Hypohidrotic Ectodermal Dysplasia

Hypohidrotic Ectodermal Dysplasia

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Hypohidrotic Ectodermal Dysplasia is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • HED
  • Anhidrotic Ectodermal Dysplasia
  • EDA
  • Christ-Siemens-Touraine Syndrome
  • CST Syndrome

Disorder Subdivisions

  • None

General Discussion

Hypohidrotic ectodermal dysplasia (HED) is a rare inherited multisystem disorder that belongs to the group of diseases known as ectodermal dysplasias. Ectodermal dysplasias typically affect the hair, teeth, nails, and/or skin. HED is primarily characterized by partial or complete absence of certain sweat glands (eccrine glands), causing lack of or diminished sweating (anhidrosis or hypohidrosis), heat intolerance, and fever; abnormally sparse hair (hypotrichosis), and absence (hypodontia) and/or malformation of certain teeth. Many individuals with HED also have characteristic facial abnormalities including a prominent forehead, a sunken nasal bridge (so-called "saddle nose"), unusually thick lips, and/or a large chin. The skin on most of the body may be abnormally thin, dry, and soft with an abnormal lack of pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. In many cases, affected infants and children may also exhibit underdevelopment (hypoplasia) or absence (aplasia) of mucous glands within the respiratory and gastrointestinal (GI) tracts and, in some cases, decreased function of certain components of the immune system (e.g., depressed lymphocyte function, cellular immune hypofunction), potentially causing an increased susceptibility to certain infections and/or allergic conditions. Many affected infants and children experience recurrent attacks of wheezing and breathlessness (asthma), respiratory infections; chronic inflammation of the nasal passages (atrophic rhinitis), scaling, itchy (pruritic) skin rashes (eczema), and/or other findings.



HED is usually inherited as an X-linked recessive genetic trait; in such cases, the disorder is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carreirs) may exhibit some of the symptoms and findings associated with the disorder. These may include absence and/or malformation of certain teeth, sparse hair, and/or reduced sweating. Researchers also have reported cases in which HED appears to be inherited as an autosomal recessive genetic trait. In such cases, the disorder is fully expressed in both males and females.

Symptoms

Hypohidrotic ectodermal dysplasia is characterized by lack of or diminished sweating (anhidrosis or hypohidrosis), abnormally sparse hair (hypotrichosis), and/or absence (hypodontia) and/or malformation of certain teeth. In addition, affected individuals often have characteristic facial abnormalities, irregularities of the skin, abnormalities of the mucous membranes lining the respiratory and gastrointestinal (GI) tracts, an increased tendency to develop certain infections and allergic conditions, and/or other abnormalities. The range and severity of the symptoms and findings associated with HED may vary from case to case.



A primary feature of HED is a lack of or diminished sweating (anhidrosis or hypohidrosis), resulting from underdevelopment of or partial or complete absence of certain sweat glands (eccrine glands). Because affected infants and children are unable to sweat appropriately when exposed to warm environments, they typically experience repeated episodes of heat intolerance and "unexplained" high fevers that may remain unexplained until the disorder is diagnosed. In individuals with HED, even mild exertion may result in extreme discomfort, incapacitation, and/or extremely elevated body temperature (hyperpyrexia). Eating hot foods may also cause extreme discomfort. In some cases, without appropriate treatment, episodes of hyperpyrexia may result in life-threatening complications, particularly during the first two years of life. In addition, according to the medical literature, episodes of hyperpyrexia during infancy or childhood may cause mental deficiency in some cases.



Abnormal sparseness of hair (hypotrichosis) is also a primary characteristic of HED and is often the first physical finding that is noted in affected infants or children. In individuals with the disorder, hypotrichosis is due to incomplete formation and reduced numbers of hair follicles. Affected individuals typically have scalp hair that is blond or lightly pigmented; abnormally sparse, short, and fine; and, in some cases, stiff, dry, and unruly. Some individuals with the disorder may also experience abnormal bald patches on the scalp (alopecia). In addition, the eyebrows and eyelashes are often scanty or absent, although, in some cases, the eyelashes may appear normal. After puberty, male patterns of hair growth (e.g., moustache and beard) may be normal in some males with the disorder; however, in other cases, this hair growth may be sparse. In affected males and females, pubic and underarm (axillary) hair is typically scant. In addition, in some cases, hair may be absent from the arms, legs, and/or trunk.



