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Case Report

Periodontal Manifestation of Leukocyte Adhesion

Deficiency Type IReem Dababneh,* Adel M. Al-wahadneh, Shamekh Hamadneh,* Antwan Khouri,

and Nabil F. Bissada

Background:Leukocyte adhesion deficiency type I(LAD-I) is an autosomal recessive immunodeficiencydisorder characterized by defects in the integrin recep-tors of white blood cells that lead to impaired adhesionand chemotaxis. Affected patients are susceptible torecurrent bacterial and fungal infections, impaired

pus formation, delayed wound healing, and peri-odontitis.

Methods:A case of generalized advanced periodon-tal destruction of the permanent and deciduousdentition in a young Jordanian girl with a severephenotype of LAD-I is presented in this report. Themedical diagnosis was made based on the character-istic clinical and laboratory findings, in particular thetotal absence of CD18, CD11b, and CD11c as deter-mined by flow cytometry sorting.

Results:Periodontal findings in this patient includethe early onset of the disease, which affected the pri-

mary teeth and permanent dentitions, the intense red-ness and inflammation of the gingiva, and the rapidperiodontal destruction that seems refractory to con-ventional non-surgical periodontal therapy.

Conclusion:This report emphasizes the importanceof the differential diagnosis of severe immunodefi-ciency disorders in children and adolescents and man-dates theimportanceof combined care by medical anddental practitioners to prevent tooth loss and controloral infection. J Periodontol 2008;79:764-768.

KEY WORDS

Case report; genetic disorder; immunodeficiency;leukocyte adhesion deficiency; periodontitis.

Polymorphonuclear neutrophils (PMNs) are amajor component of the human defense system,particularly against bacterial infection. Evi-

dence for their crucial role in the defense of periodon-tal tissues was supported by data which showed thatthedepletionor malfunctioningof neutrophils, such as

occurs in neutropenia or leukocyte adhesion defi-ciency (LAD), is accompanied by severe and rapidperiodontal destruction and early loss of teeth.1,2

Neutrophil dysfunction includes abnormalities of PMNadherence,chemotaxis,superoxide generation, phago-cytosis, and bactericidal activity.3

LAD is a rare immunodeficiency disorder inheritedas an autosomal recessive trait and characterized bydefects in integrin receptors of white blood cells.4 Theleukocyte defects include impaired adhesion and che-motaxis, which areaccompanied by an increased sus-ceptibility to infections, such as the development of

severe periodontitis at an early age. Waldrop et al.5and Page et al.6 were among the first to report an as-sociation between LAD and generalized severe peri-odontitis in children.

An initial study7 on patients with LAD found a de-fect in the neutrophil integrins CD11/CD18. Subse-quent investigations8-10 into this disorder identifiedthree types of LADs (I through III). LAD-I involves adeficiency in three membrane integrins. Lymphocytefunction-associated antigen-1,macrophageantigen-1,and p150,95 are designated CD11a, CD11b, andCD11c, respectively. Deficiency of these integrins pre-

vents neutrophils fromadhering to the blood vessel wallat the site of an infection.

Therefore, despite leukocytosis (20,000 to 80,000cells/ml), neutrophils are unable to migrate into theaffected tissues that have a clinical appearance ofinflammation but without signs of purulence.8

LAD-II is caused by a general defect in the biosyn-thesis of fucosylated structures that strongly inhibitsinteractions with endothelial selectins and results in animmunodeficiency. Patients with LAD-II show strongdevelopmental abnormalities, the most severe of which

* Dental Department, Prince Rashid Bin Al-Hassan Hospital/Royal MedicalServices, Irbid, Jordan.

Pediatric Department, King Hussein Medical Center/Royal MedicalServices, Amman, Jordan.

