immunological and metabolical studies in two siblings with papillon-lefevre syndrome

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  • Journal of Periodontal Research 17: 563-568, 1982

    Immunological and metabolicaj studies intwo siblings with Papillon-Lefevre

    syndromeToRSTFlN LYBERG

    Department of Maxilio-Facial Surgery, Dltev^l Hospital, Oslo, Norway

    Two cases of typical Papillon-Lefevre syndrome in one family were reported. Neither patient showedevidence of systemic disease as assessed by the medical history and a battery of clinical laboratory testsincluding a screening system for the detection of inborn errors of metabolism.

    A survey of ihe patients' immunological status, including lymphocyte transformation tests usingmitogens and polymorphonuclear leukoeyte chemotaxis studies, gave no indication of disturbances inimmunological functions and host defense mechanisms. Possible pathogenetic mechanisms aredi.scussed.

    (Accepted for publication August 17. 1982)


    The syndrome of palmar-plaiUar hyperkera-losis and premature destruction of periodontalsupporting tissues was first described byPapiilon and Lefevre (1924), Since then, lessthan 100 cases have been reported in the.literature. Comprehensive reviews of the con-dition are given by Jansen and Dekkcr (1956)and by Gorlin, Sedano and Anderson (1964).

    This syndrome is probably inherited as anautosomal recessive trait, and the frequency ofdisease manifestation in the general populationis estimated to be about one to four per million(Goriin et a l 1964).

    The cutaneous lesions of the palms and solesare usually manifested during the first year oflife and are usually not severe. The periodontaldestruction begins as soon as the primary teetherupt and progresses until the whole primarydentition is lost at the age of five to six years.The same events reoccur in the permanentdentition, and these patients are usually eden-tulous in the early teens.

    Periodontal lesions are characterized byrubor and swelling of the gingival tissues,

    alveolar bone breakdown, deep pockets, andmobile teelh. After the teeth are exfoliated, thegingiva assumes normal appearance.

    The histological picture of the affectedgingival tissues is characterized by epithelialhyperplasia and inl'iltration of the underlyingconnective tissue with chronic inflammatorycells which are predominantly plasmacytic innature (Giansanti, Hrabak & Waldron 1973,Gardner & Johnson 1973).

    Concomitant changes include hyperhidrosisof the palms and soles, dystrophic nails, andhyperkeratotic plaques on other sites of thebody. Calcium deposits in the tentorium andfalx cerebri have also been quoted by severalauthors. Some other pathological features havealso been claimed to be associated with thissyndrome, but they are probably coincidental.

    Due to its rare occurrence, there are fewconsiderations concerning the etiology andpathogenesis of this syndrome. Furthermore,the treatment is ineffective, and nocurehas thusbeen found.

    During the last decade, numerous reportshave appeared supporting the hypothesis thathost defense mechanisms are deranged and play

  • an important role in the pathogenesis ofperiodontal diseases, especially in cases ofjuvenile periodontitis. This refers both tospecific immunological reactions (Lehner et al.1974) and to disorders in neutrophil chemotaxisor phagocytosis (Cianciola et al. 1977, Lavine etal. 1979, Vandesteen, Altman & Page 1981).

    This paper reports the detection of twotypical cases of this particular syndrome in onefamily. The possible role of immunologicalreactions in the pathogenesis of the periodontaldestruction is evaluated on the basis of a surveyof the patients general immunological status.Furthermore, the hereditary basis of the diseaseled to the examination of possible derange-ments in intermediary metabolism.

    Material and MethodsPatient IHistory and clinical findings, A 3-year old girlwas referred to our clinic because of chronicgingival inflammation. Apart from a fewepisodes of pharyngitis tbe patient had beengenerally healthy. For almost a year she hadsuffered from red, swollen, and easy bleedinggingivae and progressive loosening of teeth.

    Oral examination revealed general gingivalinflammation, deep pockets, and mobile teeth,especially involving the incisors and firstmolars.

    Well demarcated hyperkeratotic erythemat-osquamous lesions were found on the palmsand soles (Fig. 1) and, according to the parents,the skin lesions and concomitant hyperhidrosishad been present from the age of a few months.

    Apart from a Ij-year old brother, there wasno knowledge of other affected family mem-bers. There was no history of parentalconsanguinity.

    Radiographical examinations including ortho-pantomograph and intraoral radiographs (Fig.2) showed severe alveolar bone loss around allteeth. The periodontal bone loss appeared to beproportional to the posteruptional time foreach tooth, and in the frontal region of thelower jaw, the periodontal bone border wasalmost at the level of the apices of the teeth. Ageneral skeletal radiographical survey showednormal structures. Skull radiographs did notexhibit calcification of the dura.

