SINDROMUL GORLIN-GOLTZ - O BOALĂ EREDITARĂ RARĂ ªI O

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SINDROMUL GORLIN-GOLTZ - O BOALÃ EREDITARÃRARÃ ªI O PROVOCARE DE DIAGNOSTIC

GORLIN-GOLTZ SYNDROME - A RARE HEREDITARYDISORDER AND A DIAGNOSTIC CHALLENGE

MIRCEA TAMPA*,**, ISABELA SÂRBU**, CRISTINA ªTEFAN**, MIHAELA ÞOVARU*,**, MONICA COSTESCU*,**, VASILE BENEA**, SIMONA ROXANA GEORGESCU*,**

* Universitatea de Medicinã ºi Farmacie „Carol Davila“, Bucureºti.“Carol Davila” University of Medicine and Pharmacy.

** Spitalul Clinic de Boli Infecþioase ºi Tropicale „Dr. Victor Babeº“, Bucureºti.“Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Dermatology Department.

Rezumat

Sindromul Gorlin-Goltz este o genodermatozã rarã cutransmitere autozomal dominantã care asociazã apariþia demultiple carcinoame bazocelulare (CBC) cu alte anomalii,printre care chisturi odontogene mandibulare, depresiunipalmo-plantare, calcificarea coasei creierului ºi variatemodificãri scheletale.

Prezentãm cazul unui pacient de sex masculin, învârstã de 36 de ani care se prezintã cu leziuni tumoralemultiple situate la nivelul feþei, urechilor ºi trunchiului, oparte dintre acestea fiind ulcerate. Examinarea CT cranianãa evidenþiat calcificarea coasei creierului ºi a confirmatmacrocefalia diagnosticatã clinic iar la radiografia de toraces-a decelat prezenþa unei coaste bifide. Diagnosticul desindrom Gorlin-Goltz este certificat de întrunirea a 4criterii majore (multiple bazalioame apãrute înainteavârstei de 20 ani, calcificare de falx cerebri, depresiunipalmare multiple ºi prezenþa unei coaste bifide) ºi a 2criterii minore ( macrocefalie ºi bose frontale proeminente).

Recunoaºterea manifestãrilor bolii de cãtre mediculdermatolog, pediatru sau medicul de familie poate contribuisemnificativ la stabilirea unui diagnostic precoce, aspectdeosebit de important deoarece în acest fel severitatea unoradintre complicaþii -cum ar fi tumorile maligne cerebrale ºicutanate- poate fi redusã considerabil.

Cuvinte-cheie: genodermatozã, sindrom Gorlin-Goltz, epiteliom bazocelular.

Summary

Gorlin-Goltz syndrome is a rare genodermatosisinherited in an autosomal dominant manner, whichassociates the development of multiple basal cell carcinomaswith other disorders, such as jaw odontogenic cysts, palmarand plantar pits, calcification of the falx cerebri and variousskeletal abnormalities.

We report on the case of a 36 year old male patient,from the rural area, who addresses our clinic presentingmultiple tumoral lesions located on the face, ears and trunk,some of them ulcerated. The TC examination proved thecalcification of falx cerebri and confirmed the clinicallydiagnosed macrocephaly while the chest X-ray revealed thepresence of a bifid rib. In the case we are presenting, thediagnosis was certified by the presence of 4 major criteria(multiple basal cell carcinomas which had occurred beforethe age of 20 years, calcification of the falx cerebri, multiplepalmar pits and the presence of a bifid rib) and 2 minorcriteria (macrocephaly and frontal bossing).

The recognition of the hallmarks of this condition bythe dermatologist, paediatrician or family doctor cansignificantly contribute to an early diagnosis, an aspect ofparamount importance that may contribute to decreasingthe severity of certain complications, such as cerebral andcutaneous malignant tumors.

Keywords: genodermatosis, Gorlin-Goltz syndrome,basal cell epithelioma.

Intrat în redacþie: 18.12.2012Acceptat: 6.02.2013

Received: 18.12.2012Accepted: 6.02.2013

CAZURI CLINICECLINICAL CASES

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DermatoVenerol. (Buc.), 58: 23-36

Introducere

Sindromul Gorlin-Goltz este o genoder-matozã rarã, cu transmitere autozomal domi-nantã, care asociazã apariþia de multiplecarcinoame bazocelulare (CBC) cu alte anomalii,printre care chisturi odontogene mandibulare,depresiuni palmo-plantare, calcificarea coaseicreierului ºi variate modificãri scheletale.

Patogeneza sindromului este atribuitãanomaliilor braþului lung al cromozomului 9 (înregiunea 9q22.3-q31) ºi pierderii sau mutaþiilorgenei PTCH1 cu penetranþã completã, darexpresivitate variabilã. Diagnosticul se bazeazãpe întrunirea unor criterii clinice ºi radiologice;este ideal ca diagnosticul astfel stabilit sã fieconfirmat prin analiza ADN-ului cromozomial.

Prezentare de caz

Prezentãm cazul unui pacient de sexmasculin, în vârstã de 36 de ani, din mediul rural,care se prezintã cu leziuni tumorale multiplesituate la nivelul feþei, urechilor ºi trunchiului, oparte dintre acestea fiind ulcerate.

Examenul clinic evidenþiazã un pacientafebril, echilibrat hemodinamic, cu retard mentaluºor, obezitate de gradul II ºi macrocefalie cubose frontale proeminente ºi prezenþa anumeroase depresiuni palmare, fãrã a prezentaalte modificãri patologice. Antecedentele heredo-colaterale au fost greu de stabilit din cauza uneianamneze dificile, iar interogatoriul luat mameipacientului s-a dovedit de asemenea puþinfructuos. Reþinem cã primele leziuni tumorale auapãrut încã din perioada prepubertarã la nivelulumerilor, fiind succedate de apariþia unor leziuniasemãnãtoare la nivelul extremitãþii cefalice ºi altrunchiului la intervale de timp variate înrãstimpul scurs pânã la prezentare, pentru carepacientul a fost tratat în alte servicii dedermatologie, fãrã a putea preciza cu exactitate înce mod.

