WAGR Syndrome/11p Deletion Syndrome
NORD is very grateful to Kelly Trout, RN, BSN, Health Consultant, International WAGR Syndrome/11p Deletion Syndrome Association, for assistance in the preparation of this report.
Synonyms of WAGR Syndrome/11p Deletion Syndrome
- chromosome 11p deletion syndrome
- WAGR complex
- AGR triad
- aniridia-ambiguous genitalia-mental retardation
- aniridia-Wilms' tumor association
- aniridia-Wilms' tumor-gonadoblastoma
WAGR syndrome/11p deletion syndrome is a rare genetic syndrome in which there is a predisposition to several conditions, including certain malignancies, distinctive eye abnormalities, and/or intellectual disability. "WAGR" is an acronym for the characteristic abnormalities associated with the syndrome. The acronym stands for (W)ilms' Tumor, the most common form of kidney cancer in children; (A)niridia, partial or complete absence of the colored region of the eye(s) (iris or irides); (G) Genitourinary abnormalities, such as undescended testicles or hypospadias in males, or internal genital or urinary anomalies in females; and Mental (R)etardation (intellectual disability). A combination of two or more of these conditions is usually present in most individuals with WAGR syndrome/11p deletion syndrome. The clinical picture varies, depending upon the combination of associated abnormalities.
WAGR syndrome/11p deletion syndrome is caused by defects (mutations) of adjacent genes on a region of chromosome 11 (11p13). In most cases, such genetic changes (e.g., deletions at band 11p13) occur spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). In very rare cases, the mutation may be inherited as the result of a rearrangement of parts of two chromosomes, which causes the loss of some genetic material (translocation) or other heritable genetic abnormality. The presence of more than one type of chromosomal makeup within an individual (mosaic deletion) resulting in WAGR syndrome/11p deletion syndrome has also been reported.
Since 1964, the names given to this disorder have changed frequently as variations in the combination of clinical symptoms present and the range of genetic abnormalities associated with it have been discovered. The term "WAGR syndrome" is now being replaced by "11p deletion syndrome" to more accurately reflect current knowledge about the disorder and to allow for consistent clinical diagnosis and genetic classification in the future.
WAGR syndrome/11p deletion syndrome is defined as a genetic syndrome in which there is a predisposition to Wilms' tumor; aniridia; abnormalities of the reproductive and urinary tracts (genitourinary); and intellectual disability. The specific symptoms that occur depend upon the combination of disorders present.
Wilms' tumor (nephroblastoma) is the most common form of kidney cancer in early childhood. It occurs in approximately one half of all cases of WAGR syndrome/11p deletion syndrome. In the early stages of Wilms' tumor, there are usually no symptoms. The first signs of the disease may include blood in the urine (hematuria), low-grade fever, loss of appetite, paleness, weight loss, fatigue and lack of energy (lethargy), and swelling of the abdomen. In the later stages, slight pain may occur at intervals (intermittent), or pain may be sudden and sharp. (For more information on this disorder, choose "Wilms' tumor" as your search term in the Rare Disease Database.) Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests) are not uncommon in children with WAGR syndrome/11p deletion syndrome. This tissue is noticeable on ultrasound examination, and is sometimes difficult to distinguish from Wilms' tumor. It is thought that nephrogenic rests, or clusters of rests (nephroblastomatosis), may give rise to Wilms' tumor in some cases.
In infants with aniridia that is associated with WAGR syndrome/11p deletion syndrome, the irises fail to develop normally before birth (prenatally). This results in the partial or complete absence of the round, colored (pigmented) portion of the eye (iris). Aniridia is almost always present in individuals with WAGR syndrome/11p deletion syndrome; however, at least four cases of WAGR syndrome/11p deletion syndrome have been confirmed without aniridia. In almost all cases, aniridia occurs in combination with other disorders of the eye. These accompanying disorders may include clouding of the lens of the eye (cataract); rapid, involuntary movements of the eye (nystagmus); and/or partial or complete loss of vision due to abnormally high pressure of the fluid in the eye (glaucoma). Progressive scarring and opacity of the cornea (aniridic keratopathy, also called corneal pannus) is common in adolescents and adults with aniridia, but may also occur in children. (For more information on these disorders, choose "Aniridia" and "Cataracts" as your search terms in the Rare Disease Database.)
In the medical literature, the "G" in the acronym WAGR refers to "Genitourinary abnormalities," "ambiguous Genitalia," or "Gonadoblastoma." Gonadoblastoma, a cancer of the cells that form the testes in males or the ovaries in females (gonads), occurs exclusively in people with defective development of the gonads (gonadal dysgenesis), as is the case in some infants with WAGR syndrome/11p deletion syndrome. Although gonadoblastoma is not always manifested in WAGR syndrome/11p deletion syndrome, it is important to be aware of the genetic predisposition for this potentially serious disorder so that appropriate steps can be taken. (See the "Standard Therapies" section of this report for more information.)
