i l Pathology

Naso-orbicular tissue necrosis by Streptococcusparasanguis in a patient with Fanconi anemia:Clinicai and laboratory aspectsMonica Fernandes Gomes, DDS, PhD, MSVRaquel Teodoro Santos Teixeira, DDS /̂Glauco Plens,Marcelo Miloni Silva, MDVElilânia Marinho Pontes, MDVJoâo Carlos da Rocha, DDS, PhD, MS^

Fanconi anemia (FA) is a rare autoscmal recessive disorder, characterized by pancytopenia and progres-sive hypoplasia of the bone tnarrow, A 23-y9ar-oid wotnan with FA showed severe pancytopenia and de-veloped an abscess on the infraorbicuiar region on the right side of the face fhat progressed to phlegmonand caused tissue necrosis of the nostrils, nasai septum, nasai fossa, and posterior orbital region.Laboratory examination showed Streptococcus parasanguis as the etiologic agent of the phlegmon.Supportive treatment was recommended due to donor incompatibility for bone marrow franspiant. The In-traorai examination showed spontaneous gingival bieeding, edema of the interdental papulae, hematomason the superior and inferior lips, bacteriai and fungal infections, and adequate oral hygiene. The patientwas treated with the administration of an anfibiotic (imipenem), an antifungal (amphotericin B), and moutiiwashing with antiseptic solutions, Feriodontal prophylaxis and orientation to and control of oral hygieneand diet were aiso used during the remission period. For functional and esthetic rehabilitation of the aiarregions and nasal dorsum, an acrylic resin nasal prosthesis was made, supported by a spectacle frame,(Quintessence Int 2004:35:572-576)

Key words: 3788del, FANCA gene, Fanconi anemia, infection, pancytopenia, Streptococcus parasanguis.tissue necrosis

Fanconi anemia (FA) or Fanconi aplastic anemiawas first described by tbe Swiss pediatrician Guido

Fanconi, in 1927, wbo observed several abnormalphysical conditions and bone marrow deficiency intbree brotbers,'- FA is a rare autosomal recessive dis-

iProfessor, Department of Biosciences and Oral Diagnosis, Sao José dosCampos School of Dentistry, Sao Paulo State Uniretsity-Ut^lESP, SaoJosé dos Campos, Sao Paulo, Brazil; ard Chair, Sioscierces Center lorSpecial Heaitli Care Needs and Special Healtti Care Needs Association,S io Paulo, Brazil,

^Graduate Student, Sao José dos Campos School of Dentistry, Sao PauloState Uniuersity-UNESP, Sao José Oos Campos, Sao Paulo, Brazil.

'Hematologist, Hemolerapic and Hematology Seruice of Sao José dosCampos-HEMOVIDA and Pédiatrie Oncologist Grojp-GRUPO, Sao Josedos Campos, Sao Pajlo, Brazil.

'Pediatijc Oncologist, Oncclogic Pediatry Group-GRUPO, Sao José dosCampos, Sao Paulo, Brazil,

'Professor, Department of Pédiatrie and Social Dentistry and Special CareTreatment and Study Center of tlie Sao José dos Campos School otDentistry, Sao Paulo State University-UNESP, Sao José dos Campos,Sao Paulo, Brazil.

Reprint requests: Dr Monica Fernardes Gomes, Faculdade de Odontologíade Sao Jose dos Campos-UNESP, Departamento de Biooiénoia eDiagnóstico Oral, Av. Erg. Pranoisco José Longo, 777, Cep: t3.245-000, SaoJosé dos Campos, Sao Paulo, Brazil. E-mail. mlgomes@fos)0,unesp br

order, witb a 1 in 360,000 prevalence, as well as a 2:1male predominance,' This disease is cbaracterized bypancytopenia, progressive hypoplasia of tbe bone mar-row, sidn byperpigmentation, and sbort stature, Otberanomalies include: (1) skeletal malformations of tbebip, vertebral column, or ribs; (2) absent, bypoplastic,or supernumerary thumb; (3) absent or bypoplastic ra-dius; (4) renal problems; (5) gastrointestinal tract ab-norfnalities; (6) cardiac defects; (7) bypogonadism, (8)cbromosomal aberrations; and (9) mental retarda-tion,'-^ Patients witb FA present a higb risk of devel-oping bemorrbage, infections, leukemia, and otbermalignant diseases,'''-"

