PEDIATRIC DENTISTRY/Copyright © 1990 by

CASE REPORTSThe American Academy of Pediatric DentistryVolume 12, Number 2

Oral manifestations associated with leukocyteadhesion deficiency: a five-year case studyMichael W. Roberts, DDS, MScD Jane C. Atkinson, DDS

Abstract

A five-year case study of a child with leukocyte adhesiondeficiency is presented. The report describes the generalizedprogressive periodontitis and intraoral infections associatedwith both the primary and permanent dentition. The associ-ated therapeutic challenges and largely unsuccessful treat-ment regimens utilized in the attempts to arrest the periodon-tal disease are described.

Introduction

Many previously unknown disease mechanismsnow are being described by molecular biology. A re-cently defined immunological disease, leukocyte adhe-sion deficiency (LAD), occurs when three surfaceglycoproteins are absent or defective on leukocytes(PMN), leaving affected patients susceptible to bacterialinfections (Crowley et al. 1980; Arnaout et al. 1982; Danaet al. 1984). Although the defect is rare, studies ofpatients with the disease help to determine the functionof the leukocyte surface glycoproteins in healthy indi-viduals (Fig 1).

LFA-1%,. ~M(]c-1gp 1.50,95 \ .~- C3bi

Adherence Ph(]gocytosis

/ \Migration to sites ~illin~ of b~cterieof infection

Fig 1. Represented are two neutrophil (PMN) functions andreceptors (Mac-l, gp 150,95, and LFA-1) that mediate thesepathways. PMNs from patients with LAD lack all three receptors,leaving them susceptible to bacterial infections.

The complete surface glycoproteins in normal leuko-cytes contain at least three important binding sites nec-essary for normal leukocyte adherence. These are Mac-1 (also referred to as Mol) (complement receptor type or CR3) (Buescher et al. 1985), lymphocyte function-associated antigen-1 (LFA-1) (Arnaout et al. 1984) gp 150,95 (Arnaout et al. 1982). Mac-1 binds an impor-tant complement fragment, C3bi, which also is attachedto an antigen-antibody complex. The binding of C3bi isthought to promote phagocytosis and eventual destruc-tion of foreign antigens, such as a bacterium. Withoutthe receptor for C3bi, neutrophils ingest very low levelsof bacteria. The lack of the adherence receptors LFA-1and gp 150,95 results in poor attachment of leukocytesto endothelial cells and low neutrophil accumulation atinfection sites (Anderson and Springer 1987).

This disease is the result of one defect. Each of thesurface glycoproteins lacking LAD normally is com-posed of a different ~ subunit joined to a common 6subunit (Springer et al. 1984). Individuals with LADlack only the ability to make the 6 subunit, but the c~portion is not expressed when the [~ subunit is absent.The degree of immunosuppression varies, as patientswith trace levels of the subunit have less severe diseasethan patients who produce no measurable [~ subunit(Anderson and Springer 1987).

Delayed separation of the umbilical cord with conse-quential septicemia may be the earliest clinical manifes-tation of LAD (Crowley et al. 1980). Recurrent infectionsof soft tissues, mucous membranes, and intestinal tractsoften are caused by staphylococci, gram negative bacte-ria, or other pyogenic organisms (Anderson and Sprin-ger 1987). Common infections observed in these pa-tients include multiple skin abscesses, recurrent otitismedia, and pnuemonitis. While bacterial infectionsdevelop frequently, viral infections are not a persistentclinical problem in these patients. One of the moststriking laboratory findings of these patients is a persis-tent elevation of the granulocyte count ranging from

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15,000 cells/mm3 to 161,000 cells/mm3. In spite of thehigh peripheral blood granulocyte numbers, biopsies ofinfected areas are nearly void of neutrophils. Conse-quently, abscesses occur without pus formation.

Inheritance of the disease follows an autosomal re-cessive pattern that has been mapped to chromosome 21(Anderson and Springer 1987). Several reported ho-mozygous patients had consanguineous parents whowere heterozygous for the defective chromosome.While homozygous patients have severe disease,heterozygous patients are reported to be clinicallyhealthy despite abnormalities in certain leukocyte func-tion assays.

The most dramatic oral finding associated with LADis severe periodontal disease. One reported patient hadall primary teeth extracted by age three years because ofperiodontitis (Waldrop et al. 1987). The same patientlost several permanent teeth by age 12 years as a resultof 50-90% alveolar bone loss. All homozygous patientsin this study exhibited generalized rampant periodon-tal disease involving both the primary and permanentdentitions. Attempts to control the periodontal diseasewere not successful. Gingival biopsies obtained whenteeth were extracted demonstrated only a mononuclearinfiltrate in the tissue. Additional reported oral findingsin patients with LAD include stomatitis, ulcerations ofmucous membranes, and facial cellulitis (Anderson andSpringer 1987).

