance-acanthosis nigricans-acne, 5. APERT syndrome = auto-somal dominant-acne-acrocephalosyndactyly, 6. SAPHOsyndrome = synovitis-acne-pustulosis-hyperostosis-osteitis, 7. PAPA syndrome = pyogenic arthritis-pyodermagangrenosum-acne.

Key words: acne, sever, fulminans, conglobate, PG,syndromes, PCO, SAPHO, PAPA, APERT

A. Forme severe de acnee

1. Acneea conglobatã (chisticã) este cea maigravã formã de acnee, care afecteazã aproapeexclusiv sexul masculin (1, 2). Leziunile debu-teazã la pubertate, severitatea lor se accentueazãcu trecerea anilor, atinge apogeul spre sfârºitul

* Serviciul de Dermatologie - Ambulatoriul de Specialitate al Spitalul Clinic “C.F. Witting”, Bucureºti, România./DermatologyDepartment - Specialty Ambulatory of the Clinica Hospital “C.F. Witting”, Bucharest, Romania.

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adolescenþei ºi poate persista chiar ºi dupã vârstade 50 de ani. Nu are o evoluþie cu remisiunespontanã, vindecarea este urmatã de cicatricimari, neregulate, profund deprimate sauhipertrofice (cheloidiene). Caracteristici suntnodulii inflamatori, confluenþi, dureroºi, care setransformã în abcese profunde, multiple, chistemoi pline cu lichid hematic ºi mase pãstoase,purulente, fetide, legate între ele prin traiectesinuoase, care se deschid la suprafaþa pielii, prinfistule multiple (3); scurgerile purulente sauserosanguinolente pot persista indefinit. În jurulleziunilor se dezvoltã fibrozã. Nodulii coexistã înacelaºi timp cu papulo-pustule, chiste, come-doane multiple, cicatici. Cicatricile pot acoperipânã la 1/3 din suprafaþa cutanatã. Localizareacea mai frecventã este trunchiul, în special spateleºi mai puþin faþa, gâtul, ceafa, scalpul, rãdãcinamembrelor (4). Examenele paraclinice, inclusivcele endocrinologice, nu prezintã modificãri.Uniipacienþi prezintã ºi Hidradenitã supurativã,asociat (5). Deficenþele imune nu pot fi incri-minate ca factor etiologic (1, 6). Literatura descrieasocierea extrem de interesantã a acneei con-globate cu prezenþa genotipului xyy (7). Acestaeste caracterizat de: înãlþime de 1,80 m, retardmintal ºi comportament agresiv. Incidenþasindromului este de 1:1000 nou-nãscuþi ºi de 1:35printre cei instituþionalizaþi pentru delicvenþãjuvenilã. Unul din ºapte pacienþi cu sindrom xyyprezintã acnee inflamatorie severã.Tratamentulinclude o terapie combinatã agresivã, localã ºigeneralã, dar ºi un suport psihologic adecvat.Tratamentul de elecþie este Isotretinoin 1 mg/kg/zi, 4-6 luni (5).

2. Acneea inversã . Este o formã specialã deacnee conglobatã, care intereseazã cu predilecþiepliurile (interfesier, inghino-crural, axilar), mairar scalpul sau ceafa. Termenul de acnee in-versatã sugereazã tocmai topografia neobiºnuitãa acestor leziuni (8, 9, 10). ªi acneea inversãafecteazã sexul masculin. Ea poate apãreasingurã sau se poate asocia cu alte douã boli careau patogenezã ºi modificãri histopatologiceasemãnãtoare. În cadrul aºa-numitului sindromde obstrucþie folicularã, acesta cuprinde triada:acnee conglobatã (localizatã în special pe toracefrecvent posterior, fese etc.), hidrosadenitãsupurativã (axilarã, inghinalã, perigenitalã) ºi

and sometimes persisting even after the age of 50.It does not evolve towards spontaneousremission and healing is followed by formationof big, irregular, deeply depressed or hyper-trophic (keloid) scars. Acne conglobata ischaracterized by inflammatory, confluent, painfulnodules that turn into deep, multiple abscesses,soft, purulent, fetid cysts filled with hematicliquid and creamy mass and bound together bysinuous tracts that open at the surface of the skinthrough multiple fistules [3]; purulent or sero-sanguinolent drainages can persist indefinitely.Fibrosis develops around lesions. Nodulescoexist with papulopustules, cysts, multiplecomedones, scars. Scars may cover up to 1/3 ofthe cutaneous surface. Acne conglobata mainlyaffects the trunk, especially the back and lessoften the face, the neck, the nape, the scalp andlimbs roots [4]. Paraclinical examinations,endocrinological ones included, do not showmodifications. Hydradenitis suppurativa isassociated in some patients [5]. Immunedeficiencies can be incriminated as etiologicalfactor [1, 6]. Several studies describe the veryinteresing association of acne conglobata withgenotype xyy [7], characterized by 1.80 m height,mental retardness and aggressive behaviour.Syndrome incidence is of 1:1,000 newborns andof 1:35 in young people internalized for juveniledelinquency. One out of seven patients with xyysyndrome presents severe inflammatory acne.Treatment includes both agressive local andgeneral therapy and adequate psychologicalsupport. Main treatment consists inadministration of Isotretinoin 1 mg/kg/day for4-6 months [5].

2. Inverse acne. It is a special form of acneconglobata that mainly affects intergluteal,inguinal-crural, axial folds, more seldom thescalp or the nape. The term ”inverse” acne issuggestive for the unusual topgraphy of theselesions [8, 9, 10]. Inverse acne also prevails inmales. It may develop either solely or associatedwith two other conditions with similar patho-genesis and histopathological modifications. Theso-called follicular obstruction syndromecomprises the following triad: acne conglobata(mainly localised on the thorax, often on the back,but also on the buttocks, etc), hydradenitissuppurativa (axial, inguinal, perigenital) and

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perifoliculitã ºi abcese pe ceafã ºi scalp (cumanifestãri clinice ca în acneea cheloidianã acefei). Triada devine tetradã, dacã celor de maisus li se adaugã sinus pilonidal la nivelul saudeasupra pliului anal (4). Leziunile tronculare deacnee conglubatã sunt relativ discrete faþã deinflamaþia gravã intertriginoasã, cu leziuniconfluente ºi cicatrici proeminente. Evoluþia estecontinuã (ani sau decade), mai ales cã relaþia cuacneea nu este uºor de recunoscut ºi boala esteades diagnosticatã tardiv. Acneea inversã poateevolua cu creºterea importantã a VSH-ului,leucocitozã mare (sindrom leucemoid), hipo-sideremie ºi anemie, disproteinemie, infecþii cugermeni gram-negativi, amiloidozã. Pe leziuniinflamatorii cronice foarte rar apar epitelioanespinocelulare.Etiopatogeniei inverse nu esteclarã, dar se pare cã intervine un factor ereditar ºi o florã microbianã (strepto-stafilococicã)agresivã.

3. Acneea cheloidianã a cefei. Se localizeazãla ceafã, scalp, la nivelul interliniei pãroase ºiapare frecvent la sexul masculin (5). Clinic aparefoliculitã ºi perifoliculitã (papulo-pustule, noduli,rar abcese), care genereazã plãci, placardefibroase, cu aspect de cicatrici hipertrofice(pseudocheloidiene), dure, alopecice, pe supra-faþa cãrora apar comedoane (4) ºi grupuri de firede pãr cu acelaºi punct de emergenþã. Evoluþiaeste cronicã ºi cu tendinþã la extindere. Nu s-aevidenþiat un organism specific, procesuldeclanºator putând fi o pseudofoliculitã sau ofoliculitã bacterianã sau un alt factor necunoscut(5). Existã o predispoziþie individualã. Aparefrecvent la diabetici, obezi, persoane expuse latraumatisme repetate ale regiunii nucale.

4. Hidradenita supurativã. Este o afecþiunecomplexã, care apare la adult, asociindcomedoane, abcese care comunicã între ele princanale epiteliale (celulita disecantã), sinusurifistuloase cu localizãri neobiºnuite ºi profunde.Afecþiunea poate fi extrem de invalidantã,cicatricile hipertrofice de la nivelul axilelor potcãpãta aspect monstruos, imobilizând braþele, iarpuroiul care dreneazã din multiple orificii, are unmiros fetid, foarte dezagreabil (11, 12). Boalaprogreseazã lent, pe parcursul a ani de zile ºi nuare nicio tendinþã de vindecare spontanã.

perifolliculitis and abscesses on the nape andscalp (accompanied by manifestations such askeloid acne of nape). The triad turns into a tetradif to these is added the pilonidal sinus of the orabove the anal fold [4]. Acne conglobata trocularlesions are relatively discreet as comapred to thesevere intertriginous inflammation, withconfluent lesions and prominent scars. Theevolution is continuous (and takes years ordecades), all the more as the association withacne is not easily recognisable and the disease isoften diagnosed late. Inverse acne may evolveaccompanied by a significant increase of the ESR,high leucocytosis (leucemoid syndrome),hyposideremia and anemia, dysproteinimia,gram-negative germs infections, amyloidosis.Spinocellular epitheliomas only rarely occur onchronic inflammatory lesions. The etiopathogenyof inverse acne is not yet known, but it seems thata hereditary factor and an aggressive microbian(strepto-staphylococcic) flora are involved.

3. Keloid acne of nape. It is localised on thenape, scalp, at the level of the hair interline andoften occurs in males [5]. Clinically, therefrequently appear folliculitis and perifolliculitis(papulopustules, nodules and seldon abscesses),that generate plaques, fibrous plaquards that takethe form of tough, alopecic hypertrophic(pseudokeloid) scars on whose surface occurcomedones [4] and groups of hair with the sameemergence point. The evolution is chronic andwith spreading tendency. No specific organismhas been detected so far and the triggeringprocess responsible could be a pseudofolliculitis,a bacterian folliculitis or any other unknownfactor [5]. There exists a genetic predisposition.Keloid acne of nape often involves diabetic andobese patients and people exposed to repeatedtraumas of the nape area.

4. Hydradenitis suppurativa. It is a complexcondition of the adult age that associatescomedones, abscesses communicating throughepithelial channels (dessicant cellulitis), fistulasinus tracts with unusual and deep localisations.It may take extremely disabling forms, thehypertrophic scars in the pits of the arms canbecome monstruous in aspect, immobilizing thearms, and the pus that suppurates from multipleperforations has a fetid and very unpleasantsmell [11, 12]. The disease evolves slowly, for

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Suprainfecþiile sunt oricând posibile, agravândsituaþia bolii. Evoluþia este gravã ºi poate asociacâteva complicaþii: carcinomul cu celulescuamoase sau ulcerul Marjolin, meningitabacterianã (13, 14, 10). Din punct de vederefiziopatologic, afectarea glandelor apocrine esteprivitã ca un fenomen secundar. Aceleaºifenomene distructive majore au loc ºi în absenþaglandelor apocrine. Este o boalã cronicã a careipatogenezã este încã neînþeleasã. A fostconsideratã mult timp o afecþiune a glandelorapocrine, dar astãzi se ºtie cã acestea au foartepuþini receptori androgenici, deci nu pot ficonsiderate o þintã a hormonilor androgeni.Tratamentul este foarte dificil, mulþi autorirecomandând abordarea chirurgicalã timpurie aleziunilor, ca singurã alternativã viabilã, cuadministrarea eventualã de isotretinoin pre ºipostoperator (11, 12).

5. Pyoederma faciale. Este o afecþiune rarã, oaltã variantã de acnee (15, 16, 17), care apare deobicei la femei de 20-40 ani. Se caracterizeazã prinacnee facialã explozivã, purulentã, nodulo-chisticã, dezvoltatã pe fondul unei acnei uºoare.Prognosticul este bun; se vindecã cu mai puþinecicatrici decât ar fi de aºteptat. Se deosebeºte deacneea fulminans prin absenþa semnelorsistemice. Isotretinoin 1 mg/kg/zi timp de 4-6luni, asociat în primele 30 de zile cu corticoizisistemici 40 mg/zi.