Private practice, Amman, Jordan. Department of Periodontics, School of Dental Medicine, Case Western

Reserve University, Cleveland, OH. doi: 10.1902/jop.2008.070323

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are found in the psychomotor and mental capabilitiesof patients. The immunodeficiency in LAD-II is mostobvious during the first years of life, with recurrent in-fections in the majority of patients. Later in life, the im-mune defect can become milder, with periodontitisbeing the major persistent manifestation.9

Although the defects in the adhesion cascade arerestricted to leukocytes in LAD-I and -II, all four pa-tients with LAD-III described to date also had defectsin platelet aggregation. These patients suffered fromrecurrent bacterial infections and a severe bleedingtendency.10

CASE REPORT

A 10-year-old Jordanian girl was re-ferred to the periodontology clinic atPrince Rachid Bin Al-Hassan Hospitalon November 20, 2006 complaining of

bleeding gums and loose teeth of longduration. The patient has two brothersand two sisters, all of whom are healthy;her parents, who are first cousins, arealso healthy. According to her mother,no similar periodontal disease has oc-curred in her family.

The patient had a history of recurrentskin infections involving the hands andfeet, urinary tract infections, otitis me-dia, oral ulcerations, oral candidiasis,and periorbital cellulites. The medical

history revealed three hospital admis-sions during 2000 to 2002 for oral ulcer-ations, oral candidiasis, and periorbitalcellulites. No history of delayed separa-tion of the umbilical cord was reported.Hematologic investigations revealedneutrophilic leukocytosis (white cellcount: 15,000 to 35,000/ml) with mildhypochromic microcytic anemia. Bloodchemistry was normal. No bacterialgrowth wasreported in theurine culture.In September 2006, the patient was re-ferred to a pediatric immunologist whomadethediagnosisofLAD-Ionthebasisof characteristic clinical and laboratoryfindings, which were supported by thecomplete absence of CD18, CD11b,and CD11c as determined by flow cy-tometry sorting.

The dental history revealed that thepatient was first referred to a periodon-tist in December 2001, who noticed mo-bility of her teeth and variable levels ofalveolar bone loss affecting all of her de-ciduous dentition; the first permanent

molars were erupted by that time. Based

on clinical and radiographic findings (Fig. 1), the pa-tient was diagnosed as having prepubertal periodon-titis.Moderate-to-advancedbonedestructionaroundthe permanent first molars and incisors was evident ina panoramic radiograph taken in August 2003 whenthe patient was 7 years old (Fig. 2). Periodontal treat-

ment provided over a 2-year period (December 2001through August 2003) included extraction of the twoprimary uppercentralincisors because of hypermobil-ity, multiple visits for motivation and education topractice good oral hygiene, and scaling and root plan-ing in conjunction with a local antimicrobial (0.2%

Figure 1.Panoramic radiograph (December 2001) showing alveolar bone loss around both mandibularfirst molars. Bone loss was also present around the maxillary incisors and canines, but it isnot seen easily in this radiograph. The severity of bone loss is unusual for a 5-year-old child.

Figure 2.Panoramic radiograph (2003) showing the bone loss around both mandibular first molars,

which is an unusual finding for a 7-year-old child.

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chlorhexidine gluconate) mouthrinse and two sepa-rate courses of systemic antibiotics (amoxicillin, 250mg, and metronidazole, 250 mg, three times dailyfor a week). At that time, the periodontist also referredthe patient to a pediatrician to exclude neutrophil dys-function. No medical or dental notes were included in

the medical file of the patient during 2004 and 2005.The initial dental examination in November 2006

revealed severe gingival inflammation with sites ofmarginal erythema that was more pronounced labialto the lower incisors (Fig. 3). No deciduous teeth werepresent, and all permanent teeth were erupted exceptthe third molars, and there was partial eruption of thesecond molars. All incisors and first molars wereloose, and there was severe loss of attachment andgingival recession. Grade III mobility was noted inall first molars and mandibular central incisors,whereas grade I or II mobility was observed in the re-

maining maxillary and mandibular incisors and themaxillary right first bicuspid. All of the first molars ex-hibited Class 3 furcation involvement.

