Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

Walker-Warburg syndrome

KEY TERMS

Agyri—A lack of convolutions or normal folds in the brain tissue.

Encephalocele—A gap in the skull through which membranes and brain tissue may protrude.

Hydrocephalus—The excess accumulation of cerebrospinal fluid around the brain, often causing enlargement of the head.

Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve.

Retinal dysplasia—Improper development of the retina that can lead to detachment of the retina.

encephalocele may be present as well. Microscopic examination reveals that the cells and tissues of the brain develop in a highly disorganized fashion. Seizures may occur.

Diagnosis

Prenatal ultrasound can reveal some of the brain anomalies associated with WWS, most commonly hydrocephalus and encephalocele. Lissencephaly can not be diagnosed prenatally as normal fetal brains appear smooth. After birth, diagnosis is made on the basis of physical features and ultrasound exams. MRI may be used to confirm the smooth brain feature or type II lissencephaly typical of WWS. Genetic analysis helps distinguish WWS from Fukuyama-type congenital muscular dystrophy (FCMD), which has numerous similar features. WWS can be differentiated from other syndromes that display hydrocephalus or encephalocele by the presence of eye abnormalities including retinal defects, cataracts and anterior chamber defects. Genetic testing for Fukuyama-type congenital muscular dystrophy distinguished this from WWS.

Treatment and management

The severe malformations of the brain defy treatment and many infants with WWS die within the first year of life. Supportive care is required to provide comfort and nursing needs. Seizures may be controlled with medication. Shunting may be required to control the hydrocephalus. A shunt or short plastic tube can be placed to divert the excess cerebral spinal fluid to another area of the body where it can ultimately be absorbed by the body.

Genetic counseling is recommended for families at

risk.

Prognosis

Patients have a very limited life expectancy and the syndrome is generally considered lethal. Most patients die before the age of two.

Resources

BOOKS

Menkes, John H., and Harvey B. Sarnat. Child Neurology. 6th ed. Philadelphia: Lippincott, Williams & Wilkins, 2000.

Volpe, Joseph J. Neurology of the Newborn. 4th ed. Philadelphia: W.B. Saunders, 2001.

PERIODICALS

Gasser, B., et al. “Prenatal Diagnosis of Walker-Warburg Syndrome in Three Sibs.” American Journal of Medical Genetics 76 (March 1998): 107-10.

Hung, N.A., et al. “Gonaddoblastoid Testicular Dysplasia in Walker-Warburg Syndrome.” Pediatric Developmental Pathology 1 (September-October 1998): 393–404.

Vasconcelos, M.M., et al. “Walker-Warburg Syndrome. Report of Two Cases.” Fetal Diagnostic Therapy 14 (July-August 1999): 198–200.

ORGANIZATIONS

Lissencephaly Network, Inc. 716 Autumn Ridge Lane, Fort Wayne, IN 46804-6402. (219) 432-4310. Fax: (219) 4324310. lissennet@lissencephaly.org. http://www

.lissencephaly.org .

National Hydrocephalus Foundation. 12413 Centralia, Lakewood, CA 90715-1623. (562) 402-3523 or (888) 2601789. hydrobrat@earthlink.net. http://www.nhfonline

.org .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. http://www

.rarediseases.org .

WEBSITES

“Fukuyama Congenital Muscular Dystrophy.” OMIM–Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih

.gov/entrez/dispomim.cgi?id=253800 .

“Muscular Dystrophy, Congenital, With Severe Central Nervous System Atrophy and Absence of Large Myelinated Fibers.” OMIM–Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/entrez/ dispomim.cgi?id=601170 .

“Walker-Warburg Syndrome.” OMIM–Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/entrez/ dispomim.cgi?id=236670 .

Julianne Remington

Ward-Romano syndrome see Long-QT syndrome

I Weaver syndrome

Definition

Weaver syndrome is a congenital genetic syndrome associated with rapid growth beginning in the prenatal period as well as with a specific facial appearance and certain skeletal features. It has also been referred to as Weaver-Williams syndrome.

Description

Weaver syndrome was first described by Dr. David Weaver in 1974. A number of different symptoms occur in Weaver syndrome, however, it primarily results in rapid growth beginning in the prenatal period and continuing through the toddler years and into the elementary school years. It is also strongly associated with the bones developing and maturing more quickly (advanced bone age), a distinctive appearing face, and developmental delay. Babies often have a hoarse low-pitched cry.

Genetic profile

Weaver syndrome is for the most part a sporadic condition, meaning that a child affected by it did not inherit it from a parent. In a very few families, autosomal dominant inheritance has been reported, which means that both a parent and his/her child is affected by Weaver syndrome. The cause of Weaver syndrome is not known and the gene(s) that are involved in it have not been identified.