This case report focuses on a child with LAD who hasbeen followed regularly at the National Institute ofDental Research (NIDR) Clinic for the past five years.The associated periodontal disease and eruption pat-tern is well documented longitudinally. The difficultiesin managing such a patient also are presented anddiscussed.

Case Report

Medical HistoryA black female, 3 years, 11 months old, product of

first cousin parents, was referred to the National Insti-tute of Allergy and Infectious Diseases, National Insti-tutes of Health (NIH); she had a history of mild respira-tory distress, pityriasis rosea, fever, and leukocytosis ofunknown origin shortly after birth. Throughout the firstyear following birth, the patient continued to experi-ence poor healing following minor surgery, recurrentcutaneous infections, and abscess formation withoutpurulence that nevertheless required incision anddrainage. It was observed that superficial injuries to theskin resulted in severe inflammation. A white bloodcount (WBC) of 10-20,000/ml was present throughoutthis period.

Admitting laboratory studies showed the following:hemoglobin -- 10.7; hematocrit -- 29.8%; reticulocyte

count-- 0.6%; MCV -- 75; and platelet count-- 531,000.The WBC was 19,900 with 33 segs, 50 lymphocytes, 11monocytes, 2 eosinophils, and 2 basophils. Screeningtests for thalassemia and sickle cell anemia were nega-tive. The sedimentation rate was 27. Glucose was re-ported as 57, potassium 4.8, and a serum lactic dehydro-genase 269. Immunoglobulin levels were IgG 1180, IgA487, and IgM 215. After extensive testing of the patient’sleukocytes, it was confirmed by fluorescent cell analysisand rosetting that the white blood cells lacked the C3bireceptor. Additional information and the results of ex-tensive laboratory studies of this patient have beenpublished previously (Buescher et al. 1985). The motherwas found to have a C3bi defect as well, but she deniedany illnesses except for hay fever. The father’s medicalhistory was remarkable only for post-traumatic sei-zures. The child was placed prophylactically on tri-methoprim and sulfamethoxazole (Septra) antibacterialcombination, and ferrous sulfate for anemia therapy.

Over the next 5-1/2 years the child required numer-ous hospital admissions for pneumonia, periorbitalsinusitis, and recurrent diarrhea. She was treated withvarious antibiotic combinations during these episodes.However, since November 1984 the patient has beenmaintained on prophylactic oral trimethoprim 40 mg,and sulfamethoxazole 200 mg (BactrimTM, Roche Labo-ratories, Div. of Hoffmann-La Roche, Inc., Nutley, NJ07110) twice daily with some success in preventingrecurrent infections.

Dental History

The patient first was referred at the age of 3 years, 11months to the NIDR Clinic for evaluation. An oralexamination, including panoramic radiograph, wasaccomplished. The primary dentition was complete, butthere was generalized gingival recession, abnormaltooth mobility, gingivitis, and loss of gingival attach-ment and supporting alveolar bone.

The sedated patient was given a thorough oral pro-phylaxis with deep scaling. It was recommended thatthe child’s teeth be brushed twice daily by a parent witha sodium bicarbonate paste, and that 0.4% stannousfluoride gel be applied after the evening oral hygiene.

Seven months later the child returned to the dentalclinic for reevaluation. Her oral hygiene had improved,but the generalized gingivitis still was prominent withincreasing loss of alveolar bone around all primary teeth(Fig 2). The importance of home care was reinforcedalong with the recommendation that the sodium bicar-bonate dentifrice/fluoride gel regimen be continued.Four months later the child presented with a left facialswelling of three days duration, apparently associatedwith the mandibular teeth. Panoramic and periapicalradiographs of the first and second primary left mandi-bular molars revealed the presence of a periodontal

108 ORAL EFFECTS OF A LEUKOCYTE DEFECT: ROBERTS AND ATKINSON

Fig 2. Patient at age 4 years, 6 months. Generalized bone loss isevident around all posterior primary teeth.

Fig 3. Patient at age 5 years, 4 months. There is progressive lossof tooth-supporting bone.

Fig4. Patient at age 6 years, 8 months. The premature exfol iationof primary molars and initial loss of alveolar bone aroundpermanent molars is evident.

Fig 5. Patient at age 9 years, 0 months. Note early eruption ofpremolars and generalized stunted root formation of thepermanent teeth. The periodontal disease continues to progress.

abscess associated with both teeth. The area was irri-gated with hydrogen peroxide/water, and oral potas-sium penicillin therapy was initiated with resolution ofthe swelling in eight days along with increased firmnessof the teeth.

