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BOALA DARIER: CONSIDERAÞII ETIOPATOGENICE,ANATOMO-CLINICE ªI DE DIAGNOSTIC DIFERENÞIAL

DARIER'S DISEASE: ETIOPATHOGENIC, ANATOMO-CLINICAL AND DIFFERENTIAL DIAGNOSIS

CONSIDERATIONS

MIHAELA ANCA POPESCU*, DIACONU JUSTIN-DUMITRU*, SILVIA VASILE*, MIOARA GRIGORE**, VASILE CRISTIAN***

Rezumat

Boala Darier-White, cunoscutã ºi sub denumirea de(dis)keratozã folicularã, reprezintã o genodermatozã rarã,cu transmitere autosomal dominantã, descrisã pentruprima oarã în 1889, atât de Ferdinand-Jean Darier, cât ºi decãtre J.C. White, acesta din urmã semnalând ºi agregareafamilialã a afecþiunii [1,2,3,4]. De-a lungul timpului auexistat numeroase ipoteze în privinþa etiologiei bolii, însã înprezent se considerã cã aceasta este cauzatã de producereaunor mutaþii la nivelul genei ATP2A2, ce codificã ATP-azaCa2+-dependentã a reticulului sarco/endoplasmatic(SERCA2), rezultând tulburãri ale transportuluiintracelular al calciului ºi semnalizãrii calciu-dependente[1,2,4].

Debutul keratozei foliculare se produce cel mai frecventîn primele douã decade de viaþã, fãrã o distribuþiepreferenþialã pe sexe sau grupuri etnice [1,2,4]. Afecþiuneaeste caracterizatã clinic prin apariþia de papule keratozicefoliculare grãsoase galben-maronii, ce tind sã se grupeze înplãci ºi placarde imprecis delimitate, cu distribuþiesimetricã specificã în regiunile seboreice [1,2,4,5]; aproxi-mativ 80% dintre pacienþi prezintã leziuni localizate lanivelul pliurilor (axilar, submamar, inghino-perineal), cepot evolua înspre forme vegetante, cu miros fetid [6,7].Aceste manifestãri pot fi însoþite de modificãri unghiale

Summary

Darier-White disease, also known as (dys)keratosisfollicularis, represents a rare, autosomal dominantlytransmitted genodermatosis, which was first described in1889, both by Ferdinand-Jean Darier, as well as by J.C.White, the latter also pointing out the familial aggregationof the disease[1,2,3,4]. Throughout time there have beennumerous hypotheses regarding the etiology of the disease,but nowadays it is considered that it is caused by mutationsin the ATP2A2 gene, encoding the sarco/endoplasmicreticulum Ca2+ adenosine triphosphatase isoform 2(SERCA2), resulting in disturbances of the intracellulartransport of calcium, and of the calcium-signalingpathway[1,2,4].

The onset of keratosis follicularis occurs mostcommonly during the first two decades of life, without agender or ethnicity-related preferential distribution[1,2,4].The disease is clinically characterized by the appearance ofgreasy yellow-brown keratotic follicular papules, that tendto coalesce into imprecisely defined plaques, with a specificsymmetrical distribution in seborrheic areas [1,2,4,5];approximately 80% of patients present lesions located inthe flexures (axillary, submammary, inguino-perineal),which can evolve into malodorous vegetant forms [6,7].These manifestations may be accompanied by typical nail

* Spitalul Clinic de Boli Infecþioase ºi Tropicale ”Dr. Victor Babeº” Bucureºti, Secþia Clinicã Dermatologie.The Clinical Hospital of Infectious and Tropical Diseases ”Victor Babeº” Bucharest, Department of Dermatology.

** Spitalul Clinic de Boli Infecþioase ºi Tropicale ”Dr. Victor Babeº” Bucureºti, Secþia de Anatomie Patologicã.The Clinical Hospital of Infectious and Tropical Diseases "Victor Babes" Bucharest, Department of Histopathology.

*** Spitalul Clinic de Urgenþã ”Sfântul Ioan” Bucureºti, Secþia de Radiologie.The Emergency Clinical Hospital ”Sfântul Ioan” Bucureºti, Department of Radiology.

REFERATE GENERALEGENERAL REPORTS

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Introducere

Boala Darier reprezintã o dermatozã dis-keratozicã acantolicã ereditarã caracterizatã printulburãri de keratinizare cauzate de mutaþii alegenei ATP2A2 transmise autosomal dominant, cuo penetranþã estimatã la peste 95%, deºiexpresivitatea genicã este variabilã [1,2,4,6,8].Totuºi, în literatura de specialitate au fostraportate ºi cazuri sporadice de keratozãfolicularã, într-un grup de studiu remarcându-selipsa antecedentelor heredocolaterale la 47%dintre pacienþi [1,4]. În astfel de situaþii seconsiderã fie cã bolnavii prezintã mutaþiispontane, fie cã rudele acestora ar fi putut suferide forme uºoare de boalã, ce au fost neglijate saunerecunoscute clinic [4].

La nivel mondial, s-a estimat o prevalenþã aafecþiunii de circa 1:55.000, variind de la 1 caz la26.300 de locuitori în Slovenia sau 1 caz la 30-35.000 de locuitori în nordul Angliei ºi Scoþia, pânã la 1 caz la 100.000 de locuitori în

Introduction

Darier’s disease represents a hereditaryacantholytic dyskeratotic dermatosis, charac-terized by keratinization disorders caused byautosomal dominantly transmitted mutations inthe ATP2A2 gene, with a penetrance estimated atover 95%, although gene expressivity isvariable[1,2,4,6,8]. However, sporadic cases havebeen reported in the specialty literature, onestudy group pointing out the lack of a positivefamily history in 47% of patients [1,4]. In suchcases, it is considered either that the patientsdevelop spontaneous mutations, or that theirfamily members have suffered from mild diseaseforms, which have been neglected or clinicallyunrecognized [4].

Worldwide, the prevalence of the disease hasbeen estimated at about 1:55.000, ranging 1 casein 26.300 inhabitants in Slovenia and 1 case in 30-35.000 inhabitants in northern England andScotland, to 1 case per 100.000 inhabitants in

tipice, papule keratozice localizate la nivelul feþelor dorsaleale mâinilor ºi picioarelor, hiperkeratozã punctatã palmo-plantarã, precum ºi leziuni mucoase [1,2,4,6].

Evoluþia bolii Darier este cronicã, recidivantã, deºi s-aconstatat posibilitatea ameliorãrii manifestãrilor cliniceodatã cu înaintarea în vârstã [7]. Tratamentul prezintã uncaracter paliativ, incluzând metode de profilaxie(fotoprotecþie, emoliente, anti-inflamatoare ºi antisepticelocale), terapia medicamentoasã topicã ºi sistemicã(retinoizi aromatici, corticoizi, 5-fluorouracil), precum ºimultiple alternative chirurgicale (dermabraziune,electroterapie, tratament laser, terapie fotodinamicã, exciziechirurgicalã) [1,2,4].