Demographics

Weaver syndrome is rare. About 30 to 50 cases have been published in the medical literature. It occurs in both males and females.

Signs and symptoms

Children with Weaver syndrome tend to have large heads. The faces of children with Weaver syndrome are usually very similar to each other, more so than to other family members, and include a round face, small chin, long philtrum (groove in the midline of the upper lip), large ears, and eyes that are father apart from each other than usual. Other common symptoms include hypertonia (increased muscle tone, tight muscles) as well as hypotonia (decreased muscle tone, “floppy” muscles) and a hoarse low-pitched cry in babies.

The excessive prenatal growth often results in the newborn being large with respect to weight, length and head circumference. The rapid growth continues through

the toddler and youth years with the child’s length and height often being above the 97th percentile, meaning that out of 100 children of the same age, the child is longer/taller than 97 of the children. There is very limited information on the rate of growth through adolescence and on final height, as most of the patients diagnosed with Weaver syndrome who have been reported in the medical literature have been children. In addition, given that the condition was first described 25 years ago, long-term clinical information is just becoming available.

There are a number of other features that have been associated with Weaver syndrome. The child may have difficulty extending elbows and knees completely, fingers and/or toes may be permanently flexed (camptodactyly) or have other problems such as overlapping fingers/toes or clubfoot, and the skin may appear loose. The child may have normal or delayed development; severe mental retardation is rarely seen. Speech may be delayed and when present, may be slurred. A child with Weaver syndrome may also have behavioral problems such as poor concentration, temper tantrums, which may be related to frustrations arising from communication problems, and obsessive and repetitive patterns of play.

Diagnosis

Diagnosis of Weaver syndrome is based solely upon clinical examination, medical history, and x ray data. There are no laboratory tests that can provide a diagnosis. The clinical criteria that are considered to be diagnostic for Weaver syndrome are excessive growth beginning in the prenatal and infancy period, a characteristic facial appearance, advanced bone age with the bones in the wrist being more advanced than other skeletal bones, metaphyseal flaring in the leg bones (the ends of the bone are wider than normal), and developmental delay.

There are many conditions and genetic syndromes that cause excessive growth, consequently, a baby and/or child who has accelerated growth needs to be thoroughly examined by a physician knowledgeable in overgrowth and genetic syndromes. The evaluation includes asking about health problems in the family as well as asking about the growth patterns of the parents and their final height. In some families, growth patterns are different and thus may account for the child’s excessive growth. The child will also undergo a complete physical examination. The child will also be examined in terms of his/her facial appearance with special attention paid to the shape of his/her head, width of the face at the level of the eyes, and appearance of the chin and forehead. Besides measurement of the head circumference, arm

syndrome Weaver

Weissenbacher-Zweymuller syndrome

KEY TERMS

Advanced bone age—The bones, on x ray, appear to be those of an older individual.

Congenital—Refers to a disorder that is present at birth.

Developmental milestones—Infants and toddlers develop skills at certain ages. For example, by nine months, a child should be able to grasp and toss a bottle.

Karyotype—A standard arrangement of photographic or computer-generated images of chromosome pairs from a cell in ascending numerical order, from largest to smallest.

Metaphyseal flaring—A characteristic found only by x rays. If present, it means that the ends of the bone are wider than normal.

length, leg length, and wing span will also be measured. Laboratory testing may also be done. A chromosome analysis (karyotype) may be performed as well as testing for another genetic syndrome called fragile-X syndrome. The patient’s bone age should also be assessed. Bone age is determined by x rays of the hand. It is known that a child’s age can be predicted by the appearance of the wrist bones. In some cases the bones may develop or mature more quickly than normal, or in other words, the child’s wrist bones appear to be those of an older child. This is referred to as advanced bone age. Advanced bone age is present in nearly every child with Weaver syndrome. It does not appear to result in other health problems. If the child begins to lose developmental milestones or appears to stop developing, metabolic testing may be done to evaluate for a metabolic condition called Sanfilippo syndrome. Developmental milestones refer to the skills infants and toddlers acquire as they get older, such as smiling, cooing, grasping toys, rolling over, walking, and talking.

Treatment and management

There is no cure for Weaver syndrome. However, the symptoms that cause problems can be treated and managed. Surgery may be used to correct any skeletal problems such as clubfoot or finger or toe problems. Physical and occupational therapy may help with muscle tone. Speech therapy may help with speech, and behavioral assessments and treatments may help with behavioral problems.

