Are You Confident of the Diagnosis?

What you should be alert for in the history

The age of onset for Papillon-Lefévre syndrome (PLS) is usually between 1-5 years. Be alert for thickening, dryness and fissuring of palms and soles, aggravation during winter, loosening followed by loss of deciduous teeth by the age of 5, loss of permenant teeth by the age of 17 if not treated, excess perspiration, increased sweating of the palms and soles that can be foul smelling, frequent skin infections, and thickening and discoloration of nails. The presence of palmoplantar keratoderma, and periodontosis with loss of teeth is highly suggestive of PLS.

Characteristic findings on physical examination

Characteristic findings include symmetrical, well-demarcated, erythematous keratotic and confluent plaques, usually diffuse and sometimes punctate, affecting the entire surface of the palms and soles and extending to the dorsa of hands and feet and occasionally on to the skin overlying the achilles tendon and external malleoli (Figure 1, Figure 2). Other sites that may be affected include legs, thighs, axillae, eyelids, cheeks, and labial commissures.

Figure 1.

Papillon-Lefevre syndrome affecting soles: plantar keratoderma. (Courtesy of Sancy Leachman, MD)

Figure 2.

Papillon-Lefevre syndrome: confluent plaque on knee. (Courtesy of Sancy Leachman, MD)

Other findings include severe gingival inflammation where the gingiva appears bright red and edematous and bleeds easily, dental caries, dysplastic and malformed teeth (Figure 3), degeneration of the structures that surround and support the teeth, fetor ex oris, premature exfoliation of primary dentition by the age of 4 years followed by premature exfoliation of permenant teeth by the age of 13-16 years due to gingivitis and periodontitis, loss of alveolar bone, pyogenic skin infections, nail dystrophy and increased curvature of nails, long and thin fingers and toes (arachnodactyly), flat feet, pes planus, hypertrophy of the fingernails and toenails ( onychogryphosis), and abdominal tenderness of right upper quadrant suggestive of pyogenic liver abcess.

Figure 3.

Papillon-Lefevre syndrome: malformed teeth. (Courtesy of Sancy Leachman, MD)

Expected results of diagnostic studies

Histopathological examination reveals nonspecific hyperkeratosis, acanthosis, focal parakeratosis, psoriasiform hyperplasia, tortuous capillaries in dermal papillae, and superficial lymphocytic infiltration.

Other useful studies include complete blood chemistry including liver function tests, pus for culture, and sensitivity from pyogenic skin infections and aspirate of liver abcess. Neutrophil burst test reveals abnormal production of superoxide radicals by polymorphonuclear cells.Neutrophil chemotaxis tests can detect impaired chemotaxis.

Genetic analysis can detect mutations in the Cathepsin C gene. This gene has been mapped to 11q 14.1-q14.3 and consists of seven exons; the corresponding mRNA ,1.8kb,encodes a polypeptide of 436 aminoacids. A variety of germline mutations in the Cathepsin C gene, mostly missense mutations, has been described in patients with PLS.

Orthopantomogram (OPG View ) shows resorption of alveolar bone, giving it a “floating-in-air” appearance. An x-ray of the skull skull may reveal calcification of falx cerbri, dura, choroid plexus and tentorium cerebelli, while x-ray of the hands and feet may show resorption of the phalanges (acro-osteolysis). Ultrasound of the abdomen/computed tomography (CT) abdomen can be used in cases of suspected liver abcess.

Diagnosis confirmation

Palmoplantar keratodermas without periodontosis are also seen in Mal de Meleda, Howel Evans Syndrome,Vohwinkhels syndrome, Greither’s syndrome,Keratosis punctata. Palmoplantar keratoderma associated with periodontitis is only suggestive of PLS.

An allelic variant of PLS, called as Haim-Munk syndrome or Cochin-Jewish disease, is a rare autosomal recessive disorder first described in Cochin Jews and is characterized by acroosteolysis. arachnodactyly, and onychogryphosis in addition to palmoplantar keratoderma and periodontosis. Prepubertal periodontosis is another allelic variant of PLS and is characterized by absence of palmoplantar keratoderma

Who is at Risk for Developing this Disease?

PLS is a rare autosomal recessive condition in which both parents can be phenotypically healthy with a negative family history of the disease. Both parents must carry the autosomal gene for the syndrome to appear in the offspring. When both parents are carriers there is 25% chance of producing an affected offspring.

There is no epidemiological variation in the distribution of the syndrome. Epigenetic defect in gene loci and environmental factors can contribute to the pathogenesis and increases the susceptibility to infections.

What is the Cause of the Disease?
Etiology

Mutation of Cathepsin C gene localized to chromosome 11q14-21 encoding for lysosomal protease. This gene is expressed in the commonly affected epithelial regions such as palms, soles, knees, keratinised oral gingiva, and osteoclasts, and also expressed in the immune cells including polymorphonuclear cells, macrophages and their precursors.

Pathophysiology

Cathepsin C is a lysosomal protease which processes and activates several granule serine proteases critical to immune and inflammatory responses of myeloid and lymphoid cells.

Neutrophil chemotaxis, phagocytosis and bactericidal activities are impaired. Infectious agents such as actinomyces actinomycetemcomitans, a virulent anerobic gram-negative pathogen, can cause periodontal damage and alteration in polymorphonuclear neutrophil function. Reactivity to B cell and T cell mitogens is impaired.

