Papillon-Lefevre Syndrome

A number sign (#) is used with this entry because Papillon-Lefevre syndrome (PALS) is caused by homozygous or compound heterozygous mutation in the cathepsin C gene (CTSC, or DPPI; 602365) on chromosome 11q14.

Mutations in the CTSC gene also cause Haim-Munk syndrome (HMS; 245010) and aggressive periodontitis-1 (170650).

Description

Papillion-Lefevre syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (summary by Lefevre et al., 2001).

Clinical Features

Both the milk teeth and the permanent teeth are lost prematurely. The skin lesions are very similar or identical to those of mal de Meleda (248300). Gorlin et al. (1964) suggested that calcification of the dura mater is a third component of the syndrome.

Nazzaro et al. (1988) reported 4 sibs with Papillon-Lefevre syndrome, ranging in age from 2 to 11 years. The parents were double first cousins.

Hattab et al. (1995) reported 4 cases of PLS affecting 2 Jordanian families with a total of 8 children. The patients were between 4.5 and 12 years of age and their parents, who were first cousins, were not affected. In all patients, there was a relationship between increased severity of skin lesions and seasonal variations and intensified periodontal destruction. There was an early eruption of the permanent teeth. The teeth were caries-free with no sign of root resorption.

Laass (1997) stated that the primary teeth in patients with PLS are usually lost by age 4 and permanent teeth by age 17; that periodontitis is gone after the teeth are lost; and that retinoid therapy is valuable for both the keratitis and the periodontitis.

In a study that included 47 patients with Papillon-Lefevre syndrome, Ullbro et al. (2003) ranked the severity of dermatologic and oral affections using a semiquantitative scoring system, and evaluated whether the severity of the dermatologic changes were correlated with age, degree of periodontal infection, or both. They found, with no exception, that both skin and oral changes developed early in life. The dermatologic involvement showed no correlation with age, whereas the periodontal infection was significantly worse in young children with deciduous teeth. A strong correlation was found between the condition of feet and hands, although the scores for the feet were significantly higher. No significant correlation could be demonstrated between the level of periodontal infection and severity of skin affections, supporting the concept that these 2 major components of Papillon-Lefevre syndrome are unrelated to each other.

Almuneef et al. (2003) described a Saudi male with pyogenic liver abscesses, born to consanguineous parents, who was found to have Papillon-Lefevre syndrome. They found several other reports of this association and concluded that liver abscess is an important complication of neutrophil dysfunction in PLS.

Toomes et al. (1999) summarized the clinical features of Papillon-Lefevre syndrome. The disorder is ascertained mainly by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first 3 years of life. Keratosis also affects other sites such as the elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only one or the other, and in rare individuals the periodontitis is mild or of late onset.

Murthy et al. (2005) reported ocular surface squamous neoplasia (carcinoma in situ) in a 14-year-old boy with Papillon-Lefevre syndrome.

Population Genetics

Laass (1997) stated that the frequency of PLS is approximately 1 to 4 per million.

Clinical Management

Nazzaro et al. (1988) reported that histologic abnormalities improved markedly during treatment with acitretin, the free acid of etretinate. They suggested that if treatment is started at an early age, patients with PLS should be able to have normal adult dentition.

Mapping

In 2 consanguineous families of Turkish origin and 3 multiplex families, 1 Ethiopian and 2 German, with altogether 10 affected and 5 unaffected sibs, Laass et al. (1997) demonstrated linkage of PLS with D11S937 on 11q13-q14 (maximum lod = 5.1 at theta = 0.0). The affected members of the Turkish and Ethiopian families were homozygous by descent for markers from an 18-cM interval to the gene for ultra-high-sulfur keratin (KRN1; 148021) between marker loci D11S937 and D11S4120.

Laass et al. (1997) did homozygosity mapping of PLS on the basis of 3 consanguineous families, 2 of Turkish and 1 of German origin. A traditional linkage analysis was also performed in these and 3 multiplex families. Linkage was obtained with marker D11S937 with a maximum 2-point lod score of 6.1 at recombination fraction theta = 0.00 on 11q14-q21 near the metalloproteinase gene cluster (e.g., MMP7; 178990). Multipoint likelihood calculations gave a maximum lod score of 7.35 between D11S901 and D11S1358. A 9.2-cM region homozygous by descent in the affected members of the 3 consanguineous families was positioned between markers D11S1989 and D11S4176. Haplotype analyses in all the families studied supported this localization.

Fischer et al. (1997) likewise conducted a primary genomewide search by homozygosity mapping in a large consanguineous family with 4 affected sibs. Homozygosity and linkage were demonstrated in the region 11q14. Linkage was confirmed in 4 additional families with diverse ethnic and geographic backgrounds, 2 of which were consanguineous. A maximum 2-point lod score of 8.19 was obtained for marker D11S901 at theta = 0.0. The analysis of recombination events placed the gene within a 7-cM interval between D11S901 and D11S4175. No shared haplotype was found in the 5 families analyzed.

Molecular Genetics

Based on the previous mapping of the PLS locus to 11q14-q21, Toomes et al. (1999) used homozygosity mapping in 8 small consanguineous families to narrow the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene for cathepsin C (CTSC; 602365), a lysosomal protease, was known to lie within this interval. Toomes et al. (1999) defined the genomic structure of the CTSC gene and found mutations in all 8 families. In 2 of these families, a functional assay demonstrated an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

Hart et al. (1999) found 4 mutations in the CTSC gene in 5 consanguineous Turkish families. All affected individuals were homozygous for CTSC mutations from a common ancestor. Clinical features were not seen in any of the obligate carriers. RT-PCR studies showed CTSC expression in the epithelium of the palms, soles, knees and oral keratinized gingiva.

Gorlin et al. (1976) had suggested that PLS and Haim-Munk syndrome (HMS; 245010) were clinical variants. Hart et al. (2000) found a nonsense mutation (602365.0007) in a Turkish family with PLS. They also found a missense mutation at the same codon (602365.0006) in 4 sibships of the Cochin isolate with HMS, confirming that PLS and HMS are allelic.

Hart et al. (2000) reported mutations in the CTSC gene in patients with PLS from Australia, England, Iran, Turkey, and the US. Mutations were identified in 14 of 20 families studied.

Pathogenesis

Pham et al. (2004) found that, unlike mice lacking Dppi, cytotoxic lymphocytes from humans with PLS maintained lymphocyte-activated killer cell function and significant granzyme A (GZMA; 140050) and granzyme B (GZMB; 123910) activity. Loss of DPPI activity was associated with a severe reduction in the activity and stability of neutrophil-derived serine proteases, but neutrophils from PLS patients did not uniformly have a defect in their ability to kill Staphylococcus aureus and Escherichia coli, suggesting that alternative mechanisms to serine proteases exist in humans for killing these bacteria. Pham et al. (2004) proposed that these observations provide a molecular explanation for the lack of a generalized T-cell immunodeficiency phenotype in patients with PLS.

Meade et al. (2006) found that resting natural killer (NK) cells from 2 sibs with PLS from a consanguineous family reported by Toomes et al. (1999) lacked active CTSC and GZMB. However, in the presence of IL2 (147680), GZMB activity and cytolytic function were restored in a CTSC-independent manner.