Genetic mutations: Werner Syndrome
Werner Syndrome may also be characterized by development of a
distinctive high-pitched voice; eye abnormalities, including premature clouding
of the lenses of the eyes (bilateral senile cataracts); and certain endocrine
defects, such as impaired functioning of the ovaries in females or testes in
males (hypogonadism) or abnormal production of the hormone insulin by the
pancreas and resistance to the effects of insulin (non-insulin-dependent
diabetes mellitus). In addition, individuals with Werner syndrome may develop
progressive thickening and loss of elasticity of artery walls
(arteriosclerosis). Affected blood vessels typically include the arteries that
transport oxygen-rich (oxygenated) blood to heart muscle (coronary arteries).
Some affected individuals may also be susceptible to developing certain benign
(noncancerous) or malignant tumors. Progressive arteriosclerosis, malignancies,
and/or associated abnormalities may result in potentially life-threatening
complications by approximately the fourth or fifth decade of life. Werner
syndrome is inherited as an autosomal recessive trait.
Children with Werner Syndrome often appear
unusually thin and, during late childhood, have an unusually slow growth rate.
In addition, there is absence of the growth spurt typically seen during
adolescence. Affected individuals typically reach their final height by
approximately 13 years of age. However, adult height may be reached as early as
at age 10 or as late as at age 18. Weight is also unusually low, even relative
to short stature.
Before age 20, most individuals with Werner
Syndrome develop early graying and whitening of the scalp hair (canities). By
about 25 years of age, affected individuals may experience premature loss of
scalp hair (alopecia) as well as loss of the eyebrows and eyelashes. In
addition, hair under the arms (axillary hair), in the pubic area, and on the
trunk may be unusually sparse or absent. According to reports in the medical
literature, the hair loss seen in those with Werner Syndrome may occur
secondary to impaired functioning of the ovaries in females or the testes in
males (hypogonadism), an endocrine condition associated with deficient growth
and sexual development. Both males and females with Werner Syndrome may be
affected by hypogonadism. As a result, affected males usually have an unusually
small penis and small testes. Some females with the disorder may fail to
develop secondary sexual characteristics (e.g., appearance of axillary and
pubic hair, breast development, menstruation) and have poorly developed
genitals. In other affected females, menstruation may be spare and irregular.
Due to hypogonadism, most of those with the disorder may be infertile. However,
there have been reports in the literature confirming that some affected males
and females have reproduced.
Individuals with the disorder develop an
abnormally high-pitched voice. In other cases, the voice may be squeaky or
unusually hoarse.
By approximately 25 years of age, individuals
with Werner Syndrome also develop progressive skin changes, particularly
affecting the facial area, the upper arms and hands, and the lower legs and
feet (distal extremities).
Werner Syndrome is transmitted as an
autosomal recessive 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.
In recessive disorders, the condition does
not appear unless a person inherits the same defective gene for the same trait
from each parent. If an individual receives one normal gene and one gene for
the disease, the person will be a carrier for the disease, but usually will not
show symptoms. The risk of transmitting the disease to the children of a
couple, both of whom are carriers for a recessive disorder, is 25 percent.
Fifty percent of their children risk being carriers of the disease, but
generally will not show symptoms of the disorder. Twenty-five percent of their
children may receive both normal genes, one from each parent, and will be genetically
normal (for that particular trait). The risk is the same for each pregnancy.
The parents of some individuals with Werner
Syndrome have been closely related by blood (consanguineous). In these cases,
if both parents carry the same disease gene, there is a higher-than-normal risk
that their children may inherit the two disease genes necessary for the
development of the disease.
Researchers have determined that Werner
Syndrome is caused by abnormal changes (mutations) of a gene (known as the WRN
gene) located on the short arm of chromosome 8 (8p12-11.2).* More than 80
different mutations of the WRN gene have been identified in individuals with
the disorder.
Werner Syndrome is a rare disorder that affects males and females in
equal numbers. Since the disorder was originally described in the medical
literature in 1904 (O. Werner), more than 500 cases have been reported. The
disorder’s frequency has been estimated at one to 20 per one million
individuals in the United States. Although certain associated findings are
present beginning during childhood, puberty, and young adulthood, the disorder
is most frequently recognized in the third or fourth decades of life.
