Rapp Hodgkin syndrome

BACKGROUND

Rapp-Hodgkin syndrome (RHS) is one of the ectodermal dysplasias, disorders that affect the outer layer of a developing embryo. This layer, called the ectoderm, develops into many parts of a baby's body, including the eyes, skin, nails, and hair. In ectodermal dysplasias, these parts may not develop normally.

Typical features of RHS include decreased ability to sweat (hypohidrosis), incomplete closure of the roof of the mouth (cleft palate), abnormal groove in the upper lip (cleft lip), dental problems, hair defects, and poorly developed nails. Symptoms may be present at birth or may appear later in infancy.

RHS is believed to be an inherited genetic disorder. It is extremely rare, with only about 40 cases reported in scientific journals. The exact incidence is currently unknown, but is estimated at 7 in 10,000 births worldwide. RHS affects males and females alike.

RISK FACTORS

The only known risk factor for Rapp-Hodgkin syndrome (RHS) is a family history of the disease. RHS is believed to be inherited as an autosomal dominant trait. It is extremely rare, with only about 40 cases reported in scientific journals. The exact incidence is currently unknown, but is estimated at 7 in 10,000 births worldwide.

CAUSES

General: Rapp-Hodgkin syndrome (RHS) is believed to be caused by a mutation or defect in the TP73L gene, which produces several variants of the p73-like tumor protein (p73L), known as p40, p51, and p63. The most likely pattern of inheritance is autosomal dominant.

Autosomal dominant inheritance: For a dominant disorder to appear, only one defective copy of the TP73L gene is necessary. Individuals receive two copies of most genes, one from the mother and one from the father. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.

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

Gene function: p73-like tumor protein (p73L) may have tumor suppressor function. p63 and p73 were examined for their roles in DNA damage-induced apoptosis and it was found that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage.

Although it has been suggested that the two homologs of TP53, TP73 and TP63, may not have a typical tumor suppressor gene role in human cancers, TP73 and TP63 appear to be strongly involved in malignancy acquisition and maintenance.

When a gene is mutated, the protein manufactured by its instructions may not function properly. A dysfunction in this protein may cause symptoms of RHS such as ectodermal dysplasia, limb malformations, and cleft lip.

SIGNS AND SYMPTOMS

General: The symptoms of Rapp-Hodgkin syndrome (RHS) vary greatly between patients.

Eyes: Patients with RHS may lack the small opening in the inner corner of the eye where tears emerge. They may also have problems with the tear ducts themselves. Other features may include droopy or fused eyelids and extreme light sensitivity. The lining of the eyelids may become inflamed and infected, a condition known as conjunctivitis.

Face: Facial features of people with RHS include an underdeveloped middle portion of the face and a high forehead. Additional features include a low bridge of the nose, a narrow nose, a cleft palate, and underdeveloped nostrils.

Hair: The hair of people with RHS grows slowly and tends to be sparse, dry, coarse, and wiry. Eyebrows and eyelashes are also sparse. People with RHS often lose their hair at a young age or may develop bald patches on the back of the head.

Mouth: Patients with RHS may have an incomplete closure of the roof of the mouth, or cleft palate, an incomplete closure of the upper lip, or cleft lip, or both. In addition, the uvula (the small flap of skin that can be seen hanging in the back of the throat) may be split, the mouth may be abnormally small, and the upper jaw may be underdeveloped. People with RHS may also have swallowing problems caused by structural deformities in the soft palate.

Nails: Patients with RHS may have poorly developed fingernails and toenails. Nails may grow abnormally slowly or may never grow at all. There may also be grooves in the nails.

Skin: Like most forms of ectodermal dysplasia, RHS is marked by a reduced ability or lack of ability to sweat (hypohidrosis or anhidrosis). This inability is caused by fewer than normal sweat glands. Sweating helps regulate body temperature, so patients with RHS may have impaired temperature regulation. In addition, the skin may be abnormally thin with a reduced number of pores.