    Blood analysis including Hgb, thrombocytes,calcium, phosphorus, urea, creatinine, Na" ,^K \ c r , Fe++, transferrin, glucose, ASAT,ALAT, alkaline phosphatase, AST, and ASTAwere all within normal limits. ESR variedbetween 9 and 25 on different occasions andwhite blood cell counts between 7,000 and15,600. Differential counting of white bloodcelis were performed several times during a two-

  • P A P I L L O N - L E F E V R E SYNDROME 565

    Fig. 2. Roentgenograms of teeth of patient 1 at 3 years of age showing severe bone loss in varying locations.

    month period (to exclude cyclic neutropenia)and showed normal distribution of dilTerenlgroups of white cells. Quantitation of totalserum protein and electrophoresis pattern ofserum was normal. Concentration of para-thyroid hormone in serum was within normallimits (0.35 ng/ml).

    Histologica/ examinations. Sections from gin-gival specimens stained with hematoxylin andeosin revealed hyperplastic oral and oralsulcular epithelium with marked spongiosis andpartial hyperkeratosis. The underlying connec-tive tissue showed oedema and dense infiltra-tion of chronic inflammatory cells thai werepredominantly plasmacytic and lymphocytic innature. Decalcified sections of teeth showednormal structures.

    Immunological i'.\ ami nations. Estimation ofserum immunoglobulin concentrations weredone by the method of Mancini et al. (1965) andfound to be within normal limits (IgG 10.5 g/1,lgA0.9g/l, and IgM 1.2 g/l). (Normal range for

    that age group were: IgG 6.0-15.0 g/l. IgA 0.5-2.5 g/l, and igM 0.6-2.0 g/l.)

    Determinations of selected complementcomponents of the classical and alternativeactivation pathway in serum were done by thesame technique and also showed normal values(C3 1.0 g/l, C4 0.24 g/l, and C3PA 104% ofnormal mean). (Nonnal range for C3 0.7-1.7 g/land C4 0.1-0.5 g/l.)

    Serum autoaniibody studies including anti-nuclear factor (ANF), rheumatoid factor(Waaler and lalex test), and antibodies tohuman skin were alt negative.

    Quantitation of T lymphocytes in peripheralblood was done by a rosette technique usingsheep red blood cells (Froiand & Natvig 1973)and found to be 96% of a concomitant normalcontrol.

    Mononuclear cells from peripheral bloodwere separated by the method of Boyum (1968)and stimulated with four different mitogens(Phytohuemaggiutinin, Concanavalin A, Abrusagglutinin. and Pokeweed mitogen) to get an invitro correlate of the cellular immunological

  • 566 L Y B E R G

    responsiveness. Isolated lymphocytes were in-cubated for 5 days, and DNA synthesis wasassayed by adding *H-thymidine 16 h beforeharvesting the cultures. The stimulatory indiceswere csscniially the same as for the concomitantnormal controls.

    Immunofluorescence studies on sectionsfrom frozen gingivai specimens were performedaccording to standard techniques usingfluorescein-conjugated antisera against dif-ferent immunoglobulin classes. This revealedpositive lluorescence for IgG, IgA. and IgMlocated lo mononuclear cells in Ihc connectivetissue. The majority of cells showed IgGspecificity, but no attempt was made lo exactlyquantitate the distribution of cells positive forthe various immunoglobulin classes. TheHuorescence was restricted to the inflammatorycells and not found in epithelial structures orbasal membrane zones.

    Patient polymorphonuclcar leukocytes wereseparated according to Boyum (196S). Thechemotaxis function of PMN's was investigatedby measuring their migration in agarosemedium against zymosanaclivatcd humanserum as the source of complement-derivedchemotactic principles (Nelson. Quie &Simmons 1975). The chemolactic index(chemotactic migration distance: spontaneousmigration distance) was 3.2 and within thelimits of a reference material (2.1-4.4).

    Meiabolical examinations. Urine and serumsamples were subjected to a screening system forthe detection of inborn errors of metabolism(Stokkc & Jellum 1979).

    Metabolic end products like urea, creatinine.and inorganic phosphate in urine were withinnormal limits. Multivalent dipstick tests loralbumin, blood, ketone bodies, and glucosewere negative.

    Benedict's reaction for the presence ofreducing substances, ferric chloride test forphcnylketones, nitroprussidc test for SH-compounds, and a turbidity test for increased

    amounts of mucopolysaccharides in urine wereall negative.

    The determination of organic acids in urinewas performed by a gas chromatographictechnique and showed a normal chromato-gram.

    Quantitative ion-exchange amino acid anal-ysis was applied to serum and urine samples andshowed normal amino acid profiles on twooccasions.

    Patient 2A li year old brother showed a dermatologicalpicture that closely resembled his sister's. Theperiodontal destruct