Prognosis

With appropriate treatment and management, children with Weaver syndrome appear to do well. Intellectually, most individuals with Weaver syndrome are normal. Weaver syndrome is not associated with a shortened life span.

Resources

BOOKS

Cole, Trevor R.P., N.R. Dennis, and Helen E. Hughes. “Weaver Syndrome: Seven New Cases and a Review of the Literature.” In Congenital Malformation Syndromes. New York: Chapman and Hall Medical, 1995, pp. 267-280.

ORGANIZATIONS

Sotos Syndrome Support Group. Three Danda Square East #235, Wheaton, IL 60187. (888) 246-SSSA or (708) 6828815 http://www.well.com/user/sssa/ .

Weaver Syndrome Families Support (WSFS). 4357 153rd Ave. SE, Bellevue, WA 98006 (425) 747-5382.

WEBSITES

Genetic and Rare Conditions Site.

http://www.kumc.edu/gec/support/ .

Pediatric Database (PEDBASE).

http://www.icondata.com/health/pedbase/index.htm .

The Family Village.

http://www.familyvillage.wisc.edu/index.htmlx .

Cindy L. Hunter, CGC

Weaver-Williams syndrome see Weaver syndrome

I Weissenbacher-Zweymuller

syndrome

Definition

Weissenbacher-Zweymuller syndrome (WZS) is a genetic form of dwarfism in which affected individuals are born with small, underdeveloped jaws (micrognathia), cleft palate, short arms and legs (rhizomelia), “dumbbell” shaped arm and leg bones, protruding wide spaced eyes (hypertelorism), and incompletely formed back bones (vertebral coronal clefts). Unlike most other forms of dwarfism, individuals affected by Weissebacher-Zweymuller start out being affected by dwarfism, and then have a period of gradual growth and bone change that leads to normal physical development by age 5–6 years.

Description

Weissenbacher-Zweymuller syndrome refers to a rare disorder of small underdeveloped jaws (micrognathia), delayed bone growth, and unusual bone formation first described in 1964 by Weissenbacher and Zweymuller. The formation of bones is delayed because an important structural component of bone called cartilage does not form correctly. Since bone development is delayed, early milestones like walking and physical growth are delayed. Due to cleft palate, many individuals affected by WZS have speech and language delays. In most cases, physical, motor, mental, and academic development is normal by five or six years of age. Alternate names sometimes used for WZS include Pierre Robin syndrome with fetal chondrodysplasia and heterozygous otospondylomegaepiphyseal dysplasia (OSMED).

Genetic profile

Weissenbacher-Zweymuller syndrome appears to be caused by a single change or mutation in a gene called COL11A2 located on the short arm of chromosome 6. The mutation in COL11A2 leads to the incorrect formation of collagen. Since collagen is an important structural part of cartilage and bone, a mutation in COL11A2 leads to the signs and symptoms of WZS. The specific mutation that leads to WZS is inherited in an autosomal recessive pattern. An autosomal recessive condition is caused by the inheritance of two abnormal copies of a gene.

In the 1970s and 1980s there was some confusion among geneticists who were uncertain if WZS is a separate syndrome or part of another genetic syndrome. Although this confusion is not completely resolved, in 1993 an important study compared WZS to other related genetic syndromes and concluded that WZS is a separate genetic disorder that should not be “lumped” into the category of other genetic syndromes like Stickler syndrome. Since that time, a 1998 genetic study found that WZS and another syndrome called otospondylomegaepiphyseal dysplasia (OSMED) appear to be caused by different mutations in the same gene. This finding led the authors to suggest that the term OSMED be used to encompass a broad category that includes WZS as “heterozygous” OSMED while the other syndrome now called OSMED should be called “homozygous” OSMED. Because it has been found that WZS results from both heterozygous and homozygous mutations, researchers have suggested that this disorder follows both autosomal dominant and autosomal recessive inheritance patterns.

Demographics

WZS is a very rare disorder. The ethnic origin of individuals affected by WZS is varied and is not specific to any one country or ethnic population.

Signs and symptoms

Signs and symptoms of Weissenbacher-Zweymuller syndrome include: short arms and legs (rhizomelia), short stature at birth, an underdeveloped jaw (micrognathia), cleft palate, widely spaced eyes (hypertelorism), protruding eyes, a “snub” nose (depressed nasal bridge), dumbbell shaped long leg and arm bones (widening of the metaphyses of long bones), and incompletely formed back bones (coronal cleft of the lumbar vertebrae). The most unique sign of WZS is the gradual improvement of these changes.