6. Acneea (foliculita) cu germeni Gram-negativi. Apare la pacienþii, care au suferit deacnee vulgarã cu forme inflamatorii pentru lungiperioade de timp ºi au primit tratament cronic cuantibiotice orale, de obicei Tetraciclinã. Cauzaeste înlocuirea florei foliculare normale cubacterii gram-negative rezistente la terapiaantibioticã, antiacneicã obiºnuitã.Majoritateapacienþilor sunt de sex masculin, au între 18 ºi 30ani ºi prezintã o agravare neaºteptatã a acneeicare de altfel era bine controlatã de tratament (18,19, 20).Se apreciazã cã un procent de 2-5% dintrepacienþii care primesc tratament cu antibiotice petermen lung sunt afectaþi; clinic se constatãapariþia de pustule superficiale ºi noduli. Se potdescrie douã tipuri clinice de foliculitã cugermeni gram-negativi:

years, and does not heal spontaneously.Suprainfections can occur at any time,aggravating the condition. The evolution issevere and may involve several complications:squamous cell carcinoma or Markolin ulcer,bacterian menigitis [13, 14, 10]. Physio-pathologically, the involvement of the apocrineglands is regarded as a secondary effect. Thesame major destructive phenomena take place inthe absence of apocrine glands too. Hydradenitissuppurativa is a chronic condition of yetunknown pathogenesis. Is was for a long timeconsidered a disorder of the apocrine glands, butwe presently know that these glands have veryfew androgenic receptors and therefore cannot beseen as a target for the androgen hormones.Treatment is very complex and many authorsrecommend early surgical intervention on thelesions as the only viable option, possiblyaccompanied by pre- and post-surgicaladministration of isotretinoin [11, 12].

5. Pyoderma faciale. Pyoderma faciale is arare skin condition, another acne variant [15, 16,17] that primarily affects women of 20-40 years ofage. It causes severe outbreaks of inflamedpurrulent nodules and cysts on the face anddevelops on a pre-existing mild acne. Theprognosis is good and healing leaves surprisinglyfew scars behind. It differs from acne fulminansin that it does not display systemic signs.Treatment consists in the administration ofisotretinoin 1 mg/kg/day for 4-6 months,associated with systemic corticoids 40 mg/dayfor the first 30 days..

6. Gram-negative folliculitis acne. Thisinfection may occur as a complication in patientswith acne vulgaris and usually develops inpatients who have received systemic antibiotics(primarily tetracycline) for prolonged periods. Itis caused by the replacement of normal follicularflora with gram-negative bacteria resistant to theusual antiacneic, antibacterian therapy. Mostpatients are males, aged 18 to 30, who present asudden aggravation of acne otherwise wellcontrolled by treatment [18, 19, 20]. It is estimatedthat 2 to 5 per cent of the patients receiving long-term therapy with antibiotics are thus affected;clinically, it manifests as superficial nodules andcysts. There are two clinical types of gram-negative folliculites:

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Tipul 1 – prezintã pustule mici, zemuinde, înjurul gurii ºi al nasului, iar examenul bacterio-logic evidenþiazã prezenþa Enterobacter aero-genes, Klebsiella pneumoniae sau Escherichiacoli;

Tipul 2 – prezintã noduli profunzi, iarculturile evidenþiazã un agent micobian mult maivirulent, Proteus mirabilis.

7. Acneea fulminans. AF cunoscutã ºi caacnee malignã este o afecþiune rarã, foarte severã,o acneeulcerativã cu debut acut ºi simptomesistemice, de aceea de multe ori pacientulapeleazã iniþial la un internist, ºi nu la undermatolg. Apare frecvent la bãieþii caucazieni,cu vârste cuprinse între 13-20 ani, dar nu suntexcluse persoanele de sex feminin (21, 22). Boalaare o frecvenþã mult mai scãzutã în rândulpopoarelor din Asia de Est, precum japonezii. AFa fost descrisã iniþial în 1959 , ca fiind un tip deAC cu septicemie, de Burns ºi Colville (23). În1971, Kelly ºi Burns (24) introduc exprimarea„AC acutã, febrilã ,ulcerativã cu poliartralgii”. În1975, Plewig ºi Kligman (25) disociazã aceastãafecþiune de AC ºi inventeazã termenul AF, carese referã la debutul brusc ºi severitatea afecþiunii.În 1977, Goldschmidt et al. (26) au definit AF cafiind o tulburare rarã în rândul adolescenþilor desex masculin, caracterizatã prin apariþia bruscã aunor noduli inflamatorii, hemoragici, cu crustãpe spate (28), piept ºi faþã asociatã cu simptomesistemice variate (27) (febrã,frisoane,slãbiciune,dureri musculo-scheletale), cu debut brusc. Se potasocia în plus eritem nodos, osteolizã asepticã,hepatosplenomegalie sau miozitã (29, 30). Cuaproximativ un an înainte de debutul simptomeloracute, pacienþii tipici o formã uºoarã a acneeivulgare. În ultimii ani incidenþa AF pare sã aibã otendinþã descendentã, probabil datoritã trata-mentului mai timpuriu ºi mai bun al acneei (22).

Etiologia AF rãmâne necunoscutã, dar de-alungul timpului au fost avansate mai multe teoriiºi anume:

- AF este legatã de o reacþie exploziv-imunologicã de hipersensibilitate de tip 3sau 4 la antigenii Proprinilbacterium acnes(32). Contactul puternic al sistemuluiimunitar cu antigenii P. Acnes sausubstanþele chemotactice rezultate dindegradarea acestuia poate apãrea ca

Type 1 – small, suppurative pustules developaround the mouth and the nose; bacteriologicalexamination shows the presence of Enterobacteraerogenes, Klebsiella pneumoniae or Escherichiacoli;

Type 2 – deep nodules; bacteriologicalexamination shows the presence of a much morevirulent microbian agents, Proteus mirabilis

7. Acne fulminans. AF, also known as malignacne or ulcerative acne, is a rare and very severeskin condition. It begins with acute systemicsymptoms and patients often initially refer togeneral physicians, not to dermatologists. Itprevails in Caucasian boys aged 13 to 20,although females are not spared either [21, 22].This condition is much less frequent in East-Asian populations, such as the Japanese. It wasfirst described in 1959 by Burns and Colville asacne conglobata with septicemia [23]. In 1971,Kelly and Burns described it as ”acute febrileulcerative conglobate acne with polyarthralgia”[24]. In 1975, Plewig and Kligman [25]disassociated it from AC and coined the term AF,with reference to its sudden and severebeginning. In 1977, Glodschmidt et al. [26]defined AF as a rare condition occurring in maleteenagers, characterized by sudden appearanceof hemorrhagic, inflammatory nodules withcrusts on the back [28], chest and face, associatedwith various systemic symptoms [27], such asfever, quivers, musculoskeletal pains, and withsudden eruption. AF can also associate withnodous erythema, aseptic osteolysis,hepatosplenomegalia or myositis [29, 30].Approximately one year prior to AF beginning,patients typically develop mild acne vulgaris. Inrecent years, AF incidence seems to havediminshed, probably thanks to early andimproved acne therapy [22].

AF etiology remains unclear, althoughseveral theories have been advanced throughoutthe years:

- AF is triggered by an explosive-immuno-logical hypersensitive reaction type 3 or 4to Proprinilbacterium acnes antigenes [32].A strong contact of the immunitary systemwith P. Acnes antigens or the chemotacticsubstances resulting from its degradationcan develop as a result of Isotretinoin-

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urmare a fragilitãþii canalului pilosebaceuindusã de Isotretinoin, de aceeaIsotretinoinul poate precipita AF (33, 34),dar paradoxal acesta este utlizat cu succesîn tratamenul AF, dar numai în combinaþiecu steroizi sistemici, sau alþi agenþiantiinflamtori, ºi obligatoriu precedat deaceºtia.

- O altã teorie afirmã cã AF poate fi oafecþiune autoimunã complexã. S-a afirmatcã o reacþie Arthus are loc atunci când AFse manifestã prin eritem nodos, dar nu aufost detectate complexe imune circulante(29, 35). Un factor în favorea etiologieiautoimune a AF este rãspunsul rapid alpacientului la steroizii sistemici, creºtereagama globulinelor ºi scãderea comple-mentului C3 la unii pacienþi. Complexeimune se întâlnesc ºi la pacienþii cu durerimusculo-scheletale. Deºi patogeneza AF rãmâne necunoscutã,asocierea cu sindromul SAPHO sugereazãcã citokinemia sistemicã inflamatorie,incluzând factorul de necrozã tumoralãalfa (TNF alfa), poate fi responsabil. Acestlucru este întãrit de constatarea cã agentulanti-TNF alfa, Infliximab, are efectebenefice asupra AF (36).

- Factorii genetic ºi ereditar pot juca un rolimportant în cazul anumitor pacienþi. AF afost raportatã la gemenii monozigoþi(37,38). În fiecare caz, vârsta prezentãrii ºiseveritatea afecþiunii au fost similare. Uncaracter ereditar a fost sugerat la o vârstãidenticã a prezentãrii, o imagine clinicãsimilarã ºi fenotipurile antigenului leuco-citar uman (HLA) identic la doi fraþi (39).Deºi þesutul nu indicã faptul cã aceºtipacienþi ar avea HLA-B27, în anumitecazuri poate exista o predispoziþiegeneticã, probabil asociatã cu genaHLAcw6.

- Nivelurile sanguine ridicate de testosteronpot juca un rol important în patogeneza AF(40,41). S-a constatat cã unii pacienþi careconsumaserã timp de 4 sãptãmâni, dozemari de testosteron ºi steroizi anabolizanþi,în vederea creºterii masei musculare (42) ,au dezvoltat AF ca efect secundar alautoadministrãrii. În ciuda ingestiei de

induced fragility of the pilosebaceouschannel. This is why Isotretinoin canaccelerate AF evolution [33, 34], although,on the other hand, it is successfully used inAF treatment, but only in combinationwith systemic steroids or other antiinflam-matory agents, and only preceded bythem.

- Another theory sustains that AF is acomplex autoimmune condition. AnArthus reaction may take place when AFmanifests as nodous erythema, althoughno circulating immune complexes havebeen detected [29, 35]. Factors in favour ofAF autoimmune etiology are the patient’srapid response to systemic steroids, as wellas the increase in gamma globulins anddecrease in C3 complement in somepatients. Immune complexes also developin patients with musculoskeletal pains. Although AF pathogenesis remainsunknown, its association with SAPHOsyndrome suggests that the inflammatorysystemic cytokinesis, including the tumornecrosis factor (TNF alpha), may beinvolved. This hypothesis is sustained bythe fact that the anti-TNF alpha agent,Infliximab, has beneficial effects in AF [36].

- Genetic and hereditary factors may play asignificant role in some patients. AF hasbeen reported in monozygotic twins [37,38]. In ecah case, the age the patientreferred to the dermatologist and theseverity of the condition were similar. Thehereditary factor has also been consideredresponsible in two brothers who presentedat the same age with identical humanleuokocyte antigen phenotypes (HLA)[30]. Although the tissue does not indicatethat these patients have HLA-B27, agenetic predisposition, probably asso-ciated with the HLAcw6 gene, may beinvolved.

- High testosterone levels in blood may alsoplay an important part in AG pathogenesis[40, 41]. It has been observed that somepatients who took high doses oftestosterone and anabolizing steroids forfour weeks in order to increase theirmuscular mass [42], have developed AF asa secondary effect of autoadministration.

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testosteron, nivelul acestuia s-a plasat înlimite normale. În mod fiziologic nivelultestosteronului creºte la pubertate ºi astaexplicã de ce aceastã boalã îi afecteazã înprimul rând pe adolescenþii de sexmasculin, a cãror seboree se intensificã. ªidozele mari de steroizi antrogeni sauanabolizanþi cresc secreþia de sebum încazul persoanelor de sex masculin trecutede pubertate. Crescând secreþia de sebum,creºte ºi densitatea bacteriei P. Acnes.

- Factorii infecþioºi au fost consideraþi cafiind foarte importanþi în acneeafulminans. O asociere a unei infecþii viralecu AF a fost sugeratã la debutul simpto-melor clinice la douã sãptãpmâni dupãîmbolnãvirea de pojar, ceea ce înseamnã cãpojarul poate declanºa o eliberare tranzi-torie de citokine inflamatorii, rezultândpersoane predispuse la AF (43).