Tbe susceptibility of FA patients to infections due tosevere pancytopenia impairs tbeir treatment, as well astbe repair process wben tissue damage occurs for anyreason, including surgical procedures. Among thepatbogenic bacteria. Streptococcus parasanguis sbowsa higb affinity for bard and soft surfaces of the oralcavity, Tbis is due to its adbeslve properties to epithe-lial surfaces, salivary secretions, platelets, bacterialplaque, and extracellular matrix components,'^

Currently, no clinical report on tissue necrosis oftbe face caused by S parasanguis in Fanconi anemia

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Fig 1 Myelogram showing (a) moderately hypocellular bone marrow (original magnification xlOO; Leishmann stain); (b) dysplasia of thegran^ulocytic and erytrocytic senes cell; and (c) dysplasia of the megakaryooytic series (b and o = ¿riginal magnification ¿600; Leishmann

Fig 2 Edematous face, perlorbicuiar erythema, abscess in the inlraorbioular region on theright side ot the tace, and necrosis with tissue ioss on the nostrils.

patients has been found in the literature, promptingthe present study. This article will describe the clinicaland laboratory aspects of the Fanconi anemia diagno-sis, the systemic and oral treatment of the infections,and functional and esthetic patient rehabilitation.

CASE REPORT

A 23-year-old Caucasian woman presented at theSpecial Care Treatment and Study Center at the SaoJosé dos Campos Dental School of the Sao Paulo StateUniversity-UN ESP and the Hemoterapic and Hema-toiogy Service of the Sao José dos Campos City-HE-MOVIDA, complaining of weakness, pallor, and peri-odic tonsilitis. Family history revealed a normal brotherbut two sisters exhibiting the same clinical features asthe patient. Physical examination showed a short-statured patient exhibiting fatigue, pallor, and general-ised grayish skin. The results of the laboratory testswere the foiiowing: a hemogram showing severe pancy-fopenia with 6.7 g/dL hemoglobin, l,400-mm5 leuko-cytes with 6% neutrophils, and 3,000-min5 platelets;and a myelogram showing moderately hypoceilularbone marrow with cellular dysplasia involving the

granulocytic, erythrocytic, and megakaryocytic series(Fig 1). A chromosomal study performed using thepolymerase chain reaction (PCR) method combinedwith enzymatic digestion, showed 30% chromosomalbreakage and 3788del mutation in two alíeles of theFanconi anemia complementation group A (FANCA)gene. A bone marrow transplant was not possible be-cause ber brother was human leukocyte antigen (HI_A)incompatible, and tbe only available option was sup-portive treatment (erytbrocytes and platelets-concen-trate transfusion and drug administration).

At a 7-year follow-up, tbe patient continued toshow severe pancytopenia and, after immun o suppres-sion, developed facial edema, periorbicular erytbema,and phlegmon on the infraorbicular region of tbe rigbtface (Fig 2). Computerized tomography revealed thatthis phlegmon invaded the nasal fossa diffusely, caus-ing necroses and tissue loss of the nostrils and regionsof the septum, nasal fossa, right maxillary sinus, andposterior orbital region with resulting exophthalmos(Fig 3). Material for laboratory tests was obtained byswabbing. Diagnosis was established by culture andantibiogram, verifying that S parasanguis was the etio-logic agent of the phlegmon.