Teeth: Patients with RHS may have missing, abnormally small, cone-shaped, or poorly developed teeth. Teeth may also be very prone to cavities.

Other: Males with RHS may have urinary problems, including a misplaced urinary opening. Females may have abnormally developed genitalia. Other very rare symptoms include webbing of the fingers and toes and short stature.

DIAGNOSIS

General: Rapp-Hodgkin syndrome (RHS) may be diagnosed following a thorough family history and complete physical. RHS may be suspected based on the distinctive physical characteristics associated with the condition, namely, those of the skin, hair, mouth, eyes, nails, teeth, hands, and feet.

Biopsy: In a biopsy, a very small sample of tissue is taken for examination in a lab. For a diagnosis of RHS, a biopsy of the skin may be taken to look for the presence of sweat glands.

Genetic testing: If RHS 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 TP73L gene. If this is detected, a positive diagnosis is made.

Prenatal DNA testing: If there is a family history of RHS, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose RHS. 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 TP63 gene. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

COMPLICATIONS

Ear infections: A cleft palate may cause people with RHS to develop frequent ear inflammation and infection, or otitis media. In addition, abnormal ear canals may contribute to hearing loss.

Feeding and speech problems: A cleft palate, cleft lip, small mouth, and dental and swallowing problems, may cause difficulty eating and speaking in patients with RHS.

Intermittent hyperpyrexia: Elevated body temperature may occur in infants with decreased sweating, which causes death in close to 30% of affected infants. Recurrent high fever may also lead to seizures and neurological symptoms.

TREATMENT

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

Dental care: Patients with RHS must practice good preventive dental care, including regular flossing, teeth brushing, and visits to the dentist. Dentures may be appropriate for patients with RHS who are missing teeth. Dental surgery may be needed to correct structural problems.

Hearing aids: RHS patients who experience hearing loss may benefit from hearing aids. These battery-operated devices are available in three basic styles: behind-the-ear, in-the-ear, and in the ear canal. Patients should talk to their healthcare provider to determine the type of hearing aid that is best for them. A behind-the-ear device is used for mild to profound hearing loss. The device is worn behind the ear and is attached to a plastic ear mold inside the outer ear. In-the-ear hearing aids are worn inside the outer ear, and are used for mild to severe hearing loss. Canal hearing aids are smaller hearing aids that fit inside the patient's ear canal. They are used for mild to moderately severe hearing loss.

If hearing loss is severe, patients may benefit from cochlear implants. These electronic devices are surgically implanted inside the ears. Unlike a hearing aid, which amplifies sound, a cochlear implant compensates for damaged parts of the inner ear.

Speech language therapy: Some patients with RHS may benefit from speech-language therapy because these individuals often develop communication skills more slowly than normal. During speech-language therapy, a qualified speech-language professional (SLP) works with the patient on a one-to-one basis, in a small group, or in a classroom, to help the patient improve speech, language, and communication skills. Programs are tailored to the patient's individual needs.

Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.

On average, patients receive five or more hours of therapy per week for three months to several years. Doctors typically recommend that treatment be started early to ensure the best possible prognosis for the child.

Surgery: Patients with RHS may require reconstructive surgery to correct a cleft palate or cleft lip.

Other: Patients with RHS and their families should be made aware of the potential danger of hyperthermia, or increased body temperature. Because of the reduced or absent ability to sweat, patients with RHS may not be able to regulate body temperature correctly. Precautions should be taken during exercise or during exposure to extreme heat.

INTEGRATIVE THERAPIES

Note: Currently, there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Rapp-Hodgkin syndrome (RHS). The therapies listed below have been studied for related conditions, such as ear infections or otitis media, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies.

Unclear or conflicting scientific evidence:

Belladonna: Little reliable research is currently available on the use of belladonna for ear infections. More research is needed in this area.