Systemic Implications and Complications
  • Pyogenic liver abcess. Extensive periodontal inflammation especially Staphylococcus aureus infection, leads to bacteremia and this, associated with abnormal polymorphonuclear chemotaxis and oxygen consumption, is likely to contribute to the development of pyogenic liver abcess.

  • Recurrent pyogenic skin infections

Fatal multiple abdominal liver abscess can also occur.

Treatment Options

A multidisciplinary approach is advisable.

With respect to the skin, topical treatments for palmoplantar keratoderma include emollients–urea, salicylic acid. System treatments include Etretinate, Acitretin and Isotretinoin. Although etretinate has been successfully used in the treatment of palmoplantar keratoderma and periodontosis, it has now replaced by acitretin, a free acid of acitretin. Sixteen months of treatment with acitretin is useful for the treatment of palmoplantar keratoderma and periodontosis. It is started early at a mean age of 5.5 years to prevent the loss of permenant teeth.The recomended dose of acitretin in children is 10mg [or 0.4-1.0 mg /kg/day] for every 2 or 3 days for the first 8 weeks followed by alternate days for 8 weeks and then for 2 days per week The palmoplantar keratoderma recurs after stopping treatment. It is useful to prevent the loss of permenant teeth.

Treatment for pyogenic skin infections consists of appropriate antibiotics. Treatment for the oral cavity includes improving oral hygiene, extraction of severely diseased teeth, scaling, antimicrobial irrigation, and systemic antibiotics.

Optimal Therapeutic Approach for this Disease

An optimal approach begins with counselling and educating the patients and family about the nature of the disease. Regular application of emollients is required, especially during winter, as hyperkeratosis is aggravated during winter. Maintaining good oral hygiene is vital.

Systemic retinoids like acitretin are beneficial in reducing periodontal disease and gingivitis, thereby helping in preservation of teeth. Retinoids are also used as crisis management for palmolantar keratoderma, especially during winter aggravation. Retinoids are highly beneficial but not curative. Although etretinate was extensively used for periodontosis, because of high lipophilicity it remains in the tissues for prolonged periods, thereby increasing the risk for terratogenecity. Etretinate has now been replaced by Acitretin. Systemic antibiotics fare administered or pyogenic skin infections and liver abscess.

Patient Management

Patients require lifelong use of emollients for palmoplantar keratoderma. Maintaining good oral hygiene and frequent visits to the dentist are essential. Female patients of reproductive age group on retinoids should be advised on usage of contraceptive measures, due to the risk of terratogenecity.

Patients should be informed of the need for regular monitoring of the following tests (Table I), because retinoids are known to increase triglycerides, cholesterol and liver enzymes. Rarely, it can also cause ocular side effects like reduced night vision and persistent dry eyes, and skeletal effects like diffuse skeletal hyperosteosis and premature epiphyseal closure.

Table I.
Laboratory Evaluation (monthly for the first 3-6 months, followed by every 3 months). Complete blood count Liver function tests Fasting lipid profile Urine pregnancy tests Special Tests (periodically as indicated by symptoms ) Skeletal examinations Ophthalmological examinations
Unusual Clinical Scenarios to Consider in Patient Management

None

What is the Evidence?

Janjua, SA, Khachemoune, A. “Papillon-Lefevre syndrome.Case report and review of the literature”. Dermatology Online Journal. vol. 10. 2004. pp. 13(The clinical findings, differential diagnosis management, and complications of PLS are discussed in detail.)

Lee, MR, Wong, LF, Fischer, GO. “Papillon-Lefevre syndrome treated with acetetin”. Australasian J Dermatol. vol. 46. 2005. pp. 199-201. (Successful treatment of palmarplantar keratoderma and periodontosis with acetretin and prophylactic antibiotics is reported. Treatment with acetretin at an earlier age before the onset of permanent teeth will prevent loss of permenant teeth and is a safe treament in children.)

Hart, TC, Hart, PS, Bowden, DW, Michalec MD,Callison, SA, Walker, SJ. “Mutations of the Cathepsin C gene are responsible for Papillon-Lefevre syndrome”. J Med Genet. vol. 36. 1999. pp. 881-7. (Cathesin C is expressed in junctional epithelium in gingiva, palms, soles and hence mutation in this gene results in keratoderma and peiodontosis. A major gene locus for PLS maps to 2.8 cM interval on chromosome 11q14.)

Rai, R, Thiagarajan, D, Mohandas, S, Natarajan, K, Sekar, CS, Ramalingam, S. “Haim Munk syndrome and Papillon-Lefevre syndrome-allelic mutations in cathepsin C with variation in phenotype”. Int J Dermatol. vol. 49. 2010. pp. 541-3. (Both PLS and Haim munk are palmar plantar keratodermas with periodontal destruction, but the additional findings in Haim Munk include onychogryphosis, arachnodactyly, acral osteolysis and pesplanus.Gene analysis revealed that they are allelic mutations in cathapsin C with variations in phenotype.)

Almuneef, M, Al Khenaizan, S, Al Ajaji, S, Al-Anazi, A. “Pyogenic liver abcess and Papillon-Lefevre syndrome: not a rare association”. Pediatrics. vol. 111. 2003. pp. e85-88. (Recurrent pyogenic abscess and liver abscesscan occur in patients with PLS. Pyogenic liver abscessis, not an uncommon assocition, results from hemategenous spread from peridontol infection resulting in seeding of the organism in the liver. A defective polymorphonucllear leucyte chemotaxis and oxygen consumption contributes to the infection. A course of antibiotics during active periodontosis can prevent pyogenic liver abscess.)

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