Examenul local a evidenþiat prezenþa demultiple formaþiuni tumorale ale extremitãþiicefalice, umerilor ºi trunchiului, de aspectevariate: de o parte ºi de alta a aripilor nazale, 2largi plaje tumorale de aproximativ 5/3 cm pehemiobrazul stâng, coborând pânã aproape de

Introduction

Gorlin-Goltz syndrome is a rare geno-dermatosis, inherited in an autosomal dominantmanner, associating the development of multiplebasal cell carcinomas (BCCs) with otherdisorders, such as jaw odontogenic cysts, palmarand plantar pits, calcification of the falx cerebriand various skeletal abnormalities. Thepathogenesis of the syndrome is attributed toabnormalities located on the long arm ofchromosome 9 (the 9q22.3-q31 region) and to theloss or mutations in PTCH1 gene with completepenetrance but variable expressivity. Thediagnosis is based on the fulfilment of clinicaland radiological criteria; it is ideal for theascertained diagnosis to be confirmed throughchromosomal DNA analysis.

Case presentation

We report on the case of a 36 year old malepatient, from the rural area, who addresses ourclinic presenting multiple tumoral lesions locatedon the face, ears and trunk, some of themulcerated.

The clinical examination reveals a nonfebrile,hemodynamically stable patient, with mildmental retardation, second degree obesity,macrocephaly and bossing of the forehead andnumerous palmar pits, without the presence ofother pathological anomalies. Establishing anaccurate family history was problematic due to adifficult anamnesis, the patient mothers’interrogation also proving non-rewarding. Thefirst tumoral lesions had occurred since pre-puberty on the shoulders and were succeeded bythe development of similar lesions on thecephalic extremity and the trunk, at variousperiods of time preceding the presentation, forwhich the patient asserts that he was treated inother dermatology services, but was not able tooffer precise information regarding the exacttreatment.

Local examination revealed the presence ofmultiple tumoral lesions on the cephalicextremity, shoulders and trunk, of variousappearances: on both sides of the nasal wingstwo large tumoral areas measuring 5/3 cm on theleft cheek descending and almost reaching theupper lip, and 4/2 cm on the right cheek, well

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buza superioarã, ºi 4/2 cm pe hemiobrazul drept,bine delimitate, cu contur policiclic ºi marginiperlate proeminente. Leziunile sunt ulceratecentral, mai pronunþat pe partea stângã, unde seremarcã o zonã de ulceraþie impresionantã,cvasiterebrantã ce cuprinde aripa nazalã înporþiunea ei latero-superioarã. În proximitateacantusului intern bilateral se remarcã formaþiunitumorale rotund-ovalare, bine delimitate, erite-matoase, translucide, cu contur regulat, cudimensiuni cuprinse între 1.3/1 ºi 0.9/0.7 cm, cumargini perlate.

De asemenea, am putut observa prezenþa deformaþiuni tumorale cu aceleaºi caracteristici ºicu dimensiuni variate la nivelul regiuniitemporo-zigomatice ºi fronto-temporale stângi,câteva tumori perlate, cu dimensiuni mai mici lanivelul unghiului mandibulei de partea dreaptãºi o ulceraþie cu chenar perlat la jumãtateaºanþului nazolabial stâng. Printre aceste leziunisunt prezente ºi numeroase cicatrici deprimate,rezultate cel mai probabil în urma intervenþiilorterapeutice anterioare.

Retroauricular bilateral au putut fi observatetumori de dimensiuni mai mici, bine delimitate,perlate, unele dintre acestea ulcerate, iar alteleexofitice. O ulceraþie de aproximativ 8/5 cm, cumargini bine delimitate, perlate este prezentã lanivel cervico-mandibular stâng. La nivelulumerilor ºi pãrþii superioare a trunchiului, atâtanterior cât ºi posterior se evidenþiazã multipleleziuni tumorale cu caracteristici similare celordescrise mai sus, bine delimitate, cu marginielevate, perlate, cu dimensiuni variate, între 1/2ºi 3/5 cm, unele cu tendinþã la ulcerare sau dejaulcerate. (fig.1)

Examinarea CT cranianã a evidenþiatcalcificarea coasei creierului ºi a confirmatmacrocefalia diagnosticatã clinic; la radiografiade torace s-a decelat prezenþa unei coaste bifide.

Pe parcursul internãrii s-au excizatchirurgical câteva dintre leziunile tumoraleulcerate de la nivelul feþei. Examenulhistopatologic a confirmat în toate specimenelesuspiciunea clinicã de epitelioame bazocelularede tip solid cu arii de diferenþiere keratozicã ºiinvazie în dermul profund, cu moderat infiltratinflamator polimorf intra ºi peritumoral,moderatã reacþie desmoplazicã ºi numeroasecalcificãri distrofice intra ºi peritumoral. (fig. 2)

marginated, with polycyclic rim and raised pearl-like borders. The lesions are centrally ulcerated,especially on the left side, where one can noticean impressing, quasi-terebrant, ulceration areacomprising the nasal wing in its lateral andsuperior portion. In the proximity of the internalcanthus we noticed round-oval shaped, welldemarcated tumors, with regular borders anddimensions ranging from 1.3/1 to 0.9/0.7 cm,with pearled borders.

We also noticed the presence of tumorssharing the same characteristics and of variousdimensions in the temporal-zygomatic and leftfrontal-temporal areas, a few pearl-like tumoursof smaller dimensions located at the rightmandibular angle and an ulceration with pearledborders located at the half of the nasolabial fold.Besides these lesions, numerous depressed scars,most probably resulting from previous treat-ments, were also present.

Smaller, well demarcated, pearled retro-auricular tumors, some of them ulcerated andsome exophytic, can also be observed bilaterally.An ulceration measuring about 8/5 cm, with wellmarginated pearled borders is present in the leftcervical-mandibular area. On the shoulders andthe upper part of the trunk, on both ventral anddorsal side, we notice multiple tumoral lesionssimilar to the ones described above, welldemarcated, with raised, pearled borders, ofvarious dimensions, ranging from 1/2 to 3/5 cm,some of them showing the propensity to ulcerateor being already ulcerated. (fig. 1)

The TC examination proved the calcificationof falx cerebri and confirmed the clinicallydiagnosed macrocephaly; the chest X-rayrevealed the presence of a bifid rib.