Din punct de vedere clinic s-a observat cã,înainte de debutul brusc al bolii, cele mai multepersoane prezintã forme uºoare sau moderate deacnee. AF este declanºatã de obicei de trata-mentul cu Tetraciclinã sau Isotetrinoin (22). Este oafecþiune unicã. Caracteristicile principale ale AFsunt: debut brusc, acnee severã ºi adeseaulcerativã, febrã ºi poliartritã, lipsa rãspunsuluila tratamentul antibacterian ºi rãspuns bun la celpe bazã de steroizi administraþi oral 4-6sãptãmâni, cu adãugare de Isotretinoin oral (44).La debut, AF seamãnã cu AC, prezentând mulþinoduli inflamatori, foarte dureroºi, ulcerativi,acoperiþi de cruste hemoragice, distribuiþi înmare parte în partea superioarã a toracelui, spateºi umeri (45). Aceºtia sunt atât de numeroºi încâtpacientul nu poate sta întins pe spate, leziuniledegenereazã, devin rapid supurative, transfor-mându-se în ulceraþii pline cu resturi gelatinoase,necrotice. Comedoanele închise ºi deschise suntrare ºi mici. Spre deosebire de acneea vulgarã,comedoanele poliporoase sunt absente. Spredeosebire de AC , la pacienþii cu AF se remarcã omultitudine de reacþii sistemice, prezente lamajoritatea pacienþilor, ºi anume: oboseala,indispoziþia, artralgii (uneori apare umflareaarticulaþiilor mari ca de exemplu articulaþiasacroiliacã, genunchi etc ), mialgii, febrã, anemie,VSH crescut. Factorul reumatoid ºi anticorpii

In spite of testosterone ingestion, its levelwas within normal limits. Physiologically,the level of testosterone rises inadolescence, and hence this conditionmainly affects male teenagers, whoseseborrhea increases at this age. Highdosese of androgen or anabolizing steroidsalso increase sebum secretion in maturemale patients. Since sebum secretionincreases, P. Acnes bacteria densityincreases as well.

- Infectious factors are considered as verysignificant in acne fulminans. Theassociation of one viral infection with AFhas been suggested as triggering clinicalsymptoms two weeks after measlesdeveloped in one patient. This means thatmeasles can temporarily dischargeinflammatory cytokines in patientspredisposed to AF [43].

Clinical examinations have shown that priorto the sudden occurrence of AF, most patientspresented mild or moderate acne variants. AF isusually triggered by treatment with Tetracyclineor Isotretinoin [22]. It is a unique condition. Itsmain characteristics are: sudden beginning,severe, often ulcerative acne, fever andpolyarthritis, lack of response to antibacteriantreatment and good response to therapy withsteroids administered orally for 4-6 weeks,associated with oral administration of Iso-tretinoin [44]. In the beginning, AF resembles AC,with numerous inflammatory, very painful,ulcerative nodules covered by hemorrhagiccrusts, mainly spread on the upper parts of thethorax, back and shoulders [45]. They are in sucha great number that the patient cannot lie onhis/her back and lesions degenerate, becomingsuppurative in no time and turning intoulcerations filled with gelatinous, necroticremains. Open and shut comedones are rare andsmall. As opposed to acne vulgaris, polyporouscomedones are absent. Unlike AC, in most AFpatients a multitude of systemic reactions can beobserved, including fatigue, indisposition,arthalgias (sometimes, big articulations, such assacroiliac joint, the knee, etc.), myalgias, fever,anemia, increased ESR level. The rheumatoidfactor and the antinuclear antibodies arenegative. Patients may adopt a bending position

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antinucleari sunt negative. Pacienþii pot adopta oposturã aplecatã datoritã poliartritei, careproduce dureri la mers. Pacienþii nu prezintãHLA-B27 prezent. Apar leziuni osoase osteoliticeaseptice frecvent la nivelul claviculei, sternului,oaselor lungi ale extremitãþilor, pe ºolduri,glezne, humerus ºi la nivelul articulaþiilor sacro-iliace. Aceste leziuni se vindecã lent ºi de multeori rãmân cicatrici extinse. AF lasã cele mai multecicatrici.

Constatãrile de laborator au evidenþiat:- Leucocitozã caracteristicã frecvent asociatã

cu o reacþie leucemoidã (46), cu 0,5-1,5%mieloblaste, promielocite ºi mielocite însângele periferic; un nivel crescut alleucocitelor polimorfonucleare

- VSH crescut- Niveluri crescute de PCR- Trombocitozã - Anemie normocromã- Uneori poate sã aparã hematurie micro-

scopicã ºi proteinurie - Frecvent proteinele serice sunt normale,

dar alteori pot indica albuminã scãzutã saualfaglobulinã ºi gamaglobulinã crescute

- Complexe imune circulante au fost identi-ficate la unii pacienþi care prezentau AF ºieritem nodos (29, 35).

- Spre deosebire de acneea vulgarã, pacienþiicu AF pot prezenta ºi o hipersensibilitateîntârziate la diferite antigene în cadrultestelor cutanate (47).

- Culturile de bacterii din sânge, din fluidelecomune ºi din piele sunt în general sterile,sugestive.

- Propionilbacterium acnes a fost izolatsporadic din leziunile osoase ale pacien-þilor cu AF (48), aceºtia prezentând o fluo-rescenþã roºie la nivelul osului afectat, ceeace este caracteristic bacteriei Propionil-bacterium acnes. Exista AF cu osteomielitã,având culturi bacteriene osoase negative(49).

- Nivelul anticorpilor antistafilococici ºiantistreptococici este normal, de obicei.Stafilococul auriu poate apãrea doarocazional.

- Studiile legate de imagisticã: pacienþii potprezenta leziuni litice osoase demonstrateradiologic ºi niveluri crescute ale fosfatazei

due to the polyarthritis, which causes pains whenwalking. Patients do not display HLA-B27.Aseptic osteolytic bone lesions often develop inthe cellar bone, the stern, the long bones of theextremities, on hips, ankles, humerus and thesacroiliac joints. These lesions take a long time toheal and generally leave behind extended scars.AF is the acne variant that leaves most scars.

Laboratory examinations have shown:- Specific leukocytosis, often associated with

a leukomoid reaction [46], with 0.5 up to1.5 per cent myeloblasts, promyelocytesand myelocytes in the peripheral blood; anincreased level of polymorphonuclearleucocytes

- Increased ESR level- High levels of polymerase chain reaction- Thrombocytosis - Normochrome anemia- Sometimes microscopic hematuria and

proteinuria - Seric proteins are often within normal

values, although in some cases they mayindicate low albumin and highalphaglobulin and gammaglobulin levels

- Circulating immune complexes have beendetected in some patients with AF andnodous erithema [29, 35]

- Unlike acne vulgaris, AF patients mayshow delayed hypersensitivity to variousantigens during skin tests [47]

- Bacteria cultures from blood, commonfluids and skin are generally suggestivelysterile

- Propionilbacterium acnes has beensporadically isolated from bone lesions inAF patients [48] who presented a redfluorescence in the affected bone area, atrait characteristic to Propionilbacteriumacnes bacteria. AF with osteomyelitis andnegative bone bacterian culture also occurs[49]

- Generally, the level of antistaphilococcusand antistreptococcus antibodies isnormal. Staphilococcus aureus developsonly occasionally.

- Imagery studies have shown that patientsmay present lytic bone lesions observed inradiology, as well as increased levels ofserum alkaline phosphatase [50]. Thecause of bone lesions remains unknown.

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alcaline serice (50). Cauza leziunilor osoaseeste necunoscutã. Nu a fost identificatã nicio bacterie patogenã, doar foarte rar au fostpacienþi la care a fost cultivatã bacteriaPropionilbacterium acnes (48, 51). Leziu-nile iniþiale sunt osteolitice, mai târziuapare formare periostalã de os nou,sclerozã si îngroºare. Nu s-au observateroziuni sau osificãri ligamentare. Zonelepredilecte sunt toracele anterior, frecventsternul ºi claviculele, ºoldurile, gleznele,humerusul, regiunea sacroiliacã.

Apariþia leziunilor osoase necesitã biopsiepentru a exclude afecþiunile maligne, benigne,sau infecþioase. Frecvent se poate observa uninfiltrat cu neutrofile ºi mononucleare, cu þesut degranulaþie, care poate imita osteomielita.

Din punct de vedere histopatologic, pustuleletimpurii indicã o infiltrare intensã cu neutrofile ºiocazional cu histiocite, cu invadarea ºi distru-gerea peretului folicular ºi a glandelor sebacee.Apare necrozã epidermicã, hemoragicã, datoritãsubþierii vaselor ºi a sângerãrii abundente lanivelul pielii. Aceastã necrozã este înconjuratã deun infiltrat mixt granulocitar ºi limfocitar. Uniifoliculi prezintã distensie cu celule keratinizate(microcomedoane), fãrã tendinþã de formare acomedonului. Un nodul este indiciul unuiepiderm regenerat, cu un derm care conþine uninfiltrat celular dens, mixt, hiperplazie vascularãºi numeroase celule fibroblastice stelate. Rareoritestele de imuno-fluorescenþã directã dezvãluieun IgM linear ºi o bandã de fibrinã la joncþiuneadermo-epidermicã cu depunere de fibrinã înjurul glandelor sebacee. Spre deosebire de acneeaconglobatã lipsesc chisturile mari, neinflamate,secundare ºi comedoanele poliporoase. Pot fivizualizaþi noduli neovasculari, eritematoºi.

Diagnosticul diferenþial urmãreºte:- Diagnosticul diferenþial se face cu acneea

conglobatã (AC), dar în AF manifestãriilesistemice sunt foarte pronunþate, acesteadiferenþiindu-se în mod clar; AF este maiameninþãtoare pentru sãnãtate, esterezistentã la antibiotice, presupunând oterapie specialã ºi este limitatã în timp. ACare localizare cutanatã asemãnãtoare cu AF(comedoanele sunt prezente atât în AC, câtºi în AF), dar debutul acesteia este

No pathogenic bacteria has been detectedand Propionilbacterium acnes bacteria hasbeen cultivated in very few patients [48,51]. Lesions are initiallt osteolytic and theperiosteal formation of new bones,accompanied by sclerosis and thickening,develops later. No ligament erosions orossifications have been observed. Theprevailing affected areas are theforethorax, frequently the stern and thecollar bone, the hips, ankles, humerus andthe sacroiliac area.

The occurrence of bone lesions requiresbiopsy in order to exclude malign, benign orinfectious disorders. Frequently, there appears aninfiltrate with neutrophils and mononuclears,with granulation tissue, that resemble osteo-myelitis.

Histopathologically, eraly pustules suggestan intense infiltration of neutrophils andoccasionally of histiocytes, invasion anddestruction of the follicular wall and of thesebaceous glands. Epidermic, hemorrhagicnecrosis occurs due to thinning of vessels andabundant bleeding of the skin. This necrosis issurrounded by a mixed granulocytary andlymphocytary infiltrate. Some of the folliclespresent distension with keratinised cells(microcomedones), while with no tendency todevelop the comedone. The presence of nodulessuggest a regenerated epidermis, with a dermiscontaining a dense, mixed cell infiltrate, vascularhyperplasia and numerous stellate fibrobasticcells. Direct immunofluorescence tests only rarelyshow a linear IgM and a fibrin slip at thedermato-epidermal junction, with fibrin settlingaround the sebaceous glands. Unlike acneconglobata, secondary, non-inflamed big cystsand polyporous comedones are absent. Instead,erythematous neovascular nodules can beobserved.

Dfferential diagnosis:- Differential diagnosis is performed by

comparison with acne conglobata (AC). InAF, systemic manifestations are verypronounced and specific. AF is morethreatening for health, resistant toantibiotics, requires special therapy and islimited in time. The skin localisation of ACis similar to that of AF (comedones arepresent both in AC and in AF), but AC

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incomparabil mai puþin exploziv, evoluþiaeste mai cronicã, apare la vârste maiînaintate ºi poate fi o componentã a triadei,care include ºi celulita disecantã ascalpului ºi hidradenita supurativã. Înconcluzie este important ºi corect sã nupunem AF pe seama AC severe.

- AF poate fi consideratã ca fiind o parte asindromului SAPHO, asemãnãrile clinicedintre ele conducând la ideea de boalãautoimunã. Cauza acestui sindrom nu esteînsã clarã pânã în prezent, ci doarpresupus. Criteriile sindromului SAPHOsunt: apare frecvent la copii ºi tineri;leziunile cutanate pot include: pustulozãpalmo-plantarã, acnee severã, tipuri dife-rite de psoriazis, hidradenita supurativã,dar absenþa leziunilor pielii nu excludediagnosticul de SAPHO; afectare osteo-articularã, cu sclerozã sau osteolizã sau cuambele, cel mai frecvent localizate lanivelul peretelui toracelui anterior, centuriipelvice, vertebrei ºi mandibulei. În cadrulsindromului SAPHO s-au descris ºimanifestãri sistemice ca de exempluindispoziþie ºi febrã, dar mai rar (52).