The third primary characteristic typically associated with HED is the absence (hypodontia) and/or malformation of certain teeth. In most cases, the majority of the primary (deciduous) and secondary (permanent) teeth are absent (hypodontia or partial anodontia). Remaining teeth usually include certain front teeth (incisors), teeth normally located next to the incisors (canines), and/or, in some cases, one or more molars. In most cases, the teeth that are present are widely spaced, pointed, and cone shaped. In some rare cases, individuals with hypohidrotic ectodermal dysplasia may lack all upper and/or lower teeth (edentulous).



In individuals with HED, although the jaws usually develop normally, the bony ridge (alveolar process) that holds the teeth in place often fails to form properly. In addition, due to hypodontia, the lips may protrude outward (everted) and appear abnormally thick, the gums may be abnormally small or degenerated (atrophic), and the normally exposed red portion of the upper and lower lips (vermilion border) may not be noticeable.



Many individuals with HED have additional, characteristic facial features, including a prominent forehead (frontal bossing); underdeveloped nostrils (hypoplastic alae nasi) and a low or sunken nasal bridge (so-called "saddle nose"); and underdeveloped, sunken cheeks (malar hypoplasia). In addition, some researchers suggest that, in individuals with HED, the size of the nose, mouth, and ears as well as the length of the lower two thirds of the face may be abnormally reduced.



In many cases, HED is characterized by distinctive skin abnormalities. Many affected newborns have unusual scaling or peeling of the skin, while many children develop itchy (pruritic), scaling skin rashes (eczema). In the majority of individuals with HED, the skin on most of the body is unusually thin and soft with an abnormal lack of pigmentation (hypopigmentation). However, the skin around the eyes (periorbital) may be darkly pigmented (hyperpigmentation) and finely wrinkled, appearing prematurely aged. The skin may also be extremely dry due to underdevelopment (hypoplasia) or absence (aplasia) of oil-secreting glands (sebaceous glands). In addition, in some cases, there may be abnormalities in the skin ridge patterns (dermatoglyphic patterns) on the fingers, toes, palms of the hands, and/or soles of the feet. Some individuals with the disorder have unusually thin and brittle nails.



In many individuals with HED, mucous glands within the membrane lining the respiratory and gastrointestinal (GI) tracts (e.g., in the lung, pharynx, larynx, trachea, upper esophagus, stomach, intestines) are underdeveloped (hypoplastic) or absent (aplastic). In addition, some affected infants and children have abnormally decreased function of certain components of the immune system (e.g., depressed lymphocyte function, cellular immune hypofunction). The immune system works to protect the body against invading microorganisms, toxins, and other substances that are recognized as foreign to the body. In many infants and children with HED, such mucous gland abnormalities and/or immune system irregularities cause an increased susceptibility to certain infections and/or allergic conditions. For example, many affected infants and children experience recurrent attacks of wheezing and breathlessness (asthma), respiratory infections (e.g., pneumonia, bronchitis), chronic inflammation of the nasal passages (atrophic rhinitis), eczema (discussed above), inflammation of the middle ear (otitis media), and/or, in rare cases, inflammation of the mouth (stomatitis). Such allergic, inflammatory, and/or infectious conditions may cause hoarseness (dysphonia), swallowing problems (dysphagia), feeding difficulties, hearing impairment, and/or other abnormalities. Respiratory infections without appropriate treatment may cause life-threatening complications, particularly during infancy and early childhood.



Additional abnormalities may also be associated with HED . Some individuals with the disorder have inflamed, underdeveloped (hypoplastic) salivary glands, leading to abnormal dryness of the mouth. In some cases, affected individuals have no sense of taste or smell. In addition, some individuals with HED are unable to produce tears due to underdevelopment of the glands that secrete tears (hypoplastic lacrimal glands), hypoplasia of the ducts through which the tears pass (lacrimal ducts), and/or abnormal narrowing of the small openings in the inner corners of the eyelids where tears normally drain (stenotic lacrimal puncta). In addition, some individuals with HED have eye (ocular) abnormalities including loss of transparency of the lens of the eyes (cataracts) and/or clouding of the portion of the eyes through which light passes (corneal opacities).