Diagnosis

Diagnosis of Weissenbacher-Zweymuller syndrome is usually made from physical examination by a medical geneticist and x rays of the legs, arms, and back. Careful charts of growth and development over time also help with diagnosis. Most characteristic of WZS is the gradual improvement in bone size, growth, and shape.

Prenatal diagnosis of WZS is difficult, but can sometimes be made through a level II ultrasound examination of bone growth in the late second to third trimester of pregnancy. Genetic testing may be available through an amniocentesis procedure if the exact mutations running in the family are known. In 2001, genetic testing is done on a research basis in most cases.

One of the most important aspects in the diagnosis of WZS is ruling out other diagnoses. Conditions can be eliminated based on features that are not seen in WZS or are missing in other syndromes. For example, other conditions that look like WZS usually have progressively worsening symptoms instead of WZS’s characteristic catch-up growth. Additionally, most conditions resembling WZS are inherited in an autosomal dominant pattern through the family. In an autosomal dominant condition, only one copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50/50 chance for each child to have the same or similar condition.

Conditions to rule out in differential diagnosis include:

•Stickler syndrome, in which affected individuals have eye problems and do not have short arms and legs at birth.

syndrome Zweymuller-Weissenbacher

Weissenbacher-Zweymuller syndrome

KEY TERMS

Autosomal dominant—A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Micrognathia—A term used to describe small, underdeveloped lower jaw and chin.

Rhizomelia—A term used to describe the physical growth difference of short arms and legs.

Syndrome—A group of signs and symptoms that collectively characterize a disease or disorder.

•Kniest dysplasia, in which affected individuals do not have a underdeveloped jaw, but they do have eye abnormalities.

•Marshall syndrome, in which affected individuals have hearing and eye abnormalities but do not have short limbs at birth.

•Isolated Pierre-Robin sequence, in which individuals have an underdeveloped jaw and cleft palate alone without short arms and legs.

•Diastrophic dwarfism, in which affected individuals often have club feet, joint contractures, hypermobile thumbs, and non-bulbous bones.

•Metatropic dwarfism, which is characterized by visible changes of the trunk and short limbs as the spine flattens and the bones become progressively deformed.

•Traditional oto-spondylo-megaepiphyseal dysplasia (OSMED), which includes individuals affected by deafness and abnormal growth and development of the spine and growth plates at the end of the long bones (spondyloepiphyseal dysplasia) with large growth plates at the end of the long bones (epiphyses).

In conclusion, it is important to do a thorough and long-term physical examination, a family history, and test for growth, hearing, and eyesight before making a diagnosis of WZS.

Treatment and management

The symptoms of WZS can be treated through fol- low-up and careful evaluation by a pediatric medical geneticist during the first years of life. Especially important to check are eyesight, hearing, and growth. Specific

craniofacial clinics can help individuals affected by cleft palate with surgery, speech, and other related issues. Physical, occupational, speech, and language therapy may be suggested to help reduce “catch-up” time and developmental delays. As with any other disorder that includes developmental delays, specialists providing physical and language therapy can assist in the decision on whether special classes may help an individual child develop academically.

Prognosis

The chance for an individual affected by WZS to have normal physical, motor, mental, and school development by age six or seven is very good. To help in this development, early intervention with physical, occupational, speech, and language therapy and special classes may be helpful. A detailed case report in 1991 notes that the intelligence of children with WZS is generally within normal range, though they may have mild to moderate intellectual delay in the preschool period. The same report notes that physical growth should be normal by age five or six.

Resources

BOOKS

Charles, I., et al. Dwarfism: The Family & Professional Guide.

Short Stature Foundation Press, 1994.

PERIODICALS

Gail, A., et al. “Weissenbacher-Zweymuller Syndrome: Longterm Follow-up of Growth and Psychomotor Development.” Developmental Medicine and Child Neurology 33 (1991): 1101–1109.

Pihlajamaa, T., et al. “Heterozygous Glycine Substitution in the COL11A2 Gene in the Original Patient with Weissenbacher-Zweymuller Syndrome Demonstrates Its Identity with Heterozygous OSMED (Nonocular Stickler Syndrome).” American Journal of Medical Genetics 8 (November 1998): 115–20.

ORGANIZATIONS

Pierre Robin Network. PO Box 3274, Quincy, IL 62305. (217) 224-7480. http://www.pierrerobin.org/index.html .

Stickler Involved People. 15 Angelina, Augusta, KS 67010. (316) 775-2993. http://www.sticklers.org/sip .

WEBSITES

Cleft Palate Foundation. http://www.cleftline.org/ .

