A novel large deletion combined with a nonsense mutation in a Chinese child with Papillon-Lefèvre syndrome.

BACKGROUND AND OBJECTIVE: Papillon-Lefèvre Syndrome (PLS) is a rare autosomal recessive hereditary disease (MIM245000). The syndrome is characterized by palmoplantar keratoderma and early onset periodontitis, caused by CTSC gene mutation. The mutation in CTSC previously reported is mainly point mutations. Large deletion in the CTSC gene has not yet been reported. MATERIAL AND METHODS: We collected 5 mL peripheral blood from a patient with PLS and her family members and used the direct sequencing method to perform CTSC bidirectional sequencing. We also used FISH to analyze the approximate locations of the ends of the missing fragment and then determined the fragment sequence through direct sequencing. RESULTS: The result demonstrated that the patient have a 110 kb deletion (Chr11: 88032292: 88142997(NC_000011)) combined with a nonsense mutation (Gln182Ter) in this gene. CONCLUSION: Our study reveals a compound mutation consisting of a large deletion and a nonsense mutation, which provides a new insight in the mutation type of CTSC gene.

Cytokine production by leukocytes of Papillon-Lefèvre syndrome patients in whole blood cultures.

Papillon-Lefèvre syndrome (PLS) is characterised by aggressively progressive periodontitis combined with palmo-plantar hyperkeratosis. It is caused by "loss of function" mutations in the cathepsin C gene. The hypothesis behind this study is that PLS patients' polymorphonuclear leukocytes (PMNs) produce more proinflammatory cytokines to compensate for their reduced capacity to neutralize leukotoxin and to eliminate Aggregatibacter actinomycetemcomitans. Production of more interleukin (IL)-8 would result in the attraction of more PMNs. The aim of this study was to evaluate the cytokine profile in PLS patients' blood cultures. Blood was sampled from eight PLS patients (one female) from six families (antiinfective therapy completed: six; edentulous: two) with confirmed cathepsin C mutations and deficient enzyme activity. Nine healthy males served as controls. Whole blood cultures were stimulated with highly pure lipopolysaccharide (LPS) from Escherichia coli R515 and IL-1ß plus tumor necrosis factor (TNF)-α. Thereafter, release of IL-1ß (stimulation: LPS and LPS plus adenosine triphosphate), IL-6, IL-8, interferon-inducible protein (IP)-10, and interferon (IFN)-γ (stimulation: LPS, IL-1ß/TNFα) were detected by ELISA. Medians of cytokine release were, with the exception of IP-10, slightly higher for PLS than for controls' cultures. None of these differences reached statistical significance. Increased production of IL-1ß, IL-6, IL-8, IP-10, or IFNγ as a significant means to compensate for diminished activity and stability of polymorphonuclear leukocyte-derived proteases could not be confirmed in this study. Cytokine profiles in blood cultures may not be used to identify PLS patients.

Alterations in the oxidation products, antioxidant markers, antioxidant capacity and lipid patterns in plasma of patients affected by Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) is an uncommon disease. Less than 300 cases have been described. PLS is characterized by the association between palmar plantar hyperkeratosis (PPK) and severe precocious periodontitis that results in the premature loss of both the primary and secondary dentitions. It is known that periodontitis (PE), the destructive phase of periodontal disease, is a multifactor phenomenon involving a variety of molecular species, among them free radicals and reactive oxygen species (ROS). Antioxidants have been shown to play a critical role in modulating ROS-induced damages during PE. We wondered if patients belonging to a family group with different grades of PLS severity may present altered plasma concentrations of oxidation products as well as of lipophilic antioxidants, like Coenzyme Q or vitamin E, which are molecules that possess well-known antioxidant properties and could play a role in PE processes. We also wondered about the actual plasma total antioxidant capacity of these subjects as well as a complete identification of their plasma fatty acids features, which have been never investigated before. The results we obtained indicate an impairment in the antioxidant capacity of the subjects characterized by abnormally high hydroperoxide levels and, in some cases, by altered CoQ and vitamin E contents. Moreover, an essential fatty acid deficiency (EFAD) was registered on the basis of the peculiar plasma fatty acid patterns found (i.e. low PUFA, high MUFA and high delta-9 desaturase activity). This finding would support the hypothesisby Gutteridge and co-workers (Free Radic. Res. 1998, 28: 109-114) that conditions exist in which some forms of oxidative stress can lead to changes characteristic of EFAD.

Elevated hydroperoxide levels and antioxidant patterns in Papillon-Lefèvre syndrome.

BACKGROUND: Since it has been found that reactive oxygen species seem to be involved in the pathogenesis of both periodontitis and hyperkeratotic syndromes, we studied a group of patients belonging to 3 generations of a family with different degrees of severity of Papillon-Lefèvre syndrome (PLS) to ascertain whether altered concentrations of the most important hydrophobic and hydrophilic plasma antioxidants as well as products of oxidative damage are present in PLS. METHODS: Coenzyme Q (CoQ), vitamin E, glutathione (GSH), and uric acid were evaluated by high-performance liquid chromatography (HPLC) (supplied with electrochemical detector) techniques and hydroperoxides by a spectrophotometric method. RESULTS: GSH and uric acid were in the range of reference values; CoQ was very low in both the child of the third generation and his mother, and these 2 subjects had the highest hydroperoxide levels. The child also had extremely low values of vitamin E. In general, all family members showed abnormally high hydroperoxide levels, with the exception of those members who are phenotypically healthy. CONCLUSIONS: Since the subjects with the lowest hydroperoxide contents are phenotypically healthy, whereas the affected individuals presented lower antioxidant levels and very high hydroperoxide concentrations, it has been suggested that a specific antioxidant therapy could be a promising approach in treating some PLS subjects. Moreover, unexpected manifestations of heterozygosity in the child of the third generation were also detected.

