Cohensyndrome with -inducedperiodontitis managedwith granulocytecolony-stimulating factor (G-CSF):case reports W.Kim Seow MDSc, DDSc, PhD, FRACDS P.M. Bartold BDS, PhD, FRACDS Y.H. Thong MD, DSc, FRCPath, FRACP K.Taylor MBBS, FRCPA, FRACP W.

ohen syndromewas first reported in 1973 in controls matchedfor age, gender, and degree of men- two siblings and one sporadic case.~ Features tal deficiency2 C mentionedin the original report included obe- Managementofneutropenia includes use of recom- sity/hypotonia, mental retardation, narrow hands and binant G-CSF, a glycoprotein which stimulates the feet, ocular abnormalities,and characteristic facies con- survival, proliferation, differentiation, and function of sisting of , mild micrognathia, granulocyte progenitor cells and mature short philtrum, open mouth, prominent central inci- .3°-32 Clinical trials have demonstratedef- sors, and downslanting palpebral fissures. Although ficacy of this agent in preventing infectious more than 100 cases have now been reported in the complications of severe chronic neutropenia, although medical literature, 3-21 only two previous reports have the successful use of G-CSFin the case of Cohensyn- appearedin the dental literature. Thefirst described a drome has only been recently reported in three young girl with Cohensyndrome showing typical cran- patients.3~ iofacial features such as short philtrum and prominent To date, the dental features of Cohensyndrome are incisors but no periodontal involvement.14 The second still not well known.The present report of a brother was a controlled study whichdemonstrated significant and sister with Cohensyndrome and severe neutrope- in a group of 15 Cohensyndrome nia treated with granulocyte colony-stimulatingfactor patients with neutropenia, but craniofacial features (G-CSF)aims to shed further light on the oral abnor- were3 not described. malities and dental managementin this syndrome,as Previous medical reports suggest Cohensyndrome well as the effects of medicaltherapy on the periodon- to be a heterogenousdisorder with variable expression tal condition. of the classical features, and additional abnormalities such as microcephaly,seizures, cardiac valvular defects, Casereport and .3-2~ Most studies have mentioned an Medicalhistory autosomalrecessive modeof inheritance in Cohensyn- A malesibling, aged 15 years, and his sister a~ed16 drome, although autosomal dominant patterns of years, were referred to the University of Queensland inheritance mayalso be possible.5’ ~2, 22 Althoughear- Dental School by their general practitioner for man- lier mappingstudies 19 have suggested the gene to be agement of severe periodontal destruction and at 5q33.1 or 7p15.1, more recent studies 23 have recurrent oral ulceration. The children were products mappedit to chromosome8. The gene appears to be of full-term pregnancies ofa nonconsanguineousmar- different from that of the Prader-Willi syndromewhich riage. There was an older male sibling whowas normal. shows18 someoverlapping phenotypic features. The birthweights of the female and male siblings were Chronic neutropenia, which is characterized by a 6 lb and 4 lb, 1 loz respectively. In early childhood, decrease in circulating neutrophils,24 had been previ- both children were found to have developmental de- ously25 described in a few cases of Cohensyndrome, lay with IQ assessed as 60-75, and they attended but may not be a consistent feature. As neutrophils special schools. Myopiaand retinitis pigmentosawere provide the first line of host defense against microbial also diagnosed. In addition, they suffered recurrent invasion, chronic neutropenia is generally associated oral, pharyngeal,ear, respiratory, and urinary tract in- with24 increased prevalenceand severity of , fections. These infections were associated with including26-29 oral infections and periodontal disease. persistent chronic neutropenia which had been noted The association of periodontal boneloss in Cohensyn- since birth. dromeand neutropenia was demonstrated in a recent The family had movedfrequently and although the paper which comparedCohen syndrome patients with children had been investigated extensively at major

