Skin Pigmentation
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Waardenburg syndrome (WS) is an inherited disorder often characterized
by varying degrees of hearing loss and changes in skin and hair pigmentation.
The syndrome got its name from a Dutch eye doctor named Petrus Johannes Waardenburg
who first noticed that people with differently colored eyes often had a hearing
impairment. He went on to study over a thousand individuals in deaf families
and found that some of them had certain physical characteristics in common.
One commonly observed characteristic of Waardenburg syndrome is two differently
colored eyes. One eye is usually brown and the other blue. Sometimes, one eye
has two different colors. Other individuals with Waardenburg syndrome may have
unusually brilliant blue eyes.
People with WS may also have distinctive hair coloring, such as a patch of
white hair or premature gray hair as early as age 12. Other possible physical
features include a wide space between the inner corners of eyes called a broad
nasal root. In addition persons with WS may have low frontal hairline and their
eyebrows may connect. The levels of hearing loss associated with the syndrome
can vary from moderate to profound.
Individuals with Waardenburg syndrome may have some or all of the traits of
the syndrome. For example, a person with WS may have a white forelock, a patch
of white hair near the forehead, and no hearing impairment. Others may have
white patches of skin and severe hearing impairment. The severity of the hearing
impairment varies among individuals with WS as do changes in the skin and hair.
On rare occasions, WS has been associated with other conditions that are present
at birth, such as intestinal disorders, elevation of the shoulder blade, and
disorders of the spine. A facial abnormality, known as cleft lip and/or palate,
also has been associated with WS.
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There are at least four types of Waardenburg syndrome.
The most common types of WS identified by scientists are Type 1 and Type 2.
The different types of physical characteristics a person has determines the
type of WS. Persons who have an unusually wide space between the inner corners
of their eyes have WS Type 1. Hearing impairments occur in about 20 percent
of individuals with this type of Waardenburg syndrome. Persons who do not have
a wide space between the inner corners of their eyes, but who have many other
WS characteristics are described as having WS Type 2. About 50 percent of persons
with WS Type 2 have a hearing impairment or are deaf.
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As a genetic disorder, Waardenburg syndrome is passed down from parent
to child much like hair color, blood type, or other physical traits. A
child receives genetic material from each parent. Because Waardenburg
syndrome is a dominant condition, a child usually inherits the syndrome
from just one parent who has the malfunctioning WS gene. Actually, there
is a 50/50 chance that a child of an individual with WS will also have the
syndrome.
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Scientists have identified and located four different genes for
Waardenburg syndrome: PAX3, MITF, EDNRB, and EDN3. WS type 1 and 3 have
been associated with mutations in the PAX3 gene; WS type 2 with the MITF
gene; and WS type 4 with the EDNRB and EDN3 genes. While scientists are
studying all of these genes, currently, the most information is available
on the PAX3 and MITF genes and their role in Waardenburg syndrome.
The PAX3 gene is located on chromosome 2 and controls some aspects of
the development of the face and inner ear. The MITF gene is found on
chromosome 3. It also controls the development of the ear and hearing.
Scientists are now studying these genes to better understand how they
operate in controlling the normal growth of the ear and the development of
hearing. This information will help scientists understand why persons with
WS sometimes develop hearing problems.
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Incontinentia pigmenti (IP) is one of a group of gene-linked
diseases known as neurocutaneous disorders. These disorders cause characteristic
patterns of discolored skin and also involve the brain, eyes, nails, and hair.
In most cases, IP is caused by mutations in a gene called NEMO (NF-kappaB essential
modulator). Males are more severely affected than females. Discolored skin is
caused by excessive deposits of melanin (normal skin pigment). Most newborns
with IP will develop discolored skin within the first two weeks. The pigmentation
involves the trunk and extremities, is slate-grey, blue or brown, and is distributed
in irregular marbled or wavy lines. The discoloration fades with age. Neurological
problems include cerebral atrophy, the formation of small cavities in the central
white matter of the brain, and the loss of neurons in the cerebellar cortex.
About 20% of children with IP will have slow motor development, muscle weakness
in one or both sides of the body, mental retardation, and seizures. They are
also likely to have visual problems, including crossed eyes, cataracts, and
severe visual loss. Dental problems are also common, including missing or peg-shaped
teeth. A related disorder, incontinentia pigmenti achromians, features skin
patterns of light, unpigmented swirls and streaks that are the reverse of IP.