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Fig 3 Computerized tomography showing, in coronal sections, destruction and loss ot tissue in the region of the nasai septum (a) and otthe right maxiliary sinus ¡b) and, in an axiai section, a iesion in the posterior orbital region with consequent exophthalmos was observed (c)

Fig 4 intraoral examination showing spon-taneous gingivai bieeding, edema of the in-terdental papiliae, hematomas on the supe-rior (a) and inferior (b) iips. and adequateorai hygiene

Extraoral examination sbowed an edematous facewitb eccbymosis in the infraorbicular and cervical re-gions, moderate exophthalmos on the right side, andnecrosis with tissue loss on the alar region of the rightnostril. Intraoral examination demonstrated sponta-neous gingival bleeding, edema of the interdental papil-lae, hematomas of the superior and inferior lips, and ap-propriate oral hygiene (Fig 4). A panoramic radiographshowed microdontia of the maxillary third molars, flat-tening of the sigmoid notch hilaterally, and no cades oralveolar hone loss caused hy periodontal pockets and/orperiapical lesions (Fig 5). The occlusal radiograph of tbemaxilla suggested an abscess in tbe anterior region ofthe nasal fossa floor and résorption of nasal conchae(Fig 6). Exfoliative cytology was performed, samphngthe anterior gingiva of both the maxilla and mandible.Tbis sbowed intermediary and superficial epithelial cellswith nuclear and cytoplasmic alterations. The alter-

Fig 5 Panoramic radiograph showing mi-crodontia ot the maxiiiary third moiars, a flat-tened sigmoid notch, absence of caries,and alveoiar bone ioss.

ations observed included vacuolization, lysis, precociouskeratinization, hinucleation, and an increased nuclearvolume. Tbere were also erytbrocytes, baeteria (cocci),and numerous hyphae and spores of Candida albicans.The cytology was interpreted as an inflammatoryprocess caused by bacteria and Candida and was con-sidered a Papanicolaou smear Class II (Fig 7).

Treatment consisted oí administration of an antibi-otic (imipenem) and an antifungal (amphotericin B),along with mouth washing with antiseptic solutions,Periodonta! prophylaxis and orientation to and controlof oral hygiene and diet during the disease remissionperiod was also used. For functional and esthetic reha-bilitation of the aLar regions and nasal dorsum, anacrylic resin nasal prosthesis was made, supported by aspectacle frame. The color of tbe prostbesis was ob-tained by comparison witb the skin using ceramic pig-ments for intrinsic coloring of the acrylic resin (Fig 8).

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Fig 6 Occiusai radiograph of the maviiiasuggesting abscess ot [he anterior region otthe nasai fossa floor (arrows) and résorptionof nasal conotiae.

Fig 7 E'fO'iaiivQ cyioiogy i Fig 8 Functional and esthetic rehabiiitationmalory process caused by bacteria and with manufactured acrylic resin nasai pros-üandida and Papanicoiaou smea Ci li t h iCandida and Papaniociaou smear Ciass(original magnification X1OO; Papanicoiaoustain).

thesis supported by a spectacle tiame.

DISCUSSION

The chnical manifestations and pathogenesis of Fan-coni anemia have been the topics of many reports.'-̂ •'•Ï*Infections frequently occur and can affect any region ofthe body. According to Opinya et aP and Ferretti,'^ thesusceptibihty of these individuals to infections could hedue to severe pancytopenia, causing their ¡mmunosup-pression. In the present case, the patient presented withsevere pancytopenia and developed an infection causedby S parasanguis, leading to tissue necrosis in tbe naso-orblcular region. It is believed that this tissue loss couldbe exacerbated by iirunitnosuppression as well as a defi-ciency in the repair process. TTie S parasanguis patho-genicity and the fast progression of the abscess could bedue to the close affinity of these bacteria with epithe-lium, platelets, and extracellular matrix components,which were described by Froeliger et al.'̂

EA is a disorder transmitted by a recessive autoso-mal gene. In their studies, Frohnmayer and Erohn-mayer̂ described the existence of eight genes responsi-ble for FA; therefore, any changes in one of thesegenes could cause the disease. The genes of groups A(FANCA), C (FANCC), F (FANCF), and G (FANCG)have already been isolated, cloned, and sequenced.^

