Papillon-Lefevre's syndrome

BACKGROUND

Papillon-Lefevre syndrome (PLS) is a form of ectodermal dysplasia, one of a group of syndromes deriving from abnormalities of the ectodermal structures, which include the hair, teeth, nails, sweat glands, cranial-facial structure, and hands. These are genetic disorders that can be inherited in an autosomal dominant or recessive manner.

Symptoms of PLS generally include patches of dry, scaly skin on the palms of the hands and soles of the feet, which appear between ages one and five. Starting at about age three or four, the periodontium, the tissue that provides structure to the teeth, becomes inflamed and begins to break down, causing tooth loss. Additional symptoms may include abnormal sweating of the hands and feet and poorly developed nails on the fingers and toes.

PLS is an inherited disorder, meaning that it is passed down among family members, and is caused by a mutation or defect in the cathepsin C (CTSC) gene. The inheritance pattern is recessive, meaning that individuals must inherit two copies of the genetic mutation or defect for the disease to appear.

PLS is extremely rare, with an estimated prevalence of one to four cases per million people. Males and females appear to be affected in equal numbers. No ethnic or racial population seems to be more affected by PLS than another. PLS tends to occur more frequently in children of parents who are closely related, or consanguineous.

Currently there is no known cure for Papillon-Lefevre syndrome (PLS). Instead, treatment aims to reduce symptoms and prevent or treat complications.

RISK FACTORS

Currently, the only known risk factor for Papillon-Lefevre syndrome (PLS) is a family history of the disease. PLS is inherited, or passed down among family members, as an autosomal recessive trait. However, having parents who are closely related, or consanguineous, may increase an individual's chances of inheriting PLS.

CAUSES

General: Papillon-Lefevre syndrome (PLS) is caused by a mutation or defect in the cathepsin C (CTSC) gene. The cathepsin C (CTSC) gene encodes a protein that is a member of the peptidase C1 family. This protein is a lysosomal cysteine proteinase that appears to be a central coordinator for the activation of many serine proteinases, which play critical roles in blood clotting, fibrinolysis, inflammation, the immune system, and tissue remodeling. Researchers believe that other genetic mutations may be involved in PLS but additional genes have not yet been identified.

Autosomal recessive inheritance: PLS is an autosomal recessive condition. Therefore, an individual must inherit two copies of the defective gene, one from each parent, for the disease to appear. Individuals who inherit only one copy of the defective CTSC gene generally have no symptoms and are called carriers because they can pass on the disorder to their children.

If one parent is a carrier, or has only one copy of the defective gene, then each child will have a 50% chance of inheriting one defective gene and of being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of inheriting neither defective gene. Therefore, if both parents are carriers, about one out of four children will have PLS.

Random occurrence: It is currently unknown whether PLS can occur as the result of a spontaneous genetic mutation with no family history of the disease.

SIGNS AND SYMPTOMS

Nails: The fingernails and toenails of individuals with Papillon-Lefevre syndrome (PLS) may be poorly developed. In addition, nails may be grooved or ridged.

Skin: Individuals with PLS exhibit patches of dry, scaly skin on the palms of the hands and soles of the feet. These patches may appear between ages one and five, and may extend to the backs of the hands and tops of the feet. The elbows and knees may also be affected. Skin problems may worsen in the winter and can be painful in some patients. Additional symptoms may include abnormal sweating of the hands and feet, which may be associated with a bad odor. Patients with PLS tend to be prone to frequent pus-producing skin infections.

Teeth: Starting at about age three or four, the periodontium, the tissue that provides structure to the teeth, becomes inflamed and begins to break down, causing tooth loss. Both baby teeth and permanent teeth are affected. Baby teeth tend to fall out by age five in PLS. Without treatment, most of the permanent teeth fall out by age 17.

Other: There has been at least one case of a patient with PLS who developed a white growth on the cornea of the eye. Because the eyes are frequently affected in different forms of ectodermal dysplasia, this symptom may be more common than reported. In rare cases, calcium deposits may develop in the brain tissue.

