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Papillon Lefèvre Syndrome

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Copyright 1996, 1997, 2000, 2001, 2004

Synonyms of Papillon Lefèvre Syndrome

Disorder Subdivisions

General Discussion

Papillon-Lefèvre Syndrome (PLS) is an extremely rare genetic disorder that typically becomes apparent from approximately one to five years of age. PLS is characterized by the development of dry scaly patches on the skin of the palms and the soles (palmar-plantar hyperkeratosis) in association with severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary (deciduous) teeth frequently become loose and fall out by about age five. Without treatment, most of the secondary (permanent) teeth may also be lost by approximately age 17. Additional symptoms and findings associated with PLS may include frequent pus-producing (pyogenic) skin infections, abnormalities of the nails (nail dystrophy), and excessive perspiration (hyperhidrosis).

Papillon-Lefèvre Syndrome is transmitted as an autosomal recessive trait. Genetic analysis of several affected families (kindreds) suggests that the disorder may result from changes (mutations) of a gene that regulates production of an enzyme known as cathespin C. The gene is located on the long arm (q) of chromosome 11 (11q14).

Symptoms

Papillon-Lefèvre Syndrome is a rare inherited disorder characterized by the development of dry scaly patches of skin (hyperkeratosis) usually around the age of one to five years. These patches are usually confined to the undersides of the hands and feet, but may spread to the knees and elbows. In some rare cases, the upper portions of the hands and feet, the eyelids, the lips, the cheeks, and/or other areas of the body may also be affected. Affected skin may be unusually red and thick. In addition, affected individuals may have frequently recurring, pus producing (pyogenic) skin infections. In rare cases, cysts may form on the eyelids later in life.

In individuals with Papillon-Lefèvre Syndrome the teeth usually appear to form and erupt normally. However, most affected individuals exhibit chronic severe inflammation and degeneration of the tissues that surround and support the teeth (gingivitis and periodontosis). The gums and the underlying ligaments and bone that support the teeth are usually involved. When the primary (deciduous) teeth erupt, these areas become red, swell, and bleed (gingivitis). The mouth may become inflamed (stomatitis), lymph nodes may swell (regional adenopathy), and pockets may form in the gums causing susceptibility to infections. The deciduous teeth then frequently become loose and fall out by the age of five. Without treatment, most of the permanent teeth may be lost in the same manner by the age of 16. Both deciduous and permanent teeth are usually affected in the order of their eruption.

In most cases, individuals with Papillon-Lefèvre Syndrome have fragile nails that may easily break off. Hair on the scalp and body may be sparse (hypotrichosis). Affected individuals may also exhibit excessive perspiration (hyperhidrosis) associated with an unpleasant (malodorous) odor.

Causes

Papillon-Lefèvre syndrome is transmitted as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.

Parents of several individuals with Papillon-Lefèvre syndrome have been closely related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Genetic analysis of several affected families (kindreds) has enabled researchers to identify a gene responsible for Papillon-Lefèvre syndrome. The gene, designated as the cathespin C or CTSC gene, is located on the long arm (q) of chromosome 11 (11q14).

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered.

The CTSC gene regulates (encodes for) the production of a specific type of enzyme (lysosomal protease) known as cathepsin C. The gene is expressed at high levels in various immune cells and certain bodily areas affected by PLS. These include the tightly packed cells, known as epithelial cells, that form the protective outer layer of the skin (epidermis), such as of the palms, soles, and knees, as well as certain cells of the gums (gingiva). Several different mutations of the CTSC gene have been detected in affected kindreds. Certain mutations may result in almost complete loss of cathespin C enzymatic activity in individuals with the disease-or relatively reduced activity of the enzyme in some family members who carry a single mutated copy of the gene (heterozygous carriers).

Affected Populations

Papillon-Lefèvre Syndrome is an extremely rare disorder that affects males and females in equal numbers. More than 50 cases have been reported in the medical literature. In the general population, the disorder occurs in approximately one to four individuals per million. Skin abnormalities associated with this disorder may be present at birth (congenital) or by the age of five. Other symptoms usually become apparent between the third and fifth year of life.