Symptoms of the following disorders can be
similar to those of Werner Syndrome. Comparisons may be useful for a
differential diagnosis:
Hutchinson-Gilford Progeria Syndrome is a
very rare disorder of childhood characterized by premature aging, short
stature, and characteristic facial features. The primary symptoms of this
disorder are those associated with the aging process. Children with this
disease age very rapidly and suffer with disorders of the aged while they are
young. At approximately 10 years of age, most children with Hutchinson-Gilford
Progeria Syndrome attain the height of an average 3 year old child. Arthritis
often effects bone joints during childhood and adolescence. (For more
information on this disorder, choose “Hutchinson-Gilford Progeria” as your
search term in the Rare Disease Database.)
In some cases, Werner Syndrome may be
recognized clinically as early as approximately age 15, based upon a thorough
clinical evaluation, characteristic physical findings (e.g., absence of growth
spurt at puberty, short stature, low weight), and a careful patient and family
history. However, the disorder often may not be recognized or confirmed until
the third or fourth decades of life, once certain distinctive symptoms and
findings are noted
Diagnostic testing may include monitoring of
blood sugar levels to ensure prompt detection of diabetes mellitus, bone scans
and blood tests for osteoporosis, and/or other studies. In addition, thorough
cardiac evaluations and ongoing monitoring may also be performed (e.g.,
clinical examinations, X-ray studies, specialized cardiac tests) to assess associated
cardiovascular abnormalities and determine appropriate disease management.
Individuals with Werner Syndrome should also be regularly monitored as
necessary to ensure the prompt detection and appropriate treatment of certain
malignancies or benign tumors that may occur in association with the disorder
(e.g., osteosarcoma, meningioma).
bibliography:
Junko Oshima, Ph.D,George M. Martin, M.D.. (2015). Werner Syndrome. 26/11/15, de NORD Sitio web: https://rarediseases.org/rare-diseases/werner-syndrome
TEXTBOOKS
Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th Ed: David L. Rimoin, Reed E. Pyeritz and Bruce Korf, Editors; Elsevier B.V., 2013, Pages 1-19.
Cecil Textbook of Medicine, 24th Ed.: Lee Goldman, Editor; W.B. Saunders Co., 2012. Pp.1340-1346.
Smith’s Recognizable Patterns of Human Malformation, 7th Ed.; Kenneth Lyons Jones, Marilyn Crandall Jones and Miguel Del Campo, Editors; W. B. Saunders Co., 2013. Pp. 188-201.
Syndromes of the Head and Neck, 5th Ed.: Raoul Hennekam, Judith Allanson, Ian Krantz, Editors; Oxford University Press, 2010. Pp. 586-590.
The treatment of Werner Syndrome is directed
toward the specific symptoms that are apparent in each individual. Disorder
management may require the coordinated efforts of a team of specialists who may
need to systematically and comprehensively plan an affected individual’s
treatment. Such specialists may include internists; physicians who diagnose and
treat disorders of the skeleton, muscles, joints, and other related tissues
(orthopedists); physicians who diagnose and treat abnormalities of the heart
and its major blood vessels; eye specialists (ophthalmologists); physicians who
diagnose and treat disorders of the endocrine system (endocrinologists); and/or
other health care professionals. Specific therapies for individuals with
Werner Syndrome are symptomatic and supportive. According to reports in the
medical literature, diabetes mellitus is typically mild and may often be
managed with dietary changes and appropriate medications by mouth to decrease
elevated sugar (glucose) levels in the blood (oral hypoglycemic medications).
bibliography:
Junko Oshima, Ph.D,George M. Martin, M.D.. (2015). Werner Syndrome. 26/11/15, de NORD Sitio web: https://rarediseases.org/rare-diseases/werner-syndrome
TEXTBOOKS
Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th Ed: David L. Rimoin, Reed E. Pyeritz and Bruce Korf, Editors; Elsevier B.V., 2013, Pages 1-19.
Cecil Textbook of Medicine, 24th Ed.: Lee Goldman, Editor; W.B. Saunders Co., 2012. Pp.1340-1346.
Smith’s Recognizable Patterns of Human Malformation, 7th Ed.; Kenneth Lyons Jones, Marilyn Crandall Jones and Miguel Del Campo, Editors; W. B. Saunders Co., 2013. Pp. 188-201.
Syndromes of the Head and Neck, 5th Ed.: Raoul Hennekam, Judith Allanson, Ian Krantz, Editors; Oxford University Press, 2010. Pp. 586-590.
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