350 AmericanAcademy of Pediatric Dentistry Pediatric Dentistry - 20:5, 1998 medical and genetic centers around the country, diagnosis of their medical condition had not been made previously. Previous medical investigations, which included chromosomal studies, biochemical screens, and skeletal survey had all shown normal results. General examination At initial presentation, both children appeared fairly coopera- tive for dental examination. Both showed moderate central obesity and short stature. The siblings resembled each other (Figs la, lb, 2a, 2b) They had round faces and wore spec- Figs 1 a, 1 b. Front and side views of 16-year-old female sibling with Cohen syndrome, showing typical tacles with thick corrective lenses. features of downsloping palpebral fissues, maxillary hypoplasia, mild micrognathia, mildly reduced The palpebral fissures were philtrum, and prominent incisors. down- sloping, and there was maxillary hypoplasia and mild micrognathia. Prominent incisor teeth with mildly reduced philtrum were ob- served. Physical measurements for the female sibling were height 147 cm (< 3rdpercentile), weight 70 kg (> 75th < 90th percentile) and head circumference 51cm (< 3rd percen- tile), and the male sibling height 145 cm (< 3rd percentile), weight 58 kg (> 3 <10th percentile), and head circumference 50 cm (3rd percentile). In both children, the hands and feet were long and slen- der, and the fingers and toes were tapered (Figs 3a, 3b). Dental examination and treatment Oral examination of the female Figs 2a, 2b. Front and side views of 15-year-old male sibling with Cohen syndrome, showing milder showed that all the permanent facial changes compared to his sister (Fig 1). teeth except the mandibular and maxillary right third molars were present. The enamel of all her teeth appeared hypomineralized, the most severe defects being seen in the maxillary incisors and first mo- lars which showed yellow-brown opaque discoloration, and mild (Fig 4). In the male sibling, all the per- manent teeth except the third molars and second mandibular Figs 3a, 3b. Slender hands and feet and tapering premolars were present on clinical digits of female sibling. These limb abnormalities are typical of Cohen syndrome. examination (Fig 5) As in his sis-

Pediatric Dentistry -20:5, 1998 American Academy ofPediarric Dentistry 351 val plaque and calculus deposits were noted around all teeth in both patients. The gingival tissues bled profusely upon gentle probing and generalized periodontal pocketing of between 4 and 6 mm was re- corded . The male sibling was most severely affected with the periodon- tal tissues showing a fiery red, Fig 4. Dentition of female sibling. Note severe Fig 5. Dentition of male sibling. Note severe edematous appearance, particularly gingival associated with gross gingival inflammation and loss of attachment in in the anterior regions (Fig 8a) The deposits of plaque and calculus. Also note the mandibular anterior teeth, female sibling had generally less se- generalized enamel hypomineralization defects. Hypomineralization defects (diffuse enamel vere inflammation, although there opacities) were present on most teeth, although were isolated areas of severely in- these were less severe compared to his sister's. flamed tissues, including gingival recession localized to the right man- dibular central incisor (Fig 5). Radiographs indicated early signs of bone loss around many teeth although the condition was not yet severely comproming the dentition. Subgingival plaque samples were taken from the max- illary central incisors and mandibular left first molar for each child. The male sibling had mod- erately high levels (12-42 x IO4) of Fig 6. Panoramic radiograph of female sibling. Fig 7. Panoramic radiograph of male sibling. Porphyromonas gingivalis at two of The third molars were unerupted and impacted. There was agenesis of all second premolars, and the three sites tested compared to the third molars were unerupted and impacted. his sister who showed less than 9 x IO4 of this bacteria at the sites sampled. Medical diagnosis and treatment Based on the characteristic facies, central obesity, and tapering hands and feet, a provisional diagnosis of Cohen syndrome was suggested.' Other syndromes22 presenting with obesity, mental retardation, and limb abnormalities such as the Prader-Willi and Moon-Biedel syn- dromes were excluded based on Figs 8a, 8b. Mandibular anterior teeth of male sibling before and after periodontal cleaning and differences in craniofacial appear- medical treatment with G-CSF treatment which resulted in normalization of neutrophil levels. Note ances, limb findings, and the timing marked improvement in gingival health after treatment. and character of obesity. The diagnosis of Cohen syn- drome was confirmed by medical ter, the teeth also showed hypomineralization defects although these wete specialists. Further hematological considerably less severe. investigations revealed the neutro- Both children had Class II with anterior of 6 mm phil counts to be 0.68 x 109/L for and mild anterior open bite. Panoramic radiographs (Figs 6 and 7) re- the sister and 0.13 x 109/L for the vealed impaction of third molars in both children, and confirmed agenesis brother (normal range 2.0 to 7.5 x of second premolars in the boy. 109/L). Serial neutrophil counts Periodontal examination showed consistently low numbers, and excluded cyclic neutropenia. At the initial oral examination, large deposits of supra- and subgingi-