Tratamentul AF a fost o adevãratã provocare.Combinaþia cea mai eficientã este: steroizi orali ºiisotretinoin. Steroizii sistemici (Prednison ) suntde primã alegere, ei controlând efectiv leziunilepielii, reduc febra, au un efect favorabil asuprasimptomelor musculo-scheletale; doza dePrednison este 0,5-1 mg/kg/zi, timp de 3-5 luni,descrescând apoi în funcþie de îmbunãtãþire.Dacã dozajul a fost redus prea rapid sauadministrarea opritã, recidiva apare la 2-8sãptãmâni dupã ºi se manifestã printr-o agravarea artralgiei, uneori febrã, dar nu se înrãutãþeºteaspectul nodulilor cutanaþi (22). Reducereasteroizilor se face treptat ºi se evitã prelungireainutilã pentru a evita efectele adverse. Dupã cefaza acutã inflamatorie a afecþiunii a fostcontrolatã cu steroizi sistemici se poate începetratamentul cu isotretinoin sistemic (acidul 13-cis-retinoic) (53). Foarte importantã esterespectarea ordinii steroizi ºi apoi isotretinoin,altfel în mod paradoxal isotretinoinul poateprecipita afecþiunea (54,55); în consecinþãisotretinoinul nu se înscrie în tratamentul iniþial

beginning is significantly less explosive, itsevolution more chronic, it develops atmore advanced age and can be part of thetriad also comprising diseccant cellulitis ofthe scalp and hydradenitis suppurativa. Inconclusion, it is important and accurate notto mistake AF for severe AC.

- AF can be considered as part of theSAPHO syndrome and their clinicalsimilarities lead to the idea of autoimmunedisease. The cause of this syndrome is yetunknown and only supposed. SAPHOsyndrome criteria are: it mainly occurs inchildren and youngsters; skin lesionsinclude: palmoplantar pustulosis, severeacne, various types of psoriasis,hydradenitis suppurativa, but the absenceof skin lesions does not exclude SAPHOdiagnosis; ostaeoarticular involvement,with sclerosis or osteolysis or both, mainlyaffecting the forethorax wall, the pelvicgirdle, the vertebra and mandible. WithinSAPHO syndrome, systemic mani-festations such as indisposition and feverhave also been described, but lesscommonly [52].

AF treatment is a real challenge. The mostefficacious combination consists of oral steroidsand isotretinoin. Systemic steroids (Prednison)are the first choice; they effectively control skinlesions, diminish the fever and act favourably onmusculoskeletal symptoms; Prednison dose is0.5-1 mg/kg daily for 3 to 5 months, after whichit decreases, depending on amelioration degree.If dosage is too quickly decreased or the therapyinterrupted, relapses occur in 2-8 weeks asaggravation of arthralgia, sometimes accom-panied by fever, and the aspect of the skinnodules worsens [22]. Steroids administrationshould be gradually reduced and prolonged andunhelpful treatment should be avoided, leastadverse effects should appear. After theinflammatory acute stage has been taken undercontrol by means of systemic steroids, treatmentwith systemic isotretinoin (13-cis-retinoc acid)can begin [53]. Observing the correct admi-nistration order (first steroids, then isotretinoin)is extremely important, otherwise isotretinoincan aggravate the condition [54, 55]; hence,

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de primã alegere (56, 57). Tratamentul cuisotretinoin trebuie început la 4 sãptãmâni dupãcel cu corticosteroizi, acest interval fiind absolutnecesar. Se recomandã începerea cu doze iniþialereduse (0,1 mg /kg/zi), mai ales pacienþilor, careprezintã orice urmã de crustã, evitând astfelagravarea; apoi doza creºte la 0,5 mg/kg/zi pânãla maxim 1-1,5 mg/kg/zi. Durata tratamentuluidepinde de rãspunsul fiecãrui individ ºi nu artrebui sã fie mai scurt de 3-5 luni. Sub tratamentdiminueazã semnificativ reacþia inflamatorie ºichiar dispare, dar recidivele par sã fie maifrecvente decât în acneea vulgarã. Dacã în timpultratamentului cu isotretinoin apar granuloamepiogenice (proliferãri vasculare) în mod spontan,doza de isotretinoin trebuie redusã la 0,2mg/kg/zi,

Pacienþii cu AF trebuie sã stea la pat ºi aunevoie de o perioadã de spitalizare de 3-5sãptãmâni. Tratamentul local include : debridarechirurgicalã, urmatã de comprese calde cu 20-40% soluþie uree, pentru a preveni formareacrustelor, curãþarea cu agenþi antibacterieni ºiloþiuni antiseptice, corticosteroizi topici depotenþã înaltã, aplicaþi pe nodulii ulceraþi de 2 oripe zi, timp de 7-10 zile (benefici mai ales în fazaactivã pentru a diminua intensitatea inflamaþiei ºia ulceraþiei). Alte tratamente implicate sunt celeefectuate cu laserul (Pulsed dye laser), foarteeficient în AF, necesitând aproximativ 2 ºedinþe(58) pentru a obþine vindecarea.

În cazurile foarte severe de AF (59), care nucedeazã doar la steroizii orali, se asociazãAzatioprina, obþinându-se o remisie dupã maimulte luni de tratament combinat.

În cazul în care AF se asociazã cu eritemnodos tratamentul trebuie sã includã sulfonele(dapsona) cu efect antiinflamator, antiinfecþios,doza iniþialã 50 mg/zi, care poate fi crescutã la100 sau 150 mg/zi (26). În situaþia în caredapsona nu poate fi acceptatã dintr-un anumitmotiv, aceasta poate fi înlocuitã cu retinoit.

Antiinflamatoarele nesteroidiene se utili-zeazã pentru febrã ºi simptomele musculo-scheletale, cu efecte favorabile.

ªi salicilaþii au efect pozitiv în mialgiile acuteºi în artritã.

Alte terapii includ corticosteroizi intra-articulari, injecþii, medicamente antireumatice,

isotretinoin is not to be considered as an initialfirst choice treatment [56, 57]. Isotretinointreatment should start 4 weeks after that withcorticosteroids, this lag being absolutelymandatory. The recommended initial dose is low(0.1 mg/kg daily), especially in patients withcrusts, in order to avoid aggravation of thecondition; the dose is then increased to 0.5 up to1-1.5 mg/kg/day. Treatment duration dependson each individual’s response, but it should notbe shorter than 3-5 months. Under treatment, theinflammatory reaction diminishes considerably,and even remits, although relapses seem morefrequent than in acne vulgaris. If duringisotretinoin treatment pyogenic granulomas(vascular proliferations) develop spontaneously,isotretinoin dose should be reduced to 0.2 mg/kgdaily.

AF patients should stay in bed and need aperiod of hospitalization of 3-5 weeks. Localtreatment comprises: surgical unclamping,followed by hot compresses with 20-40% ureasolution in order to prevent crust formation,cleansing with antibacterian agents andantiseptic lotions, application of highly potenttopical corticosteroids on the ulcerated nodules 2times a day for 7-10 days (especially beneficial inthe active stage for the diminuation of theinflammation and ulceration intensity). Othertreatments involved are performed with laser(pulsed dye laser), very efficacious in AF, whichrequies approximately 2 sessions [58] for healing.

In very severe AF cases [59], which do notgive way to oral steroids, Azatioprin is alsoadministered and remission is obatined afterseveral months of combined treatment.

When AF is associated with nodouserythema, treatment should include sulphones(dapsone), with antiinflammatory and anti-infectious effects, starting with 50 mg/day, a dosewhich may be increased to 100 or 150 mg/day[26]. If, out of any reasons, dapsone cannot beadministered, it can be replaced by retinoide.

Non-steroid antiinflammatories are success-fully used to control fever and musculoskeletalsymptoms.

Salicylates have also a positive effect in acutemyalgias and in arthritis.

Other therapies include intra-articularcorticosteroids, injections and antirheumatic

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care amelioreazã afecþiunea (Metotrexat, Sulfa-salazin, Cyclosporina A).

În cazul pacienþilor cu AF, care nu rãspund laterapiile convenþionale, Infliximab, este consi-derat o opþiune terapeuticã (36), sub acþiunea luinodulii cutanaþi ulcerativi încep sã descreascã înmod considerabil, iar sinovita, durerile de spateºi claviculare sunt complet rezolvate.

AF este cea mai agresivã ºi distructivã formãa acneei. Multiplele manifestãri clinice ale AF facca aceastã afecþiune sã fie uneori greu derecunoscut. În acneea fulminans, organismulpacientului pare sã-ºi distrugã propriile þeluri-pielea, maduva, oasele, rinichii. Când trata-mentul este administrat prea târziu, pacienþiisuferã cu rapiditate schimbãri distructive. Ei audureri ºi prezintã dizabilitãþi de la leziunile pielii.Au fost raportate pierderi în greutate devasta-toare de 12 kg, aproximativ 1,5 kg/sãptãmânã, ºitemperatura de 41 grade C (60). Întrerupereatratamentului poate fi urmatã de o exacerbare asimptomelor osteo-articulare. Recidiva apare deobicei la 2-8 sãptãmâni dupã atacul acut, cânddozajul de corticosteroizi este redus sauadministrarea lor este opritã, ºi se manifestã subforma agravãrii artralgiei ºi uneori febrã, dar deobicei nu se remarcã o agravare a leziunilor pielii.Începerea timpurie a terapiei poate diminuaapariþia cicatricilor ºi riscul apariþiei altormodificãri asociate acestei potenþiale afecþiunicare desfigureazã. AF recurentã este extrem derarã. Pacienþii trataþi cu corticosteroizi ºiisotretinoil au un prognostic foarte bun. Pot sãaparã recidive, când tratamentul este redus sauoprit timpuriu. Dupã un an de tratament risculde recidivã scade. O diagnosticare corectã ºi latimp a AF permite o gestionare terapeuticã bunã,evitã tratamente inutile ºi foarte important evitãleziunile reziduale cicatriciale de pe suprafaþapielii sau leziunile osoase reziduale radiologice,ca de exemplu scleroza ºi hiperostoza. Ocazional,poate persista durerea musculo-scheletalã uºoarãîn zonele afectate de boala acutã. În general, AFnu reapare dacã este corect tratatã ºi þinutã subcontrol.

8. Vasculitic/Pyoderma gangrenosum acne.Câþiva pacienþi care prezentau o acnee foarteblândã, au dezvoltat brusc un atac de vasculitãseverã, asemãnãtoare leziunilor din pyodermagangrenosum. Cicatriciile importante sunt

medicinal drugs that improve the condition(Metotrexat, Sulfasalazin, Cyclosporine A).

In AF patients who do not respond toconventional therapies, Infliximab is consideredan option [36]. Under such treatment, ulcerativeskin nodules start to decrease considerably, whilesynovitis, back and collar bone pains totallyremit.

AF is the most aggressive and destructiveform of acne. Its multiple manifestations make itsometimes difficult to diagnose. In acnefulminans, patient’s organism seems to destroyits own goals – the skin, the medulla, the bones,the kidneys. When treatment is administered toolate, patients quickly undergo destructivechanges. They are in pain and developdisabilities due to skin lesions. Devastatingweight losses of 12 kg (approximately 1.5kg/week), have been reported, as well as feversof 41ºC [60]. Treatment interruption can befollowed by an exacerbation of osteo-articularsymptoms. Relapse generally occurs 2-8 weeksafter the acute attack, when corticosteroidsdosage is reduced or its administration isinterrupted, and manifests as aggravation ofarthralgia and sometimes fever, although it is notgenerally accompanied by aggravation of skinlesions. Early beginning of therapy can diminishoccurrence of scars and the risk of othermodifications associated with this potentialcondition that disfigure recurrent AF is extremelyrare. Patients treated with corticosteroids andisotretinoil have a very good prognosis. Relapsesmay occur when treatment is reduced orinterrupted before time. The risk of relapsediminishes after one year of treatment. Accurateand early AF diagnosis allows for goodtherapeutical management, avoids residual scarlesions on skin surface or radiological residualbone lesions, such as sclerosis and hyperostosis.Occasionally, mild musculoskeletal pains persistin areas affected by the acute condition. AF doesnot generally relapse if adequately treated andkept under strict control.

8. Vasculitic/Pyoderma gangrenosum acne Some patients with very mild acne have

suddenly developed a severe attack of vasculitis,with lesions resembling pyoderma gangrenosumand significant scars as an inevitable conse-quence. The mechanism of this devastating type

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consecinþele inevitabile. Mecanismul acesteiacneei devastatoare este probabil o reacþieimunologicã la P.Acnes. Din punct de vedere altratamentului, câþiva pacienþi par sã nu rãspundãla Isotretinoin oral în monoterapie, dar asociat custeroizi orali ºi azathioprinã (200 mg/zi), efectuleste clar favorabil, dar tratamentul trebuiecontinuat pe o perioadã mai lungã de peste 3-4luni (61).

B. Sindroame asociate acneei

1. Sindromul SAPHO:- A fost descris pentru prima datã în 1987

(62)- Este o afecþiune rarã, aproape necunoscutã,

cu o prevalenþã estimatã la cel mult 1 la10000 (64), afecteazã copii ºi adulþii tinericu preponderenþã (66). S-au raportatasocieri chiar cu boli inflamatorii intesti-nale, precum boala Crohn ºi colitaulceroasã.

