NORD gratefully acknowledges Dr. Fanny Morice-Picard, Centre de Référence des Maladies Rares de la Peau, Service de Dermatologie et Dermatologie Pédiatrique, Hôpital Pellegrin-Enfants, Bordeaux, France, for assistance in the preparation of this report.
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 inherited in an autosomal recessive pattern. It results from changes (alterations) of the CTSC gene that regulates production of an enzyme known as cathepsin C.
Papillon-Lefèvre syndrome is 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. Rarely, 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, but can vary in color and texture. Skin lesions may worsen in the cold and walking may be painful. In rare instances, cysts may form on the eyelids later in life.
In affected individuals 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 periodontitis). The gums and the underlying ligaments and bone that support the teeth are usually involved. When the baby (deciduous or primary) 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. Notable bad breath, called halitosis, may develop. Chewing may be very painful. The thickened ridge of bone in which the teeth rest (alveolar process) may break down (alveolar bone lysis). The baby teeth frequently become loose and fall out by the age of four or five. Afterward, the inflammation may be reduced and the gums may appear healthier. However, without treatment, most of the adult (permanent) teeth may be lost in the same manner by the age of 16. Both baby and adult teeth are usually affected in the order of their eruption. Some affected individuals will only have mild periodontal disease, and/or will have later onset of periodontal disease.
Affected individuals may have frequently recurring, pus producing (pyogenic) skin infections. Some individuals may be at risk for other infections including liver abscesses, Infection of hair follicles (furunculosis), respiratory tract infections, and hidradenitis supportiva, a condition characterized by swollen, painful lesions occurring in the armpit, groin, anal and breast regions.
Most individuals have fragile nails that may easily break off. Hair on the scalp and body may be sparse (hypotrichosis). Some individuals may develop excessive amounts of keratin in hair follicles causing rough, cone-shaped bumps (papules) on the skin. Affected individuals may also exhibit excessive perspiration (hyperhidrosis) associated with an unpleasant (malodorous) odor. Some individuals experience the accumulation of calcium with the skull causing the affected tissue to harden (intracranial calcification).
Papillon-Lefèvre syndrome is caused by changes (alterations) in CTSC (Cathepsin C) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The CTSC gene encodes for the production of a specific type of enzyme (lysosomal protease) known as cathepsin C. The protein 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 alterations of the CTSC gene have been detected in affected kindreds. Certain alterations may result in almost complete loss of cathepsin C enzymatic activity in individuals with the disease-or relatively reduced activity of the enzyme in some family members who carry a single altered copy of the gene (heterozygous carriers).
Researchers believe that other factors in addition to alterations in the CTSC gene are necessary for the development of Papillon-Lefèvre syndrome. Most likely, defects in the immune system, specifically white blood called neutrophils or natural killer cells are involved. Neutrophils play a role in helping the body fight off infection, especially bacterial and fungal infections. Natural killer cells help to fight off viruses. However, research into such factors has not led to consistent findings and more research is necessary to understand the underlying mechanisms that lead to the development of clinical manifestation s observed in Papillon-Lefèvre syndrome.
Papillon-Lefèvre syndrome inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits 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 altered gene and 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 is 25%. The risk is the same for males and females.
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.
Papillon-Lefèvre syndrome is an extremely rare disorder that affects males and females in equal numbers and is found in all ethnic groups. More than 200 cases have been reported in the medical literature. In the general population, the disorder occurs in approximately one to four individuals per million. However, determining the incidence or prevalence of rare disorder is extremely difficult. 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.
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 instances, 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 instances, 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 people, abnormalities of the skin occur simultaneously with the loss of teeth. In addition, identification of the abnormal accumulation of calcium with in the skull (intracranial calcification) may assist in confirming a diagnosis.
A diagnosis can be made by a simple analysis of an infant’s or child’s urine (urinary analysis). The urine of a child suspected of having Papillon-Lefèvre syndrome is tested to see whether there is any activity of the enzyme cathepsin C. Little or no activity of this enzyme is diagnostic of the disorder. This is extremely important because early diagnosis and prompt treatment can potentially prevent aggressive periodontitis, tooth loss, and improve overall quality of life of people with Papillon-Lefèvre syndrome.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect alterations in the CTSC gene known to cause Papillon-Lefèvre syndrome, but is available only as a diagnostic service at specialized laboratories.
Treatment 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, physicians who evaluate and treat skin problems (dermatologists), dentist, dental surgical team, which includes a pediatric dentist, a specialist in treating disorders affecting the area supporting and surrounding the teeth (periodontist), and a specialist in the restoration and replacement of teeth (prosthodontist), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support is recommended for the entire family as well.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support is recommended for the entire family as well.
Physicians may carefully monitor affected individuals to help prevent and ensure early identification of infection. Should gum infection occur antibiotic therapy may be prescribed. Proper oral hygiene and the use of mouth rinses is recommended. If teeth are lost, they may be replaced with dental implants.
Limited success has been found in treating associated skin abnormalities with topical lubricants and moisturizers (emollients). Sometimes, medications that break down the outer layer of the skin (keratolytics) or topical steroids, which reduce inflammation of the skin, may also be used. 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).
Treatment with vitamin A derivative (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, retinoids 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.
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:
Toll-free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
(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.].
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