During admission some of the ulceratedtumoral lesions located on the face weresurgically excised. The histopathologicalexamination confirmed, in all specimens, theclinical suspicion of solid-type basal cellcarcinomas with keratotic differentiation andinvasion into the deep dermis, moderate intraand peri-tumoral polymorph inflammatoryinfiltrate, moderate desmoplastic reaction andnumerous intra and peri-tumoral dystrophiccalcifications. (fig. 2)

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Fig. 1. Aspect clinic la prezentare: formaþiuni tumorale multiple, unele dintre ele ulcerate, localizate la nivelul feþei, gâtului ºi retroauricular

Fig. 1. Clinical appearance at presentation: multiple tumoral lesions, some of them ulcerated, located on the face, neck and retro-auricular

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Pe baza aspectelor clinice, histopatologice ºi ainvestigaþiilor paraclinice, s-a stabilitdiagnosticul de sindrom Gorlin-Goltz.

În afarã leziunilor excizate chirurgical,celelalte tumori au fost tratate prin aplicaþiitopice de Imiquimod 5%, pacientul urmând sã fiemonitorizat la controale periodice ulterioarepentru aprecierea eficacitãþii tratamentului.

Discuþii

Sindromul Gorlin-Goltz sau sindromulnevoid bazocelular (engl. nevoid basal cellcarcinoma syndrome) reprezintã o boalã geneticãrarã, cu transmitere autozomal dominantã, cupenetranþã completã ºi expresivitate variabilã,caracterizatã prin prezenþa unei largi varietãþi detulburãri de dezvoltare ºi predispoziþia pentrudiverse carcinoame, în special epitelioamebazocelulare multiple cu debut în copilãrie sauadolescenþã [1, 2]. Având în vedere cã leziunilecutanate nu sunt singurele sau cele mai severemanifestãri ale bolii, se preferã termenul desindrom Gorlin-Goltz celui de sindrom nevoidbazocelular [3]

Primele publicaþii cu privire la aceastã boalãdateazã din anul 1894 când Jarisch a prezentatasocierea de multiple epitelioame bazocelulare cutulburãri ale scheletului la un pacient cu scoliozãºi retard mental. În 1960 sindromul nevoidbazocelular a fost descris în detaliu de cãtreGorlin ºi Goltz sub forma triadei clasice:carcinoame bazocelulare, chiste odontogene

Based on the clinical, histopathological andlaboratory findings we established the diagnosisof Gorlin-Goltz syndrome.

Besides the surgically excised lesions, theother tumors were treated using topical 5%Imiquimod and the patient was monitoredthrough periodic follow-up visits, in order toassess the efficacy of the treatment.

Discussions

Gorlin-Goltz syndrome or nevoid basal cellcarcinoma syndrome is a rare genetic disorderwith dominant autosomal inheritance, withcomplete penetrance and variable expressivitycharacterised by the presence of a wide variety ofdevelopmental abnormalities and predispositionfor developing various carcinomas, particularlymultiple basal cell carcinomas with childhood oradolescence onset [1,2]. Since the cutaneouslesions are not the only nor the most severemanifestations of the disease, the term of Gorlin-Goltz syndrome is preferred to the one of nevoidbasal cell carcinoma syndrome [3].

The first reports on this disease date back tothe year 1894 when Jarisch presented theassociation of multiple basal cell carcinomas withskeletal abnormalities in a patient with scoliosisand mental retardation. In 1960 the nevoid basalcell carcinoma syndrome was described in detailby Gorlin and Goltz as a classic triad: basal cellcarcinomas, jaw odontogenic cysts and skeletalabnormalities [3]. In 1969 Satinoff and Wells

Fig. 2. Aspect histopatologic: explicaþii în textFig. 2. Histopathological appearance: description in the text

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mandibulare ºi deformãri scheletice. [3] În anul1969 Satinoff ºi Wells au descoperit asociereachisturilor mandibulare cu prezenþa coastelorbifide, elemente ale sindromului Gorlin, la douãmumii datând din perioada dinasticã egipteanãprovenind din aceeaºi familie ºi au arãtat cãsindromul existã încã din anul 1000 î.Hr. [4, 5]

Incidenþa la naºtere este de aproximativ1/19000 [2], iar prevalenþa bolii variazã larg înfuncþie de zona geograficã, între 1/56000 depersoane în Marea Britanie [6] ºi 1/256000 depersoane în Italia, în Australia fiind de 1/164000de persoane. [1, 7]

Boala afecteazã ambele sexe în aceeaºimãsurã [2, 8]. Apare la toate rasele, dar cupredilecþie la caucazieni; în acest caz ºimanifestãrile cutanate sunt mult mai frecventedecât la persoanele de culoare [5, 9]

Leziunile cutanate apar în general între vârstapubertãþii ºi 35 de ani, [6] dar au fost raportate ºicazuri de debut la vârste extreme, la pacienþi cuvârsta de 2 ani ºi respectiv 65 de ani. [2].

Sindromul Gorlin se datoreazã unor mutaþiiapãrute la nivelul genei supresoare tumoralePTCH1 (patched), situate pe braþul scurt alcromozomului 9 (9q22.3-q31) [10], care producalterãri la nivelul cãii de semnalizareintracelularã hedgehog, în cadrul cãreia produsulgenei PTCH1 joacã un rol crucial. PTCH1 codificão proteinã cu 12 domenii transmembranare careare atât rolul de receptor pentru Shh (sonichedgehog protein) cât ºi rolul de a inhibaproteina transmembranarã Smo (smoothened),de care se leagã. Moleculele Shh fac parte dintr-oclasã de molecule cu trei exponenþi, alãturi de ihh(indian hedgehog) ºi dhh (desert hedgehog), fiind ceamai potentã dintre acestea; moleculele Shh joacãun rol important atât în dezvoltarea embrionarã,cât ºi în reglarea numãrului de celule stem dinpiele ºi în diferenþierea glandelor sebacee ºi afirului de pãr [11]. În cazul legãrii Shh de PTCH1,aceasta din urmã va elibera proteina Smo, aceastala rândul sãu urmând sã activeze proteinele Gli-1ºi Gli-2 (glioblastoma 1 ºi 2), proteine de tip zinc-finger cu funcþie parþial redundantã care sunt înmod normal ancorate de citoschelet unde suntlizate în mod continuu de cãtre proteazomi înmolecule mai mici, cu rol de represori aitranscripþiei. În urma activãrii cãii hedgehog,proteinele Gli nu vor mai fi clivate, ci vor

discovered the association of mandibular cystswith the presence of bifid vertebrae, elements ofGorlin syndrome, in two mummies dating fromthe Egyptian dynastic period belonging to thesame family and proved that the syndromeexisted ever since the year 1000 BC [4,5].

The incidence at birth is about 1/19 000 [2]and the prevalence of the disease widely variesdepending on the geographic areas, ranging from1/56 000 persons in Great Britain [6] to 1/256 000in Italy, in Australia being 1/164 000 persons [1,7].