The patient had exfoliated the two mandibular cen-tral incisors spontaneously at age 4 years, 6 months. Tenmonths later the child returned to the dental clinic forroutine examination. The previously observed chronicgingivitis and generalized loss of alveolar bone wasnoted to have continued, although she remainedasymptomatic (Fig 3). A month later the patient pre-sented with a complaint of pain in the right maxilla.Considerable plaque was present on the teeth, and afetid odor emanated from the oral cavity. A periodontalabscess was noted in the general area of the right max-illary primary canine extending to the second molar,with no associated facial swelling. The teeth werecleaned gently with sealers and polished with prophy-laxis paste to remove the adhering bacterial plaque.Home care was again emphasized to the child andmother. Oral potassium penicillin antibiotic therapywas initiated with good results. Chronic progressiveperiodontitis was evident at the child's regular oralexamination at age 6 years, 8 months (Fig 4).

The patient was admitted to the hospital at age 8years, 7 months with a periorbital sinusitis. She wasreferred to the dental clinic following subluxation of theright primary second maxillary molar while surgicallyattempting to enter the sinus to establish drainage. Thetooth was extremely mobile and required extractionunder local anesthesia.

The patient was asymptomatic when she returnedfive months later for her next regular dental examina-tion and oral prophylaxis. The left side of the face wasslightly swollen with associated submandibular lym-phadenopathy. Intraoral examination did not revealany findings that had not been recorded previously (Fig5). The daily use of 1.2% chlorhexidine mouth rinse wasadded to the home care regimen in an attempt to arrestthe severe chronic gingivitis.

However, eight months later the child again re-turned to the hospital in no apparent discomfort butwith a grossly swollen left cheek progressing inferiorlytoward the submandibular area. A hard, nontender, 11 /2-3 cm indurated mass was palpable along the lateralborder of the left mandible. A panoramic radiographrevealed rapid and continuous loss of alveolar bonefrom around all permanent teeth but no specific pathol-ogy to explain the swollen left cheek (Fig 6, next page).Oral temperature was 38 °C, the WBC count was 36,700,hemoglobin 7.3, hematocrit 23.3, mean corpuscularvolume (MCV) 67, mean corpuscular concentration

PEDIATRIC DENTISTRY: APRIL/MAY, 1990 ~ VOLUME 12, NUMBER 2 109

Fig 6. Patient at age 9 years, 8 months. There is virtual ly total lossof supporting alveolar bone from around the permanent teeth.

(MCH) 21, mean corpuscular hemoglobin concentra-tion (MCHC) 31.4, and platelet count was 952,000. Thedecision was made to admit the patient to the hospital toinitiate intravenous antibiotic therapy and schedule anintraoral incision and drainage the following day.

Preoperative intravenous vancomycin initially wasinfused but had to be discontinued, since the patientdeveloped urticaria which required diphenhydraminehydrochloride to supress. It was not determinedwhether this was an allergic reaction to vancomycin orthe result of too rapid infusion of the antibiotic. Never-theless, the antimicrobial agent was changed to penicil-lin.

The sedated patient was brought to the dental clinic,and, under local anesthesia, an intraoral incision wasmade into the endurated mass along the left mandible.Although no purulent exudate was detected, specimenswere taken for both aerobic and anaerobic culture andsensitivity determination. In addition, specimens weretaken from periodontal pockets associated with theright permanent mandibular first and left maxillary firstmolars. Proteus mirabilis, Pseudomonas aeruginosa, andalpha hemolytic streptococcus subsequently were re-ported in addition to other normal aerobic intraoralmicroflora. Anaerobes Eacteroides melaninogenicus andPeptostreptococcus micros also were present in smallquantities. Although branching elements were seen ona gram-stained smear, no actinomycetes were isolated.

The patient was prescribed nafcillin and penicillin,and was discharged from the hospital at the request ofthe child and mother. The parent reported improve-ment during subsequent follow-up telephone inquiries.

DiscussionLeukocyte adhesion deficiency (LAD) is a rare disor-

der characterized by recurrent infections. Althoughthere have been case reports describing associatedgeneralized severe periodontal disease (Bowen et al.1982; Waldrop et al. 1987), a longitudinal description ofthe intraoral sequela of the disorder has not been pub-

lished previously. The patient's inability to effectivelyrespond to recurrent infections apparently is related tothe severe functional defect in phagocytic chemotaxis,aggregation, and adherence. However, there are strongsuggestions that additional antigenic and functionaldeficiencies also are present. (Buescher et al. 1985;Waldrop et al. 1987).

