Ectodermal Dysplasia Essay, Research Paper

The History of the Disorder

In 1875, Charles Darwin found a new disorder that appeared in each generation of a family, affecting some of the male members and not others. This condition was more prominent in very young people. Darwin also found that the daughters were never affected although they could transmit the disease to their sons, although no males have ever transmitted the disease to their sons. Darwin started the research that led to the discovery of the gene for anhidrotic ectodermal dysplasia (EDA).10

In the early 1970’s, the EDA gene became one of the first gene linked to the X chromosome. An international team of scientists, led by Dr. Juha Kere of the University of Helsinki and Dr. Anand Srivastave from the University of Washington in St. Louis identified the location and the structure of the gene that causes the EDA disorder. The National Institute of Health, the National Institute of Dental Research, and the National Center for Human Genome Research helped sponsor this work at the National Institutes of Health. Scientists provided a molecular marker to identify female carriers of the disorder, and are a step closer to developing the therapeutic interventions to prevent or alleviate symptoms in affected individuals.2

Still, very little is known about what occurs at the molecular level to produce the features of EDA. “Dysplasia” refers to the abnormal development of the tissues, skin, hair, sweat glands, nails, and teeth. The term “anhidrotic” refers to the underdevelopment or absence of sweat glands. This could be life threatening due to the fact that it prevents the body from cooling itself down during things like fevers or hot days.

Of more than 150 different types of ectodermal dysplasia, mutations in the X chromosome account for about half of the cases. The “X linked” form of ectodermal dysplasia is associated with male children. Males have only a single X chromosome inherited from the mother, along with a Y chromosome from the father. So, males don’t have another X chromosome to cover up the infected genes. Women on the other hand, have two X chromosomes and are more likely to not show any symptoms of the abnormal gene.

Two female patients with all the symptoms of X-linked EDA led Dr. Kere, Dr. Srivastave, and other colleagues to the discovery of this gene. Earlier work by Jonathan Zonana, identified an unusual chromosomal rearrangement in one of the girls. The X chromosome had been sheared in two, with one piece sticking to the end of chromosome 9 and the remainder forming a truncated X. A similar X translocation was identified by other investigators in the second girl. Although the break points occurred in slightly different locations, both destroyed the function of the EDA gene. This indicated that the breaks occurred within the region of the chromosome that contains the gene. In other disorders where X translocations have been identified as the cause, the normal X chromosome is inactivated, leaving no functional copy of the gene. The disorder is the same as it would be in males.7

Several different studies following the inheritance pattern of the known genetic markers on the X chromosome have narrowed the position of the gene to a region called the “Xq12-q13.1” Once this region had been identified, the DNA sequences of genes needed to be studied.2

In one of the studies, scientists identified a gene in the region of the X chromosome that contained the molecular code to produce a 135-amino acid protein. This protein has a structure compatible with a transmembrane molecule, a protein that is part of the cell membrane. The protein was detected in fetal tissues and certain types of adult skin cells that are consistent with the pathology of EDA. The function of this protein still remains unknown.2

Symptoms and Progression

Before a fetus is large enough to be seen, a thin layer of cells covers the outside of the body. This layer of cells is known as the ectoderm. From this layer, skin, hair, nails, teeth nerve cells, sweat glands, parts of the eye, and parts of the ear are developed. Each of these things is then known as a ectodermal structure. There are many disorders that include one of these structures, and are not properly called ED. A combination of defects involving more than one of these structures, should be called ED.

There are many different symptoms for ED and each combination of one or more symptoms are classified in its own category. The skin is lightly pigments and appears thin, and the surface of blood vessels may be visible. The skin around the eyes is wrinkled and the skin of the palms and soles of the feet may be thick. Some other symptoms for ED may include:

? Absence of sweat glands

? Malformed finger/toe nails

? Multiple missing teeth

? Sparse hair, eyelashes and brows

? Cleft lip and palate

? Deficient tears and saliva

? Frequent respiratory infections

? Hearing or sight defects

? Missing fingers or toes

? Poorly functioning mucous membranes

? Problem with the immune system

? Other abnormalities of the ectoderm

? Prominent forehead

? Flat or depressed bridge of the nose

? Absence of mammary glands

? Peg teeth

? Foul-smelling nasal discharge

? Heat intolerance

Most individuals affected by ED cannot perspire. The sweat glands are absent, reduced in number, or may not function normally This complication causes high fevers which may, in the presence of illness, cause significant brain damage or death. The body isn’t able to regulate it’s temperature. Often the first clue that sweat glands are absent or are not functioning normally is an elevated temperature. Elevations in body temperature are often caused by high environmental temperatures, excessive activity, or heavy clothing. When the body temperature is elevated, the skin feels dry, hot and may be flushed or pale. Air conditioning in the home, school and work place is a necessity.

Most people with ED have missing or no teeth. Dental treatment is ongoing, beginning with dentures as early as age two and perhaps dental implants thereafter. Teeth that are present are spaced out, tapered, and sometimes malformed. In some cases, the enamel (outer layer of skin) is defective and there may be a number of cavities. When teeth are missing, the jawbones that they are usually embedded to, don’t develop well. This usually leads to a typical aged appearance in the face.