Avoid if allergic to belladonna or plants of the Solanaceae (nightshade) family, which includes bell peppers, potatoes, and eggplants. Avoid with a history of heart disease, high blood pressure, heart attack, abnormal heartbeat (arrhythmia), congestive heart failure, stomach ulcer, constipation, stomach acid reflux (serious heartburn), hiatal hernia, gastrointestinal disease, ileostomy, colostomy, fever, bowel obstruction, benign prostatic hypertrophy, urinary retention, glaucoma (narrow angle), psychotic illness, Sj©gren's syndrome, dry mouth (xerostomia or salivary gland disorders), neuromuscular disorders such as myasthenia gravis, or Down's syndrome. Avoid if pregnant or breastfeeding.

Calendula: Calendula has been studied for reducing pain caused by ear infections. Some human studies suggest that calendula may possess mild anesthetic properties equal to those of similar nonherbal eardrop preparations. Further studies are needed before a recommendation can be made in this area.

Avoid if allergic to plants in the Aster/Compositae family, such as ragweed, chrysanthemums, marigolds, and daisies. Severe allergic reaction, or anaphylactic shock, has been reported after gargling with a calendula preparation. Caution is advised while driving or operating machinery. It is not clear whether calendula is safe for use during pregnancy or breastfeeding.

Chiropractic: There is currently not enough reliable scientific evidence to draw conclusions about the effects of chiropractic techniques in the management of otitis media in children.

Use extra caution during cervical adjustments. Use cautiously with acute arthritis, conditions that cause decreased bone mineralization, brittle bone disease, bone softening conditions, bleeding disorders, or migraines. Use cautiously with a risk of tumors or cancers. Avoid with symptoms of vertebrobasilar vascular insufficiency, aneurysms, unstable spondylolisthesis, or arthritis. Avoid with agents that increase the risk of bleeding. Avoid in areas of paraspinal tissue after surgery. Avoid if pregnant or breastfeeding.

Lavender: Limited human study has used a naturopathic eardrop called NHED (containing Allium sativum, Verbascum thapsus, Calendula flores, Hypericum perfoliatum, lavender, and vitamin E in olive oil) with and without an antibiotic and topical anesthetic. It was found that the ear pain was self-limiting and resolved after a few days with or without antibiotics. This evidence is preliminary and further research is needed before a conclusion about this treatment can be made.

Avoid if allergic or hypersensitive to lavender. Avoid with history of seizures, bleeding disorders, eating disorders (anorexia, bulimia), or anemia (low levels of iron). Avoid if pregnant or breastfeeding.

Mullein: There are some clinical studies using mullein (Verbascum thapsus) in combination with other herbal products as an eardrop to treat otitis media. It is not clear what effect mullein has alone on otitis media, as the product studied was a combination of different herbs. Additional study is needed before a firm conclusion can be made.

Avoid if allergic/hypersensitive to mullein (Verbascum thapsus), its constituents, or to members of the Scrophulariaceae (figwort) family. Use cautiously if taking anticoagulants (blood-thinners). There are reports that mullein may contain a toxin called rotenone, which is an insecticide. Avoid if pregnant or breastfeeding.

Sanicle: Little reliable research is currently available on the use of sanicle for ear infections. Traditionally, sanicle has been used orally for mild respiratory inflammation and catarrh, and laboratory research indicates potential antiviral effects. Limited human evidence suggests potential favorable results of a Sanicula aqua heuristic homeopathic preparation for recurrent otitis media. High-quality clinical studies are needed before any recommendation can be made.

Avoid if allergic to sanicle, its constituents, or members of the Apiaceae family. Phytodermatosis has been reported with Sanicula europaea. Avoid when taking antihypertensives or diuretics. It is not clear whether sanicle is safe for use during pregnancy or breastfeeding. Use caution with a history of gastrointestinal irritation.

PREVENTION

General: Because Rapp-Hodgkin syndrome (RHS) 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 RHS.

Genetic testing and counseling: Individuals who have RHS can be screened for the TP73L gene and may meet with a genetic counselor to discuss the risks of having children with the disease. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).

Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective TP63 gene, and only the embryos that are not affected may be selected for implantation. Because RHS 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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