352 American Academy ofPediatric Dentistry Pediatric Dentistry - 20:5, 1998 Marrowexamination of both siblings showednormal Our study has also shownthat the children’s neu- cellularity and adequatemyeloid precursors, but reduc- tropenia can be effectively controlled by regular G-CSF tion in mature myelopoeisis. Tests for antineutrophil injections, which leads to a marked decrease in the antibodies were negative, and cytogenetic studies ex- numberof general infections suffered by the children. cluded22 Fanconi syndrome. Also, great improvementin gingival health was noted A family history revealed that no other membersof after G-CSFtherapy which resulted in normal neutro- the family were affected. The motherand normalsib- phil numbers, together with periodontal scaling and ling did not showfeatures of Cohensyndrome. cleaning(Figs 8a, 8b). Althoughthe effects of treatment Treatment of the neutropenia was commencedwith by G-CSFin Cohensyndrome have not been described daily subcutaneousrecombinant granulocyte stimulat- previously, successfulresults on the periodontaltissues ing factor3°-33 (G-CSF,filgastrim) at an initial dose have been reported after G-CSFtherapy in other neu- 12 p.g/kg. Neutrophil counts normalized to around 3 tropenic patients such as .34 Longterm x 1 09/L within a week, and the dosage was reduced to complications of G-CSFtherapy include splenomegaly, maintenanceschedule of 3-5 lag/kg/day. Regular fol- hepatic dysfunction, renal dysfunction, , fluid re- low-up confirmed persistence of normal neutrophil tention, pericardial and pleural effusions, and cardiac counts with these dosages, associated with markedre- arrythmias. However,apart from mild long bone pain duction in infections requiring antibiotic use. at the beginningof therapy, these children sufferedmini- Dental treatment consisted of oral hygiene instruc- malside-effects. tion, including suggestion for the use of an electric The present study also demonstrates that toothbrush. Full-mouth subgingival debridement was hypomineralizationenamel defects maybe a feature of attempted using local anesthesia and nitrous oxide se- Cohensyndrome that have not been reported before. dation. However, cooperation of the patients was Similar enameldefects have been observed in manysyn- limited under these managementtechniques, and full dromeswith ophthalmiclesions, 22’ 35, 36 suggestingsimilar subgingival debridement and scaling, together with susceptibility of ophthalmicand dental enameltissues removal of the third molars, was subsequently per- to developmentalinsults, probablyassociated with their formedunder general anesthesia. commonorigin from neural crest cells. Thus, as Cohen In both children, there wasexcellent responseof the syndromealso demonstrates ophthalmic involvement, periodontal tissues to treatment. Inflammation and it is reasonableto propose that the enameldefects are pocket depths were reduced considerably within a few likely to part of this syndrome. weeks after treatment (Fig 8b). No post-treatment On other hand, the coincidental presence of the microbiological assays were performed. enameldefects cannot be completely excluded. In this regard, the positive history of toothpaste ingestion and Discussion residence in water-fluoridatedareas during infancy sug- The pediatric dentist occasionally encounters chil- gest that the enamel lesions mayhave resulted from dren with undiagnosed dysmorphology, and may thus fluorosis, whichpresents a similar clinical appearance. be the first to diagnosea patient’s condition. In these In viewof their high susceptibility to periodontaldis- case reports, the diagnosis of Cohen syndromeex- ease and enamelbreakdown, preventive care consisting plained the craniofacial, limb, and ophthalmic of regular professional prophylaxis,scaling, and topical abnormalities, as well as the obesity, mental retarda- fluoride application shouldbe central to the dental man- tion, and neutropenia. Also, definitive diagnosis of the agementof Cohensyndrome. It is unclear if correction condition enabled institution of correct medical man- of Class II malocclusionwith orthodontic appliances agementstrategies, including genetic counselling. wouldbe stable because of the abnormalmuscle tone. Althougha few previous studies have described the In view of the mental retardation, behavior manage- neutropenia in Cohensyndrome to be intermittent and ment maybe challenging. In addition to psychological relatively harmless,ll the present cases showedsignifi- support, conscious sedation with nitrous oxide maybe cant systemic infections and periodontal disease. Our required for routine dental work.In the present report, findings are thus similar to those of the study of although the children benefited from nitrous oxide Alaluusua and coworkers,3 in which patients with sedation for minor procedures, general anesthesia was Cohensyndrome showed significantly more periodon- necessary for complete deep scaling and debridement. tal destruction compared to matched controls. In Dr. Bartold is professor of Periodontologyand Dr. addition, as in that study, higher levels of periodontal Seowis associate professor in Pediatric Dentistry, Uni- pathogens, particularly Porphyromonasgingivalis,were versity of Queensland Dental School, Brisbane, also foundin our patients. Theincreased levels of these Australia. Dr. Thongis professor of Child Health, bacteria are likely to be the result of depressed num- University of Queensland, Australia, and Dr. Taylor bers of neutrophils and lowered host defence is director of CancerServices, MaterPublic Hospitals, mechanismsin the gingiva. South Brisbane, Australia.

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354American Academy of PediatricDentistry PediatricDentistry - 20:5, 1998