Papillon-lefevre syndrome: Case series and review of literature.

Papillon-lefevre syndrome (PLS) belongs to a heterogeneous group of skin diseases that are characterized by hyperkeratosis of palms and soles. It is a type IV palmoplantar keratosis (PPK) while the palmoplantar keratodermas share some features of PPK, they are etiologically heterogeneous. PLS differs from other types of PPK by the presence of severe and early onset periodontitis. Genetic studies have shown that mutation in the major gene locus of chromosome 11q14 with the loss of function of cathepsin-C (CTSC) gene is responsible for PLS. CTSC gene mutations are causative for PLS. The resultant loss of CTSC function is responsible for the severe periodontal destruction seen clinically. This report represents two siblings with classical signs and symptoms of PLS.

INTRODUCTION

Papillon-lefevre syndrome (PLS) was first described in 1924 by Papillon and Lefevre.[1] It is a rare heritable, autosomal recessive disorder[2] caused by the deficiency in cathepsin-C (CTSC),[34] characterized by hyperkeratosis of palms and soles and severe destructive periodontal disease affecting both the primary and permanent teeth. It has prevalence of 1-4 cases per million persons,[5] without sex and racial predominance.[67] The sharply demarcated erythomatous keratotic plaque may occur focally, but usually involve the entire surface of the palms and soles, sometimes extending on to the dorsal surfaces. Often, there is associated hyperhidrosis of the palms and soles resulting in a foul-smelling odor.[5] The genetic basis for most PLS cases appears to be mutation affecting both alleles of the CTSC gene, located on chromosome 11q14.1-q14.3.[89] Biochemical assays of CTSC indicated that CTSC mutation associated with PLS and related conditions dramatically reduces its enzymatic activity. Heterozygous carriers of the mutation have approximately 50% of enzymatic activity, while subjects in whom both CTSC alleles are mutated show lesser than 10% of normal activity in hydrolysis of the synthetic substrate glycyl-L-arginin-7-amino-4-methylcoumarin.[910]

Coming to oral changes, following the eruption of primary teeth gingiva becomes inflamed, followed by rapid destruction of periodontium and premature loss of primary teeth. Gingiva appears normal after exfoliation of primary teeth. The aggressive periodontal destruction repeats after the eruption of permanent teeth and most of the permanent dentition is lost during teenage years.[810]

Conventional periodontal treatment usually fails in patients with PLS and the rapid progression of periodontitis results in the severe loss of alveolar bone.[2911] To preserve the alveolar bone early extraction of periodontally involved permanent teeth and replacing them with titanium implants has been considered a mode of treatment.[12]

This paper presents the etiology, clinical features and highlights different treatment modalities, which can be used to rehabilitate oral cavity in patients with PLS.

Etiology

Genetic etiology

CTSC involvement in the etiology of PLS

The cause of PLS is not well-understood, but recently, two research groups have reported that loss of function mutations affecting both alleles of the CTSC gene, located on chromosome 11q14.1-q14.3,[89] were associated with PLS. The CTSC gene encodes a cysteine-lysosomal protease also known as dipeptidyl-peptidase I, which functions to remove dipeptides from the amino terminus of the protein substrate. It also has endopeptidase activity. The CTSC gene is expressed in epithelial regions commonly affected by PLS such as palms, soles, knees and keratinized oral gingiva. It is also expressed at a high level in various immune cells including polymorphonuclear leukocytes, macrophages and their precursors. Several mutations have been reported in the CTSC gene in individuals from diverse ethnic groups.[913]

Immunological defects

CTSC is involved in a wide variety of immune and inflammatory responses. It plays an essential role in activating serine proteinases expressed in the granules of bone marrow derived cells from both the myeloid and lymphoid series. The serine proteinases are implicated in a variety of inflammatory and immune processes, including phagocytic destruction of bacteria and activation of phagocytic cells and T-lymphocytes. Therefore, deficiency of CTSC function will result in loss of immunological response, leading to liability of infection. Recently, impairment of natural killer (NK) cell cytotoxic function is the first consistent immune dysfunction reported in PLS. This suggests that the impaired NK cell cytotoxicity might contribute to the pathogenesis of PLS associated periodontitis.[14] A defect that principally interferes in phagocytic function is likely to give rise to aggressive periodontitis of PLS since nearly identical features occur in other defects of phagocytic function. The loss of CTSC function and subsequent inactivity of neutrophil serine proteinases may cause deregulation of localized polymorphonuclears response in inflamed periodontal tissues, leading to the severe tissue destruction in PLS.[1516]