În cadrul lucrãrii de faþã prezentãm cazul uneipaciente în vârstã de 37 de ani, cu un grad minim de retardmental, cunoscutã cu afecþiuni asociate din sferaendocrinologicã, care a solicitat internarea în clinicanoastrã în urma apariþiei unor leziuni papularepruriginoase, hiperpigmentate, de culoare maroniu-negricioasã, debutate în urmã cu circa 13 ani, iniþial axilar,extinse ulterior ºi la nivelul extremitãþii cefalice, toraceluiºi regiunii genitale. În urma efectuãrii anamnezei ºiexamenului clinic obiectiv a fost ridicatã suspiciunea deacanthosis nigricans tipul 2, apãrut în contextultulburãrilor endocrine asociate, însã examenulhistopatologic al materialului bioptic prelevat de la bolnavãa stabilit diagnosticul de certitudine – boala Darier.

Cuvinte cheie: boala Darier, keratozã folicularã,genodermatoze, acanthosis nigricans.

Intrat în redacþie: 4.11.2013Acceptat: 12.12.2013

Received: 4.11.2013Accepted: 12.12.2013

changes, keratotic papules located on the dorsa of the handsand feet, palmoplantar punctuated hyperkeratosis, as wellas mucosal lesions[1,2,4,6].

The evolution of Darier disease is chronic, recurrent,although the possibility of improving the clinicalmanifestations with age has been observed[7]. The treatmentpresents a palliative character, including preventionmethods (photoprotection, emollients, local anti-inflammatory and antiseptic agents), topical and systemicmedical therapy (aromatic retinoids, corticosteroids, 5-fluorouracil), and also multiple surgical alternatives(dermabrasion, electrotherapy, laser treatment,photodynamic therapy, surgical excision) [1,2,4].

In the current paper we present the case of a 37-year-old female patient with a minimum degree of mentalretardation, know to suffer from endocrine associatedconditions, who requested admission into our clinic afterthe appearance of pruritic, hyperpigmented, brown-blackish, papular lesions, with an onset about 13 years ago,initially axillary and subsequently extended onto thecephalic extremity, thorax and genital area.Following theanamnesis and clinical exam, the suspicion of type 2acanthosis nigricans - occurred in the context of theendocrine associated conditions, was raised, but thehistopathological exam of the biopsy material taken from thepatient established the certainty diagnosis –Darier’sdisease.

Keywords: Darier’s disease, keratosis follicularis,genodermatoses, acanthosis nigricans.

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Danemarca, cu o distribuþie egalã pe sexe ºigrupuri etnice [1,2,4,8,10].

Debutul afecþiunii se produce în mod uzualîn primele douã decade de viaþã, cel mai frecventîntre 6-20 de ani ºi în mod tipic în preajmaadolescenþei, deºi în literatura de specialitate aufost raportate atât apariþia timpurie a primelormanifestãri ale bolii, la vârsta de 4 ani, cât ºicazuri cu debut la vârste înaintate, chiar la 70 deani [4,8].

Printre factorii de risc, ce pot exacerbakeratoza folicularã, sunt incluºi: expunerea laradiaþii ultraviolete, îndeosebi de tip UVB,cãldura ºi umiditatea, transpiraþia, infecþii, agenþimedicamentoºi (litiu, corticoizi orali), trauma-tisme mecanice, precum ºi factori hormonali,uneori fiind raportatã agravarea bolii în relaþie cuciclul mentrual [2,4]

De-a lungul timpului au existat variateipoteze privind etiopatogenia afecþiunii, Darier(1889) incriminând un parazit protozoar din genulPsorospermium, în timp ce Peck (1938) aconsiderat cã boala ar fi produsã de o deficienþã avitaminei A [11].

Prima menþiune cu privire la agregareafamilialã a afecþiunii a fost fãcutã de cãtre J.C. White, în urma remarcãrii apariþiei bolii la 2membri ai aceleiaºi familii – mamã ºi fiicã, iarprimul caz catalogat drept keratozã folicularãcongenitalã a fost diagnosticat în urma efectuãriiunei biopsii cutanate la un copil cu antecedenteheredocolaterale de boalã Darier prezente la celpuþin 3 generaþii precedente acestuia [4,9].Ulterior, odatã cu identificarea localizãrii geneiresponsabile la nivelul benzii cromozomale12q23-q24.1 (1993), a fost demonstratã aparte-nenþa keratozei foliculare la grupul geno-dermatozelor [2,4].

În perioada 1993-1998 au fost realizatemultiple studii vizând cartografierea geneticã abolii Darier, prin intermediul fiecãruiaobþinându-se restrângerea dimensiunii locusuluice conþine gena bolii Darier (DAR), astfel încât, în1998, Ikeda ºi colaboratorii au restrâns acest locusla un interval de 3.3 megabaze (Mb) de la nivelulcromozomului 12 [10,12]. Tot în 1998, Monk ºicolaboratorii au construit un fragment cromo-zomal artificial suprapus parþial, cu continuitateexactã de secvenþã (”contig”), derivat-P1, cudimensiunea de 2.4 Mb, conþinând regiunea

Denmark, with an equal gender and ethnic groupdistribution [1,2,4,8,10].

Onset of the disease typically occurs withinthe first two decades of life, most commonlybetween 6-20 years, and typically aroundadolescence, although the early appearance of thefirst symptoms, at the age of 4, as well as caseswith an onset in older ages, even at 70 years, havebeen reported in the specialty literature[4,8].

Among the risk factors that exacerbatekeratosis follicularis, the following are included:exposure to ultraviolet radiation, particularlyUVB, heat and humidity, sweating, infection,pharmacologic agents (lithium, oralcorticosteroids), mechanical injuries, as well ashormonal factors, aggravation of the disease inrelation to the menstrual cycle having beenreported [2,4]

Throughout time there have been varioushypotheses concerning the etiopathogenesis ofthe disease,Darier (1889) incriminating a parasiticprotozoa of the Psorospermium genus, while Peck(1938) considered that the disorder could becaused by a vitamin A deficiency[11].

The first mention of the disease’s familialaggregation was made by J.C. White, followingobservation of the disorder’s occurrence among 2members of the same family – mother anddaughter, and the first case classified ascongenital keratosis follicularis was diagnosedafter performing a skin biopsy from a child witha family history of Darier disease in at least threeprevious generations[4,9]. Subsequently, alongwith the identification of the responsible gene’slocation in the 12q23-q24.1 chromosomal band,the affiliation of keratosis follicularis to thegenodermatoses group has been proven (1993)[2,4].

During the 1993-1998 period, multiplestudies regarding Darier’s disease gene mappinghave been conducted, each of them narrowingdown the size of the locus containing Darier’sdisease gene (DAR), so that, in 1998, Ikeda et alhad confined the locus to a 3.3 megabase (Mb)interval on chromosome 12[10,12]. Also in 1998,Monk et al have constructed a 2.4 Mb, P1-derived, artificial, partially overlapped chromo-some fragment with an exact continuity sequence

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cromozomului 12 candidatã pentru gena DAR(12q23-q24.1) [10,13].