The disease affects both genders in the samemanner [2,8]. It occurs in all the races, but with apredilection for the Caucasians; in this last casethe cutaneous manifestations are also much morefrequent than in black skin individuals [5,9].

The cutaneous lesions generally occurbetween the age of puberty and 35 years [6], butthere have been reports of cases debuting atextreme ages, in patients aged as little as 2 and aselder as 65 years old [2].

Gorlin syndrome is caused by mutationsoccurring in the tumoral suppressor gene PTCH1(patched), located on the short arm ofchromosome 9 (9q22.3-q31) [10], which producealterations in the hedgehog intracellular signallingpathway, in which the product of the PTCH1gene plays a crucial role. PTCH1 encodes aprotein with 12 transmembrane domains whichplays both the role of receptor for Shh (sonichedgehog protein) and the role of inhibiting theSmo (smoothened) tramsmembrane protein, bybinding it. The Shh molecules belong to a class ofmolecules comprising three exponents, alongwith ihh (indian hedgehog) and dhh (deserthedgehog); Shh are the most potent of them all;the molecules play an important role in bothembrionary development and adjusting thenumber of stem cells from the skin and thedifferentiation of sebaceous glands and hair cells[11]. When Shh binds to PTCH1, the latter willrelease the Smo protein, which will activate Gli-1and Gli-2 proteins (glioblasoma 1 and 2), zinc-finger proteins with partially redundant functionwhich are normally anchored to the cytoskeletonwhere they are continuously lysed byproteasomes into smaller molecules which act astranscription repressors. After the activation ofthe hedgehog pathway, the Gli proteins will nolonger be cleaved and will penetrate the nucleuswithout being lysed, where they will act as

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pãtrunde în nucleu fãrã a fi lizate ºi vor acþiona cafactori activatori ai transcripþiei pentrunumeroase molecule cu rol în proliferareacelularã. PTCH1 blocheazã activarea acestei cãide semnalizare în absenþa Shh; alterãrile PTCH1apãrute în cazul mutaþiilor la nivelul 9q22.3-q31determinã o funcþionare anormalã a PTCH1 carenu va mai lega în mod corespunzãtor proteinãSmo ºi în consecinþã calea Smo-Gli-1,2 va fiactivatã constituþional, producând un semnalcelular de proliferare care duce în cele din urmãla apariþia epitelioamelor bazocelularecaracteristice sindromului Gorlin [12]. Mai mult,în oncogenezã se pare cã un rol important îl joacãºi stimularea expresiei proteinei antiapoptoticeBcl-2 via proteina Gli-2, împiedicarea apoptozeiprin Bcl-2 ducând la supravieþuirea exageratã acelulelor tumorale [13,14]. (fig 3)

activating transcription factors for numerousmolecules having cellular proliferation role.Whereas PTCH1 blocks the activation of thissignalising pathway in the absence of Shh,PTCH1 alteration occurred in mutations at9q22.3-q3 determine an abnormal functioning ofPTCH1 which will no longer adequately bind theSmo protein and the Smo-Gli-1-2 pathway willsubsequently be constitutionally activatedproducing a cell proliferation signal which willfinally lead to the development of basal cellcarcinomas which are typical for Gorlinsyndrome [12]. Moreover, the stimulation of theBcl-2 anti-apoptotic protein expression via Gli-2protein also plays an important role inoncogenesis, the disturbance of apoptosisthrough Bcl-2 leading to exaggerate survival ofthe tumor cells [13, 14]. (fig 3)

Fig. 3. Calea de semnalizare intracelularã hedgehog. PTCH1: gena supresoarã tumoralã patched 1, Smo - proteinatransmembranarã smoothened, Gli 1 - glioblastoma 1, Gli 2 - glioblastoma 2, Pr - proteazom, Shh - protein sonic hedgehog

Fig. 3. Hedgehog intracellular signalling pathway. PTCH1: tumoral suppressor gene (patched1), Smo- smoothenedtransmembrane protein, Gli 1 - glioblastoma 1 protein, Gli 2 - glioblastoma 2 protein, Pr- proteasome, Shh-sonic hedgehog protein

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Din punct de vedere clinic, sindromul Gorlin-Goltz asociazã numeroase anomalii:

Afectarea cutanatã:CBC din cadrul sindromului nu pot fidiferenþiate de cele sporadice decât prinnumãrul mare în care apar de la o vârstãfragedã. [15] Aspectul este variat: tumori mici,hemisferice, translucide, cu telangiectazii pesuprafaþã, ferme la palpare, cu diametrul de 1-10 mm [16]. Numãrul leziunilor variazã,putând ajunge chiar la câteva sute în rarecazuri. [6] CBC apar mai frecvent la nivelulfeþei ºi toracelui, dar pot fi localizate ºi lanivelul zonelor abdomenului sau genital. [10]depresiunile palmo-plantare, deºi inconstante,sunt foarte caracteristice [16]. Reprezentândmici defecte ale stratului cornos de culoare roz[15], ele au rareori dimensiuni mai mari de 2-3mm. [16]. Se gãsesc mai frecvent pe palmedecât pe plante ºi nu reprezintã precursori aiepitelioamelor bazocelulare. [10]alte leziuni cutanate: nevi multipli, milia,chisturi epidermoide [10]

Afectarea stomatologicã: chisturile odontogene mandibulare ºi maxilareapar la 60-90% dintre pacienþi. [16] Pot fiasimptomatice ºi diagnosticate radiologicîntâmplãtor sau pot produce eroziuni osoaseînsoþite de durere, tumefacþie ºi pierdereadinþilor. [15] Prezintã o capsulã externã,fibroasã ºi sunt cãptuºite de un epiteliuscuamos stratificat keratinizat; reprezintã celmai constant ºi specific semn pentrusindromul Gorlin-Goltz în prima ºi a douadecadã a vieþii. [10]alte afectãri stomatologice: malocluzie,prognatism mandibular, cheilo/palatoschizis,ectopie sau heterotopie dentarã, ageneziedentarã, hiperplazie bilateralã a procesuluicoronoid al mandibulei [10, 17].