A complete periodontal examination was under-taken using plaque and gingival indices11,12 to assessoral hygiene and the gingival condition. The meanplaque index was 1.12 (range: 0 to 3), and the meangingival index was 2.34 (range: 0 to 3). Probing depth(PD) and clinical attachment level (CAL) were re-corded at six sites per tooth. Mean PD was 4.31 mm(range: 3 to 10 mm), and mean CAL was 4.97 mm(range: 2 to 12 mm). Profuse bleeding on probing

(BOP) was noted at almost allsites, but none exhibitedpurulent exudate. Radiographs showed moderate tosevere bone destruction associated with almost allerupting teeth, especially around the first molars(Fig. 4). The case was diagnosed as periodontitisassociated with LAD-I. The patient received initial-phase therapy and was recalled monthlyfor prophylaxis (scaling and polishing),although no reduction in PD or BOP wasobserved during the follow-up visits.

DISCUSSION

LAD-I is a rare disorder that occurs inone in 10 million births.13 It was de-scribed first in patients with delayedseparation of the umbilical cord, neu-trophilia, neutrophil defects, and sys-temic bacterial infections.7 Theseverity of the disease is based on therelative expression of CD18;

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A recent publication15 reported 15 cases of LAD-I inIran during a 14-year period. The ages of the patientsranged from 10 months to 14 years (median, 4 years);10 were males, and five were females; and 93% of theparents had consanguineous marriages. The mostcommonly occurring manifestations were recurrent

infections (93.3%), poor wound healing (86%), oral ul-cers (86%), and skin abscesses (80%). With regard toperiodontal disease, gingivitis was reported in 64% ofthe cases. Six of the patients died; four had a severephenotype, and two had a moderate phenotype. Thepatients ages at the time of death ranged from 4 to96 months (mean, 36.4 17.21 months).

Although this report15 provides epidemiologic dataon LAD, there is doubt as to whether periodontal dis-ease is also present. First, six of the patients died;mostweretooyoungtohavehadtheirperiodontalcon-dition diagnosed; second, none of the investigators

were periodontists or dentists who would have beenable to diagnose the disease properly. Therefore, thepossibility exists in this report for misdiagnosis andan underestimation of the prevalence of periodontaldisease.

According to the International Workshop for a Clas-sification of Periodontal Diseases and Conditions in1999,16 the term prepubertal periodontitis in partic-ular the generalized type was replaced by the termperiodontitis as a manifestation of systemic dis-eases.Systemicdiseaseswithneutrophildysfunctionare involved on the basis of this classification and

need to be considered in the differential diagnosis ofperiodontitis in children and adolescents. The reviewarticle by Deas et al.4 provides comprehensive datafor dentists about the differential diagnosis of thesedisorders.

The intraoral clinical findings in this report aresimilar to the characteristics of generalized prepu-bertal periodontitis,17 including the early onset ofthe disease that affected the primary and permanentdentitions, the intense redness and inflammation ofthe gingiva, and the rapid periodontal destructionthat seems refractory to conventional periodontaltherapy.

Examination of the three panoramic radiographs(2001, 2003, and 2006) showed that moderate toadvanced alveolar bone loss affected most primaryteeth by the age of 5 years and the permanent firstmolars and incisors by the age of 7 years, with exten-sion to the remaining dentition by 10 years. Thesefindings also seem comparable to what was reportedby Waldrop et al.,5 who described the oral conditionsin a family of six who had LAD-I. The children pre-sented with acute gingival inflammation of the pri-mary and permanent dentitions, as well as gingivalproliferation, recession, tooth mobility, and patho-

logic migration.

Conventional periodontal treatment provided fromDecember 2001 to August 2003, which included ex-traction of hypermobile teeth, multiple visits for moti-vation and education to practice good oral hygiene,and scaling and root planing with local and systemicantimicrobial therapy, was unsuccessful. Periodontal

treatment for patients with periodontitis related toneutrophil disorders is empirical and without consis-tent success; the end result is usually tooth loss.4Also,a 5-year case study18 of a child with LAD-I describedthe generalized progressive periodontitis and intraoralinfections associated with the primary and permanentdentitions and concluded that the associated thera-peutic challenges used in the attempts to arrest theperiodontal disease were largely unsuccessful. Themoderate type of LAD-I has the same progressive de-struction pattern of the periodontium that is resistantto treatment; however, the authors of this report con-

cluded that teeth must be preserved whenever possi-ble, and periodontal disease should be controlled withperiodic oral prophylaxis for the sake of maintainingthe normal physical and psychological developmentof the child.19