- Sindromul SAPHO înglobeazã: sinovitã,leziuni osteoarticulare aseptice, hiper-ostozã, osteitã, acnee, pustulozã (69,70)

- Au fost propuse trei criterii de diagnosticpentru acest sindrom, ºi anume: a) Osteomielitã multifocalã recurentã cro-

nicã cu sau fãrã manifestãri ale pieliib) Artritã asepticã acutã sau cronicã

asociatã fie cu acnee severã, fie cupsoriazis pustulos palmoplantar

c) Osteitã sterilã asociatã cu una dintremanifestãrile cutanate Oricare dintrecele trei prezentãri este suficentãpentru diagnosticarea sindromului(63). Este o artropatie caracterizatã prinfaptul cã are factor reumatoid negativ,la care se asociazã manifestãri der-matologice cu grade diferite de seve-ritate, cum ar fi: acneea, hidradenitasupurativã, celulita disecantã ascalpului, psoriazis vulgar, psoriazispustulos palmoplantar, sindromulSweet, boala Sneddon-Wilkinson ºipioderma cangrenosum (67, 68).Atunci când apare acneea, ca mani-festare cutanatã, ea poate îmbrãcadiferite forme clinice de la medie laseverã conglobatã sau fulminans.

- Manifestãrile cutanate pot apãrea conco-mitent, pot precede sau pot urmaimplicarea oaselor (65). Un studiu efectuat

of acne probably involves an immunologicalreaction to P. Acnes. As regards the treatment,some of the patients seem not to respond tomonotherapy with orally administered Iso-tretinoin, although the effect is definitelyfavourable in association with oral steroids andazathioprine (200 mg/day); treatment shouldnevertheless continue for more than 3-4 months[61].

B. Acne-associated syndromes

1. SAPHO syndrome:- Was first described in 1987 [62]- It is a rare, almost unknown condition,

with a prevalence estimated to 1 in 10,000people at the most [64] and mainlyaffecting children and young adults [66].Associations with intestinal inflammatorydiseases, such as Crohn disease andulcerous colitis, have also been reported.

- SAPHO syndrome includes: synovitis,aseptic osteoarticular lesions, hyperostosis,osteitis, acne, pustulosis [69, 70].

- Three diagnosis criteria have beensuggested for this syndrome: a) Recurrent multifocal osteomyelitis,

with or without skin condition b) Acute or chronic aseptic arthritis,

associated either with severe acne orwith palmoplantar pustular psoriasis

c) Sterile osteolysis associated with a skincondition. Any of the three above-mentioned aspects suffices forsyndrome diagnosis [63]. SAPHOsyndrome is an arthropathy with anegative rheumatoid factor associatedwith dermatological manifestations ofvarious severity degrees: acne,hydradenitis suppurativa, dissecantcellulitis of the scalp, psoriasisvulgaris, palmoplantar pustularpsoriasis, Sweet syndrome, Sneddon-Wilkinson disease and pyodermagangrenosum [67, 68]. When acne ispresent as skin condition, it may takevarious clinical forms, from average tosevere conglobata or fulminans.

- Skin conditions can appear simultane-ously, prior or after bones involvement[65]. A long-term follow-up study

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pe termen lung, pe 120 de cazuri con-firmate, a prezentat: 66 pacienþi (55%) cupustulozã palmoplantarã, 37 pacienþi(30,8%) cu psoriazis vulgar, 30 de pacienþi(25%) cu acnee severã ºi 19 pacienþi (15,8%)fãrã manifestãri cutanate (66). Leziunileosoase pot fi osteoarticulare (sinovitã),hiperostozã, osteitã multifocalã. Loca-lizãrile osoase cele mai frecvente sunt lanivelul pieptului (torace anterior), lanivelul articulaþilor sacroiliace ºi la nivelulextremitãþilor. Leziunile osoase care seregãsesc în acest sindrom cum sunt celeosteolitice, zonele de sclerozã pot fievidenþiate radiografic, scintigrafic, tomo-grafic (acesta fãcând diagnosticul dife-renþial cu procese tumorale metastazice aleoaselor), RMN (care detecteazã multiplelefocare cu leziuni osteitice, unele dintreacestea fiind chiar asintomatice, localizatearticular axial sau non-axial) explorareaimagisticã fiind clar cea care punediagnosticul timpuriu (94).

Etiopatogenia acestui sindrom este neclarã.Nu a fost identificatã nicio bacterie patogenã, auexistat doar cazuri izolate, în care s-a cultivatbacteria P.Acnes ºi de aceea aceasta a fostsuspectatã ca un posibil factor etiologic (71).P.Acnes induce producerea de IL-8 ºi TNF-alfa,PMN care este mai gravã în SAPHO decât înartrita reumatoidã sau artrita psoriazicã (72). Unalt studiu recent a evidenþiat interleukina (IL)-8 ºifactorul de necrozã tumoralã (TNF)-alfa, generatde neutrofilia polimorfonuclearã (PMN) ca fiindmai mari la pacienþii cu sindrom SAPHO (72).Deci concluzia ar fi cã sindromul SAPHO poate fideclanºat de o stare infecþioasã, cauzatã probabilde P. Acnes, conducând cãtre rãspunsuriputernice umorale ºi inflamatorii celulare, dar cusiguranþã aceastã bacterie nu este triggerulprincipal în aceastã afecþiune (73), lucru susþinutde altfel de cazurile în care leziunile osoase nurãspund la tratamentul cu antibiotice.

Terapia actualã este aproape empiricã, pentrucã se bazeazã pe experienþe limitate în tratareaunor grupuri mici de pacienþi (74). S-au utilizatantiinflamatoare nesteroidiene (AINS), cortico-steroizi, metotrexat, ciclosporina, sulfone, aza-tioprinã, sulfasalazinã, Infliximab, calcitoninã,

conducted on 120 confirmed cases hasshown that 66 patients (55 per cent)presented palmoplantar pustulosis, 37patients (30.8 per cent) psoriasis vulgaris,30 patients (25 per cent) severe acne and 19patients (15.8 per cent) no skin condition[66]. Bone lesions can be osteoarticular(synovitis), hyperostosis, multifocalosteitis. Main bone lesions localisations arethe chest (the forethorax), the sacroiliacjoints and the extremities. In bone lesionsin SAPHO syndrome, such as theosteolytic ones, sclerosis areas can bedetected by radiography, scintigraphy,tomography (for the differential diagnosiswith bone metastatic tumoral processes),MRI (that detects multiple foci withosteolytic lesions, some of them evenasymptomatic, with articular, axial or non-axial localisation), resonance imagingbeing by far the examination of choice inearly diagnosis [94].

SAPHO syndrome etiopathogenesis is stillunclear. No pathogenic bacteria has beendetected, there were only isolated cases where P.Acnes bacteria has been cultivated, hence it wassuspected as a posiible etiological factor [71]. P.Acnes induces production of IL-8 and TNF-alpha,PMN being more severe in SAPHO than inrheumatoid or psoriasis arthritis [72]. One recentstudy has shown that interleukine (IL)-8 and theTNF-alpha tumor necrosis factor, generated bythe polymorphonuclear neutrophil (PMN), arehigher in patients with SAPHO syndrome [72].Thus, we may conclude that SAPHO syndromecan be triggered by an infectious conditionprobably caused by P. Acnes, leading to stronghumoral and cell inflammatory responses,although this bacteria is by no means the maintrigger in this disease [73], a fact otherwiseconfirmed by the cases in which bone lesions didnot respond to the treatment with antibiotics.

Present therapy is almost empirical, beingbased on experiences limited to the treatment ofsmall lots of patients [74]. It has mainly consistedso far in the administration of non-steroidantiinflammatories (AINS), corticosteroids,metrotexate, cyclosporine, sulphones, aza-tioprine, sulphasalazine, Infliximab, calcitonin,

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leflunomidã etc, utilizate în terapii unice sauasociate (de exemplu corticosteroizi ºi retinoizi).Implicarea factorului de necrozã tumoralã alfa(TNF alfa) în patogenezã este întâritã deconstatarea cã agentul anti TNF alfa, adicãInfliximab (75), are efecte benefice, chiar încazurile refractare (75), obþinându-se efectefavorabile prelungite pânã la 10 luni (75).Tratamentul complet trebuie sã urmãreascã atâtefectele osteoarticulare, cât ºi manifestãrilecutanate. În acest sens se utilizeazã cu succesIsotretinoinul pentru leziunile de tip acneeasociate cu leziuni osoase (76). Manifestãrilecutanate ºi cele osteoarticulare trebuie tratateconcomitent, pentru a obþine o regresie asimptomatologiei de ambele pãrþi (76). Eficenþaterapiei orale sau intravenoase cu bifosfonat afost raportatã în multe cazuri ºi poate fi explicatãprin activitatea lor antiinflamatorie prin supresiasecreþiei IL-1 beta, IL-6 ªI TNF-alfa (95,96).

Sindromul SAPHO este o tulburare cronicã,cu exacerbãri inermitente ºi remisiuni, dar care seîmbunãtãþesc cu timpul.

2. Sindromul SAHA. Asocierea seboreei ºiacneei cu hirsutismul ºi/sau alopecia andro-genicã la femei, a fost definitã în 1982 casindromul SAHA (77). Acesta include mani-festãrile dermatologice ale excesului deandrogeni la femei, pe baza nivelurilor circulantemari de androgeni sau datoritã capacitãþiiaparatului pilosebaceu de a rãspunde cu osensibilitate crescutã nivelului androgenuluicirculant normal (78,79). Sindromul SAHA seclasificã în tipul idiopatic, ovarian, suprarenal ºihiperprolactinenic ºi poate fi asociat cu ovarelepolichistice, mastitã chisticã, obezitate, insulino-rezistenþã ºi infertilitate (80).Toate cele patrusemne majore ale sindromului SAHA suntprezente la 20% dintre pacienþi. Seboreea esteîntâlnitã întotdeauna, alopecia androgenicã aparela 21% dintre cazuri, acneea la 10% din cazuri, iarhirsutismul la 6% (78, 80, 81). Excesul androgenicla femei este considerat unul dintre cele maifrecvente tulburãri endrocrine, care afecteazã 5-10% dintre pacientele aflate la vârsta repro-ducerii. Excesul androgenic poate fi cauzat desinteza crescutã de androgeni la nivelul glandelorsuprarenale ºi ovare, incluzând ºi activareaandrogenilor la nivelul pielii (82,83). Glanda

leflunomide, etc., either in monotherapy or inassociations (for instance, corticosteroids plusretinoids). The involvement of the tumor necrosisfactor TNF-alpha in its pathogenesis is stressedby the fact that this anti alpha agent, i.e.Infliximab [75], yields favourable prolongedeffects of up to 10 months even in refractary cases[75]. A complete treatment should focus both onosteaoarticular and skin conditions. For instance,Isotretinoin is successfully used for acne lesionsassociated with bone lesions [76]. Skin andosteoarticular manifestations should be treatedconcomitantly in order to obtain a regression inboth symptoms [76]. Oral or intravenousdiphosphonate therapy has proven efficacious inmany cases; this is explained by its anti-inflammatory actvity due to the suppression ofIL-1 beta, IL-6 and THF-alpha secretion [95, 96].SAPHO syndrome is a chronic disorder, withintermittent exacerbations and remissions thatnevertheless ameliorate in time.