Afectarea sistemului nervos central:calcificãri ectopice ale sistemului nervoscentral: calcificarea lamelarã a coasei creieruluiapare la 70-85% dintre pacienþi ºi este un semnde mare specificitate.[3, 10]. Mai rar, au fostraportate calcificãri ale cortului cerebelului,diafragmei ºeii turceºti ºi osificarea completãsau incompletã a ºeii turceºti [10]

Clinically, Gorlin-Goltz syndrome associatesnumerous abnormalities:

Cutaneous abnormalities:BCCs related to the syndrome can only bedifferentiated from the sporadic forms throughthe large number in which they arise from anearly age [15]. The appearance varies: small,hemispheric, translucid tumors presentingtelangiectasias on the surface, ferme, rangingfrom 1 to 10 mm in diameter [16]. The numberof lesions varies and can even reach a fewhundreds in some persons [6]. BCCs occurmore frequently on the face and trunk, but canalso be located on the abdomen and genitalia[10].palmar-plantar pits, though inconstant, arehighly characteristic [16]. They represent pink,small defects of the squamous layer [15] andrarely exceed 2-3 mm [16]. They are morefrequently encountered on the palms than thesoles and are not precursors of basal cellcarcinomas [10].other cutaneous lesions: multiple nevi, milia,epidermoid cysts.

Stomatologic abnormalities:odontogenic keratocysts of the jaws occur in60-90% of the patients [16]. They can beasymptomatic and radiologically diagnosedby hazard or they can produce bone erosionsaccompanied by pain, tumefaction and loss ofteeth [15]. They present a fibrous, externalcapsule and an internal lining of keratinizedstratified squamous epithelium and representthe most consistent and specific sign forGorlin-Goltz in the first and second decades oflife [10]. other stomatologic changes: malocclusion,mandibular prognathism, cleft palate and lip,dental ectopy and heterotopy, dental agenesis,bilateral hyperplasia of the mandibularcoronoid processes [10, 17].

Central nervous system abnormalities:ectopic calcifications of the central nervoussystem: lamellar calcification of the falx cerebrioccurs in 70-85% of the patients and representsa highly specific sign [3,10]. Rarelly, there havebeen reports of calcifications of the tentoriumcerebelli, the diaphragma sellae and completeor partial bony bridging of the sella turcica[10].

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meduloblastomul are o frecvenþã deaproximativ 3-5% ºi reprezintã o complicaþieredutabilã a bolii. [6, 18] retardul mental apare la aproximativ 5% dintrepacienþi ºi este legatã frecvent de asocierea cutumori cerebrale precum meduloblastomulsau sarcomul cerebelar. [3, 18]alte afecþiuni: hidrocefalie, meningioame,anosmie, surditate centralã, personalitateschizoidã, agenezia sau disgenezia corpuluicalos [19]

Afectare scheletalã:pacienþii sunt mai înalþi decât media, iaraproximativ 70% dintre pacienþi au anomaliicranio-faciale reprezentate de bose frontale ºiparietale proeminente, macrocefalie, rãdãcinanasului lãrgitã ºi hipertelorism [10].anomaliile cutiei toracice reprezentate decoaste bifide, scolioza,coaste largi, sinostozecostale sau agenezii costale. [8, 10]alte anomalii: sindactilie, cifoscoliozã,polidactilie, spina bifida ocultã, anomalieSprengel (umãr ridicat congenital), chisteosoase ale degetelor ºi scurtarea celui de-alpatrulea metacarpian [3, 8, 17].

Afectare ocularã:hipertelorism (40%), exoftalmie, amaurozãcongenitalã, strabism convergent saudivergent, glaucom, cataractã [19]

Afectarea sistemului genitourinar:la femei: chiste ºi fibroame ovariene, calcificãriovariene, leiomisarcoame uterine, fibrosarcoameovarienela bãrbaþi: hipogonadism, criptorhidie, distri-buþia ginoidã a pãrului pubian, ginecomastieambele sexe: rinichi în potcoavã, agenezierenalã unilateralã, chiste renale [10, 17, 19]

Afectarea sistemului cardiovascular:fibroame cardiace [17]aritmii [10, 18]

Pentru stabilirea diagnosticului sunt necesareobþinerea unui istoric al bolii, examinarea clinicãpe aparate ºi sisteme, examinãri radiologice,ecografie ovarianã, ecocardiografie ºi, nu înultimul rând, testarea geneticã în vedereadecelãrii mutaþiilor PTCH1 în cazurile în carediagnosticul este incert. [10, 20]

Pentru stabilirea diagnosticului Evans ºicolab. au propus o listã de criterii (1993) [7, 18]acestea fiind ulterior modificate de cãtre Kimonisºi colab. (1997) - tabelul 1 [17, 21, 22].

Medulloblastoma appears with a frequency ofapproximately 3-5% and represents aredoubtable complication of the disease [6,18].Mental retardation occurs in about 5% of thepatients and is frequently related to theassociation of brain tumors such asmedulloblastoma or cerebelli sarcoma) [3,18].other changes: hydrocephaly, meningiomas,anosmia, central deafness, schizoidpersonality, agenesis or disgenesis of thecorpus callosum [19].

Skeletal abnormalitiespatients are taller than average and about 70%have cranial-facial anomalies represented byprominent frontal and parietal bossing,macrocephaly, wide nose root andhypertelorism [10].thoracic anomalies represented by bifidvertebrae, scoliosis, splayed ribs, fused ormissing ribs [8,10].Other anomalies: sindactyly, kyphoscoliosis,polydactyly, spina bifida occulta, Sprengelanomaly (congenital elevation of theshoulder), cysts in the bones of the fingers,short fourth metacarpal [3,8,17].

Ocular abnormalities:hypertelorism (40%), exophthalmus,congenital amaurosis, internal or externalstrabismus, glaucoma, cataract [19]

Genito-urinary system abnormalities:in women: ovarian cysts and fibromas, ovariancalcifications, uterine leiomyocarcomas,ovarian fibrosarcomasin men: hypogonadism, cryptochidism, femalepubic escutcheon, gynecomastiaboth genders: horseshoe kidney, unilateralrenal agenesis, renal cysts [10, 17, 19]

Cardiovascular system abnormalities:cardiac fibromas [17]arrhythmias [10, 18]

In order to establish the diagnosis, attaining ahistory, the system organ class clinicalexamination, radiological examinations, ovarianechography, echocardiography and, last but notleast, genetic testing for detecting PTCH1mutations for cases with uncertain diagnosis, aremandatory [10, 20].