În 1999, Sakuntabhai ºi colaboratorii auidentificat 12 gene situate în intervalul respectiv,iar în urma screening-ului acestora, s-a constatatprezenþa unor mutaþii la nivelul genei ATP2A2,ce codificã ATP-aza calciu-dependentã areticulului sarco-endoplasmatic (SERCA2 –Sarco/Endoplasmic Reticulum Ca2+-ATPase type2 isoform), o pompã ionicã aparþinând familieiATP-azelor calciu-dependente de tip P, cu rol înmenþinerea unei concentraþii scãzute a calciuluiintracelular [1,2,10,14]. Gena ATP2A2 se întinde pe osuprafaþã de 76 kilobaze (kb), este organizatã în21 de exoni ºi codificã un transcript de 4.4 kb ceîmbinã 3 izoforme, dupã cum urmeazã:SERCA2a, exprimatã la nivelul musculaturiicardiace ºi muºchilor scheletici cu contracþielentã, respectiv SERCA2b ºi SERCA2c, careprezintã o expresie ubicuitarã, deºi s-a remarcatpredilecþia epidermicã a SERCA2b, precum ºiprezenþa acesteia la nivel cerebral [1,2]. PompaSERCA2 catalizeazã hidroliza ATP cuplatã cutranslocarea a 2 ioni de Ca2+ din citosol înlumenul reticulului endoplasmatic, astfel încât s-a ajuns la concluzia cã mutaþiile genei ATP2A2 arconduce la tulburãri în semnalizarea calciu-dependentã ce regleazã adeziunea intercelularã ºidiferenþierea epidermului, iar aceste modificãriau fost considerate responsabile pentruproducerea keratozei foliculare [1,2,4,10,14].

În urma asocierii descoperirilor luiSakuntabhai ºi colab. cu informaþiile legate deidentificarea precedentã a numeroase gene cu rolîn integritatea structuralã cutanatã, ce au fostincriminate în apariþia unor afecþiuni precumepidermoliza buloasã, hiperkeratoza epidermo-liticã, ihtioza buloasã Siemens, keratodermiapalmoplantarã sau pahionichia congenitalã,Peacocke ºi Christiano (1999) au subliniat faptulcã tulburãrile produse în semnalizareaintercelularã ar deþine o deosebitã importanþã îndiferenþierea epidermicã, susþinând astfel ipotezarolului jucat de mutaþiile genei ATP2A2 înproducerea bolii Darier [10,15].

În urma unui studiu realizat pe un grupcompus din 19 familii afectate ºi 6 cazurisporadice de keratozã folicularã, Sakuntabhai ºicolaboratorii (1999) au identificat ulterior încã 24de mutaþii adiþionale ale genei ATP2A2, mai mult

(“contig”), spanning the DAR candidate regionon chromosome 12 (12q23-q24.1) [10,13].

In 1999, Sakuntabhai et al have identified 12genes within that interval, and after havingscreened them, the presence of mutations wasfound in the ATP2A2 gene, which encodes theSarco/Endoplasmic Reticulum Ca2+-ATPase type2 isoform (SERCA2), an ion pump belonging tothe P-type calcium ATPase family, that plays arole in maintaining a low intracellular calciumconcentration[1,2,10,14]. ATP2A2 gene spans an areaof 76 kilobases (kb), is organized into 21 exons,and encodes a 4.4 kb transcript, which is splicedinto three isoforms, as follows: SERCA2a,expressed in cardiac muscle and slow-twitchskeletal muscles, respectively SERCA2b andSERCA2c, that present an ubiquitous expression,although the epidermal propensity of SERCA2bhas been remarked, as well as its presence in thebrain[1,2]. SERCA2 catalyzes the hydrolysis ofATP coupled with the translocation of 2 Ca2+ionsfrom the cytosol into the lumen of theendoplasmic reticulum;thereby, it was concludedthat mutations in the ATP2A2 gene would lead toalterations of the calcium-signaling pathway,which regulates intercellular adhesion andepidermal differentiation, and these modifi-cations were considered responsible for theappearance of keratosis follicularis[1,2,4,10,14].

Following the association of the findingsmade by Sakuntabhai et al with informationabout previous identification of numerous genesinvolved in the structural integrity of the skin,which have been incriminated in the occurrenceof disorders such as epidermolysis bullosa,epidermolytic hyperkeratosis, ichthyosis bullosaof Siemens, palmoplantar keratoderma orpachyonychia congenita, Peacocke andChristiano (1999) pointed out that alterationsproduced in intercellular signaling hold a greatimportance in epidermal differentiation,therefore supporting the hypothesis of the rolethat the ATP2A2 gene plays in the occurrence ofDarier’s disease[10,15].

Through a study conducted on a group of 19affected families and 6 sporadic cases of keratosisfollicularis, Sakuntabhai et al (1999) subsequentlyidentified 24 additional mutations in the ATP2A2

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de 50% dintre acestea determinând apariþiaprematurã a unui codon terminator (”stop”), cuafectarea unor domenii funcþionale ale genei,astfel încât s-a considerat cã transmiterea bolii s-ar produce printr-un mecanism de haplo-insuficienþã [10,16].

Cu toate cã mecanismul biochimic deproducere a bolii este incomplet elucidat, existãnumeroase ipoteze în acest sens [1,4]. Astfel, înurma unui studiu realizat pe un model in vitroconþinând o linie celularã fibroblasticã cu 51 demutaþii prezente în boala Darier, s-au constatatdefecte în expresia proteicã ATP2A2, hidrolizaATP, precum ºi în transportul, legare ºi cineticamoleculelor de calciu [4, 19]. În cadrul altor studii,s-a observat cã agregatele proteice mutanteSERCA2 ar produce suprasolicitarea reticululuiendoplasmatic, cu eºuarea mecanismelorcompensatorii, iar modificarea concentraþieicalciului ar perturba sinteza, plierea ºi traficulproteinelor desmozomale (îndeosebi desmo-plakina), ce ar putea determina ulterior apoptozacelulelor [1,2,4, 20,21].

Pânã în prezent au fost identificate peste 130de mutaþii familiale ºi sporadice ale geneiATP2A2 în rândul pacienþilor suferind de boalaDarier, majoritatea fiind mutaþii de tip nonsens(50%) sau deleþie ºi inserþie (8%), ce determinãsinteza unor proteine anormale structural,precum ºi mutaþii nonsens (12%) sau permutaþii(23%), rezultând în apariþia prematurã a unuicodon ”stop” ºi degradarea ARN-ului mesager,cu decodificare nonsens [2,4]. Totuºi, datoritãremarcãrii unei marcate variabilitãþi fenotipiceinter- ºi intrafamiliale a bolii, precum ºi a faptuluicã tentativele de realizare a unor corelaþiigenotip-fenotip nu au produs rezultate satis-fãcãtoare, a fost sugeratã posibilitatea existenþeiunor factori adiþionali – genetici sau de mediu, cear influenþa atât producerea afecþiunii, cât ºiexpresia sa clinicã [2,4,10,17,18].

Din punct de vedere clinic, boala Darier estecaracterizatã prin apariþia unei erupþiipruriginoase alcãtuitã din papule keratozicefoliculare galben-maronii, cu texturã grãsoasã ºisuprafaþa asprã, adeseori verucoasã, cu tendinþade a se grupa în plãci ºi placarde imprecisdelimitate, cu distribuþie simetricã specificã înregiunile seboreice – la nivelul extremitãþiicefalice (tâmple, frunte, ºanþuri nazogeniene,

gene, more than 50% of them leading to apremature termination codon (“stop”), impairingfunctional domains of the gene, so it wasconsidered that disease transmission could occurthrough a haploinsufficiency mechanism[10,16].