2. SAHA syndrome. The association ofseborrhea and acne with hirsutism and/oralopecia in women was first defined in 1982 asthe SAHA syndrome [77]. SAHA comprisesdermatological manifestations of androgenexcesses in females due to the high androgencirculating levels or to the capacity of thepilosebaceous apparatus to respond withincreased sensitivity to the normal androgencirculating level [78, 79]. SAHA syndrome isclassified into the idiopathic, ovarian, suprarenaland hyperprolactinemic types and can beassociated with polycystic ovaries, cysticmastitis, obesity, insulin resistance and infertility[80]. All four major signs of SAHA are present in20 per cent of the patients. Seborrhea is alwayspresent, androgen alopecia in 21 per cent of thecases, acne in 10 per cent and hirsutism in 6 percent [78, 80, 81]. Androgen excess in women isone of the most common endocrine disorders,affecting 6 to 10 per cent of women ofreproductive age. Androgen excess may becaused by the increased synthesis of androgens inthe suprarenal glands and ovaries, includingactivation of androgens at skin level [82, 83]. Thesebaceous gland plays an important part in theactive formation of androgens and de novotestosterone biosynthesis [84, 85]. In women, up

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sebacee este un organ important al formãriiactive de androgeni ºi a biosintezei de novo atestosteronului (84,85). La femei pânã la 50% dintestosteronul circulant total este produs în piele ºiîn alte organe periferice. Androgenii, prin legareade receptorii androgeni nucleari prezenþi în piele,afecteazã numeroase funcþii cutanate, cum ar ficreºterea ºi diferenþierea unitãþilor pilosebacee ºihomeostazia barierei epidermice.Excesul deandrogeni poate creºte dimensiunea ºi numãrullobulilor glandei sebacee, precum ºi excreþia desebum. Cei mai mulþi pacienþi cu acnee prezintãniveluri normale circulante ale androgenilor ºiseveritatea acneei nu se coreleazã cu nivelurileserice de androgen (84,86,87,88). Se crede cãandrogenii pot juca un rol important în iniþiereadezvoltãrii acneei sau aceasta poate fi rezultatulunei supraproducþii de androgeni la nivelul pielii(87). Hirsutismul ºi oligomenoreea suntsimptome obiºnuite asociate cu hiperandrogenia(78). Pacienþii cu hirsutism manifestã frecvent oactivitate crescutã a 5 alfa-reductazei ºi nivelurimai mari ale androstendionului ºi sulfatuluiDHEA. Testosteronul total nu diferã semnificativîn rândul pacienþilor cu hirsutism, alopecie sauacnee (82,89). Pe de altã parte excesul deandrogen conduce la alopecia androgenicã(90,91). Diagnosticul sindromului SAHA pre-supune o anamnezã completã, o examinare fizicãpentru a evidenþia excesul de androgeni,investigaþii de laborator adecvate (incluzândhormoni precum sulfatul DHEA, testosteronul,prolactina ºi 17-OH-progesteron) pentru aexclude hiperandrogenia (78,84). Tratamenteleinclud modificarea stilului de viaþã, contraceptiveorale, medicaþie antiandrogenicã ºi insulino-sensibilizantã (87, 92, 93).

3. Sindromul PAPA. Triada clinicã: artritãsterilã piogenicã, pioderma gangrenosum (PG) ºiacneea conglobatã au fost observate la mai multefamilii ºi apar descrise cu acronumulsindromului PAPA în 1997 (97). În 2002 gena CD-2 legând proteina 1 (CD2 BP1, de asemeneadenumit proline/serine/threonine phosphatase-interacting protein 1, PSTPIP1) pe cromozomul15q24-25.1 a fost identificatã ca o genã cecauzeazã sindromul (98,99). Punctul mutaþiilor,fie A230T sau E250Q, au fost confirmate în 5familii cu acest sindrom, cu excepþia unui caz cu

to 50 per cent of the total circulating testosteroneis produced in the skin and other peripheralorgans. By binding with the nuclear androgenreceptors in the skin, androgens affect numerousskin functions, such as the the growth anddifferentiation of pilosebaceous units and theepidermal barrier homeostasis. Androgen excessmay cause increase of the number and size of thesebaceous gland lobules as well as sebumexcretion. Most acne patients display normalandrogen circulating levels and acne severity isnot correlated with the androgen serum levels[84, 86, 87, 88]. It is believed that androgens playan important role in initiating acne development,although acne can also be the result of anoverproduction of androgens at skin level [87].Hirsutism and oligomenorrhea are symptomscommonly associated with hyperandrogenia [78].Hirsutism patients often display a more intenseactivity of 5 alpha-reductase and higherandrostenedione and DHEA sulphate levels.Total testosterone level does not significantlydiffer in patients with hirsutism, alopecia or acne[82, 89]. On the other hand, angrogen excess leadsto androgen alopecia [90, 91]. SAHA syndromediagnosis requires complete anamnesis, aphysical examination meant to detect angrogenexcess, adequate laboratory investigations(including hormones such as DHEA sulphate,testosterone, prolactine and 17-OH-progesterone)in order to exclude hyperandrogenia [78, 84].Treatments aim at modifying the life style, oralcontraceptives, antiandrogen and insulin-sensitizing medication [87, 92, 93].

3. PAPA syndrome. The clinical triad:pyogenic sterile arthritis, pyoderma gan-grenosum (PG) and acne conglobata has beenobserved in several families and was described in1997 under the acronym PAPA syndrome [97]. In2002, the CD-2 gene that binds protein 1 (CD2PB1, also named proline/serine/threoninephosphatase-interacting protein 1, PSTPIP1) onthe chromosome 15q24-25.1, was identified assyndrome-causing gene [98, 99]. The mutations,being they A230T or E25-Q, have been confirmedin 5 families with this syndrome, with theexception of a case with a negative family historyand in the absence of an identifiable mutation inthe gene CD2BP1 [97, 100-104]. Within the group

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o istorie familialã negativã ºi în absenþa uneimutaþii identificabile în gena CD2BP1. (97,100-104). În grupul bolilor autoinflamatoare,mutaþiile diferitelor proteine cheie, precumCD2BP1. pentru sindromul PAPA ºi pyrinãpentru febra familialã Mediteraneeanã, pot fiimplicate în patogeneza bolilor obiºnuite (99).Proteina CD2BP1 leagã pyrina, care este uninhibitor al procesului inflamator. În acestsindrom, proteina mutantã CD2BP1 împiedicãacþiunea antiinflamatoare a pyrinei (105).Cantitatea redusã a pyrinei nelegate induceinfiltrare neutrofilicã în artritã, acnee, PG ºi altedermatoze neutrofilice (98,99,106). Manifestareasindromului PAPA cu triada sa clinicã variazã lamembrii familiei afectate. Artrita este cel maiimportant semn urmat de acnee ºi PG. O pacientãcu sindrom PAPA confirmat de studiul genetic aavut acnee ºi PG cu debut târziu, la 49 de ani ºifãrã artritã (103). Unii pacienþi cu acest sindromnu au acnee sau PG (97). Frecvent, artrita este celmai precoce semn care apare între 1 ºi 16 ani(107). Fiind asepticã ºi seronegativã, artrita non-axialã ºi pauci-articularã, afecteazã de obiceimâinile, coatele, genunchii ºi gleznele.Articulaþiile axiale au fost implicate doar încâteva cazuri (102). La pubertate se dezvoltã oacnee nodulochisticã severã. PG apare înadolescenþã sau la maturitate, dar de obicei dupãapariþia acneei. Motivul tranziþiei în cadrulacestrui sindrom de la artrita inflamatorie lamanifestãrile cutanate cu acnee ºi PG la pubertateeste necunoscut, suspectându-se aici roluletiologic posibil al testosteronului (102). S-aconstat cã sindromul PAPA se poate asocia ºi cualte boli, ca de exemplu hepatita idiopaticã,uveita, proteinurie, diabet zaharat insulinodependent, hipogama globulinomie etc (97, 102,108). Datoritã faptului cã niciuna dintre acesteboli nu este constant prezentã, asocierea poate fio simplã coincidenþã. În cadrul acestei triade, PGºi acneea pot fi prezent pe parcursul mai multordecenii. Artrita piogenicã sterilã este în generalautolimitatã, dar artrita pe termen lung poateconduce la distrugerea articulaþiilor ºi ladiformitate. În ceea ce priveºte tratamentul,inflamaþia artritei piogenice, a PG ºi a acneei estesensibilã la glucocorticoizi administraþi sistemicsau local. Chirurgia invazivã este nocivã ºicontrindicatã. De obicei, terapia antimicrobianã

of autoinflammatory conditions, mutations ofvarious key proteins, such as CD2BP1 for PAPAsyndrome and pyrine for the Mediterraneanfamilial fever, may be involved in thepathogenesis of common disorders [99]. Theprotein CD2BP1 binds pyrine, an inhibitor of theinflammatory process. In this syndrome, themutant protein CD2BP1 blocks the anti-inflammatory activity of pyrine [105]. Thereduced amount of unbound pyrine inducesneutrofil infiltration in arthritis, acne, PG andother neutrofil dermatoses [98, 99, 106]. PAPAsyndrome manifestations and its clinical triadvary in members of the affected family. Arthritisis the most important sign, followed by acne andPG. In one female patient with PAPA syndromeconfirmed in the genetic study, acne and PGdeveloped late, at age 49, and were not associatedwith arthritis [103]. Some PAPA syndromepatients do not have acne or PG [97]. Arthritis isgenerally the earliest sign, developing between 1and 16 years of age [107]. Being aseptic andseronegative, the non-axial and pauciarticulararthritis commonly affects de hands, elbows,knees and ankles. Axial joints have been involvedin only a couple of cases [102]. A severenodulocystic acne develops at puberty. PGappears in adolescence or adulthood, usuallyafter acne develops. In PAPA syndrome, thereason for the transition from inflammatoryarthritis to the skin condition of acne and PG isunknown, although the etiologic role oftestosterone is suspected [102]. It was alsoobserved that PAPA syndrome can associate withother disorders, such as idiopathic hepatitis,uveitis, proteinuria, insulin-dependent diabetesmellitus, hypogammaglobulinemia, etc. [97, 102,108]. Since none of these disorders is constantlypresent, the association can be a mere coin-cidence. Within this triad, PG and acne canpersist for several decades. Sterile pyogenicarthritis is generally self-limited, although long-term arthritis may lead to joints destruction anddifformity. As regards the treatment, pyogenicarthritis inflammation, PG and acne are sensitiveto systemically and locally administeredglucocorticoids. Invasive surgery is detrimentaland counter-indicated. Antimicrobian therapy is

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este ineficentã. Unele medicamente anti-reumatice, cum ar fi leflunomida sausulfasalazina, pot reduce durerea articulaþiilor ºiprevin progresia bolii (102). Dapsona este utilãdatoritã efectului sãu anti-neutrofilic (104),Terapia biologicã este o potenþialã alegere detratament ( Infliximab ºi receptorul antagonist-anakinra-), care ºi-a demonstrat eficienþa însindromul PAPA ºi alte boli autoinflamatoare(107, 109).

4. Sindromul CAH. CAH este acronimulpentru hiperplazie suprarenalã congenitalã, careconstã în grupul heterogen al afecþiunilorautozomal moºtenite, care se datoreazã unorefecte enzimatice (implicate în biosintezacortizolului ºi/sau al dosteronului) rezultânddeficit de glucocorticoizi, mineralocorticoizi ºiexces de androgen (110). Excesul de androgen ºideficitul de mineralocorticoizi ºi glucocorticoiziafecteazã unitatea pilosebacee rezultândmanifestãri cutanate: alopecia androgenicã,hirsutism, acnee, seboree (110). 95% din cazurilede CAH se datoreazã deficitului de 21-hydroxylazã (21-OH), cauzatã de mutaþii în gena21-hydroxylazã (CYP21, 6p21.3) (111). Existãdouã variante, boala clasicã asociatã cu pierdereacompletã a funcþiei enzimei, care apare înperioada neonatalã ºi se evidenþiazã la 1/15000de naºteri ºi varianta CAH non-clasicã, cu debuttârziu, adicã NCAH (hiperplazia adrenalãcongenitalã non-clasicã, care apare mai frecventafectând 1% din populaþia totalã (112). Acneea ºihirsutismul, principalele manifestãri cutanate aleCAH sunt apãrute frecvent în timpul ado-lescenþei. În CAH clasic, manifestãrile clinice (virilizare, deficenþe în fertilitate, staturã micã,apariþia devreme a pilozitãþii faciale, axilare,pubiene ºi acneea), sunt cauzate de deficitele deglucocorticoizi ºi mineralocorticoizi ºi deandrogenii în exces (110, 113). NCAH este deasemenea asociat cu simptome hiperandrogenice,ca de exemplu hirsutism, alopecie androgenicãsau seboree (114, 115). Acneea chisticã severãrefractarã la antibiotice orale ºi Isotretinoin aufost asociate cu NCAH (116,117). Unele femei cuNCAH prezintã ºi PCOS (118). Existã paciente cuacnee refractarã, hirsutism ºi dereglãrimenstruale, care prezintã PCO ºi NCAHconfirmate de genotipul CYP21 (117). Femeile cu

usually inefficient. Some antirheumatic drugs,such as leflunomide and sulphasalazine, canreduce pain in the joints and prevent the progressof the condition [102]. Dapsone is useful owing toits anti-neutrofil effect [104]. Biological therapy isa potentially adequate choice (Infliximab and theantagonist- anakinra-receptor), which has provenefficacious in PAPA syndrome and otherautoinflammatory conditions [107, 109].