Evans & all established a list of criteria forascertaining the diagnosis (1993) [7, 18], which

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Pentru stabilirea diagnosticului de sindromGorlin-Goltz sunt necesare întrunirea fie a 2criterii majore ºi a unui criteriu minor, fie a unuisingur criteriu major ºi a 3 criterii minore [17]. Încazul pacientului prezentat, diagnosticul estecertificat de întrunirea a 4 criterii majore(multiple bazalioame apãrute înaintea vârstei de20 ani, calcificare de falx cerebri, depresiunipalmare multiple ºi prezenþa unei coaste bifide) ºia 2 criterii minore (macrocefalie ºi bose frontaleproeminente).

Diagnosticul diferenþial trebuie fãcut cu altesindroame care prezintã carcinoame bazocelularemultiple:

sindromul Bazex (Bazex-Dupré-Christol):genodermatozã cu transmitere X-linkatãcaracterizatã prin CBC multiple ce apar înspecial la nivelul feþei în a doua decadã a vieþii;atrofodermie folicularã cu precãdere la nivelulfeþei, mâinilor, coatelor ºi picioarelor;hipotricozã; hipohidrozã. [23]sindromul Rombo: genodermatoza cutransmitere autozomal dominantã carac-terizatã prin apariþia de multiple CBC, înasociere cu atrofodermie vermiculatã facialã,milia, telangiectazii, hipotricozã, trico-epitelioame ºi vasodilataþie perifericã. [6, 24)

was later revised by Kimonis & all (1997) - table 1[17, 21, 22].

The presence of 2 major criteria and oneminor criterion or 1 major criterion and threeminor criteria are necessary to establish thediagnosis of Gorlin-Goltz syndrome [17]. In thecase we are presenting, the diagnosis is certifiedby the presence of 4 major criteria (multiple basalcell carcinomas which had occurred before theage of 20 years, calcification of the falx cerebri,multiple palmar pits and the presence of a bifidrib) and 2 minor criteria (macrocephaly andfrontal bossing).

The differential diagnosis must considerother syndromes presenting multiple basal cellcarcinomas:

Bazex syndrome: (Bazex- Dupré-Christol):genodermatosis with X-linked inheritancecharacterised by multiple BCCs which developmainly on the face during the second decade oflife; follicular atrophoderma, especially on theface, hands, elbows and feet; hypotrichosis;decreased sweating [23].Rombo syndrome: genodermatosis inheritedin an autosomal dominant manner,characterised by the development of multipleBCCs associated with facial atrophodermavermiculata, milia, teleangiectasias,

Tabelul 1. Criterii de diagnostic - sindromul Gorlin-Goltzdupã Evans, modificat Kimonis (17)

Criterii majore:

CBC multiple cu debut înaintea vârstei de 20 de anichiste odontogene ale maxilarelor, diagnosticate prinexamen histopatologic3 sau mai multe depresiuni palmare ºi/sau plantare calcificãri bilamelare ale falx cerebricoaste bifide sau sinostoze costalerude de gradul I diagnosticate cu sindrom Gorlin-Goltz

Criterii minore:

macrocefaliemalformaþii congenitale: palatoschizis saucheilopalatoschizis, bose frontale proeminente,hipertelorismalte tulburãri ale scheletului: anomalie Sprengel (umãrulridicat congenital), sindactilieanomalii radiologice: accentuarea ºeii turceºti, anomaliivertebrale precum fuziunea sau elongarea corpilorvertebrali fibrom ovarianmeduloblastom

Table 1. Diagnosis criteria - Gorlin-Goltz syndrome, after Evans modified by Kimonis (17)

Major criteria:

Multiple basal cell carcinomas occurring under the age of20 yearsHistologically proven odontogenic keratocysts of the jawThree or more palmar or plantar pits Bilamellar calcifications of the falx cerebriBifid or fused ribsFirst degree relatives with nevoid basal cell carcinomasyndrome

Minor criteria:

MacrocephalyCongenital malformation: Cleft lip or cleft palate, frontalbossing, hypertelorismOther skeletal abnormalities: Sprengel deformity, markedsyndactyly Radiological abnormalities: Bulging of sella turcica,vertebral anomalies such as fusion or elongation ofvertebral bodiesOvarian fibromaMedulloblastoma

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sindromul Rasmussen–afecþiune autozomaldominantã caracterizatã prin asocierea decilindroame, tricoepitelioame ºi milia. [25]xeroderma pigmentosum: genodermatozã cutransmitere autozomal recesivã caracterizatãprin sensibilitate crescutã la soare, pacienþiidezvoltând carcinoame bazocelulare multiple,alãturi de alte neoplazii cutanate.[6]

Managementul pacienþilor

Pacienþii vor fi sfãtuiþi sã evite expunerea lasoare ºi sã foloseascã creme-ecran cu factor deprotecþie solarã ridicat [6, 15].

Fiecare leziune trebuie abordatã individual,punându-se accentul pe distrugerea leziunilortumorale în stadii precoce. Excizia chirurgicalãnu este întotdeauna posibilã, cu precãdere atuncicând existã un numãr mare de leziuni, deoarecese asociazã cu riscul desfigurãrii severe apacientului, mai ales dacã se încearcãîndepãrtarea tumorii cu margini de siguranþãoncologicã.

Chirurgia Mohs este o alternativã, puþinaccesibilã însã din cauza costurilor ridicate. [6,15]. Metodele non-chirurgicale pot fi folosite maiales în cazul tumorilor multiple, superficiale.Astfel chiuretarea, electrocauterizarea saucrioterapia pot fi utilizate în tratamentul CBC dela nivelul trunchiului. [6]. Aplicaþiile locale de 5-FU ºi imiquimod pot fi de asemenea folosite înCBC superficiale cu rezultate bune [15, 26, 27].Totodatã, acolo unde numãrul mare de leziunisuperficiale împiedicã folosirea terapiilorconvenþionale, terapia fotodinamicã reprezintã oalternativã bunã de tratament, prezentândavantajul abordãrii unor suprafeþe cutanate mailargi (engl. „field therapy“). [28, 29]. Tratamentuloral cu retinoizi este eficient, dar doar la doze lacare efectele adverse sunt severe [15]. Dupã uniiautori radioterapia nu reprezintã o opþiune detratament deoarece radiaþiile pot creºte riscul deapariþie a carcinoamelor. [10, 15]. Recent au fostsintetizaþi mai mulþi compuºi care acþioneazã cainhibitori ai Smo, cum ar fi GDC-0449 sau NVP-LDE225 [30, 31, 32], actualmente aflaþi în stadiulde studii clinice de faza a II-a. În cazulpacientului nostru s-a recurs la exciziachirurgicalã a unora dintre leziunile ulcerate de la

hypotrichosis, trichoepitheliomas, peripheralcyanosis. [6,24]Rasmussen syndrome: autosomal dominantaffliction characterised by the association ofcylindriomas, trichoepitheliomas and milia.[25]xeroderma pigmentosum: autosomal recessivegenetic disorder characterised by increasedsensibility to sunlight, the patients developingmultiple basal cell carcinomas, along withother cutaneous cancer. [6]