DIAGNOSIS

General: Papillon-Lefevre syndrome (PLS) becomes apparent from approximately one to five years of age and is diagnosed based on physical examination. PLS is characterized by the development of dry scaly patches on the skin on the palms of the hands and the soles of the feet (palmar-plantar hyperkeratosis) and severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary, or baby, teeth frequently become loose and fall out by about age five. Without treatment, most of the secondary, or permanent, teeth may be lost by approximately age 17. Additional symptoms and findings associated with PLS may include frequent pus-producing skin infections, abnormalities of the nails, and excessive perspiration.

Biopsy: In a biopsy, a small sample of tissue is taken and analyzed in a laboratory for the skin changes characteristic of PLS. A positive biopsy may show hyperkeratosis, which is an excess of keratins in the skin resulting in thickening of the skin, and mildly dilated blood vessels in the upper layer of the skin.

Blood tests: A sample of blood may be taken to count the number of different types of blood cells present. This should be done during a physical examination of an individual suspected of having PLS because it may reveal a decrease in immune function, which, although not a characteristic of PLS, should still be detected and treated.

Genetic testing: If PLS is suspected, a cytogenetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the cathepsin C (CTSC) gene. If PLS is suspected, DNA sequencing can be performed to determine whether the individual carries a mutated cathepsin C (CTSC) gene. If this mutation is detected, a positive diagnosis is made.

Imaging: X-rays may be taken to look for presence of calcium deposits in the brain tissue.

Prenatal DNA testing: If there is a family history of PLS, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose PLS. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.

During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.

During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the cathepsin C (CTSC) gene. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

COMPLICATIONS

Blood cell counts: In some instances, patients with Papillon-Lefevre syndrome (PLS) may have decreased immune function even though this is not a characteristic of the disease. Patients with decreased immune function may have decreased numbers of different types of cells, including neutrophils, lymphocytes, and monocytes. This decrease in immune cells may increase an individual's susceptibility to infection by bacteria.

Cancer: In rare cases, people with PLS may develop certain types of skin cancer, in particular malignant cutaneous neoplasms.

Liver problems: People with PLS may be at increased risk of a liver problem called pyogenic liver abscess, which is a pus-filled cavity in the liver. There are many potential causes of liver abscesses. They can be caused by an abdominal infection such as appendicitis; diverticulitis, which is inflammation of an abnormal pouch in the intestinal wall; or a perforated bowel. Other causes may be an infection in the blood, an infection of the biliary (liver secretion) tract, or trauma that damages the liver.

Periodontal disease: People with PLS are at high risk for gum, or periodontal, disease, including inflamed gums and tooth loss.

TREATMENT

There is currently no known cure for Papillon-Lefevre syndrome (PLS). Instead, treatment aims to reduce symptoms and prevent or treat complications. Patients with PLS should be seen regularly by a pediatrician, dermatologist, ophthalmologist, periodontist, and various surgeons.

Liver abscess treatment: Typically, a liver abscess can be treated through surgical or percutaneous (through the skin, with a needle) drainage of the abscess, which is accompanied by prolonged antibiotic therapy. Sometimes antibiotics alone can cure the infection.

Oral care: In addition to proper oral care, which includes regular brushing, flossing, and dental visits, people with PLS may require tooth extraction and oral antibiotics, such as metronidazole and amoxicillin, to treat periodontal disease.

Retinoids: Retinoids are a form of vitamin A taken by mouth to help improve the condition of the skin. These drugs, including acitretin, etretinate, and andisotretinoin, may benefit the problems associated with the teeth and the skin in PLS. Treatment may be most effective if it is started by the time the baby teeth first emerge and maintained until the permanent teeth have appeared. However, it should be noted that retinoids have been associated with toxicity and should be used with caution.