Related Disorders

Symptoms of the following disorders can be similar to those of Papillon-Lefèvre Syndrome. Comparisons may be useful for a differential diagnosis:

Cochin Jewish Disorder, also known as Keratosis Palmoplantaris with Periodontopathia and Onychogryposis is a rare inherited disorder. It is characterized by reddening and overgrowth of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) and overgrowth of the fingernails and toenails (onychogryphosis). Affected individuals may also have flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); and/or a heightened sensitivity to cold temperatures and loss of bone tissue in the fingers and toes (acroosteolysis). Degeneration of the structures that surround and support the teeth (periodontosis) may also be present. Cochin Jewish Disorder is inherited as an autosomal recessive genetic trait. Some researchers believe the disorder may be a variant of Papillon-Lefèvre Syndrome.

Schopf-Schulz-Passarge Syndrome is a rare inherited disorder characterized by the development of dry scaly skin on the palms of the hands and the soles of the feet (palmoplantar keratosis), fragile nails, and/or the development of cysts on the eyelids. Other symptoms may include the early loss of primary (deciduous) teeth, absence of some or all of the permanent teeth (hypodontia), and/or lack of body and/or scalp hair (hypotrichosis). Schopf-Schulz-Passarge Syndrome is believed to be inherited as an autosomal dominant genetic trait.

Jadassohn-Lewandowsky Type Pachyonychia Congenita is a rare inherited disorder characterized by reddening, dryness, and a scaly appearance of the skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), and/or overgrowth of the fingernails and toenails (onychogryposis). In addition, affected infants may have teeth that are present at birth (neonatal teeth). Additional features may include loss of hair, excessive sweating (hyperhidrosis) of the hands and feet, hoarseness, and/or, in some cases, respiratory distress. Mental retardation may be present in some cases. Jadassohn-Lewandowsky Type Pachyonychia Congenita is believed to be inherited as an autosomal dominant genetic trait.

Mal de Meleda is an extremely rare disorder characterized by the slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). Affected skin may be unusually red and become abnormally thick. Affected children may also exhibit abnormalities of the nails, excessive sweating (hyperhidrosis) associated with an unpleasant odor, and/or development of small, firm raised lesions (lichenoid plaques). In addition, some affected children may have heart defects (cardiac abnormalities), such as an abnormally large heart (cardiomegaly). Mal de Meleda is believed to be inherited as an autosomal recessive genetic trait.

Ichthyosis, Sjogren-Larsson Syndrome is a rare inherited disorder characterized by the development of dry scaly skin (ichthyosis), hardened reddened skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), and/or discoloration of certain areas of skin (ecchymosis). In addition, affected infants may exhibit mental retardation, lack of voluntary movements of the arms and legs (spastic tetraplegia), seizures, and/or eye abnormalities. Ichthyosis, Sjogren-Larsson Syndrome is thought to be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "Ichthyosis, Sjogren Larsson Syndrome" as your search term in the Rare Disease Database.)

Fitzsimmons Syndrome is an extremely rare inherited disorder characterized by slow progressive development of dry scaly skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), mental retardation, and lack of control of voluntary movements of the legs (spastic paraplegia). In some cases, children may exhibit an abnormally high arch of the foot (pes cavus). Fitzsimmons Syndrome is thought to be inherited as an X-linked genetic trait.

There are several additional disorders that are characterized skin abnormalities similar to those seen in Papillon-Lefèvre Syndrome. These may include Psoriasis, Dyskeratosis Congenita, Epidermolytic Hyperkeratosis, and some of the Ectodermal Dysplasias. (For more information on these disorders, choose "Psoriasis," "Dyskeratosis Congenita," "Epidermolytic Hyperkeratosis," and "Ectodermal Dysplasia" as your search terms in the Rare Disease Database.)

Standard Therapies

The diagnosis of Papillon-Lefèvre Syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and identification of characteristic physical findings. In some cases, skin abnormalities may be apparent at birth (congenital) or during infancy including characteristic skin abnormalities on the palms of the hands and the soles of the feet. In most cases, the diagnosis of the disorder may not be confirmed until inflammation and degeneration of the tissues surrounding and supporting the teeth (periodontium) become apparent. This usually occurs between the third and fifth year of life, when the infant teeth (deciduous) begin to erupt. In many cases, abnormalities of the skin occur simultaneously with the loss of teeth. In addition, identification of the abnormal accumulation of calcium in the outside membrane that covers the spinal cord and brain (ectopic calcification of the dura mater) may assist in confirming a diagnosis of Papillon-Lefèvre Syndrome.

The treatment of Papillon-Lefèvre Syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dentists, physicians who evaluate and treat skin problems (dermatologists), specialists in treating disorders affecting the area supporting and surrounding the teeth (periodontists), and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Physicians may carefully monitor affected individuals to help prevent and ensure early identification of infection. Should gum infection occur antibiotic therapy may be prescribed.