Patient management

The patients will be advised to avoid sunlightand use sunscreens with high solar protectionfactor. [6, 15]

Each lesion must be approached separately,with emphasis on the precocious destruction ofthe tumor lesions. Surgical excision is no alwayspossible, particularly when there exists anincreased number of lesions, because it isaffiliated with the risk of severe disfiguration ofthe patient, especially when trying to remove thetumor within safety margins.

Mohs microsurgery is a less accessiblealternative due to the high expenses. [6,15] Non-surgical methods can be used mainly for thetreatment of multiple, superficial tumors.Therefore, the curettage, electrosurgery orcryotherapy can be used in the treatment of BCCslocated on the trunk [6]. Topical 5-FU andImiquimod can also be used for the treatment ofsuperficial BCCs with good results [15, 26, 27].Also, when the large number of lesions impedesthe use of conventional therapies, photodynamictherapy is a good treatment alternative, havingthe advantage of approaching wide cutaneousareas (“field therapy”). [28, 29]. Oral treatmentwith retinoids is efficient but only at doses thatare associated with severe adverse events [15].Some authors suggest that radiotherapy is not avalid treatment option because the radiation canincrease the risk of cancer development [10, 15].Recently several types of compounds acting asSMO inhibitors have been synthetized, such asGDC-0449 or NVP-LDE225 [30, 31, 32], at presentfound in second phase clinical trials. In ourpatients’ case we resorted to the surgical excisionof some of the ulcerated lesions of the face, the

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nivelul feþei, restul leziunilor fiind tratate prinaplicaþii locale de Imiquimod 5% cremã.

Întrucât 70-80% dintre pacienþi moºtenescdefectul genetic ºi la doar 20-30% defectulgenetic apare de novo, sfatul ºi analiza geneticãsunt deosebit de importante. Având în vederefaptul cã boala are penetranþã completã, riscul detransmitere la descendenþi este de 50%. [7].

Pentru diagnosticul antenatal, ecografiapoate fi utilã în detectarea precoce amalformaþiilor. În cazul sarcinilor cu risc se poateefectua analizã ADN-ului fetal obþinut prinamniocenteza în sãptãmânile 15-18 de sarcinã saubiopsia de vilozitãþi coriale în sãptãmânile 10-12de sarcinã [10, 33].

În afarã asocierii cu meduloblastomul, carepoate reprezenta o cauzã de moarte prematurã,prognosticul vital al bolii este în general bun, spredeosebire de prognosticul estetic care esterezervat, mai ales în cazul prezentãrii tardive. [10]

Concluzii

Sindromul Gorlin-Goltz este o geno-dermatozã rarã, ce asociazã numeroase anomaliide dezvoltare cu prezenþa de multiple epi-telioame bazocelulare. Recunoaºterea manifestã-rilor bolii de cãtre medicul dermatolog, pediatrusau medicul de familie poate contribuisemnificativ la stabilirea unui diagnostic precoce,aspect deosebit de important deoarece în acest felseveritatea unora dintre complicaþii, cum ar fitumorile maligne cerebrale ºi cutanate poate firedusã considerabil.

rest of the lesions being treated with topicalapplications of Imiquimod cream 5%.

Since 70-80% of the patients inherit the geneticabnormality and only in 20-30% of the cases thegenetic defects appears de novo, the genetic adviceand analysis have a paramount importance.Considering the fact that the disease has acomplete penetrance, the risk of transmitting theaffliction to the descendants is 50% [7].

The echography can be useful for theprecocious prenatal diagnosis of malformations.For pregnancies at risk the analysis of foetal DNAobtained through amniocentesis during weeks15-18 of pregnancy or corial vilosities biopsyduring weeks 10-12 of pregnancy can be useful[10, 33].

Besides the medulloblastoma affiliation,which can represent a cause of premature death,the vital prognosis is generally good, as comparedto the aesthetic prognosis which is reserved,particularly in delayed presentations [10].

Conclusion

Gorlin-Goltz syndrome is a rare genoder-matosis associating various developmentalanomalies with the presence of multiple basal cellcarcinomas. Recognising the hallmarks of thedisease by the dermatologist, the paediatrician orfamily doctor can significantly contribute to anearly diagnosis, which is very important inconsiderably decreasing the severity of certaincomplications, such as cerebral and cutaneousmalignant tumors.

Bibliografie/Bibliography

1. Lo Muzio L, Nocini PF, Savoia A, Consolo U, Procaccini M, Zelante L, Pannone G, Bucci P, Dolci M, Bambini F,Solda P, Favia G. Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet1999: 55: 34 – 40. © Munksgaard, 1999.

2. Elizabeth A. Jones, Mohammed Imran Sajid, Andrew Shenton, and D. Gareth Evans. Basal Cell Carcinomas inGorlinSyndrome: A Review of 202 Patients. Hindawi Publishing Corporation Journal of Skin Cancer Volume 2011, ArticleID 217378, 6 pages doi:10.1155/2011/217378.

3. P. J. Fitzpatrick, G. A. Thompson. Gorlin's syndrome, or nevoid basal cell carcinoma syndrome.Can Med Assoc J.1982 September 15; 127(6): 465-470.

4. Merton I. Satinoff and Calvin Wells (1969). Multiple Basal Cell Naevus Syndrome in Ancient Egypt. Medical History,13, pp 294-297 doi:10.1017/S0025727300014563.

5. Robert J Gorlin. Nevoid basal cell carcinoma (Gorlin) syndrome. Genetics in Medicine (2004) 6, 530–539;doi:10.1097/01.GIM.0000144188.15902.C4.

35


6. Tony Burns, Stephen Breathnach, Neil Cox, Christopher Griffiths. Rook’s Textbook of Dermatology. Wiley-Blackwell.2010. Eighth edition. 52.6-52.8. ISBN: 978-1-4051-6169-5.