The clinical and radiographic appearance of ourpatient resembled generalized juvenile periodontitis(Hormand and Frandsen 1979) or prepubertal perio-dontitis (Page et al. 1983). However, comparison ofpatients with LAD to patients with generalized juvenileperiodontitis is difficult. LAD involves neutrophils,lymphocytes, and monocytes, while generalized juve-nile periodontitis has been associated primarily withonly neutrophil defects (Van Dyke et al. 1985).

Actinobacillus actinomycetemcomitans previously hasbeen associated with juvenile periodontitis (Slots et al.1980). However, there was no evidence of the gramnegative rod, A. actinomycetemcomitans by anaerobicculture from the periodontal abscess or other selectedperiodontal pockets in our patient. Specific serum IgGantibody levels against the organism were not obtained.It is much more probable that the periodontal diseaseresulted from an inability to fight off numerous invasiveand/or opportunistic organisms, rather than being theconsequence of one particular pathogen. Aggressiveperiodontal disease also has been described in childrenwith a broad range of systemic disorders such as theneutropenias (Cohen and Morris 1961; Baehni et al.1983) and Papillon-Lefevre syndrome (Gorlin et al.1964).

An aggressive oral hygiene and professionally deliv-ered regimen of care failed to arrest the chronic gingivi-tis, rapid loss of gingival attachment, destruction of thesupporting periodontal tissues and supporting alveolarbone. Although antibiotics appeared to suppress acuteorally related infections successfully, the use of a so-dium bicarbonate dentifrice, brush-on 0.4% stannousfluoride gel, and a 1.2% chlorhexidine mouthrinse alsowere apparently ineffective. Unfortunately, it wasimpossible to determine the degree of parental andpatient compliance with home care recommendations.

The importance of maintaining the dentition andpreserving the vertical dimension for as long as possiblein the child's developing orofacial complex was one ofour primary concerns in the initial philosophy of treat-ment. However, we also were unaware of the difficultywe would encounter in attempting to arrest the inces-sant periodontal destruction. In retrospect, it could beargued that reducing the risk for future infections wasthe most important consideration, and our resistance toextracting the severely involved teeth put the child atgreater peril.

110 ORAL EFFECTS OF A LEUKOCYTE DEFECT: ROBERTS AND ATKINSON

Conclusion

Patients with LAD effectively demonstrate thatmaintenance of the periodontium depends on an intactdefense system. These patients most likely will be en-countered with increasing frequency due to improved¯ antibiotic and support therapy. A few patients havebeen treated successfully with bone marrow transplants(Anderson and Springer 1987), and others may be can-didates for gene therapy. However, they will continueto present unusual and difficult challenges for clinicaldental management.

At the time of writing, Dr. Roberts was Chief, Patient Care and ClinicalStudies Section, Clinical Investigations and Patient Care Branch, andDeputy Clinical Director at the National Institute of Dental Research(NIDR). Currently, Dr. Roberts is Graduate Program Director forPediatric Dentistry at the University of North Carolina at Chapel Hill.Dr. Atkinson is Senior Sta ff Fellow, Clinical Investigations and PatientCare Branch, at NIDR. Reprint requests should be sent to: Dr. MichaelW. Roberts, Dept. of Pediatric Dentistry, School of Dentistry CB#7450,University of North Carolina, Chapel Hill, NC 27599-7450.

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Anderson DC, Springer TA: Leucocyte adhesion deficiency: an inher-ited defect in the Mac 1, CFA 1 and p150,95 glycoproteins. AnnuRev Med 38:175-94, 1987.

Arnaout MA, Pitt J, Cohen HJ, Melamed J, Rosen FS, Colten HR:Deficiency of a granulocyte-membrane glycoprotein (gp150) in boy with recurrent bacterial infections. N Engl J Med 306:693-99,1982.

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Baehni PC, Payot P, Tsai C, Cimasoni G: Periodontal status associatedwith chronic neutropenia. J Clin Periodontol 10:222-30, 1983.

Bowen TJ, Ochs HD, Altman LC, Price TH, Van Epps DE, BrautiganDL, Rosin RE, Perkins WD, Babior BM, Klebanoff SJ, WedgwoodRJ: Severe recurrent bacterial infections associated with defectiveadherence and chemotaxis in two patients with neutrophils defi-cient in a cell-associated glycoprotein. J Pediatr 101:932-40, 1982.

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The American Board of Pediatric Dentistryis Pleased to Announce the Following

New Diplomates

Suzanne P. Berger - Camarillo, CA Judith S. Pabst ~ Canoga Park, CARoy V. Green - Fort Myers, FL F. William Taylor ~ Hendersonville, TN

Beverly A. Largent ~ Paducah, KY Clara Turner ~ Gainesville, FLGuy C. Lichty II ~ E1 Cajon, CA Robert M. Willard - Springfield, IL

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