Precautions must be taken to limit upper respiratory infections. The linings of the nose, larynx, trachea, and the lungs are moistened by various glands. Some of these glands may be defective in cases of ED. Respiratory problems are therefore common. Care for the skin must be provided also to prevent cracking, bleeding, and infection.

The generalized underproduction of body fluids also leads to several problems. People with ED produce little saliva, causing problems with chewing, tasting, and swallowing foods. The secretions of mucous in the nose are excessively thick, forming a crusty mass. Nasal infections are very common. A hoarse, raspy voice is also common. Excessive ear wax may be produced. The most frequent problem is the accumulation of ear wax in the ear canal. Hearing loss may be the result of this due to the impacted wax or nerve damage.

People with ED may have scalp hair that is absent, sparse, fine, lightly pigmented, or abnormal in texture. It may also be fragile and unruly; sticking out in all directions and difficult to comb. The hair is also dry because of the poor developed or even absent oil glands. Some of the defects are evident at birth, while others aren’t noticed until later in life. Many times the hair grows slow and hair cuts aren’t often needed. In men, beard growth is usually normal. After a person with ED reaches puberty, hair growth sometimes improves.

In the eyes, tears are reduced, causing severe irritation, conjunctivitis, and extreme sensitivity to sunlight. There may also be cloudy corneas or cataracts associated with ED. Professional care helps to minimize the effects of sight.

Most people with ED don’t have any visible nail abnormalities, but the nails are frequently dry and rough. On of the distinctive findings in one of the forms of ED is a short nail that fails to grow to the end of the finger. In others, the nails may be thin and fragile, thick and distorted, or brittle and slow-growing. Nails with any of these abnormalities may be more prone to infection.

Some of the tests used to diagnose ED are a biopsy of the mucus membranes (shows absent mucous glands, hypo plastic mucous membranes) and a biopsy of the skin (shows absent or hypo plastic sweat glands)

Cause

There are many different types of ectodermal dysplasia, but the X-linked anhidrotic ectodermal dysplasia is the most common. This condition affects only males. An autosomal dominant form exists in which female s and males are equally affected and is symptomatically almost identical to the X-linked form of the disease.

In anhidrotic ectodermal dysplasia (EDA), most of the ectodermal layers of the body are affected. The EDA gene encodes isoforms of a trans membrane protein known as ectodysplasin. The sequence of the longest form of ectodysplasin is a collagenous area of 19 Gly-X-Y repeats and a pattern conserved in the tumor necrosis factor (TNF), a related ligand family. Similar to other members of collagenous membrane proteins and members of TNF-related ligands, ectodysplasin is a type II membrane protein and forms trimers. The membrane localization of ectodysplasin is asymmetrical and is found on the uppermost and lateral surfaces of the cells where it co-localizes with cytoskeleton structures. The TNF-like motif and cysteines are necessary for correct transport to the cell membrane. The ectodysplasin in a new member in the TNF-related ligand family is involved in the early epithelial-mesenchymal interaction that regulates ectodermal appendage formation.

The X-linked EDA gene has lesions that cause the anhidrotic ectodermal dysplasia. Scientists have cloned a 1.6-kilobase 5’-collateral region of the human EDA gene and used it to analyze features of transcriptional regulation. Primer extension analysis located a single transcription initiation site about the translation start site. When the cloned fragment was placed about a reporter gene (luciferase) and transferred into a series of cultured cells, expression comparable with that conferred by an SV40 promoter-enhancer was observed. The region lacks a TATA box sequence, and basal transcription from the unique start site is dependent on two binding sites for the Sp1 transcription factor.

Current Treatment

There is no specific treatment for this disorder. Cosmetic and functional improvements can be made through the use of wigs, when there is no scalp hair, and through the use of dentures for missing teeth. Synthetic tears are available to replace normal tearing and prevent drying of the eyes. The nose may have to be irrigated regularly to get rid of purulent debris and prevent infections. Temperature control is a constant problem. Affected people require a cooler climate and may require frequent cooling water baths to maintain normal body temperature. One suck cooling device is called a “cooling suit”. This device is a vest-like suit that includes a coolant that is circulated through the garment by a battery operated power jack. These suits are not practical because they attract unwanted attention to people with ectodermal dysplasia. Sun glasses may be worn to prevent eye injuries. Nail polish may be used to help make the nails look better. Hearing aids are available to help promote better hearing.

Gene therapy is a new medical procedure that complements faulty a gene with a healthy or working gene. Gene therapy is working for the people that have tried it, but is still not widely available.

Propose Treatments That Should Be Investigated

Not much is currently known about what causes all the problems at the molecular level, but I would suggest that this be researched primarily. Treatments for the gradual destruction of the cornea of the eye and the possibility of potential blindness should be researched. Research could lead to medical treatment for this particular symptom, which is a devastating manifestation of the disease.

Expression of the bone and tooth formation should also be further studied to know what happens to this particular gene when affected by ED and why it can’t function properly. There is a lot of research being done on ED currently. Finding the exact genes that are affected would assist scientists and researchers in finding a cure for ED.