Microbial defects

In PLS, neutrophil function test showed reduced response to staphylococcus spp. and Actinobacillus actinomycetemcomitans. There is a hypothesis that herpes viruses together with pathogenic bacteria, including A. actinomycetemcomitans and underlying host defense disorders, participate in the development of PLS periodontitis.[15161718] Presence of numerous virulence factors such as leukotoxin, collagenase, endotoxin, epitheliotoxins and fibroblast-inhibiting factor, suggests that PLS is mediated bacteriologically and therefore could be treated to some improvement with antibiotics.[19] The serum of the patients showed high immunoglobulin G (IgG) titer against A. actinomycetemcomitans. Moreover, A. actinomycetemcomitans colonies were cultured in high percentages from the pocket samples. Antibiotic therapy was associated with elimination of A. actinomycetemcomitans from the periodontal pockets and serum IgG titers against A. actinomycetemcomitans decreased in the patients.[20]

Case Reports

Case 1

A 14-year-old girl, visited to outpatient Department of Periodontia, Government Dental College and Hospital, Ahmedabad, India with chief complain of premature loss of deciduous and permanent teeth and mobility in remaining teeth.

She was the first child born to apparently healthy non-consanguineous parents. History revealed that her deciduous teeth had erupted normally, but exfoliated gradually by the age of 4-5 years. Similarly, her permanent teeth were lost prematurely after erupting normally. Patient was having complained of mobility and bleeding gum before 2 years, visited a periodontist and undergone treatment in the form of periodontal flap surgery. After one and half year, patient was having same complain and came to Government Dental College and Hospital, Ahmedabad.

There was no family history of ichthyosis or hereditary or acquired palmoplanter keratodermas. The patient also gave a history of development of fissures, thickening and flaking in the skin of palms and soles that resulted in peeling off of skin leaving red thin area underneath since age of 3-4 years. She had exacerbation and remissions of the skin lesions since early childhood, visiting dermatologist regularly, but no improvement was seen. She repeatedly contracted systemic infections.

Clinical examination

Extra-oral examination

On extra-oral examination, patient presented with well-demarcated, yellowish, keratotic plaques over the skin of palms and soles extending on to the dorsal surfaces. Skin of both palms and soles was peeling off leaving underlying red shiny area suggestive of keratoderma [Figure 1]. Well circumscribed, psoriasiform, erythematous, scaly plaques were also present on the elbows and knees bilaterally along with dystrophy and transverse grooving of the nails. The fingers were pointed giving clawed appearance.

Figure 1

Case-1 – Palm and sole

Intra-oral examination

Intra-oral examination revealed edentulous area between teeth 44 and 33 and 11, 21 and 22 were also missing. Edentulous maxillary and mandibular ridges were covered with normal mucosa. The teeth present were 12, 13,14,15,16,22, 24, 25, 26, 33, 34, 35, 36, 44, 45 and 46 covered with soft deposits and band of subgingival calculus. Gingiva was fiery red in color with inflammatory gingival enlargement Iva Ingle Classification grade II. Pathological migration was associated with 12, 14, 23, 24, 33 and 34. On assessment grade III mobility was present in relation with 14, grade II in relation with 24, 25, 33, 34, 36 and 44. Remaining teeth were present with grade I mobility. There was the presence of recession grade III in relation with 14 and 33 [Figures 2–4].

Figure 2

Case-1 – Anterior view

Figure 4

Case-1 – Right posterior view

Case-1 eft posterior view

Radiographic findings

Orthopantogram showed extensive alveolar bone loss in all remaining teeth. The alveolar bone around the mobile teeth was devoid of definable lamina dura. An extensive alveolar bone loss was noted, giving the teeth 31, 41 and 43 a “floating in air appearance,” which were extracted afterwards [Figure 5].

Figure 5

Case-1 – Orthopantogram

Case 2

Second patient was a 6-year-old sister of the above patient. She was asymptomatic before 2 years. Her father noticed mobility in relation with some of her deciduous teeth and then early exfoliation of same. Her elder sister had same complain, so he brought her also for a checkup and treatment at Government Dental College and Hospital, Ahmadabad.

Extra-oral examination

She complained about dry scaly skin of palms and soles like her sister, but she has not taken any dermatological treatment for that. On examination, well-demarcated keratotic plaques over the skin of her palms and soles, extending on to dorsal surfaces were present [Figures 6 and 7].

Figure 6

Case-2 – Palm

Figure 7

Case-2 – Sole

Intra-oral examination

She showed the presence of 16, 26, 31, 36, 46, 41 and 53 in the oral cavity. There is grade III recession and grade II mobility in 53. Remaining teeth revealed the presence of soft deposits and grade I mobility [Figure 8].

Figure 8

Case-2 – Anterior view

Radiographically, right and left lateral oblique radiographs show angular bone loss and periodontal widening present in relation with 36 and 46. There are developing tooth germs of permanent tooth are also seen [Figure 9].