Females who carry a single copy of the disease gene for X-linked HED (heterozygote carriers) may have no symptoms or physical abnormalities or may have some of the characteristics associated with the disease. Such symptoms are typically milder than those associated with the fully expressed disorder. Female carriers of X-linked HED may have dental abnormalities such as absence of certain teeth (hypodontia) and/or abnormally small, pointed, conical teeth; sparse hair (hypotrichosis), reduced sweating; and/or irregular dermatoglyphic patterns. In some cases, abnormalities of the breasts and nipples have been reported, and approximately 80 percent of carriers may experience difficulties nursing.

Causes

In the majority of reported cases, hypohidrotic ectodermal dysplasia is inherited as an X-linked recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.



X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome may be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons. Thus, in summary, when HED is inherited as an X-linked recessive trait, the disorder is fully expressed in males only and it is transmitted through the maternal X chromosome.



In some females who inherit a single copy of the disease gene (heterozygote carriers) for HED, the disease may not be "masked" by the normal gene on the other X chromosome. As a result, in such cases, some females exhibit some of the symptoms associated with the disorder.



The gene responsible for X-linked HED is located on the long arm (q) of chromosome X (Xq12.2-q13.1). Chromosomes, which are present in the nucleus of human cells, 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 many bands that are numbered. For example, "chromosome Xq12.2-q13.1" refers to bands 12.2-13.1 on the long arm of chromosome X.



The exact function of the HED gene on chromosome X is not yet understood. However, many researchers suggest that the protein regulated (encoded) by the HED gene plays an important role during early embryonic development. Such researchers have shown that the HED gene is normally expressed in the sweat glands, hair follicles, certain cells (keratinocytes) forming the thin outer layer of the skin, and other fetal and adult cells.



Researchers also have reported cases in which HED appears to be inherited as an autosomal recessive genetic trait. In such cases, the disorder is fully expressed in both males and females. The existence of an autosomal recessive form of HED is supported by reports in the medical literature of severely affected females with the fully expressed disorder and multiple affected family members with parents who are closely related by blood (consanguineous). If both parents carry the same disease gene, there is a higher than normal risk that their children may inherit the two genes necessary for the development of the disease.

Affected Populations

X-linked hypohidrotic ectodermal dysplasia is a rare disorder that is fully expressed in males only. However, females who carry a single copy of the disease gene (heterozygote carriers) may exhibit milder symptoms associated with the disorder. In those rare cases when HED is inherited as an autosomal recessive genetic trait, males and females are affected in equal numbers. Because the vast majority of cases of HED are thought to be X-linked, it is suspected that approximately 90 percent of affected individuals are male.



HED is thought to occur in approximately one in every 100,000 births. Several hundred cases have been reported in the medical literature since the disorder was originally described in 1848 (J. Thurman) and in 1875 (C. Darwin).



Although some symptoms and findings associated with the disorder are present shortly after birth (neonatal period) such as heat intolerance, unexplained fever, and/or extensive peeling of the skin, the characteristic facial abnormalities may not be apparent in affected infants. Therefore, the disorder often is not recognized in affected infants and children until associated dental and hair abnormalities become apparent.

Standard Therapies

Diagnosis

Because the gene responsible for X-linked hypohidrotic ectodermal dysplasia (HED) has been identified, precise genetic testing may be possible for males with the X-linked form of HED and for females who carry a single copy of the disease gene (heterozygotes). Although genetic testing to aid in accurate diagnosis and to assist in diagnosis before birth (prenatally) and carrier determination is possible, such testing may only be available through research laboratories with a special interest in this disease and therefore is not widely available.



In some cases, hypohidrotic ectodermal dysplasia may be diagnosed prenatally by microscopic examination (i.e., light and electron microscopy) of small samples of skin tissue removed (biopsied) during fetoscopy. During this procedure, a small fiber-optic instrument (fetoscope) is introduced through a small incision in the mother's abdomen and is used to visualize the developing fetus and/or to obtain fetal cells, amniotic fluid, and/or blood for study. Such skin biopsy samples removed from different areas of the developing fetus may reveal abnormal reduction or absence of hair follicles, oil-secreting glands of the skin (sebaceous glands), and/or eccrine sweat glands, findings that may suggest HED. The week of fetal development during which fetoscopy is performed affects which findings are considered diagnostic. For example, if fetoscopy is performed during week 20, lack of hair follicles and sebaceous glands may be considered diagnostic criteria suggestive of HED. However, reduction or absence of eccrine sweat glands may not be considered diagnostic at that time, since such structures do not begin to develop until approximately week 20 to 24 of fetal development.