Associated neurological problems are similar.
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The skin abnormalities of IP usually disappear by
adolescence or adulthood without treatment. Diminished vision may be
treated with corrective lenses, medication, or, in severe cases,
surgery. A specialist may treat dental problems. Neurological
symptoms such as seizures, muscle spasms, or mild paralysis may be
controlled with medication and/or medical devices and with the
advice of a neurologist.
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Although the skin abnormalities usually regress,
and sometimes disappear completely, there may be residual
neurological difficulties.
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Xeroderma pigmentosum (pronounced: zer-oder- ma/pig-men-toe-sum),
XP, is a very rare inherited disease that causes extreme sensitivity to the
sun’s ultraviolet rays. Unless patients with XP are protected from sunlight,
their skin and eyes may be severely damaged. This damage may lead to cancers
of the skin and eye. XP has been identified in people of every ethnic group
all over the world.
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Many persons with XP will get an unusually
severe sunburn after a short sun exposure. The
sunburn will last much longer than expected,
perhaps for several weeks. This type of sunburn
will usually occur during a child’s first
sun exposure, and it may be a clue to the diagnosis
of XP. However, some people with XP
will not get a sunburn more easily than others,
and the disease will be undetected until unusual
skin changes appear over time.
Most patients with XP will develop many
freckles at an early age. Continued sun exposure
will lead to further changes in the skin,
including irregular dark spots, thin skin, excessive
dryness, rough-surfaced growths (solar
keratoses), and skin cancers. These skin
changes will resemble those of elderly people
who have spent many years in the sun. In
people with XP, these changes caused by sun
damage often begin in infancy, and almost
always before age 20.
The eyes of a person with XP are often painfully
sensitive to the sun and may easily become
irritated, bloodshot, and clouded. Noncancerous
and cancerous growths on the eyes may occur.
Skin cancers
A series of skin changes leads to the formation
of skin cancers. The first skin cancer may develop
before a person is 10 years old, and many
other skin cancers may continue to form in
the future. Cancers develop most often on the
face and other sun-exposed parts of the body
including the eyes, lips, and tip of the tongue.
All three common types of skin cancer (basal
cell carcinoma, squamous cell carcinoma, and
melanoma) occur much more often in people
with XP. Basal cell and squamous cell carcinomas
usually do not spread to internal organs, but
they do destroy the local skin and underlying
tissues. Melanoma can be fatal if it is not
removed before it has spread to internal organs.
Other medical problems
In addition to skin and eye changes, about 20
percent of XP patients may have one or more
nerve-related problems including the following:
deafness, poor coordination, spastic muscles,
or developmental delay. A few people with
XP will have all of these problems, and some
also may be very short and may not develop
normal sexual characteristics.
Some people with XP will develop only mild
neurological symptoms in late childhood or
adolescence. Whenever neurological problems
do occur, however, they usually tend to worsen
over time.
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Two factors combine to cause the abnormalities
in XP. First, a person inherits traits from each
parent which, when combined, lead to an
unusual sensitivity to the damaging effects of ultraviolet light. Second, exposure to the
sun, which contains ultraviolet light, leads
to changes in the skin and eyes.
Problems with DNA damage and repair
Ultraviolet light damages the DNA in cells
and disrupts normal cell functioning. DNA
(deoxyribonucleic acid) within our genes
contains all the coded information needed
to direct cell functions.
Damaged DNA is mended by the DNA repair
system. But the DNA repair systems of people
with XP do not function properly. As a result,
unrepaired DNA damage builds up and causes
cancerous cell changes or cell death.
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XP can usually be diagnosed in the laboratory
by measuring the DNA repair defect. This test
is performed on skin or blood obtained from
the patient. Soon, only a few cells may be
needed to make this diagnosis.
Different types of XP
There are eight genetic types of XP. Each type
is characterized by a different genetic change
in the DNA repair system. Seven of the eight
types show reduced activity in one DNA repair
system. The eighth form shows reduced activity
in another DNA repair system.
This last type of XP is referred to as the
“variant” form, while the other seven types
are known as groups A, B, C, D, E, F, and G.