Papillon-Lefèvre syndrome. Analysis of peripheral blood lymphocyte subsets.

We have studied the peripheral blood lymphocyte populations in our 6 patients (2 female and 4 male) with a mean age of 11.19 with Papillon-Lèfevre Syndrome (PLS) using adequate monoclonal antibodies and double coloured flow cytometry. Total B, T, CD4, CD8, CD29, CD45RA, NK, HLA-DR cells were studied. Total B, T, CD4 and CD8 lymphocytes were within normal limits. We have observed an increase in the CD29 lymphocytes and NK cells and a decrease in CD45RA lymphocytes. We think that these findings are important in explaining B lymphocyte activation and in the pathogenesis of the PLS.

Papillon-Lefèvre syndrome. Characterization of peripheral blood and gingival lymphocytes with monoclonal antibodies.

A 14-year-old boy with typical features of Papillon-Lefevre syndrome (PLS) is presented. The purpose of this report was to study the immunopheno-typic features of the peripheral blood and gingival tissue lymphocytes with monoclonal antibodies in the patient. Peripheral blood T-cells, helper-T cells, suppressor-T cells, HLA-DR+ cells and IL-2R+ cells were determined using appropriate monoclonal antibodies and indirect immunofluorescence methods. B-cells were identified using the direct immunofluorescence technique. The gingival tissue was processed for both histopathological and immunohistological examinations. Gingival tissue lymphocytes were identified using monoclonal and polyclonal antibodies with the immunoperoxidase technique. Although we have not detected any significant alterations in the peripheral blood B-cell and T-cell populations, NK cells were significantly increased. HLA-DR+ cells and IL-2R+ cells were within normal limits. Histopathology of the diseased tissue revealed predominance of plasma cells in the lamina propria. The majority of the plasma cells were bearing IgG isotype. Most of the CD3+ T-cells were located beneath the pocket epithelium with an almost equal distribution of CD4+ and CD8+ T-lymphocytes, in situ. These findings indicate that PLS is a IgG+ plasma cell dominated lesion with the participation of T-lymphocytes, having similar distributions of both subsets. While the etiopathogenesis of the syndrome still has to be elucidated, these immunohistological findings could be used for further studies in this intriguing entity.

Periodontitis associated with Papillon-Lefèvre syndrome.

The predominant subgingival microflora, host immune response, and genetic history of a 14-year-old girl with Papillon-Lefèvre Syndrome (PLS) are reported. The patient had high counts of Actinobacillus actinomycetemcomitans and surface translocating bacteria. She had significantly raised levels of antibodies to five of the bacterial species studied with the levels to A. actinomycetemcomitans remaining high after antibiotic therapy. The polymorphonuclear leukocytes (PMN) also released significantly increased amounts of O2 compared to controls. The data presented support a role for A. actinomycetemcomitans and PMN dysfunction in the pathogenesis of PLS.

In vitro studies of monocyte function in two siblings with Papillon-Lefèvre syndrome.

Blood monocytes were isolated from two siblings with Papillon-Lefèvre syndrome (PLs) and compared to corresponding cells from their healthy cousin. The number of monocytes isolated were within normal limits in all three test participants. Aggregating tendency was increased when PLs monocytes were cultured in the presence of autologous sera. The monocyte ability of specific immune phagocytosis was decreased in PLs patients. The monocyte morphology, non-specific phagocytosis, lysosomal enzyme activities, and response to E. coli endotoxin were similar in patients and control.

[Functional anomalies of polymorphonuclears in Papillon-Lefèver disease (author's transl)]. / Anomalies fonctionnelles des polynucléaires dans la maladie de Papillon-Lefèvre. Trois observations.

Polymorphonuclear functions were studied in 3 patients of the same brotherhood with Papillon-Lefèvre disease (hyperkeratosis palmaris and plantaris and acute periodontosis resulting in loss of teeth) who developed severe and recurrent infections. Chemotaxis, oxygen consumption and production of H2 O2 were investigated by polarography, O2 production by quantitative reduction of nitroblue tetrazolium and iodination by the Pinus and Klebanoff technique. functional anomalies of polymorphonuclears involving chemotaxis, induced O2 consumption and H2 O2 production were detected in all three patients. This study confirms the presence of polymorphonuclear functional anomalies in patients with Papillon-Lefèvre disease. Analysis of the family tree of the patients, which went back to 1761, showed that this was probably not a chance association.

Hyperkeratosis palmoplantaris with periodontosis (Papillon-Lefevre syndrome): report of three cases, two occurring in siblings.

Three cases of palmar-plantar hyperkeratosis with periodontosis, two cases of which occurred in siblings, are reported. The parents were unaffected, and parental consanguinity was present in all three cases. All essential features of the syndrome were present in these cases.