In most cases, however, HED is diagnosed during early childhood when characteristic dental and hair abnormalities become apparent and prompt further testing. Such diagnosis is based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, and specialized laboratory testing. In some cases, during the newborn period, heat intolerance, unexplained fevers, and/or extensive skin peeling may lead to an earlier diagnosis.



Specialized diagnostic testing may include microscopic examination of small samples of skin tissue removed from the palm, confirming partial or complete absence of eccrine sweat glands. In some cases, other types of sweat testing may be used to determine the reduction or absence of perspiration. One such test that is particularly helpful in detecting females who carry a single copy of the disease gene for X-linked HED (heterozygotes) consists of the application of an iodine-in-alcohol solution over the entire back, followed by the application of a corn starch/castor oil suspension. During such testing, sweat glands become highlighted by a black dot. In heterozygous females, characteristic streaks will appear on the back in the shape of a "V", demonstrating those areas that are devoid of sweat glands. Another method frequently used is the counting of sweat pores by direct observation. In cases of X-linked hypohidrotic ectodermal dysplasia, direct observation reveals no sweat pores in affected males and decreased numbers of sweat pores in female carriers. In males and females with the autosomal recessive form of HED, such a count will also reveal decreased number of sweat pores.



Additional diagnostic tools are available and may include a test in which the sweat glands are stimulated by a drug called pilocarpine through the use of direct current (iontophoresis) and the resulting perspiration is measured and analyzed. In some cases, application of the substance o-phthalaldehyde may be applied directly to the skin (topically) of the palm. Such testing may reveal absence or reduction of sweating in affected individuals and female carriers.



In addition, dental x-rays to verify the absence of certain teeth and to further characterize associated dental abnormalities play an essential role in helping to confirm a diagnosis of HED or identify carrier status.



Treatment

The treatment of hypohidrotic ectodermal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists who need to systematically and comprehensively plan an affected individual's treatment. Such specialists may include pediatricians or internists, physicians who treat disorders of the skin (dermatologists), dental specialists, physicians who diagnose and treat disorders of the ears, nose, and throat (otolaryngologists), allergists, and/or other health care professionals.



If possible, it is recommended that individuals with hypohidrotic ectodermal dysplasia live in a cool climate. Physicians may carefully monitor affected infants and young children and recommend supportive measures to help prevent episodes of severely elevated body temperature (hyperpyrexia). For children and adults with the disorder, preventive and protective measures should include avoidance of physical exertion, protection from high temperatures, and, during warm weather, large amounts of dietary fluids, cooling by water such as use of cool cloths and sponge baths, air conditioning, and/or other supportive measures.



Early dental intervention and restoration is also important. Artificial teeth and/or other devices (prosthetics) may be used to replace absent teeth. Braces, bridges, dental surgery, and/or other corrective measures may be used to help correct dental abnormalities and ensure appropriate nutrition. In addition, in affected individuals with alopecia, hairpieces or wigs may be helpful.



Physicians may recommend that impacted nasal secretions be carefully removed on a regular basis to help prevent or limit the severity of rhinitis. Physicians may also regularly monitor affected infants and children to help prevent respiratory infections and to ensure prompt, aggressive treatment should such infections occur.



In affected individuals with impaired tear secretion (alacrima), the use of artificial tears may help to prevent possible corneal damage.



Early intervention is important to ensure that children with hypohidrotic ectodermal dysplasia reach their potential. Special services that may be beneficial to affected children may include special education and special social support, and/or other medical, social, and/or vocational services.



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

Investigational Therapies

The National Foundation for Ectodermal Dysplasias (NFED) is involved with programs in dental schools to provide dental implants to individuals affected by ectodermal dysplasia. Interested individuals should contact NFED. Such individuals must have ectodermal dysplasia, be missing a majority of teeth in the lower jaw (mandible), and not have any complicating factors. In addition, they must be willing to participate in the related research project, which requires periodic check-ups. For more information, please contact the National Foundation for Ectodermal Dysplasias, which is listed in the Resources section below.



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

References

TEXTBOOKS

Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:540-41.



Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:597-98, 600-01, 607-08.