Family Village. http://www.familyvillage.wisc.edu/index

.html .

LPA (Little People of America) Online. http://www.lpaonline

.org/ .

Robin, Nathaniel H., and Matthew L. Warman. “Stickler Syndrome.” GeneClinic http://www.geneclinics.org/profiles/ stickler/index.html .

“Weissenbacher-Zweymuller Syndrome.” On-line Mendelian Inheritance in Man http://www.ncbi.nlm.nih.gov/entrez/ dispomim.cgi?id=277610 .

Dawn A. Jacob, MS

I Werner syndrome

Definition

Werner syndrome is a very rare, inherited disease that resembles premature aging. Since the gene responsible was discovered in the mid-1990s, Werner syndrome has greatly interested researchers as a possible model for the study of human aging. It is also being extensively studied for insights it may eventually supply into a number of other diseases including cancer, diabetes mellitus, and atherosclerosis.

Description

This syndrome is named for the German physician C.W. Otto Werner (1879-1936). Werner was a medical student in 1903 when he first observed the syndrome in four siblings, all about 30 years of age. The following year, Werner wrote about these observations in his “Inaugural Dissertation.”

The clinical signs and symptoms of Werner syndrome start to appear during the teen or early adult years, after which patients appear to age rapidly and have a greater-than-usual chance of developing cancer, cardiovascular disease, or diabetes mellitus. By the time the patient is 30–40 years old, he or she has the look of old age. The most common cause of death is heart attack.

While in many ways the signs and symptoms of Werner syndrome resemble those of premature aging (referred to in adults as progeria), there are also some significant differences. For instance, the tumors commonly seen in Werner syndrome patients are commonly derived from the cells of the mesoderm, a middle layer of the embryo that gives rise to a variety of tissues including cartilage, muscle, bone, kidneys, and connective tissue. In normal aging, tumors are more likely to be derived from the epithelial cells that cover the body’s exterior and line most of its hollow structures. Osteoporosis and soft-tissue calcium deposits are found both in Werner syndrome and normal aging, but the distribution of these conditions within the body is different in patients with Werner syndrome. In addition, patients with Werner syndrome do not generally experience symptoms of Alzheimer disease or premature cognitive

KEY TERMS

Atherosclerosis—Hardening of the arteries caused by cholesterol and fat deposits. Increases risk of heart disease, stroke, and other complications.

Progeria—Genetic abnormality that presents initially as premature aging and failure to thrive in children.

Systemic sclerosis—A rare disorder that causes thickening and scarring of multiple organ systems.

decline, as do their aging counterparts in the general population.

Researchers are uncertain whether the symptoms of Werner syndrome are really a speeding-up of normal aging, or whether the many similarities are coincidental. There is nonetheless considerable optimism that further research into Werner syndrome may lead to a better understanding of aging, cancer, diabetes, systemic sclerosis, atherosclerosis, cataracts, and other conditions.

Genetic profile

Werner syndrome results from mutation of a single gene. In 1992, the gene responsible (WRN) was mapped to chromosome 8p11-12. In 1996, a research group based in Seattle cloned the WRN gene. It was also discovered that the syndrome resulted from an autosomal recessive mutation that affects a member of a family of enzymes known as helicases that unwind deoxyribonucleic acid (DNA) and, in some cases, ribonucleic acid (RNA).

Despite the discovery that Werner syndrome is caused by a genetic defect, researchers are unable to explain exactly how this defect causes the disease. The purpose of helicases in the body is not fully understood, but they are known to unwind DNA, splitting the doublestranded molecules into separate single-stranded molecules. In this way, the enzymes are involved in the repair, recombination, replication, and transcription of DNA. There appear to be many damaged sites in DNA taken from patients with Werner syndrome. It has therefore been suggested that Werner syndrome may be caused by failure in these DNA-related processes, and that the somatic cells of those with Werner syndrome may be particularly prone to mutations.

The WRN gene is not known to bind to DNA damage, but recent research has suggested it might be able to sense the presence of damaged DNA. Since the discovery of the WRN gene, more than 10 mutations have been

syndrome Werner

Werner syndrome

Individuals with Werner syndrome often have skin abnormalities and may develop severe ulcerations, such as that seen on this foot. (Custom Medical Stock Photo, Inc.)

uncovered. Many of these mutations were in the Japanese population. It has been suggested that the relatively high incidence of Werner syndrome in that country may be related to traditions of marriages between closely related individuals in some areas of Japan.

As of 2001, researchers were seeking an animal model to allow them to further study Werner syndrome. Specifically, they hoped to create mice with a genetic equivalent of the WRN gene, and to determine whether these mice would age more quickly than normal mice.