7. D Gareth Evans, Peter A Farndon. Nevoid Basal Cell Carcinoma Syndrome. 2002 Jun 20 in: Pagon RA, Bird TD, DolanCR, et al., editors. GeneReviews.

8. Shruthi Hegde, Shishir Ram Shetty. Radiological features of familial Gorlin-Goltz syndrome. Imaging Sci Dent. 2012March; 42(1): 55–60. doi: 10.5624/isd.2012.42.1.55.

9. M. Ljubenovi, D. Ljubenovi, I. Bini, D. Jovanovi, M. Stanojevi. Gorlin-Goltz syndrome. Acta Dermatoven APA Vol16, 2007, No 4.

10. Lorenzo Lo Muzio. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. 2008; 3: 32.Published online 2008 November 25. doi: 10.1186/1750-1172-3-32.

11. Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol.2006 Sep;15(9):667-77.

12. A Neil Crowson. Basal cell carcinoma: biology, morphology and clinical implications. Modern Pathology (2006) 19,S127–S147. doi:10.1038/modpathol.3800512.

13. Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, Esterbauer H, Hauser-Kronberger C,Frischauf AM, Aberger F. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction ispredominantly mediated by GLI2. Cancer Res. 2004 Nov 1;64(21):7724-31.

14. Ruiz i Altaba A, Sánchez P, Dahmane N Gli and hedgehog in cancer: tumours, embryos and stem cells. 2002May;2(5):361-72.

15. Klaus Wolff, Lowell A. Goldsmith, Stephen I. Katz, Barbara A. Gilchrest, Amy S. Paller, David J. Leffell. Fitzpatrick’sDermatology in General Medicine. Mc. Graw-Hill Professional; Seventh edition. 2007. pag. 1047. ISBN-10: 0071466908.

16. Saurat J. H., Grossihans E., Laugier P, Lachapelle J.M. Dermatologie et maladie sexuellement transmisible. 3e edition.Masson. ISBN 2-225-83670-1.

17. Priya Shirish Joshi, Vijay Deshmukh, Someshwar Golgire. Gorlin-Goltz syndrome. Dent Res J (Isfahan). 2012 Jan-Mar; 9(1): 100–106. doi:

18. D G Evans, E J Ladusans, S Rimmer, L D Burnell, N Thakker, and P A Farndon. Complications of the naevoid basal cellcarcinoma syndrome: results of a population based study. J Med Genet. 1993 June; 30(6): 460–464.

19. Aitziber Ortega García de Amezaga, Olatz García Arregui, Sergio Zepeda Nuño, Amelia Acha Sagredo, José M.Aguirre Urizar. Gorlin-Goltz syndrome: Clinicopathologic aspects. Med Oral Patol Oral Cir Bucal.

20. Ashutosh Agrawal, Aditi Murari, Sunil Vutukuri, Arun Singh. Gorlin-Goltz Syndrome: Case Report of a RareHereditary Disorder. Case Reports in Dentistry Volume 2012 (2012), Article ID 475439, 4 pagesdoi:10.1155/2012/475439.

21. Kimonis VE, Mehta SG, Digiovanna JJ, Bale SJ, Pastakia B. Radiological features in 82 patients with nevoid basal cellcarcinoma (NBCC or Gorlin) syndrome. Genet Med. 2004 Nov-Dec;6(6):495-502.

22. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ. Clinical manifestationsin 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. 1997;69(3):299–308.

23. Rolf H Sijmons. Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndromeHeredCancer Clin Pract. 2008; 6(1): 22–57.

24. van Steensel MA, Jaspers NG, Steijlen PM. A case of Rombo syndrome. Br J Dermatol. 2001 Jun;144(6):1215-8.25. Rasmussen JE., A syndrome of trichoepitheliomas, milia, and cylindromas, Arch Dermatol. 1975 May;111(5):610-4.)26. Ferreres JR, Macaya A, Jucglà A, Muniesa C, Prats C, Peyrí J. Hundreds of basal cell carcinomas in a Gorlin-Goltz

syndrome patient cured with imiquimod 5% cream. J Eur Acad Dermatol Venereol. 2006 Aug;20(7):877-8.27. Stockfleth E, Ulrich C, Hauschild A, Lischner S, Meyer T, Christophers E. Successful treatment of basal cell carcinomas

in a nevoid basal cell carcinoma syndrome with topical 5% imiquimod. Eur J Dermatol. 2002 Nov-Dec;12(6):569-72.28. Mougel F, Debarbieux S, Ronger-Savlé S, Dalle S, Thomas L. Methylaminolaevulinate photodynamic therapy in patients

with multiple basal cell carcinomas in the setting of Gorlin-Goltz syndrome or after radiotherapy. Dermatology.2009;219(2):138-42. Epub 2009 Jul 8.

29. Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cellcarcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg. 2004 Jul;30(7):1054-61.

30. Von Hoff DD, LoRusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R, Weiss GJ, Borad MJ, Hann CL, Brahmer JR,Mackey HM, Lum BL, Darbonne WC, Marsters JC Jr, de Sauvage FJ, Low JA. Inhibition of the hedgehog pathway inadvanced basal-cell carcinoma. N Engl J Med. 2009 Sep 17;361(12):1164-72. Epub 2009 Sep 2.

36


31. Pan S, Wum X, Jiang J et al. (2010b) Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS MedChem Lett 1:130–4

32. Hans Skvara, Frank Kalthoff. Topical Treatment of Basal Cell Carcinomas in Nevoid Basal Cell Carcinoma Syndrome witha Smoothened Inhibitor. Journal of Investigative Dermatology (2011) 131, 1735–1744; doi:10.1038/jid.2011.48;published online 24 March 2011.

33. Petrikovsky BM, Bialer MG, McLaughlin JA, Bale AE. Sonographic and DNA-based prenatal detection of Gorlinsyndrome. J Ultrasound Med. 1996 Jun;15(6):493-5.

Conflict de interese Conflict of interestNEDECLARATE NONE DECLARED

Adresa de corespondenþã: Mircea TampaUniversitatea de Medicinã ºi Farmacie „Carol Davila“, Bucureºti Dionisie Lupu 37, 020022 Bucureºti, Româniatelefon: +40758040752e-mail: [email protected]

Correspondance address: Mircea Tampa“Carol Davila” University of Medicine and Pharmacy Bucharest Dionisie Lupu 37, 020022 Bucureºti, Româniatelefon: +40758040752e-mail: [email protected]

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