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There is no cure for XP, but much can be
done to prevent and treat some of the problems
it causes:
- protection from ultraviolet light
- frequent skin and eye examinations
- prompt removal of cancerous tissue
- neurological examination
- psychosocial care.
Problems from ultraviolet light As soon as the diagnosis of XP is
suspected, a patient should be completely protected from ultraviolet rays.
This will greatly reduce the frequency and severity of skin and eye problems
(including cancers).
There are two types of ultraviolet light: short wavelength and long wavelength.
The main source of harmful, short wavelength ultraviolet light is sunlight.
These ultraviolet rays are also found in the light given off by germicidal
lamps, artificial sunlamps (including those found in tanning booths), and
mercury vapor lamps. Ultraviolet-measuring instruments, if available, may
be used to detect sources of ultraviolet radiation.
The small amount of long wavelength ultraviolet light from sunlight that
has passed through window glass (or produced by unfiltered daylight fluorescent
bulbs) is of less risk but probably should be avoided. Regular incandescent
light bulbs do not give off ultraviolet light.
To limit a person’s exposure to harmful ultraviolet rays, outdoor activity
should be restricted to nighttime.
Damaging ultraviolet radiation from sunlight is most intense at midday.
In some patients, even a few minutes of sun exposure at midday may cause
a severe sunburn. If daytime exposure is unavoidable, it should be limited
to the very early morning or very late afternoon hours—a time of day when
your shadow is much longer than your height.
When XP patients are indoors or in a car, the windows should always be
closed because glass blocks harmful ultraviolet rays from sunlight.
Tips for protecting children
- Children with XP should not play outdoors during the day unless they
are under ultraviolet light-blocking shelters and away from reflective surfaces
such as snow, sand, or water. Clouds do not block out harmful rays.
- Special arrangements for children with XP should be made at school to
ensure that they are not exposed to sunlight from an open window, that they
are not exposed to any unfiltered (bare) fluorescent light bulbs, and that
they are not permitted outside for gym, recess, fire drills, or other activities.
Daily protection outdoors
- When patients with XP are outdoors in daylight, they should wear long
sleeves, long pants, and wide-brimmed hats. Two layers of clothing protect
more than one layer. Tightly woven fabrics generally give more sun protection
than loose weaves. Wear clothing that you can’t see the light through. Some
companies make light-weight clothing specifically designed to provide a
high degree of sun protection.
- Choose eyeglasses or sunglasses specifically labeled to block ultraviolet
light completely. Glasses with side-shields protect the eyelids and skin
around the eyes. Long hair styles help protect the neck and ears.
- While sun protection by clothing is most effective, any skin not covered
by clothing or hair should be protected by sunblocks such as zinc oxide,
titanium dioxide, sunblocking makeup, or sunscreens. Sunscreens with a sun
protection factor of 15 or higher should be used. They should be applied
at least 30 minutes before going out in the sun. Lip moisturizers containing
sun blocking agents also give protection.
- A sunscreen may also be used indoors to protect against unrecognized
sources of ultraviolet light.
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Laboratory tests indicate that sunlight is the major DNA damaging agent
to the cells of XP patients. However, tobacco smoke and some drugs (such
as psoralens, used with ultraviolet light for treating psoriasis) can cause
similar DNA damage. People with XP should avoid exposure to tobacco smoke
and should not use tobacco products because they are probably at greater
risk for developing lung cancer.
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Frequent skin examinations Patients should be examined often by a family
member or another person who has been taught to recognize the signs of skin
cancer.
Any suspicious spot or growth should be immediately reported to the patient's
doctor. Exami-nations should include the eyes, scalp, ears, mouth, tongue,
nostrils, and all other areas of the skin, even those that do not have sun
exposure (for example, the buttocks).
Examination by a dermatologist (a doctor specializing in skin disorders)
should take place at least every 3 to 6 months. The dermatologist can help
detect skin cancers before they have grown or spread to internal organs.
A small piece of suspicious skin growths may be removed (biopsied) and examined
for cancer.
Prompt removal of cancerous tissue
Skin cancer treatment for XP patients is similar to that for anyone with
skin cancer. Treatment may include removal of the cancer by freezing, use
of an electric needle, or surgery. Depending on the size, type, and location
of the cancer, a small cancerous growth can usually be treated in a doctor’s
office. Large tumors may require extensive surgery and skin grafting. Dermabrasion
or removing large portions of skin with grafting has been used for some
patients with extensive involvement. X-ray treatment has also been used
safely. Precancerous growths, such as solar keratoses, may be frozen with
liquid nitrogen.