Although the biochemical mechanism of thedisease is incompletely elucidated, numeroushypotheses exist in this regard [1,4]. Thus, as aresult of a study conducted on an in vitro modelcontaining a fibroblast cell line with 51 mutationspresent in Darier’s disease, there have beenfound defects in ATP2A2 protein expression, ATPhydrolysis, as well as in calcium transport,binding and kinetics[4, 19]. In other studies, it wasobserved that mutant SERCA2 proteinaggregates could cause stress to the endoplasmicreticulum, and modification of calciumconcentration could disrupt desmosomal proteinsynthesis, folding and traffic (especiallydesmoplakin), which might subsequently causecell apoptosis [1,2,4, 20,21].

So far, there have been identified more than130 familial and sporadic ATP2A2 mutationsamong patients suffering from Darier’s disease,mostly nonsense mutations (50%) or deletionsand insertions (8%), which result in synthesis ofstructurally abnormal proteins, as well asnonsense mutations (12%) or permutations (23%)resulting in premature termination codons andnonsense mRNA decay[2,4]. However, due toobservations of a marked inter- and intrafamilialphenotypic disease variability, and of the fact thatattempts to achieve genotype-phenotypecorrelations have not produced satisfactoryresults, it was suggested that it was possible foradditional factors to exist – albeit genetic orenvironmental, which could influence bothdisease occurrence, and its clinical expression[2,4,10,17,18].

From a clinical point of view, Darier’s diseaseis characterized by the appearance of pruriticyellow-brown, keratotic follicular papules, with agreasy, rough-textured, often verrucous surface,that have a tendency to coalesce into impreciselydefined plaques, with a specific symmetricaldistribution on seborrheic areas (temple,forehead, nasogenian folds, retrocervical,retroauricular), and on the trunk (presternal,

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retroauricular, laterocervical) ºi la nivelultrunchiului (presternal, interscapulovertebral,periombilical ºi în regiunea sacralã) [1,2,4,5,6].

Aproximativ 80% dintre pacienþi prezintãleziuni discrete localizate la nivelul pliurilor(axilar, submamar, inghino-perineal), deºi în 10%din cazuri acestea pot evolua înspre formevegetante, cu miros fetid [4,6,7].

Leziunile cutanate sunt adeseori însoþite demodificãri unghiale tipice, precum striurilongitudinale, alternanþã de benzi longitudinaleeritematoase ºi albe, pahionichie cu unghii fragileºi fisurate, marginea liberã crestatã în ”V” sauhiperkeratozã subunghialã [1,2,3,4,6].

În circa 15% din cazuri pot fi remarcate ºileziuni mucoase, afectând mucoasa bucalã, limba,epiglota sau mucoasele faringianã, esofagianã,rectalã ºi vulvarã [1]. Cel mai frecvent este afectatãmucoasa bucalã, cu apariþia unor papule albeombilicate, ce pot conflua sau pot realiza unmodel în ”piatrã de pavaj”, mimând leucoplakia,respectiv stomatita nicotinicã; de asemenea, înunele cazuri se pot observa hipertrofie gingivalãsau îngustarea subclinicã ºi obstrucþia glandelorsalivare [1,4].

În literatura de specialitate, pe lângã formaclasicã a bolii, au mai fost descrise o serie devariante clinice de keratozã folicularã, cum ar fiformele veziculo-buloase, erozive ºi buloase sauvegetante, precum ºi douã variante particulare -forma acralã hemoragicã ºi o formã localizatã,segmentarã a afecþiunii, caracterizatã prin pre-zenþa nevilor epidermici diskeratozici acan-tolitici, dispuºi de-a lungul liniilor Blaschko[1,2,10].

Afectarea palmo-plantarã este întâlnitã la 95%dintre pacienþi, incluzând hiperkeratozã punctatãpalmo-plantarã (80%), depresiuni palmare (80%),macule hemoragice (<10%) sau papule keratozicelocalizate la nivelul feþelor dorsale ale mâinilor ºipicioarelor (50%), acestea din urmã neputând fideosebite clinic de leziunile din acrokeratozaveruciformã Hopf [1,2,4,6,10]. De altfel, în cadrulunor studii recente, au fost identificate o serie demutaþii ale genei ATP2A2 în rândul pacienþilorsuferind de acrokeratozã veruciformã Hopf,suprapunerea fenotipicã sugerând faptul cãaceasta din urmã ar putea reprezenta o formãlocalizatã a bolii Darier [4,10].

interscapulovertebral, umbilicus and sacralarea)[1,2,4,5,6].

Approximately 80% of patients presentdiscrete flexural lesions (axillary, mammary,inguino-perineal), although these can evolvetowards vegetant, malodorous forms in 10% ofthe cases[4,6,7].

Cutaneous lesions are often accompanied bytypical nail changes, such as longitudinal ridges,alternating white and red longitudinal bands,pachyonychia with brittle and fissured nails, a”V”-shaped nick at the margin of the nail, orsubungual hyperkeratosis [1,2,3,4,6].

In 15% of the cases there can be observedmucosal lesions, affecting the oral mucosa, tongue,epiglottis, and pharyngeal, esophageal,rectal orvulvar mucosas[1]. The most commonly affectedis the oral mucosa, with the occurrence of whiteumbilicated papules, which may coalesce orrealize a ”cobblestone” pattern, mimickingleukoplakia or, respectively, nicotine stomatitis;also, in some cases, gingival hypertrophy orsubclinical narrowing and obstruction of thesalivary glands can be observed[1,4].

In addition to the classic form of the disease,a series of clinical variants of keratosis follicularishave been described in the specialty literature,such as vesiculobullous, erosive and bullous orvegetant forms, as well as two particular variants–the acral hemorrhagic form and a localized,segmental form of disease, characterized by thepresence of acantholytic dyskeratotic epidermalnaevi along the lines of Blaschko[1,2,10].

Palmoplantar involvement is seen in 95% ofpatients, including palmoplantar punctuatedhyperkeratosis (80%), palmar pits (80%),hemorrhagic macules (<10%) or keratotic papuleslocated on the dorsum of the hands and feet(50%), the latter being clinically indistinguishablefrom the lesions seen in acrokeratosisverruciformis of Hopf[1,2,4,6,10]. Moreover, in somerecent studies, several mutations in the ATP2A2gene have been identified among patientssuffering from acrokeratosis verruciformis ofHopf, the phenotypic overlap suggesting that thelatter could represent a localized form of Darier’sdisease [4,10].

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Caz clinic

În lucrarea de faþã prezentãm cazul uneipaciente în vârstã de 37 de ani, din mediul urban,cunoscutã cu boalã Basedow-Graves operatã înurmã cu 8 ani (tiroidectomie subtotalã), aflatã întratament de substituþie tiroidianã culevotiroxinã 150 µg/zi, precum ºi cu dismenoreeºi oligomenoree post-partum, care a solicitatinternarea în clinica noastrã în urma apariþieiunei erupþii papulare pruriginoase, hiper-pigmentatã, de culoare maroniu-negricioasã,debutatã în urmã cu circa 13 ani, iniþial axilar,extinsã ulterior ºi la nivelul extremitãþii cefalice,toracelui ºi regiunii genitale.

Din antecedentele heredocolaterale alepacientei reþinem cã tatãl acesteia suferã dediabet zaharat non-insulinodependent.

În privinþa antecedentelor personale fizio-logice, de menþionat cã pacienta a dus la termen 2sarcini, cu o evoluþie normalã a acestora ºinaºterea unor copii sãnãtoºi, însã cu instalareaunor manifestãri de tip dismenoree-oligomenoree post-partum (afirmativ în urmaultimei naºteri).