Skin care: Skin softeners known as keratolytics, such as salicylic acid, may be used to treat the skin on the hands, feet, elbows, and knees in patients with PLS. For those patients who develop skin cancer, traditional treatments for skin cancer would apply and include surgery, radiation therapy, and chemotherapy.

INTEGRATIVE THERAPIES

Note: Currently there is a lack of available scientific evidence on the use of integrative therapies for the treatment or prevention of Papillon-Lefevre syndrome (PLS). The therapies listed below have been studied for gum disease or periodontis, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies or preventive measures.

Good scientific evidence:

Borage seed oil: Early evidence suggests that borage has anti-inflammatory effects that may make it beneficial in treating gum disease, or periodontitis. Additional research is needed to determine the optimal dosing and administration of borage oil.

Avoid if allergic or hypersensitive to borage, its constituents, or to members of the Boraginaceae family. Use cautiously in patients with bleeding disorders or those taking warfarin or other anticoagulant (anticlotting) or antiplatelet (blood thinning) agents. Use cautiously in patients with epilepsy or in those taking anticonvulsants. Avoid in patients with compromised immune systems or similar immunological conditions. Avoid if pregnant because borage oil may have teratogenic (causing birth defects) and labor-inducing effects. Avoid if breastfeeding.

Unclear or conflicting scientific evidence:

Bloodroot: Early study has not suggested a benefit of sanguinarine, a constituent of blood root, for periodontal disease, although results are mixed. Additional study is needed.

Bloodroot can be toxic even if taken at low doses. Avoid if allergic or hypersensitive to bloodroot (Sanguinaria canadensis), its constituents, or to members of the Papaveraceae family. Use cautiously if taking anti-H. pylori or antimicrobial agents, opioids, or central nervous system depressants, or tobacco products. Avoid sanguinarine-containing dentifrices or pastes, liquids, or powders used to help maintain good oral hygiene, or with oral lesions (mouth wounds). Avoid if pregnant or breastfeeding.

Coenzyme Q10: Preliminary human studies suggest possible benefits of CoQ10 taken by mouth or placed on the skin or gums in the treatment of periodontitis. Better research is needed before a strong conclusion can be drawn.

Rash and itching have been reported rarely. Stop use two weeks before surgery/dental/diagnostic procedures with bleeding risk and do not use immediately after these procedures. Use caution with a history of blood clots, diabetes, high blood pressure, heart attack, or stroke, or with anticoagulants (blood thinners) or antiplatelet drugs, or blood pressure, blood sugar, cholesterol, or thyroid drugs. Avoid if pregnant or breastfeeding.

Iodine: Povidone-iodine mouthwash has been suggested to reduce mouth flora with periodontitis or before or after oral surgery. Evidence in this area is not conclusive.

Reactions can be severe, and deaths have occurred with exposure to iodine. Avoid iodine-based products if allergic or hypersensitive to iodine. Do not use for more than 14 consecutive days. Avoid Lugol solution and saturated solution of potassium iodide (e.g., Pima, SSKI) with high amounts of potassium in the blood, fluid in the lungs, bronchitis, or tuberculosis. Use cautiously when applying to the skin because it may irritate or burn tissues. Use sodium iodide cautiously with kidney failure. Avoid sodium iodide with gastrointestinal obstruction. Iodine is considered to be safe in recommended doses for pregnant or breastfeeding women. Avoid povidone-iodine for perianal preparation during delivery or postpartum antisepsis.

PREVENTION

General: Because Papillon-Lefevre syndrome (PLS) is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of PLS.

Genetic testing and counseling: Individuals who have PLS may meet with a genetic counselor to discuss the risks of having children with the disease. Genetic counselors can explain the options and associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS). DNA sequencing can be conducted to determine whether one carries the defective CTSC gene, however, this would be done only during genetic counseling to determine whether there is a risk that the parents could conceive a child with the disease.

Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective CTSC gene, and only the embryos that are not affected may be selected for implantation. Because PLS can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

AUTHOR INFORMATION

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

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