The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth: A clinical and genetic analysis of the Papillon-Lefèvre syndrome

doi:10.1016/S0022-3476(64)80014-7

The Journal of Pediatrics

Volume 65, Issue 6, Part 1, December 1964, Pages 895-908

https://doi.org/10.1016/S0022-3476(64)80014-7 Get rights and content

Statistical analysis of 46 well-documented cases of the syndrome of (a) hyperkeratosis palmoplantaris and (b) premature periodontoclasia has suggested that possibly an additional component should be added making the syndrome a triad: (c) calcification of the dura. The family history data are compatible with the hypothesis that the syndrome results from homozygosity for autosomal recessive genes. There is no evidence for nongenetic causes. The frequency of the disorder is estimated roughly at 1 to 4 per million persons in the general population. Careful documentation of additional cases with permit more adequate genetic analysis. The carrier frequency appears to be 2 to 4 per 1,000 population.

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Citation Excerpt :
Loss of function mutations in the CatC gene (CSTC) is associated with Papillon-Lefèvre syndrome (PLS) [15,16]. PLS (MIM 245000) is a rare autosomal recessive disease characterized by severe periodontitis and hyperkeratosis of the hand, palms and foot soles [17,18]. The investigation of elastase-like proteases in neutrophils collected from PLS patients has demonstrated both reduced proteolytic activities and very low protein levels [11,13,19].
Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of a N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine protease activities and cause Papillon-Lefèvre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome analysis of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. We aimed to experimentally inactivate and lower neutrophil elastase-like proteases by pharmacological blocking of CatC-dependent maturation in cell-based assays and in vivo. Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. We confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. We also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclinical results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacological inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans.
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Papillon–Lefevre syndrome (PALS) is a rare, autosomal recessive disorder characterized by periodontitis and hyperkeratosis over the palms and soles. Mutations in the cathepsin C gene (CTSC) have been recognized as the cause of PALS since the late 1990s. More than 75 mutations in CTSC have been identified, and phenotypic variability between different mutations has been described. Next generation sequencing is widely used for efficient molecular diagnostics in various clinical practices. Here we investigated a large consanguineous Saudi family with four affected and four unaffected individuals. All of the affected individuals suffered from hyperkeratosis over the palms and soles and had anomalies of both primary and secondary dentition. For molecular diagnostics, we combined whole-exome sequencing and genome-wide homozygosity mapping procedures, and identified a recurrent homozygous missense mutation (c.899G>A; p.Gly300Asp) in exon 7 of CTSC. Validation of all eight family members by Sanger sequencing confirmed co-segregation of the pathogenic variant (c.899G>A) with the disease phenotype. This is the first report of whole-exome sequencing performed for molecular diagnosis of PALS in Saudi Arabia. Our findings provide further insights into the genotype–phenotype correlation of CTSC pathogenicity in PALS.
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^†: This study was made possible by United StatesPublic Health Serivec Program Grant No. DE-01770-01 in Oral Pathology.

^*: Department of Oral Pathology, School of Dentistry, University of Minnesota, Minneapolis, Minn.

^**: Department of Oral Pathology, School of Dentistry, University of Minnesota, from University of Litoral, Rosario, Argentina.

^***: Dight Institute for Human Genetics, University of Minnesota, Minneapolis, Minn.

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The syndrome of palmar-plantar hyperkeratosis and premature periodontal destruction of the teeth: A clinical and genetic analysis of the Papillon-Lefèvre syndrome†

J. Pediat.

Deux cas de keratodermie palmarie et plantaire symetrique familiale (Maladie de Meleda) chez le frère et la soer. Coexistance dans le deux cas d'alterations dentaíres graves

Soc. franç. Dermat. et Syph.

Periodontosis in a child with hyperkeratosis palmo-plantaris

J. Perio.

Le caractere heréditaire de l'hyperkeratose palmo-plantaire avec paradentose (Papillon-Lefèvre)

J. Genet. Hum.

Hyperkeratosis palmo-plantaris with periodontosis (Papillon-Lefèvre)

Dermatologica

Keratosis palmo-plantaris mit Periodontopathie. (Papillon-Lefèvre)

Dermatologica

Cheratosi Palmo-Plantare e Allotopa Associata a Grave Malattia Dentaria in Due Fratelli Mononati

Acta Genet. med. e Gemell.

Hyperkeratosis palmo-plantaris čum paradentosis seu morbus Papillon-Lefèvre

Č. Stomat.

Polyalveolyse chez deux enfants atteintes d'une keratodermie palmoplantaire

Rev. Stomat.

Keratosis palmaris et plantaris with dental alterations

Arch. Dermat. & Syph.

Periodontitis og tiddlig tap av temporaere og permanente tenner hos barn med keratosis palmaris et plantaris

To kasus, Norske Tann. Tid.

Ein ungewöhnlicher Fall von jugendlicher Paradentose

Paradentium

Papillon-Lefèvre Syndrome, Case Presentation

Über Insufficientia parodontalis (Parodontosis, Amphodontosis bei Kindern)

Deutsche Stomat.

Über die erblichen Hyperkeratosen der Handinnenflächen und Fussohlen unter besonderer Berücksichtigung der Hyperkeratosis palmo-plantaris mitParodontosis (Papillon-Lefèvre)

A case of alveolar atrophy of unknown origin in a child

Am. J. Ortho. & Oral Surg.

Hyperkeratosis Palmoplantaris with Periodontosis. (Papillon-Lefèvre)

Arch. Dermat.

A case of keratoderma and loosened teeth

Stomatologiya (Moskow)

Papillon-Lefèvre syndrome

Australian Dent. J.

Papillon-Lefèvre syndrome

Stomatologiya (Moskow)

Paradentopathie Fugendlicher und Keratoma palmare et plantare

Deutsche zahnärzt. Ztschr.

Umschau auf dem Gebiet der Paradentose

Zentralbl. f. gesamt. Zahn-, Mund-, und Kieferheilk.

Umschau auf dem Gebiete der Paradentopathien

Zentralbl. ges. Zahn, Mund-, und Kieferheilk.

Personal communication

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J. All India Dent. A.

Papillon-Lefèvre syndrome, precocious periodontosis with associated epidermal lesions

J. Perio.

Queratodermia palmoplantar con paradentosis (Papillon-Lefèvre)

Arch. Argent. Dermat.

Report of three patients experiencing juvenile periodontosis and early loss of teeth

J. Dent. child.

Beiträge zur Klinik und Pathologie seltener Hornhauterkrankungen

Ztschr. Augenheilk.

Hyperkeratosis palmo-plantaris čum paradentosi (Papillon-Lefèvre)

Časic Dermat.

Dos casos de grave reabsorción alveolar en la infancia

Rev. Odont. Bs. A.

Die dystrophische Parodontitis im Milchgebis als Manifestation einer ektodermalen Akropathie (parodontopathia acroectocermalis)

Deutsche Stomat.

Keratoma plantare et palmare hereditarium

Rev. M. Technol.

Keratoderma with periodontopathy

Dermatologica

Un nuevo caso de paradentosis en la infancia

Rev. Odont. Bs. As.

Periodontosis associated with gingival lesions in a child

J. Periodont.

Les parodontoses des keratodermies palmoplantaires, La maladie de Meleda

Rev. Stomat.

Morbidity of children from consanguineous marriages

Progr. M. Genet.