4. CAH syndrome. CAH is the acronym forcongenital adrenal hyperplasia; it refers toseveral autosomal recessive diseases resultingfrom mutations of genes and enzymes (involvedin cortisol and/or dosterone biosynthesis), withglucocorticoids and mineral corticoids deficit andandrogen excess [110]. Androgen excess andglucocorticoids and mineral corticoids deficitaffect the pilosebaceum unity, with resulting skinmanifestations: androgen alopecia, hirsutism,acne, seborrhea [110]. 95 per cent of CAH casesare due to the deficit of 21-hydroxylase (21-OH),caused by muttations in 21-hydroxylase gene(CYP21, 6p21.3) [111]. There are two variants ofthis condition: the classical disorder, associatedwith complete loss of the enzyme function,developing in neonatal period, was detected in1/15,000 births; and the non-classical form, withlate development, i.e. NCAH (non-classicalcongenital adrenal hyperplasia), more commonlyencountered and affecting 1 per cent of the totalpopulation [112]. Acne and hirsutism, the mainskin symptoms in CAH, frequently developduring adolescence. In classical CAH, clinicalmanifestations (virilization, fertility defficiency,low height, early facial, axilar and pubic hair,acne) are caused by glucocorticoids and mineralcorticoids deficit and androgen excess [110, 113].NCAH is also associated with hyperandrogensymptoms, such as hirsutism, androgen alopeciaor seborrhea [114, 115]. Severe cystic acnerefractary to oral antibiotics and Isotretinoin hasbeen associated with NCAH [116, 117]. SomeNCAH female patients also present PCOS [118].There are patients with refractary acne, hirsutismand menstrual disorders that also present PCOand NCAH confirmed by CYP21 genotype [117].Women with NCAH may also display insulin

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NCAH pot prezenta isulinã rezistenþã. Oricum,asocierea acesteia cu apariþia acneei, nu a foststudiatã la pacienþii cu NCAH (119). De notat cãacneea poate fi singurul semn prezent în NCAH,la femei cât ºi la bãrbaþi (117, 120). NCAH trebuiediferenþiat de PCOS, sindromul CUSHING,hiperprolactinemie sau tumori androgensecretante (110,118). Pentru NCAH mai blând custeroizi suprarenali normali bazal, esterecomandat testul de stimulare a CAH (114).Acest test trebuie fãcut dimineaþa la începutulfazei foliculare (ziua 3-7 a ciclului menstrual).Tratamentul pentru CAH clasic constã înreducerea producþiei de androgen cu ajutorul sauprin intermediul cortizolului ( cu glucocorticoiziorali) sau când este necesar, corectând deficitul dealdosteron cu fludrocortizon (112). Tratamentulpentru NCAH depinde de principala problemã apacientului, acnee sau hirsutism. Pentru acneeaasociatã cu NCAH se administreazã gluco-corticoizi orali pentru a contracara producþiasuprarenalã de androgen (121). Doze reduse deprednisolon 2,5-5 mg pe zi sau doze reduse dedexamethasone 0,25-0,75 mg, pot fi administrate,cu mare atenþie însã la riscul crescut de supresie aglandei suprarenale. Pentru a ne asigura cãglucocorticoizii sunt eficenþi, DHEA estemonitorizat pentru reducere sau normalizare(110).

5. Sindromul PCO. Sindromul PCO este odereglare endocrinã complexã, care afecteazã 5-20% dintre femei, fiind strâns legatã de originealor etnicã. Se caracterizeazã prin hiperandro-genism cu oligo ºi/sau anovulaþie ºi ovarepolichistice (122). Hiperandrogenismul, secreþiamodificatã de gonadotropinã precum ºi re-zistenþa la insulinã sunt implicate în patogenezasindromului PCO. Un nou aspect în pato-fiziologia PCO îl reprezintã implicarea lipseivitaminei D, care poate fi cauza ºi/sau consecinþatulburãrilor de reglare a insulinei (123). Oricum,nu doar femeile pot fi afectate de problemelemetabolice sau hormonale. Bãrbaþii faþã defemeile cu PCO tind sã manifeste tulbãrãri înglucozã ºi profilul androgenetic ºi pot reprezentaun fenotip special al sindromului metabolic (124).Acest sindrom are la bazã o origine geneticãimportantã (125). Genele implicate pot fi grupateîn 4 categorii: cele legate de insulino rezistenþã,

resistance. In any case, its association with acnehas not been studied in NCAH patients [119].Noteworthy, acne is the only NCAH symptomaffecting both women and men [117, 120]. NCAHmust be differentiated from PCOS, CUSHINGsyndrome, hyperprolactinemia or secretingandrogen tumors [110, 118]. In milder NCAHwith normal basal suprarenal steroids, the CAHstimulating test is recommended [114]. This testshould be performed in the morning, at thebeginning of the follicular phase (day 3-7 of themenstrual cycle). Treatment for classical CAHconsists in the reduction of androgen productionwith the help of or by means of cortisol (with oralglucocorticoids) or, if necessary, by correctingaldosterone deficit with fludrocortisone [112].NCAH treatment depends on the main symptomaffecting the patient, hirsutism or acne. In acneassociated with NCAH, oral glucocorticoids areadministered in order to counteract androgensuprarenal production [121]. Low doses ofprednisole of 2.5-5 mg/day or of dexamethasone(0,25-0.75 mg) may be administered, but withmuch care, taking into account the high risk ofsuprarenal glands suppression. To ensure efficacyof glucocorticoids, DHEA is monitorised toachieve reduced or normal levels [110].

5. PCO syndrome. PCO syndrome is acomplex endocrine disorder that affects 5 to 20per cent of the female population and is tightlyrelated to women’s ethnic origin. It is charac-terized by the presence of hyperandrogenismwith oligo and/or anovulation and of polycysticovaries [122]. Hyperandrogenism, changed levelsof gonadotropine as well as insulin resistance areall involved in PCO syndrome pathogenesis. Anew aspect in PCO pathophysiology is theabsence of vitamin D, which may be the causeand/or the consequence of insulin regulatingdisorders [123]. In any case, not only women areaffected by metabolical or hormonal problems.As opposed to women, men with PCO displaydisturbances in the glucose level and theandrogenetic profile and may present a specialphenotype of the metabolic syndrome [125]. Thegenes involved can be divided into fourcategories: insulin-resistance related ones, genes

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cele care interferã cu biosinteza ºi acþiuneaandrogenilor, cele care codificã cytokineleinflamatorii ºi alte gene canditate (126). O relaþieclarã cu genele asociate obezitãþii, a fostdescoperitã recent (127). Afecþiunea este frecventasociatã cu insulino rezistenþa acompaniatã dehiperinsulinemie compensatorie, creând un risccrescut pentru dezvoltarea diabetului zaharat detip II. Obezitatea joacã un rol cheie la aproximativ50% dintre femeile cu acest sindrom (122). Denotat, cã obezitatea este un simptom comun darnu esenþial în PCO, care poate la rândul sãu sãgenereze o subestimare a acestui sindrom lafemeia slabã. Oricum, atât femeile obeze, cât ºicele slabe prezintã riscul apariþiei hiperinsuli-nemiei, urmatã în consecinþã de efecte cardio-vasculare ºi metabolice. În plus, femeia cu PCOprezintã frecvent infertilitate, hirsutism, acnee ºialopecie (80). Obezitatea ºi hirsutismul ca ºiproblemele de fertilitate sunt considerate ade-vãrate poveri psihologice, pentru femeile cu acestsindrom, iar rezultatele prezintã o ratã de suicidde 7 ori mai mare. Acneea este prezentã la 23-35%dintre pacienþii cu acest sindrom, în timp ceprevalenþa PCO în grupul acneeicilor a fostestimatã la 26,9% într-un studiu recent sau maimult în alte studii (129).

PCOS apare cu prevalenþã mai mare la femeicu acnee severã, cu debut târziu ºi care prezintãrezistenþã la terapiile convenþionale. Examinareaclinicã include mãsurãtori antropometrice ºicotaþia (gradul) hirsutismului, care sunt ele-mente obligatorii pentru diagnosticarea sindro-mului PCO (130). În plus determinarea para-metrilor endocrinologici incluzând androgenii,este obligatorie pentru diagnostic. Multe altediagnostice ar trebui excluse, ca de exemplu:CAH, Cushing sindrom, hyperprolactinemia ºialtele mai puþin frecvente. Pentru a evalua risculmetabolic al femeilor cu sindrom PCO, trebuieefectuat un test de toleranþã la glucozã, test careinclude insulina ºi determinãrile c-peptide ºihormonul luteinizant (LH) (trebuie efectuatetestele hormonale pentru a analiza receptivitateahipofizei cu o creºtere pronunþatã caracteristicã aLH-ului). Determinarea lipidelor serice ºiobezitatea sunt factori importanþi pentru risculcardiovascular (131). Examinarea ginecologicã derutinã include ecografia transvaginalã ovarianã ºitestele pentru cancerul endometrial, precum ºi

interfering in biosynthesis and androgens action,genes that codify inflammatory cytokines andothers [126]. A clear relationship with genesassociated with obesity has been recentlydiscovered [127]. PCO is commonly associatedwith insulin resistance accompanied bycompensatory hyperinsulinemia, which increasesthe risk of developing diabetes mellitus type II.Obesity plays a key role in approximately 50 percent of females with this syndrome [122].Noteworthy, obesity is a common, but notessential symptom in PCO, which in turn cancause an underestimation of this syndrome inthin women. Anyway, both obese and thinwomen run the risk of developing hyper-insulinemia, followed by cardiovascular andmetabolical consequences. Besides, PCO femalesare often infertile and suffer from hirsutism, acneand alopecia [80]. Obesity and hirsutism, as wellas infertility, are considered psychologicalburdens for women with this syndrome, inwhom studies have shown a 7 times highersuicide rate. Acne is present in 23 to 35 per cent ofPCO patients, while prevalence of PCO in acnepatients has been estimated to 26.9 per cent inone recent study, as well as in many otherinvestigations [129].

PCOS appears in greater prevalence inwomen with severe acne at late ages and isresistant to conventional therapies. Clinicalexamination includes anthropometric measure-ments and hirsutism quotation (degree),obligatory elements in PCO diagnosis [130].Determination of endocrinological parameters,androgens included, are also necessary indiagnosis. Many other diagnoses should beexcluded, such as CAH, Cushing syndrome,hyperprolactinemia and less common others. Forthe evaluation of the metabolical risk in womenwith PCO syndrome, a test of tolerance to glucoseshould be performed, including insulin, c-peptides and the luteinizing hormone (LH) –hormone tests are to be conducted in order toanalyze hypophysis receptivity with apronounced specific increase of LH. Serum lipidsand obesity evaluation are important factors incardiovascular risk [131]. Routine gynecologicalexamination includes ovarian transvaginalechography and tests for endometrial cancer, as

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testele de ovulaþie ºi verificarea calendaruluimenstrual. Cele mai frecvente mãsuri terapeutice,pentru managementul sindromului, constã înmodificãri în stilul de viaþã, utlizarea contra-ceptivelor orale ºi folosirea sensibilizatorilor deinsulinã. Tratamentul trebuie individualizat.Controlul greutãþii este foarte important pentrufemeile obeze cu PCO, dar controlarea cu succesa greutãþii este adesea limitatã (132), iarprincipiul controlului greutãþii nu se aplicã ºi lapacienþii slabi cu PCO. Tratamentul insulinorezistenþei se face cu Metformin, care poate sã nufie eficient pentru scãderea în greutate, darregleazã rezistenþa la insulinã ºi determinãscãderea importantã a androgenilor (133). Esteevident cã Metforminul este benefic pentruprevenirea avortului spontan, menþine stabil ºi înechilibru metabolismul glucozei la femeileînsãrcinate (134). Oricum, utilizarea acesteia lapacienþii cu PCO nu este foarte corespunzãtoaredin cauza lipsei unor studii ample cerute pentruaprobarea de cãtre FDA sau EMEA. Alte terapiipentru insulino rezistenþã sunt de regulãnecompatibile cu sarcina ºi ar trebui sã fie folositedoar în cazuri particulare, cum ar fi variantelerare ale sindromului genetic PCO. Suplimentareavitaminei D este recomandatã în cazurile cuinsuficenþã sau deficit sever al 25-OH vitamina D,care ar putea sã ajute în corectarea tulburãrilormetabolice. Utilizarea contraceptivelor orale cueficacitatea antiandrogenicã clarã pot ajuta sãcontroleze atât nivelul androgenic cât ºisimptomele cutanate ºi hirsutismul. Princontrast, intervenþiile chirurgicale cum sunt celelaparoscopice au fost pe larg folosite in trecut ºipoate fi o opþiune alternativã terapeuticã în maimulte cazuri.