Other skin treatments
Some patients with XP who have had many skin cancers have prevented new
cancers by taking a drug called isotretinoin, a derivative of vitamin A.
However, this medicine has serious side effects that prevent its use in
all but the most severe cases.
A cream containing a DNA repair enzyme is currently being studied.
Frequent eye examinations
Examination by an ophthalmologist (a doctor specializing in the eye) should
take place regularly. The ophthalmologist can help detect eye cancers and
other lesions before they become a problem.
Artificial tears or soft contact lenses may soothe abnormally dry or irritated
eyes. If the corneas of the eyes become so clouded that the patient cannot
see, a corneal transplant may be considered to restore vision.
Treatment of neurological problems
About 20 percent of patients develop neurological problems. While nothing
can prevent or stop these problems from occurring, it is important to be
aware of them. Early testing and treatment for potential neurological problems
may lessen the unfortunate results of undetected abnormalities.
For example, detection of hearing loss and subsequent use of a hearing
aid may lessen difficulties in communication and in school. Patients with
XP should have a neurological examination (including a hearing test) once
a year through age 20.
The role of sun exposure in the development of neurological problems
Researchers do not believe that sun exposure affects the development of
neurological problems in patients with XP. The sun’s ultraviolet rays are
absorbed by the skin and do not penetrate the brain or other internal organs.
But no matter how small his or her sun exposure, a person with XP who is
genetically prone to develop neurological symptoms will do so. While the
cause of the neurological problems is unclear, it appears that persons with
the most severe reductions in their DNA repair ability are the most likely
to have such problems.
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Persons with XP and their families face many challenges in daily living.
This disease has many long-term physical, emotional, social, and economic
consequences.
Skin changes, including cancers at an early age and other physical problems,
may affect school experiences, employment opportunities, recreational activities,
and social relationships.
Coping with chronic illness and disability is very difficult. Some people
have problems with health insurance or finances while others may feel anxious
or depressed. Persons with XP need a great deal of support from family,
friends, and their communities to provide encouragement, build confidence,
and give hope. Patients with XP and their families may obtain assistance
from their physician, nurse, or social worker.
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Many people with XP will die at an early age from skin cancer if they are
untreated and unprotected from sunlight. However, if a person is diagnosed
early, has no severe neurological problems, is protected from ultraviolet
light, and followed carefully for early cancer detection, a normal life
span is possible. The life spans of most persons with XP will fall between
these extremes. A reduced life span is to be expected, but there are great
differences among patients with XP.
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XP is a recessive condition. This means that a person must have two XP
genes (one from each parent) to develop the disease. Both parents of a person
with XP are carriers of the XP trait because each parent has one XP gene
and one normal gene. Neither parent has symptoms of XP. Recent advances
in understanding XP make it possible to test if someone is a carrier of
some forms of XP by analyzing that person’s DNA.
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There is a one in four chance that any child of the same parents of a patient
with XP will also have XP. XP among affected children in the same family
is usually of similar severity. For example, if the first child with XP
has severe neurological problems, the next affected child may have similar
problems.
Prenatal diagnosis of XP has been done in research laboratories, but it
is not a routine test. Parents of a child with XP should seek genetic counseling
before considering having another child.
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Most people with XP have normal sexual development and functioning, and
they are able to have children. The advisability of a person with XP becoming
a parent would be affected by the person’s own ability to care for a family.
The probability of a person with XP having a child with XP is very small.
This would occur only if the other parent also has XP or is a carrier for
the XP trait. In some cases, carriers of the XP trait can be detected by
a laboratory test of their DNA repair genes.
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Researchers in the United States and throughout the world are learning
about XP and trying to correct the DNA repair defect in laboratorygrown
cells from patients with XP. The genes causing most types of XP have been
identified. Many laboratories in the US, Europe, and Japan are studying
XP genes and trying to understand what they do. Clinical studies on skin
cancer prevention with oral medications and evaluating patients with unusual
features are also being conducted at the National Institutes of Health.
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Laboratory
of Molecular Genetics
National Organization
for Rare Disorders (NORD)
National Eye Institute
(NEI)
National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Age Spots