Clinical case

In the current paper we present the case of a37-year-old female patient of urban provenience,known to suffer from Basedow-Graves diseasethat was surgically treated 8 years ago (subtotalthyroidectomy), undergoing thyroid substitutiontherapy with levothyroxine 150 mg/day, as wellas with postpartum dysmenorrhea andoligomenorrhea, who requested admission intoour clinic following the appearance of pruritic,hyperpigmented, brown-blackish, papularlesions, with an onset about 13 years ago, initiallyaxillary and subsequently extended onto thecephalic extremity, thorax and genital area.

From the patient’s family history, wereport that her father is suffering fromnoninsulin-dependent diabetes mellitus.

Regarding the personal physiologicalbackground, we mention that the patient carriedto term 2 normally-evolved pregnancies, givingbirth to two healthy children, but that werefollowed by postpartum dysmenorrhea andoligomenorrhea (affirmatively after the lastbirth).

Fig. 1. Boala Darier - papule hiperkeratozice hiperpigmentateperianogenitale, cu tendinþã de extindere

înspre mucoasa genitalãFig. 1. Darier's disease - perianogenital hyperpigmented,

hyperkeratotic papules, with a tendency to extend towards thegenital mucosa

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În privinþa stilului de viaþã ºi regimuluiigieno-dietetic, de reþinut cã pacienta estefumãtoare (7PA), consumã cafea, neagãconsumul de alcool ºi nu lucreazã în mediu toxic.

La examenul clinic dermatologic a fostremarcatã o erupþie pruriginoasã hiperpig-mentarã maroniu-negricioasã, pe alocuri custriuri albe, alcãtuitã din papule hiperkeratozicerugoase, acoperite de scuamo-cruste aderente, cutendinþa de confluare în plãci ºi placarde dedimensiuni variabile, cu contur neregulat, relativbine delimitate, localizate la nivelul extremitãþiicefalice (faþã, gât), axilar bilateral, toraceluianterior ºi perianogenital, cu tendinþa deextindere înspre mucoasa genitalã. La nivelulscalpului se remarcã discret eritem ºi scuamegãlbui, grãsoase.

La examenul clinic general s-a constatatprezenþa unei minime exoftalmii ºi ahipertelorismului ocular, un indice de masãcorporalã în limite normale (IMC = 21.1. kg/m2),precum ºi multiple adenopatii de consistenþãfermã, neaderente ºi nedureroase, dupã cumurmeazã: laterocervicale bilaterale (3/1.5 cmdreapta, 2/1 cm stânga), retroauricularebilaterale (1/0.7 cm dreapta, 0.7/0.3 cm stânga),axilarã dreaptã (3.5/2 cm) ºi multiple adenopatiiinghinale bilaterale cu dimensiuni sub 1 cm. Laexamenul clinic al aparatului respirator s-auevidenþiat un murmur vezicular înãspritbilateral, diminuat la nivelul hemitoracelui drept,raluri crepitante înmulþite ”în ploaie” dupã tuseîn baza câmpului pulmonar drept ºi tuse cuexpectoraþie muco-purulentã. Examenul clinic alaparatului cardiovascular a relevat o matitatecardiacã în limite normale, ritm de galop alzgomotelor cardiace, fãrã sufluri valvulare, TA =123/70 mmHg, AV = 85 bpm. Examenul apa-ratului digestiv nu a evidenþiat modificãri clinice,însã pacienta a acuzat pirozis ºi meteorismabdominal apãrute postprandial. În privinþaritmului somn-veghe, adaptãrii la variaþii termiceºi statusului psiho-emoþional, nu au putut firemarcate manifestãri sugestive pentru undezechilibru hormonal. Totodatã, s-a evidenþiatun grad minim de retard mental. În rest,examenul clinic general a fost în limite normale.

În ceea ce priveºte explorãrile paraclinice,hemoleucograma completã a evidenþiat leuco-citozã (12.200/µl) cu neutrofilie (7900/ µl), iar la

Concerning the lifestyle and hygienic-dietaryregimen, we report that the patient is a smoker(7PY), consumes coffee, denies alcoholconsumption and does not work in a toxicenvironment.

Upon dermatological clinical exam, weobserved pruritic, hyperpigmented, brown-blackish lesion with patchy white streaks,consisting of rough hyperkeratotic papulescovered by adherent scales, with a tendency tocoalesce into irregularly-shaped, relatively well-defined plaques of variable dimensions, locatedon the cephalic extremity (face, neck), axillarybilaterally, anterior thorax and perianogenital,tending to extend towards the genital mucosa.On the scalp, a discrete erythema and greasyyellow scales were noticed.

General physical exam revealed the presenceof minimal exophthalmia and ocular hyper-telorism, a body mass index within normal range(BMI = 21.1. kg/m2), as well as multiple firm,mobile, painless adenopathies, as follows:laterocervical bilaterally (right 3/1.5 cm, left 2/1cm), retroauricular bilaterally (right 1/0.7 cm, left0.7/0.3 cm), right axillary (3.5/2 cm) and severalbilateral inguinal adenopathies sized under 1 cm.Examination of the respiratory system revealed adecreased vesicular murmur in the righthemithorax, with a rough tonality bilaterally,crackles multiplied by coughing in the rightpulmonary field, and coughing withmucopurulent sputum.Clinical examination ofthe cardiovascular system revealed a cardiacdullness within normal range, a gallop rhythm ofthe heart sounds, absence of valvular murmurs,BP=123/70 mmHg, HR=85 bpm. Examination ofthe digestive system showed no clinical changes,but the patient accused postprandial pyrosis andabdominal meteorism. In respect of the circadianrhythm, thermoregulation and psycho-emotionalstatus, there could not be observed anymanifestations suggesting a hormonal imbalance.Concurrently, a minimum degree of mentalretardation was noticed. Otherwise, generalphysical examination was within normal range.

Regarding paraclinical examinations, thecomplete blood count revealed leukocytosis(12.200/µl) with neutrophilia (7900/ µl), andurine analysis showed microscopic hematuria(25RBC/HPF).

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sumarul de urinã s-a constatat hematuriemicroscopicã (25 eritrocite/câmp).

În urma efectuãrii anamnezei ºi a examenuluiclinic obiectiv, a fost stabilit diagnosticul deprezumþie de acanthosis nigricans tip 2, încontextul tulburãrilor endocrine asociate.Totodatã, manifestãrile respiratorii au fostconsiderate de naturã infecþioasã viralã,concluzie susþinutã de modificãrile paraclinice(leucocitozã cu neutrofilie), iar tulburarea de ritmcardiac s-a suspectat a fi în relaþie cu tratamentulde substituþie tiroidianã urmat de pacientã.

Discuþii

Evaluarea paraclinicã a pacienþilor cu boalãDarier include efectuarea examenului histo-patologic al piesei prelevate prin intermediulbiopsiei cutanate, precum ºi recomandareacartografierii genetice, în vederea evidenþieriimutaþiilor genei ATP2A2 [4].