6. Sindromul HAIR-AN. Acest sindromeste echivalent cu hiperandrogenismul (HA)-insulino rezistenþa (IR)- ºi acanthosis nigricans(AN). Acest sindrom poate fi considerat unsubtip unic al PCO sindrom la femei (136),prezent la aproximativ 5% dintre tinerele cu HA(137). Pacienþii cu HA, prezintã seboree,hirsutism acnee, menstre neregulate, alopecieandrogenicã, îngroºarea vocii, schimbãri în masamuscularã, clitorimegalie. IR cu simptomediabetice ca ºi AN (138). S-a observat asocierea cualte boli autoimmune sau endocrine, ca deexemplu: tiroidita Hashimoto, boala lui Grave,

well as ovulation tests and checking of themenstrual calendar. The most commontherapeutical measures in PCO syndromemanagement consist in changes in life style, useof oral contraceptives and insulin sensitizers. Thetreatment must be customized. Weight control isextremely important for obese PCO women,although successful control is often limited [132]and weight control principle does not apply tothin PCO patients. Treatment of insulin resistanceis made with Metformin, which may not lead toweight loss but regulates insulin resistance anddetermines a significant decrease in androgens[133]. It is also known that Metformin isbeneficial in preventing spontaneous abortion; italso maintains the stability and balance ofglucose metabolism in pregnant women [134]. Inany case, its utilization in PCO patients is notentirely adequate, in the absence of ample studiesrequired by regulating bodies such as FDA andEMEA. Other insulin resistance therapies areusually incompatible with pregnancy and shouldbe administered only in specific cases, such asrare variants of the PCO genetic syndrome.Vitamin D supplements are recommended incases of severe 25-OH vitamin D insufficiency ordeficit, which can contribute to control of boththe androgenic level and skin and hirsutismsymptoms. By contrast, surgical interventionssuch as laparoscopic ones, have been widely usedin the past and may still represent a therapeuticalalternative in many cases.

6. HAIR-AN syndrome. This syndrome isequivalent to hyperandrogenism (HA)-, insulinresistance (IR)- and acanthosis nigricans (AN). Itcan be considered a subtype of the PCOsyndrome in women [136], affecting approxi-mately 5 per cent of young HA woman patients[137]. HA patients present seborrhea, hirsutism,acne, irregular menstrual cycles, androgenicalopecia, voice thickening, changes in themuscular mass, clitorimegalia, IR with diabeticsymptoms and AN [138]. Associations with otherautoimmune or endocrine conditions have beenobserved: Hashimoto tyroiditis, Grave’s disease,vitiligo, Cushing syndrome, Cohnen syndrome,acromegalia, CAH and insulinoma [138-140].Generally, these patients present high insulin

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vitiligo, sindromul Cushing, sindromul Cohnen,acromegalie, CAH ºi insulinomul (138-140). Îngeneral aceºti pacienþi au prezentat niveluriridicate de insulinã, ºi niveluri ridicate saunormale de testosterone ºi androstendionã, darniveluri normale de LH ºi prolactinã. Primaanormalitate la pacienþii cu acest sindrom sepresupune a fi IR cu o creºtere compensatorie anivelului insulinei, care poate avea un efect scurtºi direct în reglarea steroidogenezei în ovare,conducând la o superproducþie ulterioarã deandrogeni (136). Severitatea hiperinsulinemiei secorecteazã în mod direct cu nivelurile deandrogen (89). Hiperinsulinemia ºi hiperandro-genia stimuleazã împreunã proliferarea epitelialãºi acumularea de melaninã rezultând mani-festãrile cutanate ale AN. S-a observat o scãdereimportantã a receptorilor insulinei sau mutaþii îngena receptorului cre au fost întâlnite la câþivapacienþi cu HAIR-AN (141). Recent, a fostraportatã o mutaþie a receptorului factorului decreºtere a fibroblastului (FGFR)3 asociatã cu AN,hiperinsulinemie ºi diplazie scheleticã (142).Acumularea lipidicã intracelularã în ficat ºi înmuºchi s-a gãsit în sindromul IR, indicând rolulreceptorilor IGF în metabolismul lipidic (143).Insulina sau IGF-1 pot stimula lipogenezasebocitelor (144). Lipogeneza glandelor sebaceeeste cauzatã de IGF-1 ºi poate duce indirect laseboree ºi acnee la pacienþii cu HAIR-AN.Maniera abordatã în prezent pentru acestsindrom, seamãnã cu cea din SAHA ºi PCO. Seutilizeazã spironolactone ºi flutamida (caantiandrogen) care pot fi utilzaþi singuri sau încombinaþie cu contraceptivele orale (145). Cândtratamentul medical eºueazã se abordeazãtratamente chirurgicale biliopancreatice saurezecþia bilateralã a ovarelor (146), însã toateacestea nu au un efect benefic constant pe termenlung ºi în consecinþã de cele mai multe oristatusul preoperator revine în câteva luni. Alteoriîndepãrtarea ovarelor nu reuºeºte sãîmbunãtãþeascã IR, aceasta fiind un defectmetabolic genetic. Operaþia în combinaþie cusupresia hormonilor gonadotropi este probabilcea mai eficace terapie curentã, valabilã pentrucazurile refractare.

7. Sindromul APERT. A fost descris pentruprima datã în 1906 (148). Este un sindromcongenital rar tip I, manifestat cu acrocefalo-

levels and high or normal testosterone andandrostendione levels, but normal LH andprolactine levels. The first abnormality in patientswith this syndrome is supposed to be an IR withcompensating increase of insulin level, with apossible short and direct effect in steroido-genesis regulation in the ovaries, leadingafterwards to androgen overproduction [136].Hyperinsulinemia severity is directly correctedwith androgen levels [89]. Both hyperinsulinemiaand hyperandrogenism stimulate epithelialproliferation and melanin accumulation,resulting in skin AN manifestations. A significantdecrease in insulin receptors or mutations in thereceptor gene have been observed in severalHAIR-AN patients [141]. A mutation in thefibroblast growth factor receptor (FGFR)3,associated with AN, hyperinsulinemia andskeletal dysplasia, has been recently reported[142]. Intracellular lipidic accumulation in theliver and muscles has been found in IR syndromepatients, suggestive of the part played by IGFreceptors in lipid metabolism [143]. Insulin orIGF-1 can stimulate sebocyte lypogenesis [144].Sebaceous glands lypogenesis is caused by IGF-1and may indirectly lead to seborrhea and acne inHAIR-AN patients. Therapies used at present inthis syndrome are similar to those applied inSAHA and PCO. Spironolactones and flutamide(as antiandrogen) are used in monotherapy or incombination with oral contraceptives [145].When medicinal treatment fails, specialists resortto biliopancreatic surgical intervention or thebilateral resection of the ovaries [146], which donot however bear a constant long-tern beneficialeffect and, consequently, the presurgical statusreinstals in a couple of months. In other cases, theremoval of ovaries does not improve the IR,which is a genetic metabolical deficiency. Surgerycombined with suppression of gonadotrophormones is probably the most efficacious of thecurrently used therapies, viable in refactary cases.

7. APERT syndrome. This syndrome was firstdescribed in 1906 [148]. It is a rare congenitalsyndrome type I, characterized by acro-cephalosyndactyly, with an estimated prevalenceof 15/100,000 people, based on a recent

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sidactilie, cu o prevalenþã estimatã la 15/1000000,aceasta având la bazã un studiu demograficrecent, ce constituie aproximativ 4% din cazurilede craniosinostozã (149). Acest sindrom estemoºtenit autozomal dominant ºi este caracterizatprin sinostoze ale extremitãþilor, cu închideripremature ale epifizelor, care au ca rezultatdeformarea mâinilor, picioarelor (frecventdegetele), craniului, sinostoze vertebrale (148,150). Acest sindrom a devenit cunoscutdermatologilor în 1970, dupã ce Solomon adescris cãþiva pacienþi cu acnee moderatã spreseverã, cu o repartiþie neobiºnuitã cu leziuniextinse spre antebraþe. Caracteristicele facialeanormale sunt hipertelorism, occiput plat,prognatism, exoftamie datoratã orbitelor mici,nasul ca un cioc de papagal, degete scurte ºilipite. Erupþii întârziate ale dinþilor, incisivi subformã de lopeþi ºi malocluzia dinþilor.Anormalitãþile pãrþilor superioare ºi inferioareale cãilor respiratorii include, fisuri uºoare pecerul gurii (palatine), omuºor bifid (151). Este oasociere între acnee ºi APERT sindrom (152, 153),cei mai mulþi adolescenþi cu aceste probleme suntpredispuºi la a dezvolta acnee severã postuloasã,care se poate extinde de la zonele tipice spretrunchi ºi suprafaþa antebraþelor ºi fese (154).Închiderea timpurie a epifizelor ca ºi acneea estemediatã androgenic. Nu a fost demonstratã niciodiferenþã în expresia recptorului androgen, întrepacienþii cu APERT sindrom comparativ cu ceilalþi,acest lucru sugerând cã aceastã problemãsubsidiarã din APERT sindrom evidenþiazã osensibilitate (receptivitate) anormalã la un nivelnormal de androgen circulant mai curând decât unexces numeric de receptori androgenici (155-157).Alte modificãri cutanate în APERT includseboreea, hiperhidroza, onicodistrifia, hiper-cheratoza asupra feþelor plantare ºi hipo-pigmentarea ocularã ºi cutanatã (158). Acestsindrom poate fi moºtenit ca un autozomaldominant, dar cele mai multe mutaþii sunt noi ºi deorigine paternã, cu un risc de 1%, ca al doilea copilsã fie afectat. Defectul genetic este o mutaþieinexplicabilã a substituþiei amino acidului adipeptidei serinei-prolinei în exonul 7( segmentulunei gene care conþine informaþii folosite pentrua codifica sinteza de proteine) al cromozomului10, receptorul fibroblastului de creºtere (FGFR-2)(159). În acest sindrom, acneea rãspunde mai

demographic study, covering approximately 4per cent of the craniosynostosis cases [149]. It isan inherited autosomal dominant disordercharacterized by synostosis of extremities,premature epiphyses closing resulting in hand,legs (toes most commonly), skull deformities andvertebral synostoses [148, 150]. This syndromebecame known to dermatologists in 1970, afterSolomon described several patients with mildand severe acne with unusual spreading andextensive lesions on the forearms. Abnormalfacial traits include hypertelorism, occipitalplane, prognathism, exophtalmy due to smallorbits, parrot beak nose, short or bound togetherfingers, delayed teeth eruptions, paddle-likeforeteeth and teeth malocclusion. Abnormalitiesof the upper and lower parts of the respiratorytracts include small fissures on the palatine,uvula bifidus [151]. There is an associationbetween acne and APERT syndrome [152, 153] –most teenagers with Apert are predisposed tosevere pustular acne, which may extend fromtypical areas towards the trunk, forearms andbuttocks [154]. Premature epiphyses closing isandrogenically mediated, like in acne. Nodifference has been noted between the androgenreaction expression in patients with APERTsyndrome as compared to others, which suggeststhat this subsidiary problem in Apert syndromeevinces an abnormal sensitivity (receptivity) to anormal circulating androgen level, and not anexcess in the number of androgen receptors [155-157]. Other skin modifications in APERTsyndrome include seborrhea, hyperhydrosis,onycodystrophy, hyperkeratosis of the plantarsides and ocular and skin hypopigmentation[158]. This syndrome can be inherited as anautosomal dominant disorder, although mostmutations are new and of paternal origin, with a1 per cent risk of contamination in the secondborn child. The genetic deficiency consists in anunexplainable substitution of the aminoacid ofthe dipeptide serine-proline in exon 7 (a genesegment containing information used to codifyprotein synthesis) of the chromozome 10, thefibroblast growth factor receptor (FGFR-2) [159].In this syndrome acne responds less to theadministration of oral or topical antibiotics.

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puþin la administrarea antibioticelor orale sautopice. Tratamentul cu Isotretinoin (160,161) arerezultate clare ºi de aceea este utilizat în toatecazurile inclusv în cele refractare (162). Pentru amenþine efectul terapeutic constant, se foloseºtepe termen lung o dozã redusã de Isotretinoin, a lalong. Din punct de vedere al dietei, trebuieevitate produsele lactate ºi carbohidraþiihiperglicemici.

Intrat în redacþie: 20.01.2012

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Isotretinoin treatment [160, 161] yields clearresults and is used in all cases, refractory onesincluded [162]. In order to keep the therapeuticaleffect constant, a small dose of Isotretinoin isused a la longue. As to the diet, patients shouldavoid dairy products and hyperglycemiccarbohydrates.

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Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresã de corespondenþã: Aura VlãduþiCorresponding address: Serviciul de Dermatologie- Ambulatoriul de Specialitate al Sp. Clinic “C.F. Witting”

Bucureºti, Tel.: 0723235601E-mail: [email protected]

forme severe de acnee ªi sindroame asociate acneei … · câteva complicaþii: carcinomul cu...

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