Champion RH, et al., eds. Textbook of Dermatology. 5th ed. Cambridge, MA: Blackwell Scientific Publications; 1992:335-37.



Behrman RE, ed. Nelson Textbook of Pediatrics, 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:1837.



Gorlin RJ, et al., eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:451-56.



JOURNAL ARTICLES

Glavina D, et al. Hypohidrotic ectodermal dysplasia: dental features and carrier detection. Coll Antropol. 2001;25:303-10.



Kargul B, et al. Hypohidrotic ectodermal dysplasia: dental, clinical, genetic and dermatoglyphic findings of three cases. J Clin Pediatr Dent. 2001;26:5-12.



Kere J, et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet. 1996;13:409-16. Comment in: Nat Genet. 1996;13:379-80.



Blume-Peytavi U, et al. Anhidrotic ectodermal dysplasia. Disorder of the differentiation of hair follicles and sweat glands leads to abnormal keratinization. Hautarzt. 1994;45:378-84.



Zonana J. Hypohidrotic (anhidrotic) ectodermal dysplasia: molecular genetic research and its clinical applications. Semin Dermatol. 1993;12:241-46.



Crawford PJ, et al. Clinical and radiographic dental findings in X linked hypohidrotic ectodermal dysplasia. J Med Genet. 1991;28:181-85.



Goodship J, et al. Possible genetic heterogeneity in x linked hypohidrotic ectodermal dysplasia. J Med Genet. 1990;27:422-25.



Zonana J, et al. Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis. Am J Med Genet. 1990;35:132-35.



Sybert VP. Hypohidrotic ectodermal dysplasia: argument against an autosomal recessive form clinically indistinguishable from x-linked hypohidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome). Pediatr Dermatol. 1989;6:76-81. Comment in: Pediatr Dermatol. 1990;7:242.



Gilgenkrantz S, et al. Hypohidrotic ectodermal dysplasia. Clinical study of a family of 30 over three generations. Hum Genet. 1989;81:120-22.



Bixler D, et al. Characterization of the face in hypohidrotic ectodermal dysplasia by cephalometric and anthropometric analysis. Birth Defects Orig Artic Ser. 1988;24:197-203.



Ward RE, et al. Anthropometric analysis of the face in hypohidrotic ectodermal dysplasia: a family study. Am J Phys Anthropol. 1987;74:453-58.



Clarke A, et al. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child. 1987;62:989-96.



Blanchet-Bardon C, et al. Use of morphological markers in carriers as an aid in genetic counseling and prenatal diagnosis. Curr Probl Dermatol. 1987;16:109-19.



Arnold ML, et al. Prenatal diagnosis of anhidrotic ectodermal dysplasia. Prenatal Diagn. 1984;4:85-98.



Davis JR, et al. Cellular immunodeficiency in anhidrotic ectodermal dysplasia. Acta Derm Venereol. 1976;56:115-20.



FROM THE INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 305100; Last Update: 8/22/97.Entry No: 224900; Last Update: 8/22/97. Entry No: 2/19/98; Last Update: 129900. Entry No: 8/21/97; Last Update:129500.

Resources

National Foundation for Ectodermal Dysplasias

6 Execuitive Drive

Suite 2

Fairview Hiights, IL 62208

Tel: (618)566-2020

Fax: (618)566-4718

Email: info@nfed.org

Internet: http://www.nfed.org



March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

Information Clearinghouse

One AMS Circle

Bethesda, MD 20892-3675

USA

Tel: (301)495-4484

Fax: (301)718-6366

Tel: (877)226-4267

TDD: (301)565-2966

Email: NIAMSinfo@mail.nih.gov

Internet: http://www.niams.nih.gov/



NIH/National Institute of Dental and Craniofacial Research

Building 31, Room 2C39

31 Center Drive, MSC 2290

Bethesda, MD 20892

USA

Tel: (301)496-4261

Fax: (301)480-4098

Tel: (866)232-4528

Email: nidcrinfo@mail.nih.gov

Internet: http://www.nidcr.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Ectodermal Dysplasia Society

Unit 1 Maida Vale Business Centre

Leckhampton

Cheltenham

Gloucestershire

England, GL53 7ER

United Kingdom

Tel: 4401242261332

Tel: 4407805775703

Email: diana@ectodermaldysplasia.org

Internet: http://www.ectodermaldysplasia.org



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