Papillon-Lefevre syndrome associated with albinism. Clinical and immunological study
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ELSEVIER Journal of the European Academy of Dermatology and Venereology
6 (1996) 246-251
Papillon-Lefevre syndrome associated with albinism. Clinical and immunological study
Mohammed Amer a, * , Fawzia Farag Mostafa a, Zenab Tosson a, Ahmmed Hegazi b a From the Department of Dermatology, lJniversi@ of Zagazig, Faculty of Medicine, Zagazig, Egypt
b National Research Center Dokki, Cairo, Egypt
Background: We report the first association of Papillon-Lefevre syndrome (PLS) with tyrosinase-nega- tive albinism in two brothers. Also, we studied T-lymphocytes and mononuclear cell activity in them and in two other cases of PLS not associated with albinism.
Objective: To recognize clinical and immunological correlation. Methods: Four PLS patients from 3 different families were studied clinically and immunologically.
Two brothers (albino) in one family had recurrent infections. The other two patients from two other families had no infection. The patients healthy parents were also included in the study.
Results: A decreased lymphocyte proliferative response to phytohaemaglutinin and in mononuclear cell activities were detected not only in the PLS patients with recurrent pyogenic infection, but also in their healthy parents. Further investigations of these patients showed impaired humoral and cellular immune response. PLS patients with no infection and their parents showed normal immunologic parameters.
Conclusion: We suggest dividing PLS on clinical and immunological bases into two variants: PLS with pyogenic infections and the other variety without such infection. PLS with pyogenic infections is associated with immunologic dysfunction. Periodontosis could not be explained on an immunological basis.
Keywords: Papillon-lefevre; Keratosis palmoplantaris
The syndrome of keratosis palmoplantaris with periodontopathy, was first described by Papillon
* Corresponding author.
and Lefevre [l] in 1924. The syndrome is inher- ited as an autosomal recessive trait and its fre- quency has been estimated at approximately one to four per million persons in the general popula- tion [2,3]. There is evidence that this syndrome is associated with increased susceptibility to infec- tions in about 20% of patients . No cases of pigment abnormalities have been reported in the
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M. Amer et al. /J. Eur. Acad. Dermatol. Venereal. 6 (1996) 246-251 241
literature to date. T-lymphocyte, mononuclear cell most teeth. Thick crusted lesions were seen on activities and other immunologic parameters were his lower limbs only. History of previous internal studied in order to recognize their roles in the infection was irrelevant. Staphylococcus aureus pathogenesis of periodontosis and recurrent in- was the only organism isolated from the skin. fection if any in PLS. Roentgenogram of the skull was normal.
2. Report of Cases
Case 1. An 18 year-old male patient was re- ferred to us from Chest Outpatient Clinic where he had been under observation and follow-up for many years. Past history of the patient revealed that he was suffering from recurrent massive pyo- genie chest and cutaneous infection. He had been hospitalized most of the time since infancy. After he had taken massive antibiotic therapy and fre- quent chest aspiration his chest became free. But he still had recurrent cutaneous infections. On examination we found that the patients skin colour was pink, his hair sparse and white, and the iris of his eye was red. He had irregular nystagmus, with head nodding and diffuse well demarcated, yellowish, palmoplantar kerato- derma with extension of the keratosis to the sides of the hands, and feet up to the Achilles tendon. Symmetric, psoriasiform plaques were observed. Stomatologic examination showed loss of most of the teeth. Heavy crusted skin lesions were seen on the chest, thighs and lower limbs. Roentgenograms of the skull failed to reveal ec- topic intracranial calcification. Staphyl0coccus au- yeus was the only organism isolated from cuta- neous lesions. Past history of the patients family revealed that his brother and his great-grand- father had the same association of dyschromia, loss of teeth, keratotic changes and recurrent cutaneous infections.
Case 3. A 20 year-old male showed palmoplan- tar keratoderma with keratotic lesions on the dorsal aspects of the hands and feet. Keratotic plaques were present on the elbows, knees and Achilles tendons. Oral examination revealed loss of all teeth. Skull roentgenogram was normal. History of infection in this patient was irrelevant.