Limited success has been found in treating associated skin abnormalities with topical lubricants. In some cases, surgery and skin grafts may be used to alleviate skin problems. Use of antiperspirants and deodorants may help with excessive perspiration (hyperhidrosis).

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Physicians at Washington University School of Medicine have developed a family registry so that individuals with Papillon-Lefèvre syndrome, Haim-Munk syndrome, and prepubertal periodontitis may be followed over time. It has recently been shown that the three conditions result from abnormal changes in the same gene. Therefore, families with any of these three conditions are invited to participate.

Patients and members of their families will be asked to complete a written questionnaire and submit a sample of blood for analysis. Each person who chooses to participate will be contacted once a year for updated health information.

For information, contact the registry directors, Drs. Tim Ley and Christine Pham, at (314) 362-8831 or the registry coordinator, Jennifer Ivanovich at (314) 454-5076. There is a web site: http://hematology.wustl.edu/registry.

Treatment with vitamin A (retinoids) has been found helpful in treating some individuals with Papillon-Lefèvre Syndrome. Etretinate, isotretinoin, and acitretin have been used to reduce chronic inflammation of the gums, resulting in a decreased loss of teeth in some affected individuals. In some cases, vitamin A may also alleviate skin abnormalities and help to minimize recurrent pus producing (pyogenic) skin infections associated with the disorder. Early identification of Papillon-Lefèvre Syndrome is essential for potentially effective treatment with vitamin A (retinoids). More research must be conducted before the long-term safety and effectiveness of using retinoids to treat Papillon-Lefèvre Syndrome can be determined.

Research on genetic disorders and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic and familial disorders in the future.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Papillon Lefèvre Syndrome Resources

(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., dental and skin abnormalities, etc.].

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Disorders of keratinization. In: Behrman, RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA; W.B. Saunders Company; 1996:1872.

Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Dover, MA; Blackwell Scientific Publications, Inc.; 1992:1377-1379.

Buyse ML. Birth Defects Encyclopedia. Dover, MA; Blackwell Scientific Publications, Inc.; 1990:904, 1213.

JOURNAL ARTICLES
Hewitt C, et al. The role of cathepsin C in Papillon-Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum Mutat. 2004;23:222-8.

Mahajan VK, et al. Papillon-Lefèvre syndrome. Indian Pediatr. 2003;40:1197-200.

Ullbro C, et al. Dermatologic and oral findings in a cohort of 47 patients with Papillon-Lefèvre syndrome. J Am Acad Derm. 2003;48:345-51.

Hart TC, et al. Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome. J Med Genet. 1999;36:881-887.

Toomes C, et al. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. 1999;23:421-424.

Laass MW, et al. Localisation of a gene for Papillon-Lefèvre syndrome to chromosome 11q14-q21 by homozygosity mapping. Hum Genet. 1997;101: 376-382.

Hattab FN, et al. Papillon-Lefèvre syndrome: a review of the literature and report of 4 cases. J Periodontol. 1995;66:413-420.

Ishikawa I, et al. Clinical, bacteriological, and immunological examinations and the treatment process of two Papillon-Lefèvre syndrome patients. J Periodontol. 1994;65:364-371.

Posteraro AF. Papillon-Lefèvre syndrome. NY State Dent J. 1991;57:49-50.Karg E, et al. Keratosis palmoplantaris cum periodontopathy (Papillon-Lefevre syndrome). Dermatol Monatsschr. 1989;175:107-110.

Nazzaro V, et al. Papillon-Lefèvre syndrome. Ultrastructural study and successful treatment with acitretin. Arch Dermatol. 1988;124:533-539.

Reynaldo Arosemena M, et al. Papillon-Lefèvre syndrome. Presentation of a case. Med Cutan Ibero Lat Am. 1984;12:245-249.

Bravo-Piris J, et al. Papillon-Lefèvre syndrome. Report of a case treated with oral retinoid RO 10-9359. Dermatologica. 1983;166:97-103.

Galanter DR, et al. Case report. Hyperkeratosis palmoplantaris and periodontosis: the Papillon-Lefèvre syndrome. J Periodontol. 1969;40:40-47.

FROM THE INTERNET
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 245000; 11/30/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?245000.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 602365; 12/2/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?602365.

Report last updated: 2008/05/15 00:00:00 GMT+0