În cazul pacientei prezentate, examenulhistopatologic al materialului bioptic prelevat dela nivelul toracelui anterior, respectiv de la nivelgenital a relevat marcatã hiperkeratozã, focal cuformare de dopuri keratozice foliculare, marcatãacantozã ºi papilomatozã. La mai multe niveluriau fost constatate zone de acantolizã, cu formarede lacune/spaþii de clivaj suprabazale, cuperetele inferior neregulat, acoperit de puþinerânduri de celule bazale, precum ºi alte zone declivaj mãrginite inferior de proeminenþe papilaredermale tapetate de celule bazale epidermale;intralacunar ºi la nivelul stratului cornos, s-auobservat celule diskeratotice cu citoplasmãpuþinã ºi nuclei de talie micã (corpi tip ”grains”).La nivelul straturilor spinoase superficiale, aufost remarcate depozite intracitoplasmatice dekeratohialin ºi celule diskeratotice mari, cunucleu rotund, central ºi halou clar perinuclear(”corps ronds”). La nivel dermal s-a evidenþiatmoderat infiltrat inflamator cronic, limfocitar, cunumeroase melanofage.

Diagnosticul keratozei foliculare esteorientat de cãtre informaþiile relevate deanamnezã (antecedente heredocolaterale ºipersonale, debut, evoluþie), precum ºi de cãtreaspectul clinic, însã confirmarea unui diagnosticde certitudine are la bazã rezultatele examenuluianotomopatologic [4,8], la fel ca ºi în cazulpacientei prezentate în lucrarea de faþã –

After conducting the anamnesis and theobjective clinical exam, a presumption diagnosisof acanthosis nigricans type 2 was established, inthe context of the associated endocrine disorders.At the same time, the respiratory manifestationswere considered to be most likely of viral origin,a conclusion that was supported by laboratorychanges (leukocytosis with neutrophilia), and thecardiac dysrhythmia was suspected to be relatedto the thyroid substitution therapy that thepatient was ongoing.

Discussions

The paraclinical evaluation of Darier diseasepatients includes the histopathological exam of thetissue sample obtained by performing a skinbiopsy, as well as the recommendation of geneticmapping, in order to identify mutations in theATP2A2 gene[4].

In regards to the presented patient, thehistopathological exam of the biopsy materialtaken from the anterior thorax, respectively fromthe genital area revealed marked hyperkeratosis,with focal formation of follicular keratotic plugs,as well as marked acanthosis and papillomatosis.Acantholytic regions could be observed at severallevels, forming lacunae/ suprabasal cleavageareas with an irregular inferior wall covered by afew rows of basal cells, as well as other cleavageareas inferiorly bordered by dermal papillaryprojections lined with epidermal basal cells;within the lacunae and in the stratum corneum,dyskeratotic cells with condensed cytoplasm andsmall nuclei (”corps grains”) were observed.Intracytoplasmic keratohyalin deposits and largedyskeratotic cells with round, central nucleusand a clear perinuclear halo (”corps ronds”) werenoticed in the superficial spinous layers. Achronic lymphocytic inflammatory infiltrate wasevidenced in the dermis.

The diagnosis of keratosis follicularis isoriented by the information revealed byanamnesis (family and personal history, onset,evolution), as well as by the clinical appearance,but the confirmation of a certainty diagnosis isbased upon the results of the histopathologicexam[4,8], just like in the case of the patientpresented in the current paper – the highlightedhistopathologic findings being characteristic ofDarier’s disease, although some joint features

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modificãrile histopatologice evidenþiate fiindcaracteristice bolii Darier, deºi au putut firemarcate ºi trãsãturi comune cu acan-thosis nigricans (hiperkeratozã, papilomatozã,acantozã, prezenþa pigmentului melanic dermal).

with acanthosis nigricans could be observed(hyperkeratosis, papillomatosis, acanthosis, thepresence of dermal melanic pigment).

The differential diagnosis of keratosisfollicularis includes various disorders,depending on the clinical expression of the

Fig. 2. Boala Darier, hematoxilinã-eozinã (HE, lupã, detaliu – obiectiv 40x): hiperkeratozã (♦), acantozã («), diskeratozã + corpi tip ”grains” (­), acantolizã + lacunã suprabazalã (n)

Fig. 2. Darier disease, hematoxylin-eosin (HE, magnifying glass, detail - 40x): hyperkeratosis (♦), acanthosis («), dyskeratosis + "corps grains" (­) , acantholysis + suprabasal lacuna (n)

Fig. 3. Boala Darier, HE (10x,40x): dop keratozic folicular, acantozã (Ó); corpi ”ronds” ( )

Fig. 3. Darier disease, HE (10x,40x): follicular keratotic plug, acanthosis(Ó); "corp ronds" ( )

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Fig. 4. HE, 4x: papilomatozã hiperkeratozã (♦); acantozã («) papillomatosis, hyperkeratosis (♦), acanthosis («)jos: detalii 10x, 40x - corpi ”ronds” ( ) down: details 10x, 40x - ”corp ronds” ( )

sus, jos: detalii/up, down: details 10x, 40x - ”corp ronds” ( ), melanofage/melanophages(p)

Fig. 4. HE, 4x: papilomatozã hiperkeratozã (♦); acantozã («) papillomatosis, hyperkeratosis (♦), acanthosis («)jos: detalii 10x, 40x - corpi ”ronds” ( ) down: details 10x, 40x - ”corp ronds” ( )

sus, jos: detalii/up, down: details 10x, 40x - ”corp ronds” ( ), melanofage/melanophages(p)

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Diagnosticul diferenþial al keratozei foli-culare include afecþiuni variate, în funcþie demanifestãrile clinice ale bolii. Astfel, forma clasicãtrebuie distinsã de dermatita seboreicã, kera-tozele seboreice, acnee sau de eczema discoidã,iar leziunile de la nivelul pliurilor se pot asemãnacelor observate în intertrigo-ul candidozicsubmamar, acanthosis nigricans sau boalaDowling Degos; forma veziculo-buloasã poatemima dermatoza acantoliticã tranzitorie (boalaGrover), forma vegetantã poate simula unpemfigus vegetant, iar în forma acralã se impuneadeseori diagnosticul diferenþial cu acrokeratozaveruciformã Hopf, deºi leziunile pot fi similare ºiverucilor plane [1,2,4]. Nu în ultimul rând, formeleerozive ºi buloase trebuie deosebite de pemfigusulbenign familial Hailey-Hailey, pemfigusulvulgar, histiocitoza cu celule Langerhans ºiinfecþiile candidozice sau bacteriene (impetigo)[2]. De reþinut suprapunerea clinicã dintre boalaDarier ºi pemfigusul benign familial Hailey-Hailey - singurele genodermatoze autosomaldominante cauzate de anomalii ale ATP-azeicalciu-dependente, unii autori considerând cãboala Hailey-Hailey ar reprezenta o variantãclinicã buloasã a keratozei foliculare [10].

Tratamentul bolii Darier prezintã un caracterpaliativ ºi include metode de profilaxie(fotoprotecþie, emoliente, anti-inflamatoare ºiantiseptice locale), terapia medicamentoasãtopicã ºi sistemicã (retinoizi aromatici, corticoizi,5-fluorouracil), precum ºi multiple alternativechirurgicale (dermabraziune, electroterapie,tratament laser, terapie fotodinamicã, exciziechirurgicalã) [1,2,4].

În privinþa cazului prezentat, pacienta abeneficiat de tratament topic cu o soluþie pe bazãde fluocinolon, alantoinã ºi dimetilsulfoxid,menþinut pânã la obþinerea rezultatuluiexamenului histopatologic, iar evoluþia a fostsatisfãcãtoare, cu diminuarea pruritului, însã fãrãa putea fi remarcate modificãri semnificative aleleziunilor cutanate.