Case 4. A 17 year-old male presented with premature loss of all teeth. Skin examination showed extensive palmoplantar keratoderma, also on the dorsal aspects of the hands and feet. Psoriasiform plaques were present on elbows and knees. Increased susceptibility to infection in his past or present history was irrelevant; skull roentgenogram was normal.
Parental consanguinity was present in all cases. Roentgenogram of jawbone was done in all cases. Cases 1 and 2 were brothers but cases 3 and 4 were from two other families. Hair bulb test was performed [4,5] in order to determine the type of albinism. Blood samples were taken from all cases and their parents. To evaluate lymphocyte and mononuclear cell activities the following tests were done.
Case 2. A 14 year-old male patient, brother of the first propositus complained of recurrent cuta- neous infections. On examination, the patients skin colour was pink, his hair sparse and white and the iris of his eye was red. He also had irregular nystagmus with head nodding. His skin showed a diffuse well demarcated yellowish pal- moplantar keratoderma. Symmetric psoriasiform plaques were obsereved on both elbows and knees. Stomatologic examination showed loss of
Lymphocyte transformation test according to Hall and Gordon [61: blood was collected by venesection into sterile gamma irradiated vactain- ers containing 20 units of phenol-free heparin per ml of blood. After the blood was mixed, an ali- quant was removed for determination of mononuclear cells count. Viable lymphocytes were analysed with haemocytometer (improved Neu Bauer l/400 mm2 l/10 mm deep, Levy Ulone, Adams, New York, USA); viability should exhibit 95%. Cell concentration was adjusted to lo6 cells/ml. The lymphocyte cultures were per- formed with addition of phytohaemagglutinin to obtain the mitogenic stimulation. The mitogenic ratio as well as stimulation index were calculated
248 M. Amer et al. /J. Eur. Acad. Dermatol. Venereal. 6 (1996) 246-251
after the lymphocyte culture was pulsed with [ 3-H]thymidine.
Separation of peripheral blood mononuclear cells, according to Thorsby and Bratile . 10 ml blood was collected by venesection; after mixing in ratio of 1:3 Ficoll the blood was centrifuged at 2000 rpm for 30 min. The supernatant was de- canted and the leucocyte layer was collected. The leucocytes were washed 3 times in PRMI-1640 medium, then incubated in a glass Pitery dish for collection of glass adherent cells. These cells af- ter collection were used for bactericidal activity of E. coli according to Hegazi et al. .
Further evaluation of case 1 and 2 include: total serum protein, latex agglutination test against staphylococcus aureus, antistreptolysin 0 titre and tuberculin test according to Doumus , Dickson and Marples [lo], Curickshank et al. [ll] and Seaton et al.,  respectively. Flow cytomet- ric study was carried out on these patients using a facscan (Becton Dickinson) according to Abdel- Naser et al. .
Cases 1 and 2 brothers and both had PLS associated with tyrosinase negative albinism (Figs. 1,2). This is confirmed when incubation of plucked anagen hair bulbs in a solution of dopa from these patients does not darken in comparison with control. Family history revealed that their
Table 1 Results of lymphocyte transformation and bactericidal activity
Parameters Control Case
Ia 2= 3 4
Stimulation index 6.4 3.1 4.3 6.1 6.3 (patients)
Mother 6.3 5.2 b 5.2 b 6.2 6.4 Father 6.8 5.4 b 5.4 b 6.6 6.0 % of mononuclear 84 30 37 75 80
cell activity (patients)
Mother 86 42b 4Zb 81 83 Father 85 45 b 45 b 79 76
a Brothers. b Father and mother are the same in cases 1 and 2.
Table 2 Further immunologic evaluation
Parameters Control Case
Total serum protein 6.2 3.6 3.8 Latex agglutination test l/320 l/80 l/160 Antistreptolysin 0 titre +ve -ve --Ye Tuberculin test +ve -ve -ve
T cells subset Total T cells 83% 84% 70% Total I3 cells 16% 6% 16%
Suppressor/cytotoxic cells 33% 39% 28% Helper/inducer cells 51% 48% 48% Help/supp. Ratio 1.5 1.2 1.7 Activated T cells 9% 7% 13% NK cells 7% 10% 13%
great-grandfather had the same association. Both cases had suffered from recurrent pyogenic infec- tions. Infections were severe in case,l, as they had involved skin and lung since infancy (Fig. 2a,b). In case 2 the infections were less severe as they were confined to the skin. T-cell and mononuclear cell functions proved to be impaired not only in the patients, but also in their parents, as shown in Table 1.