Demographics

Because of the limited number of cases, the demographic distribution of Werner syndrome is difficult to determine. Estimates of the number of people affected range from one in 95,000 to one in 1,000,000 people. Unlike progeria, which can be diagnosed at birth or soon after, Werner syndrome is not usually detected prior to adolescence. It is commonly noticed only after patients have failed to undergo the normal growth spurt associated with their teen years. The full range of symptoms is not usually seen until patients reach their 20s or 30s. Werner syndrome is more common in families in which a close biological relationship exists between parents. It occurs equally in both sexes. There is no evidence of a birth-order effect.

Signs and symptoms

The cardinal signs and symptoms of Werner syndrome start to appear after the age of 10. They are:

•Cataracts. These occur in both eyes, and usually develop by age 25 or 30.

•Skin problems including tight, shiny, smooth skin, ulceration, general wasting of the skin and localized

wasting of the subcutaneous area underneath it, pigmentary changes, a thickening of the horny outer layer of the skin, and a characteristic bird-like facial appearance, including a beaked or pinched nose and unusually prominent eyes.

•Shortness of stature.

•An affected sibling or a close biological relationship between parents (3rd cousin or closer).

•Earlier-than-usual graying and/or thinning of scalp hair, usually by age 20.

•Excess amounts of hyaluronic acid (more commonly found in the body’s connective tissues and in the fluids of the eyes and joints) in the urine.

Additional signs and symptoms of Werner syndrome include the following:

•Diabetes mellitus. This is usually mild, but can be found in between 44% and 67% of Werner syndrome patients.

•Impaired function of the ovaries or testes, as indicated by small or poorly developed genitalia or reduced fertility.

•Osteoporosis, most commonly in the upper limbs and spine, as well as in the lower limbs, feet, and ankles. In patients with Werner syndrome, osteoporosis is unlikely to be found in the skull or the torso.

•Unusually high bone density in the extremities of the finger and toe bones. This must be established by an x- ray examination.

•Deposits of calcium salts in soft tissues of the body. Common locations are around the Achilles tendon and the tendons of the elbow and the knee.

•Evidence pointing to earlier-than-usual arterial disease, such as a prior heart attack or abnormal electrocardiograms, etc.

•Rare or multiple tumors, or tumors derived from the mesoderm, the middle layer of the embryo. Werner syndrome is not marked by increased occurrence of all forms of tumors, but by selectively higher proportions of certain cancers that are relatively rare.

•Changes to the voice, rendering it squeaky, hoarse, or high-pitched.

•Flat feet.

In addition to the above signs and symptoms used for formal diagnostic purposes, other clinical observations have been reported, including loss of eyelashes and eyebrow hair, nail deformities, as well as the presence of thin limbs with a stocky trunk. A possible link to lung cancer has also been proposed.

In some cases, Werner syndrome can occur in a slower and milder partial form, with only some of the symptoms present.

Diagnosis

A definite diagnosis of Werner syndrome is established by the presence of all of the cardinal signs and symptoms listed above, plus at least two of the additional signs and symptoms.

A probable diagnosis is indicated by the presence of all of the first three cardinal signs, plus any two from the additional list.

A possible diagnosis is suggested by the presence of either cataracts or the skin manifestations, plus any four of the other signs or symptoms.

Werner syndrome may be ruled out if the above signs and symptoms appear prior to adolescence. The exception to this rule is shortness of stature, because patterns of pre-adolescent growth are not sufficiently understood.

Diagnosis may involve x rays to study hormone excretion, skin biopsies, and a blood-sugar test to determine whether diabetes mellitus is present. Werner syndrome can also be diagnosed by mutational analysis of the WRN gene.

Treatment and management

There is no known cure for Werner syndrome, so treatment is related to the specific symptoms present. For example, cataracts can be corrected by surgery and skin ulcers can be treated with grafts.

Prognosis

Because it mimics the human aging process, Werner syndrome significantly reduces life expectancy in most patients. Average life expectancy for a Werner symptom patient is somewhere between 40 and 47 years. The most common causes of death are heart attacks, cerebrovascular accidents, and cancers.

Resources

BOOKS

Thoene, Jess G., ed. Physicians’ Guide to Rare Diseases. 2nd ed. Montvale, NJ: Dowden Publishing Company Inc., 1995.

ORGANIZATIONS

International Progeria Registry. IBR Dept. of Human Genetics, 1050 Forest Hill Rd., Staten Island, NY 10314. (718) 4945333. wtbibr@aol.com.