Pe durata internãrii s-a putut remarca ºiremiterea virozei respiratorii, în urma instituiriiunui tratament anti-inflamator (paracetamol),expectorant (erdosteinã) ºi a antibioterapieiprofilactice (amoxicilinã 500 mg/acid clavulanic125 mg).

La externare, pacienta a primit recomandarearespectãrii unui regim igieno-dietetic adecvat,

disease. Thus, the classic form must bedistinguished from seborrheic dermatitis,seborrheic keratosis, acne or discoid eczema, andflexural lesions may resemble submammarycandida intertrigo, acanthosis nigricans orDowling Degos disease; the vesiculo bullous formmay mimic transient acantholytic dermatosis(Grover disease), the vegetant form can simulatepemphigus vegetans, and the acral form oftenimposes a differential diagnosis with acrokerato-sis verruciformis of Hopf, although lesions maybe similar to verruca plana[1,2,4]. Lastly, erosive andbullous forms must be distinguished from Hailey-Hailey benign familial pemphigus, pemphigusvulgaris, Langerhans cell histiocytosis, andcandidal or bacterial infections (impetigo)[2]. It isimportant to keep in mind the clinical overlapbetween Darier’s disease and Hailey-Haileybenign familial pemphigus– the only autosomaldominant genodermatoses caused byabnormalities of the calcium ATPase, someauthors considering that Hailey-Hailey diseasemight represent a bullous clinical variant ofkeratosis follicularis[10].

The treatment of Darier disease presents apalliative character and includes preventionmethods (photoprotection, emollients, local anti-inflammatory and antiseptic agents), topical andsystemic medical therapy (aromatic retinoids,corticosteroids, 5-fluorouracil), and also multiplesurgical alternatives (dermabrasion,electrotherapy, laser treatment, photodynamictherapy, surgical excision)[1,2,4].

Regarding the presented case, the patientreceived topical treatment with a fluocinolone,allantoin and dimethyl sulfoxide-based agent,which was maintained until the results of thehistopathological exam were obtained, and theevolution was satisfactory, with a diminishmentof the pruritus, although no significant changesof the cutaneous lesions could be noted.

During the hospitalization period, remissionof the respiratory viral infection was alsoobserved, following anti-inflammatory(paracetamol) and mucolytic (erdosteine)treatment, and also prophylactic antibio-therapy(amoxicillin 500 mg/clavulanic acid 125mg).

At discharge, the patient received therecommendation to abide by an adequatehygienic-dietary regimen, including permanent

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incluzând fotoprotecþie permanentã, evitareaexpunerii la radiaþii UV, intemperii ºi infecþiiintercurente, a traumatismelor ºi stresului psiho-emoþional, precum ºi interzicerea fumatului. Deasemenea, a fost menþionatã importanþacontinuãrii tratamentului dermatologicrecomandat ºi a tratamentului propriu cu vizãendocrinologicã, cu indicaþia efectuãrii unorreevaluãri clinico-paraclinice ºi terapeuticeperiodice, precum ºi a unor controale urologic,gastroenterologic ºi cardiologic vizând hematuriamicroscopicã, respectiv acuzele digestive ºitulburarea de ritm decelatã la auscultaþiacardiacã. Nu în ultimul rând, a fost recomandatãefectuarea unei tomografii computerizate toraco-abdomino-pelvine, în vederea evaluãriimultiplelor adenopatii constatate la examenulclinic obiectiv.

Odatã cu obþinerea rezultatului examenuluihistopatologic, a fost propusã o schemãterapeuticã cu retinoizi topici ºi sistemici, însã,datoritã faptului cã pacienta a refuzatadministrarea de acitretin, s-a optat pentruasocierea dintre aplicarea localã de tretinoin ºitratamentul sistemic cu vitaminã A (150.000U.I/zi).

Evoluþia bolii Darier este cronicã, recidivantã,variabilã din punctul de vedere al severitãþii, launii pacienþi constatându-se ameliorareamanifestãrilor clinice odatã cu înaintarea învârstã, în timp ce în alte cazuri a fost raportatfenomenul opus [2,7].

Complicaþiile afecþiunii sunt îndeosebi denaturã înfecþioasã, în rândul pacienþilor cu boalãDarier remarcându-se o susceptibilitate crescutãpentru infecþii cutanate virale (virus herpessimplex ºi poxvirus) sau piodermite [2,4].Îngustarea subclinicã ºi obstrucþia glandelorsalivare pot determina stazã, cu tumefierearecurentã a acestora, creând condiþii favorabilepentru apariþia litiazei glandelor salivare [1,22]. Deasemenea, rareori, a fost raportatã prezenþa unorulceraþii corneene recidivante, ce au evoluatînspre perforaþie [2].

Nu în ultimul rând, trebuie amintitã asociereakeratozei foliculare cu o serie de comorbiditãþi denaturã neuropsihiatricã (tulburãri de învãþare,retard mental, boalã bipolarã, schizofrenie,epilepsie) ºi anomalii osoase variate (cel maifrecvent, chisturi asimptomatice ale oaselor

photoprotection, avoiding exposure to UVradiation, adverse climatic conditions,intercurrent infections, local trauma and psycho-emotional stress, as well as prohibition ofsmoking. Also, the importance of continuingboth the suggested dermatological treatment andher endocrinologically-targeted therapy wasmentioned, with the indication of periodicclinical and paraclinical reevaluation, as well asurological, gastroenterological and cardiologicalspecialized consultations, regarding themicroscopic hematuria, respectively the digestivecomplaints and the dysrhythmia detected duringcardiac auscultation.Not the least, it wasrecommended that a thoraco-abdomino-pelvicCT scan would be performed, in order to assessthe multiple adenopathies detected upon theobjective physical examination.

Once the result of the histopathological examwas obtained, a therapeutic course consisting oftopical and systemic retinoids was proposed;however, due to the fact that the patient refusedadministering acitretin, we opted for theassociation of topical tretinoin and systemicvitamin A treatment (150.000 I.U/day).

The evolution of Darier’s disease is chronic,recurrent, variable in terms of severity, in somepatients an improvement of clinicalmanifestations being ascertained with age, whilein other cases the opposite phenomenon wasreported[2,7].

The complications of the disease areparticularly of an infectious nature, an increasedsusceptibility to viral cutaneous infections(herpes simplex virus or pox virus) being noticedamong patients with Darier disease [2,4].Subclinical narrowing and obstruction of thesalivary glands can determine stasis, with theirrecurrent swelling, creating favorable conditionsfor the occurrence of salivary gland lithiasis[1,22].Also, the presence of recurrent corneal ulcers,evolving towards perforation, has rarely beenreported [2].

Lastly, it must be noted that keratosisfollicularis can be associated with a series ofcomorbidities of a neuropsychiatric nature(learning disorders, mental retardation, bipolardisorder, schizophrenia, epilepsy) and variousbone abnormalities (most commonly,asymptomatic cysts of the long bones)[1,2,4,10,22]. It

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lungi) [1,2,4,10,22]. Este important de menþionat cã,în cadrul unui studiu efectuat pe o populaþie deºoareci transgenici cu haploinsuficienþã SERCA2,au fost constatate tulburãri ale contractilitãþiicardiace ºi o incidenþã crescutã a carcinoamelorscuamocelulare – îndeosebi gastrointestinale,deºi aceste descoperiri nu corespund celorîntâlnite în rândul pacienþilor suferind de boalãDarier [1].