Table 2 shows that there was a significant difference in total protein, agglutination test, an- tistreptolysin 0 titre and tuberculin test between case 1, 2 and control. Separation of T-cells subset revealed a decrease in total B-cells in case 1 only.
Cases 3 and 4 had no history of infection. T-cell and mononuclear cell activities in both patients and their parents showed normal values (Table 1). Roentgenogram of jawbone showed periodontosis in all cases (Fig. 3, as an example).
Both PLS and tyrosinase negative albinism are conditions transmitted as autosomal recessive traits. To our knowledge the association of PLS with albinism had not been reported before. This association could be explained by either of two possibilities. The first is that by chance the two traits had segregated from both parents and that they are independent. The second explanation,
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assumes that both traits represent manifestations of the same gene mutation. In favour of the second hypothesis is the presence of the same association in their great-grandfather and ab- sence of single trait transmission to any member of the family. The exact nature of this association has yet to be clarified.
response and pyogenic infections in PLS patients could be related to these immune defects. The immunological abnormalities were negative in those subjects with no evidence of infections.
A patient with PLS presented with a prema- ture loss of both deciduous and permanent teeth. Other abnormalities such as psoriasiform hyperk- eratosis and frequent infections could be seen. The mechanism for this aberration has not been clarified as yet . The skin is reported to be the most common site affected by infections in sus- ceptible PLS patients. Internal organs, such as liver, lung, kidney and gut are less frequently involved [3,151.
The mechanisms for rapid destructive peri- odontosis in all PLS patients remain to be deter- mined. Pathogenesis of periodontosis on an im- munological basis alone is a subject of contro- versy.
The suscepibility of some PLS patients to re- current infections have prompted investigations of their immune status. Some investigators have shown disturbance in both polymorphonuclear leukocyte motility and bactericidal functions [16,17] or in bactericidal functions alone . Similarly, disturbances in various lymphocyte stimulatory responses of PLS patients were ob; served [19,20]. In the present study we have drawn attention to a defect of mononuclear function, and a decreased lymphocyte proliferative re,- sponse to phytohaemagglutinin in the cases asso- ciated with pyogenic infections and also in then parents, in different percent.
The possible role of neutrophil dysfunction in the pathogenesis of the periodontal involvement has been reported . However it constantly occurs even in cases without any immunologic defect. Schroeder et al.  mentioned that fac- tors other than neutrophil defects may be respon- sible for rapid destructive periodontitis in cases where PLS is not associated with increased sus- ceptibility to infection. Recently, Actinobacillus actinomycetemcomitans has been recorded as the major pathogen involved in pathogenesis of peri- odontosis associated with PLS . From results of our study and all cases reported with PLS we found that loss of both deciduous and permanent teeth are a fixed symptom and sign of the disease in all patients with or without immunologic dys- function. So we could not consider loss of teeth on an immunologic basis.
Repeated access to patients associated with infections to look at the antibody response showed decrease in their humoral immune response, it is indicated by decrease of total serum protein, neg- ative antistreptolysion 0 titre and decreased ag- glutination test to staphylococci. B-cells showed decrease in one patient.
Lastly, in view of the recent suggestion that this syndorme is associated with increased sus- ceptibility to infections, we suggest dividing the syndrome into two varieties: PLS with pyogenic infections and the other variety with no infection. PLS with pyogenic infections is associated with immunological dysfunction.
Tuberculin test was negative in both cases. We could conclude that PLS may lead to immuno-
[l] Papillon MM, Lefevre P. Deux cas de keratodermie palmaire et plantaire symetrique familiale (maladie de
logic defect in both humoral and cellular immune Meleda) chez le f&e et la soeur. Coexistance dans les
Fig. 1. Case 1: PLS associated with albinism.
Fig. 2a Case 1: Pyogenic infections on chest (site of lung aspiration). Fig. 2b. Case 1: Pyogenic infections of lower limbs.
Fig. 3. Roentgenogram of jawbone to show periodontosis (Case 1).
M. Amer et al. /J. Eur. Acad. Dermatol. Venereol. 6 (1996) 246-251 251
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