David L. Helwig

Whistling face syndrome see Freeman-

Sheldon syndrome

I Williams syndrome

Definition

Williams syndrome is a genetic disorder caused by a deletion of a series of genes on chromosome 7q11. Individuals with Williams syndrome have distinctive facial features, mild mental retardation, heart and blood vessel problems, short stature, unique personality traits, and distinct learning abilities and deficits.

Description

Williams syndrome, also known as Williams Beuren syndrome, was first described in 1961 by Dr. J.C.P. Williams of New Zealand. At that time it was noted that individuals with Williams syndrome had an unusual constellation of physical and mental findings. The physical features include a characteristic facial appearance, heart and cardiovascular problems, high blood calcium levels, low birth weight, short stature, and other connective tissue abnormalities. The intellectual problems associated with Williams include a mild mental retardation and a specific cognitive profile. That is, individuals with Williams syndrome often have the same pattern of learning abilities and disabilities, as well as many similar personality traits.

The findings in Williams syndrome are variable— that is, not all individuals with Williams syndrome will have all of the described findings. In addition to being variable, the physical and mental findings associated with Williams syndrome are progressive—they change over time.

Genetic profile

Williams syndrome is a genetic disorder due to a deletion of chromosome material on the long arm of

Williams syndrome

KEY TERMS

de novo deletion—A deletion that occurs for the first time in the affected individual. The cause of de novo deletions is not known.

Hypercalcemia—High levels of calcium in the blood.

Stellate—A star-like, lacy white pattern in the iris. Most often seen in light-eyed individuals.

chromosome 7. A series of genes are located in this region. Individuals with Williams syndrome may have some or all of these genes deleted. Because of this, Williams syndrome is referred to as a contiguous gene deletion syndrome. Contiguous refers to the fact that these genes are arranged next to each other. The size of the deletion can be large or small, which may explain why some individuals with Williams syndrome are more severely affected than others. If you think of these genes as the letters of the alphabet, some individuals with Williams syndrome are missing A to M, some are missing G to Q and others are missing A to R. While there are differences in the amount of genetic material that can be deleted, there is a region of overlap. Everyone in the above example was missing G to M. It is thought that the missing genes in this region are important causes of the physical and mental findings of Williams syndrome.

Two genes in particular, ELN and LIMK1, have been shown to be important in causing some of the characteristic symptoms of Williams syndrome. The ELN gene codes for a protein called elastin. The job of elastin in the human body is to provide elasticity to the connective tissues such as those in the arteries, joints, and tendons. The exact role of the LIMK1 gene is not known. The gene codes for a substance known as lim kinase 1 that is active in the brain. It is thought that the deletion of the LIMK1 gene may be responsible for the visuospatial learning difficulties of individuals with Williams syndrome. Many other genes are known to be in the deleted region of chromosome 7q11 responsible for Williams syndrome and much work is being done to determine the role of these genes in Williams syndrome.

Williams syndrome is an autosomal dominant disorder. Genes always come in pairs and in an autosomal dominant disorder, only one gene need be missing or altered for an individual to have the disorder. Although Williams syndrome is an autosomal disorder, most individuals with Williams syndrome are the only people in

their family with this disorder. When this is the case, the chromosome deletion that causes Williams syndrome is called de novo. A de novo deletion is one that occurs for the first time in the affected individual. The cause of de novo chromosome deletions is unknown. Parents of an individual with Williams syndrome due to a de novo deletion are very unlikely to have a second child with William syndrome. However, once an individual has a chromosome deletion, there is a 50% chance that he or she will pass it on to their offspring. Thus individuals with Williams syndrome have a 50% chance of passing this deletion (and Williams syndrome) to their children.

Demographics

Williams syndrome occurs in 1 in 20,000 births. Because Williams syndrome is an autosomal dominant disorder, it affects an equal number of males and females. It is thought that Williams syndrome occurs in people of all ethnic backgrounds equally.

Signs and symptoms

Williams syndrome is a multi-system disorder. In addition to distinct facial features, individuals with Williams syndrome can have cardiovascular, growth, joint, and other physical problems. They also share unique personality traits and have intellectual differences.

Infants with Williams syndrome are often born small for their family and 70% are diagnosed with failure to thrive during infancy. These growth problems continue throughout the life of a person with Williams syndrome and most individuals with Williams syndrome have short stature (height below the third percentile). Infants with William syndrome can also be extremely irritable and have “colic-like” behavior. This behavior is thought to be due to excess calcium in the blood (hypercalcemia). Other problems that can occur in the first years include strabismus (crossed eyes), ear infections, chronic constipation, and eating problems.