Because the periodontal status in patients with LADis primarily related to their host defect, it is possible toimprove their periodontal condition if the host defectis corrected. Various medical treatment modalitieshave been used for patients with LAD-I including whiteblood cell transfusions, antibiotics, and interferon, butan allogenic stem cell transplant has been held out as

the best curative option.20

Ideally, patients with LADshould be referred for transplant at a young age beforedeveloping multiple, resistant infections.21 Bone mar-row transplantation has proven to be the most effec-tive, as well as curative, therapy for the disease withmatched22 or mismatched human leukocyte antigenI antigen donors.23 Most of the cases of reported trans-plantation were performed during the first 2 years oflife.21-24 However, not all patients with severe LADare candidates for early bone marrow transplanta-tion.25 The treatment plan for the patient includes abone marrow transplant, but a suitable donor hasnot been found.

Although periodontitis is a major clinical character-istic of this disease, dental reports on patients withLAD-I are very rare in the literature compared to med-ical reports, and there is some controversy and am-biguity regarding the periodontal status in thosepatients. Cooperation between dentists and pediatric-ians is crucial for a better understandingof this diseasethrough referral of such cases to the periodontist. Thisreport also emphasizes the importance of the differen-tialdiagnosisincasesofsevereperiodontitis.Thiscaseillustrates the desirability of combined dental andmedical diagnosis and treatment of this rare immuno-

logic condition. Such a cooperative approach will help

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to prevent tooth loss and aid inthe control of oralinfec-tion in these patients.

ACKNOWLEDGMENT

The authors report no conflicts of interest related tothis case report.

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7. Hayward AR, Leonard J, Wood CBS, Harvey BAM,Greenwood MC, Soothill JF. Delayed separation ofthe umbilical cord, widespread infections, and defec-tive neutrophil mobility. Lancet 1979;1:1099-1101.

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II. Advances and open questions. FEBS J 2006;273:4390-4398.

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15. Movahedi M, Entezari N, Pourpak Z, et al. Clinical andlaboratory findings in Iranian patients with leukocyteadhesion deficiency (study of 15 cases). J Clin Im-munol 2007;27:302-307.

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17. Oh T-J, Eber R, Wang H-L. Periodontal diseases in thechild and adolescent. J Clin Periodontol2002;29:400-410.

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19. Majorana A, Notarangelo LD, Savoldi E, et al. Leuko-cyte adhesion deficiency in a child with severe oralinvolvement. Oral Surg Oral Med Oral Pathol OralRadiol Endod 1999;87:691-694.

20. Engel ME, Hickstein DD, Bauer TR Jr., et al. Matchedunrelated bone marrow transplantation with reduced-intensity conditioning for leukocyte adhesion defi-

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21. Yoshimoto A, Hashii Y, Kashiwagi H, et al. Successfulallogeneic stem cell transplant for leukocyte adhesiondeficiency using an adjusted busulfan-containing reg-imen. Pediatr Transplant 2007;11:453-455.

22. Al-wahadneh AM, Haddadin I, Hamouri M, Omari K,Aejellat F. Bone marrow transplantation for leukocyteadhesion deficiency-I: Case report. Saudi J Kidney DisTranspl2006;17:564-567.

23. Hattori H, Tsuruta S, Horikoshi Y, et al. Successfulhuman leukocyte antigen one antigen-mismatchedrelated bone marrow transplantation in a 6-year-oldboy with leukocyte adhesion deficiency syndrome.

Pediatr Int 2001;43:306-309.24. Suliaman F, Abdul Jabbar M. The association ofleukocyte adhesion defect type I and persistent hyper-insulinemic hypoglycemia of infancy in a Saudi Ara-bian family. Brief report. Pediatr Hematol Oncol2002;19:429-432.

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Correspondence: Dr. Nabil F. Bissada, Department ofPeriodontics, School of Dental Medicine, Case WesternReserve University, 10900 Euclid Ave., Cleveland, OH

44106-4905. Fax: 216/368-3204; e-mail: nabil.bissada@case.edu.

Submitted June 5, 2007; accepted for publication August29, 2007.

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