Figure 9

Case-2 – Right and left lateral cephalogram

Investigations

Radiographic analysis

Complete blood count

Liver function transaminase levels

Total bilirubin

Alkaline phosphatase

Urine analysis.

DISCUSSION

Several case reports in literature showed phenotypic variation among patients affected by this syndrome. The oral feature of this syndrome is severe periodontitis, which starts at the age of 3-4 years affecting both primary and permanent dentition.

CTSC gene mutation affects onset, progression and severity of periodontitis, as it is required for proteolytic activation of neutrophil serine protease, cathepsin G, elastase and proteinase 3, resulting in deregulation of the host immune response to microbial infection.[78] In addition to the skin and oral findings, patients may have decreased neutrophil, lymphocyte or monocyte functions and an increased susceptibility to bacterial infection.[21]

Increase in the percentage of gram negative microorganisms is recognized to be the primary factor in the etiology of periodontitis. In case of PLS, the inflammatory infiltrate at the sites of periodontal infection is not under regulatory control. Increase neutrophil influx and retention of inflammatory infiltrate and their proteases play a significant role in continued periodontal destruction. It makes difficult to control and limit periodontitis once lesions are established and disease becomes unresponsive to traditional periodontal treatment.

Clinical findings such as liver abscesses[2122] and cranial calcifications[23] have been reported in many cases, were absent in current cases. Given the high rate of parental consanguinity reported for PLS cases, it is possible these rarer findings are the result of the high degree of homozygosity of another alleles in addition to the CTSC locus.

It may be possible to prevent inflammation related destruction of permanent teeth by the combination of more intense conventional mechanical and antimicrobial therapy at younger age.[24] Good dental care and use of antibiotics to eradicate A. actinomycetemcomitans minimizes periodontitis and loss of teeth. A course of antibiotics should be tried to control the active periodontitis on an effort to preserve the teeth and to prevent bacteremia and subsequently pyogenic liver abscess. The risk of pyogenic liver abscess should be kept in mind in evaluating these patients when they present with fever of unknown origin.

Following extraction or exfoliation of all teeth, healing is uneventful suggesting that microbial challenge is requisite for inflammatory response. Several reports have documented successful osseointegration and function of dental implants in PLS cases.[122526]

Treatment

A multidisciplinary approach involving the Dermatologist, Periodontist, Pedodontist and Pediatrician is important for the overall care of patient with PLS.

Periodontal treatment

Aim of periodontal treatment is to eliminate the reservoir of causative organisms. It is generally agreed that the response to local debridement or to systemic antibiotic alone or in combination provide at best a transitory response.[24272829]

Ullbro et al.[2] proposed a mode of periodontal therapy for patients with PLS as shown in Table 1.

Table 1

Dental treatment protocol for patients with Papillon-lefevre syndrome

In this two cases:

Conventional periodontal treatment in the form of scaling and root planning

0.2% chlorhexidine gluconate mouthwash and oral hygiene instruction was employed to control disease activity

Systemic antibiotic treatment was given for 4 weeks amoxicillin (20-50 mg/kg/d) + metronidazole (15-35 mg/kg/d) in divided doses every 8 h as an adjunctive with conventional treatment

Teeth with hopeless prognosis were extracted

In teeth having deep periodontal pockets, periodontal flap surgery was done

To restore masticatory function, partial dentures were inserted

On maintenance visits of 3 months, mobility of 25 and 36 was markedly increased, we planned to extract them. As we were unable to prevent periodontal disease activity, we are planning to extract remaining teeth gradually and replacing them with dental implants.

In recent years, dental implant offers not only considerable better stability and retention of prosthesis, but also improved comfort, masticatory efficiency and esthetics. There is data available that dental implants are successful mode of rehabilitation in patients with PLS.[122526] We have planned for implant supported prosthesis in patients after growth period is over.

Dermatological treatment

The skin manifestations of PLS are usually treated with emollients. Salicylic acid and urea may be added to enhance their effect. Oral retinoids including acitretin, etretinate and isotretinoin are the mainstay of the treatment of both the keratoderma and periodontitis associated with PLS.[30] After 8 weeks of oral acitretin, there was a dramatic improvement with marked reduction of keratodermas.

Treatment may be more beneficial if it is started during the eruption and maintained during the development of the permanent teeth.

CONCLUSION

In summary, PLS is a rare autosomal recessive disorder. The conflicting findings of PLS management could be related to the severity of the condition, the age at which treatment was instituted, timing and duration of antibiotic therapy, professional supervision, supportive treatment plan and home care. The complex etiopathogenesis of PLS means that successful treatment of the periodontal component of this syndrome remains challenging. It is hoped that with identification of the gene defect, better treatment modalities can be developed. In cases where patient reports late or not responding to periodontal treatment, dental implants are successfully advised.