Individuals with Williams syndrome can have distinct facial features sometimes described as “elfin” or “pixie-like.” While none of these individual facial features are abnormal, the combination of the different features is common for Williams syndrome. Individuals with Williams syndrome have a small upturned nose, a small chin, long upper lip with a wide mouth, small widely spaced teeth, and puffiness around the eyes. As an individual gets older, these facial features become more pronounced.

People with Williams syndrome often have problems with narrowing of their heart and blood vessels. This is

thought to be due to the deletion of the elastin gene and is called elastin arteriopathy. Any artery in the body can be affected, but the most common narrowing is seen in the aorta of the heart. This condition is called supravalvar aortic stenosis (SVAS) and occurs in approximately 75% of individuals with Williams syndrome. The degree of narrowing is variable. If left untreated, it can lead to high blood pressure, heart disease, and heart failure. The blood vessels that lead to the kidney and other organs can also be affected.

Deletions of the elastin gene are also thought to be responsible for the loose joints of some children with Williams syndrome. As individuals with Williams syndrome age, their heel cords and hamstrings tend to tighten, which can lead to a stiff awkward gait and curving of the spine.

Approximately 75% of individuals with Williams syndrome have mild mental retardation. They also have a unique cognitive profile (unique learning abilities and disabilities). This cognitive profile is independent of their IQ. Individuals with Williams syndrome generally have excellent language and memorization skills. They can have extensive vocabularies and may develop a thorough knowledge of a topic that they are interested in. Many individuals are also gifted musicians. Individuals with Williams syndrome have trouble with concepts that rely on visuospatial ability. Because of this, many people with Williams syndrome have trouble with math, writing and drawing.

People with Williams syndrome also often share personality characteristics. They are noted to be very talkative and friendly—sometimes inappropriately—and they can be hyperactive. Another shared personality trait is a generalized anxiety.

Diagnosis

The diagnosis of Williams syndrome is usually made by a physician familiar with Williams syndrome and based upon a physical examination of the individual and a review of his or her medical history. It is often made in infants after a heart problem (usually SVAS) is diagnosed. In children without significant heart problems, the diagnosis may be made after enrollment in school when they are noted to be “slow learners.”

While a diagnosis can be made based upon physical examination and medical history, the diagnosis can now be confirmed by a DNA test.

Williams syndrome is caused by a deletion of genetic material from the long arm of chromosome 7. A specific technique called fluorescent in situ hybridization testing, or FISH testing, can determine whether there is

genetic material missing. A FISH test will be positive (detect a deletion) in over 99% of individuals with Williams syndrome. A negative FISH test for Williams syndrome means that no genetic material is missing from the critical region on chromosome 7q11.

Prenatal testing (testing during pregnancy) for Williams syndrome is possible using the FISH test on DNA sample obtained by chorionic villus sampling (CVS) or by amniocentesis. Chorionic villus sampling is a prenatal test that is usually done between 10 and 12 weeks of pregnancy and involves removing a small amount of tissue from the placenta. Amniocentesis is a prenatal test that is usually performed at 16–18 weeks of pregnancy and involves removing a small amount of the amniotic fluid that surrounds the fetus. DNA is obtained from these samples and tested to see if the deletion responsible for Williams syndrome is present. While prenatal testing is possible, it is not routinely performed. Typically, the test is only done if there is a family history of Williams syndrome.

Treatment and management

Because Williams syndrome is a multi-system disorder, the expertise of a number of specialists is required for management of this disorder.

The height and growth of individuals with Williams syndrome should be monitored using special growth curves developed specifically for individuals with Williams syndrome. Individuals who fall off these growth curves should be worked up for possible eating or thyroid disorders.

A cardiologist should evaluate individuals with Williams syndrome yearly. This examination should include measurement of blood pressure in all four limbs and an echocardiogram of the heart. An echocardiogram is a special form of ultrasound that looks at the structure of the heart. Doppler flow studies, which look at how the blood flows into and out of the heart, should also be done. Individuals with supravalvar stenosis may require surgery to fix this condition. The high blood pressure caused by this condition may be treated with medication. Examinations should take place yearly as some of these conditions are progressive and may worsen over time.

Individuals with Williams syndrome should also have a complete neurological examination. In addition, the blood calcium levels of individuals with Williams syndrome should be monitored every two years. High levels of calcium can cause irritability, vomiting, constipations and muscle cramps. An individual found to have a high level of calcium should consult a nutritionist to make sure that their intake of calcium is not higher than 100% of the recommended daily allowance (RDA).

syndrome Williams