Mutations of the genes FANCA, FANCC, andFANCG occurred in 65%, 15%, and 10%, respectively,of the patients with FA.^"."« The FANCA gene wasmapped in chromosome 16q24.3, but its function thusfar remains unknown.'«'» In 1997, Levran et al*" stud-ied the mutation spectrum of these genes and discov-ered that the most common mutations were the mi-crodeletions 378S-3790deI. This is observed in 10% ofthe patients studied and is typical among Brazilians,

emphasizing the genetic findings of this cUnica! case.Such researchers concluded that the group A gene forEA is highly polymorphous and can be hypermutant.According to Frohnmayer and Frohnmayer,̂ this highmutation potential may explain the high percentage ofgroup A patients with EA, and also increases the riskof neoplasia development; the present study's patientbelongs to group A.

According to Opinya et aP and Engel et ai,' the di-agnosis of FA is made typically between 4 and 7 yearsof age, and death occurs during the first decades oflife, due to bone marrow complications, FA in the cur-rent patient was diagnosed when she was 11 years old,and the pafient was 22 years old at the time of presen-tation. TTiis is in contrast to the data of most other re-ports.'^-'

Patients with FA may develop soft fissue, bone, andhématologie malignant neoplasms at an earlier agethan the normal population. There is predominance ofthis pathology in women.^"' Myelodysplastic syn-drome (5%) and leukemia (10%) comprise many of thecases. The risk of a patient with EA developing one orboth of these diseases can reach up to 50% of all cases.Other neoplasms may occur in the mouth, pharynx,esophagus, gastrointestinal tract, and reproductive sys-tem, with spindle cell carcinoma being the most fre-quent. '̂''̂ " '̂̂ Many scholars report the occurrence ofspindle cell carcinoma in the oral mucosa, predomi-nantly in the tongue.''-'̂ '-'* According to Somers et al,'many factors can contribute to the development ofthese malignancies. Immunodeficiency, therapeuticstrategies, and bone marrow transplant have particu-larly been imphcated. No neoplasm was observed intbe present case.

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Therefore, patients with FA must avoid contactwith tohacco, organic solvents, herhicides and pesti-cides, formaldehyde, gasoline, and toxic gases.^ It isbelieved that chromosomal breakage susceptibility andthese predisposing factors may increase the risk ofneoplasia.

Treatment alternatives for FA may he bone marrowtransplant, genetic therapy, transfusions, and medica-tion to prevent and control infections.^'* In the pres-ent study, there was no HLA compatibility betweenthe patient and her brother for a bone marrow trans-plant. Therefore, tbe only option was supportive treat-ment througb transfusion of erytbrocytes and plateletconcentrate, administration of imipenem and ampbo-tericin B, and oral cavity prophylaxis. Tbis treatmentsought to control the severe anemia, bemorrbages,and infections as well as prevent periodontal disease.

Patients witb FA often present witb extensive alveo-lar bone loss, resulting in severe periodontitis andtootb loss.'' This probabiy occurs due to the severepancytopenia, emphasizing the pathogenicity of theoral microbiota, as suggested in the studies of Opinyaet aP and Valdez and Patton.'* in the present case,spontaneous gingival bleeding and edema of the inter-dental papillae were found. However, there was nobone loss, and oral hygiene was adequate.

For functional and esthetic rehabilitation of the loststructures, implant-supported and adhesive siUconeprostheses were avoided due to the disease character-istics and systemic condition of the patient. It is be-lieved that these materials may cause adverse tissuereactions, such as severe hemorrhage, implant rejec-tion, and hypersensitivity and/or hematoma in theprosthesis seating. Therefore, an acrylic resin prosthe-sis with internal relief was manufactured and attachedby a spectacle frame. Although the esthetic resuhswere less than optimal, this kind of prosthesis avoidedundesirahle pressure, which could cause lesions in tberemaining tissues.

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