Prognosticul vital al pacienþilor cu boalãDarier este bun, aceºtia prezentând o speranþã deviaþã similarã populaþiei generale, cu excepþiasituaþiilor când dificultãþile întâlnite în stabilireadiagnosticului de certitudine, cu instituireatardivã a tratamentului adecvat, conduc cãtre oevoluþie fatalã a complicaþiilor infecþioase [4].

De reþinut faptul cã simptomatologia ºimanifestãrile clinice ale bolii – cu precãderepruritul sau aspectul ºi mirosul fetid al leziunilorvegetante, precum ºi afecþiunile asociate din sferaneuropsihiatricã, determinã un disconfortpsihosocial deloc neglijabil ºi pot influenþacapacitatea de desfãºurare a activitãþilor coti-diene, afectând calitatea vieþii pacienþilor [4].

În cazul pacientei prezentate, se poate estimaun prognostic vital bun, însã observaþiile legatede evoluþia afecþiunii nu sunt semnificative,întrucât bolnava a dat dovadã de o slabãcomplianþã, nerespectând recomandarea re-evaluãrii periodice.

Concluzii

Boala Darier reprezintã o tulburare dekeratinizare rarã, cu evoluþie cronicã, transmisãautosomal dominant, cauzatã de mutaþii alegenei ATP2A2, ce codificã ATP-aza Ca2+-dependentã a reticulului sarco/endoplasmatic(SERCA2), rezultând în tulburãri aletransportului intracelular al calciului ºisemnalizãrii calciu-dependente [1,2,3,4]. Afecþiuneaeste frecvent asociatã cu tulburãri de ordinneuropsihiatric, iar evidenþierea expresieiSERCA2 la nivel cerebral, precum ºi remarcareaimportanþei semnalizãrii calciu-dependenteneuronale, au atras atenþia asupra relaþiei dintreafecþiunile dermatologice ºi cele neuropsihiatrice– mai exact asupra posibilitãþii ca acestea sãreprezinte expresia aceleiaºi anomalii genetice,problematicã ce a fost ridicatã adeseori înliteratura de specialitate [2].

is important to mention that, in a studyconducted on a population of transgenic micehaploinsufficient for SERCA2, impaired cardiaccontractility and an increased incidence ofsquamous cell carcinomas - particularlygastrointestinal, were observed, although thesefindings do not correspond to those encounteredamong patients suffering from Darier’s disease[1].

Vital prognosis of patients with Darierdisease is a good one, with a life expectancysimilar to the general population, except forsituations when the difficulties encountered inascertaining a certainty diagnosis, with belatedestablishment of the appropriate treatment, leadtowards a fatal evolution of infectiouscomplications [4].

It is retainable that the symptomatology andclinical manifestations of the disease – especiallythe pruritus and the malodorous vegetantlesions, as well as the associated neuropsychiatricdisorders, determine a psychosocial discomfortthat cannot be taken lightly, and may affect theability to conduct daily activities, affecting thepatients’ quality of life[4].

In the case of the presented patient, a goodvital prognosis can be estimated, butobservations related to the evolution of thedisease are not significant, since the patientshowed poor compliance, disregarding therecommendation of regular revaluation.

Conclusions

Darier’s disease is a rare chronic ker-atinization disorder with an autosomal dominanttransmission, which is caused by mutations in theATP2A2 gene that encodes the Sarco/Endoplasmic Reticulum Ca2+-ATPase type 2isoform (SERCA2), resulting in impairment ofintracellular transport of calcium and of thecalcium-signaling pathway[1,2,3,4]. The disorder isfrequently associated with neuropsychiatricconditions, and evidencing SERCA2 cerebralexpression, as well as observing the importanceof the neuronal calcium-signaling pathway, havedrawn attention to the relationship betweencutaneous diseases and neuropsychiatricdisorders – namely the possibility that theyrepresent an expression of the same genetic

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Aceste observaþii, alãturi de constatareasuprapunerii clinice a bolii Darier cu altegenodermatoze (acrokeratoza veruciformã Hopf,pemfigusul benign familial Hailey-Hailey), suntde naturã sã stimuleze interesul medical învederea investigãrii genetice suplimentare aafecþiunii.

Cazul de faþã a fost prezentat datoritã raritãþiibolii, particularitãþii manifestãrilor clinice, cuafectarea pliurilor ºi mucoasei genitaleasemãnãtoare acanthosis nigricans, precum ºi dincauza asocierii unor tulburãri de naturãneuroendocrinã, cardiacã ºi gastroenterologicã(minim retard mental, antecedente de boalãBasedow-Graves operatã, aflatã în tratament desubstituþie tiroidianã, dismenoree ºi oligo-menoree post-partum, ritm cardiac de galop,pirozis ºi meteorism abdominal apãrutepostprandial).

anomalies, an issue that has often been raised inspecialty literature[2].

These findings, along with the acknowl-edgement of the clinical overlap betweenDarier’s disease and other genodermatoses(acrokeratosis verruciformis of Hopf, Hailey-Hailey benign familial pemphigus), are capableof stimulating medical interest towards furthergenetic investigation of this condition.

The current case was presented due to therarity of the disease, the particularity of clinicalmanifestations, affecting flexural regions and thegenital mucosa in a fashion similar to acanthosisnigricans, and because of the association withneuroendocrine, cardiac and gastroenterologicaldisorders (minimum mental retardation, ahistory of operated Basedow-Graves diseaseundergoing thyroid substitution therapy,postpartum dysmenorrhea and oligomenorrhea,gallop cardiac rhythm, postprandial pyrosis andmeteorism).

Bibliografie/Bibliography

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Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresa de corespondenþã: Spitalul Clinic de Boli Infecþioase ºi Tropicale ”Dr. Victor Babeº”, Secþia Clinicã Dermatologie, ªoseaua Mihai Bravu nr. 281, Sector 3, Bucureºti, Tel.: 021.317.27.27

Correspondance address: The Clinical Hospital of Infectious and Tropical Diseases ”Dr. Victor Babeº”, Department of Dermatology, ªoseaua Mihai Bravu nr. 281, Sector 3, Bucharest, Phone: 021.317.27.27

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families with intrafamilial variability. Br J Dermatol. Apr 2004;150(4):652-7.18. Bchetnia M, Charfeddine C, Kassar S, Zribi H, Guettiti HT, Ellouze F. Clinical and mutational heterogeneity of

Darier disease in Tunisian families. Arch Dermatol. Jun 2009;145(6):654-6.19. Miyauchi Y, Daiho T, Yamasaki K, et al. Comprehensive analysis of expression and function of 51

sarco(endo)plasmic reticulum Ca2+-ATPase mutants associated with Darier disease. J Biol Chem. Aug 112006;281(32):22882-95.

20. Wang Y, Bruce AT, Tu C, et al. Protein aggregation of SERCA2 mutants associated with Darier disease elicits ERstress and apoptosis in keratinocytes. J Cell Sci. Nov 2011;124:3568-80.

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22. Cihangir Aliagaoglu, Ali Yhsan Güleç, Ümran Yýldýrým, Hülya Albayrak. Is Pruritus Trigger Bandlike PatternDarier Disease: Positive Koebner Phenomenon?. Eur J Gen Med. 2007; 4(2):95-7.