Other abnormalities of the reproductive and urinary tracts (genitourinary) may be present in many children with WAGR syndrome/11p deletion syndrome. In males, these may include the failure of one or both testes to descend into the scrotum (cryptorchidism) and placement of the urinary opening (meatus) on the underside of the penis (hypospadias). In females, these abnormalities may include underdeveloped (streak) ovaries, and malformations of the uterus, fallopian tubes, or vagina. These abnormalities may also include duplicate ureters or horseshoe kidney.
In addition, individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism).
Intellectual disability is common in children with WAGR syndrome/11p deletion syndrome. However, the severity of the impairment varies greatly from case to case, ranging from severe to mild intellectual disability (IQ of 20 to 70) ). Some children with WAGR syndrome/11p deletion syndrome may have normal intelligence (IQ at or above 100).
A variety of behavioral and psychiatric disorders have been reported in WAGR syndrome/11p deletion syndrome. These include autism spectrum disorders, attention-deficit disorder (with or without hyperactivity), obsessive-compulsive disorder, other anxiety disorders, and depression.
Although hearing is usually normal in people with WAGR syndrome/11p deletion syndrome, many individuals have difficulty with the way the brain processes auditory information, particularly with recognizing and interpreting the sounds involved with speech (auditory processing disorder).
Metabolic abnormalities present in some individuals with WAGR syndrome/11p deletion syndrome may include early-onset overweight (obesity), and high serum cholesterol (hyperlipidemia). Some individuals with WAGR syndrome/11p deletion syndrome have a combination of conditions including insulin resistance, high blood pressure, and high serum cholesterol which can increase the risk for coronary artery disease, stroke, and type 2 diabetes (metabolic syndrome).
Chronic kidney failure occurs in approximately 60% of individuals with WAGR syndrome/11p deletion syndrome, most often after age 12. This failure is usually the result of Focal Segmental Glomerulosclerosis (FSGS) a disorder which results in scarring of the filtering tubes of the kidneys. Chronic kidney failure may occur in an individual with WAGR syndrome/11p deletion syndrome regardless of their history of Wilms tumor.
Frequent, recurrent upper respiratory infections, ear and sinus infections, asthma, and pneumonia are common in WAGR syndrome/11p deletion syndrome, particularly in young children with the disorder. Delayed loss of primary teeth and severely crowded or uneven teeth (dental malocclusion) are also common. A temporary suspension of breathing occurring repeatedly during sleep (sleep apnea) may occur in both children and adults with WAGR syndrome/11p deletion syndrome.
Abnormalities of muscle tone or strength (hypertonia/hypotonia) are common in WAGR syndrome/11p deletion syndrome, particularly during infancy and early childhood. Seizure disorder (epilepsy) has been reported frequently and chronic inflammation of the pancreas (pancreatitis) has also been reported.
In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may be present at birth (congenital) may include: defects of the heart or kidneys, partial or complete absence of the structure which connects the two hemispheres of the brain (agenesis of the corpus callosum) a weak area of the abdomen which allows part of the intestines to push through (inguinal hernia) an abnormal opening in the diaphragm which allows part of the abdominal organs to migrate into the chest cavity (diaphragmatic hernia) extra fingers or toes (polydactyly) webbing or fusing of fingers or toes (syndactyly) absence or closure of ducts which drain bile from the liver (biliary atresia) weakness or floppiness of the walls of the windpipe (tracheomalacia) and hearing impairment.
In rare cases, other symptoms of WAGR syndrome/11p deletion syndrome which may develop or be diagnosed after birth may include: an abnormal enlargement of a part of the body (hemihypertrophy), growth retardation, communication disorders, inability of the brain to integrate information received from the body's five sensory systems (sensory integration disorder) feeding/swallowing disorders, gastroesophageal reflux, multiple bony lumps or spurs on the bones (multiple exostoses) and curvature of the spine (scoliosis).
The disorders most commonly associated with WAGR syndrome/11p deletion syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and intellectual disability) as well as those listed above may appear together or in a variety of combinations. In the medical literature, these various groupings (disorder subdivisions) have been referred to as distinct disorders including "Aniridia-Wilms' Tumor Association" (AWTA); "Aniridia-ambiguous Genitalia-mental Retardation" (AGR triad); or "Aniridia- Wilms' Tumor-Gonadoblastoma." While all individuals with WAGR syndrome/11p deletion syndrome will be found to have deletions in chromosome 11p13, great variation in the size and nature of these deletions is possible among individuals. These variations in missing genetic material are thought to account for the differences in symptoms and manifestations of the disorder.
WAGR syndrome/11p deletion syndrome is known as a "contiguous gene syndrome", meaning that it is caused by defects (mutations) of adjacent genes on a particular chromosome. In many affected individuals, the syndrome is thought to result from deletion of one copy of chromosome 11 at band p13 (monosomy). Chromosomes are found in the nucleus of all body cells. They 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 bands that are numbered.
In most individuals with WAGR syndrome/11p deletion syndrome, deletion of the short arm of chromosome 11 at band p13 occurs spontaneously during early embryonic development (de novo) for unknown reasons (sporadic). The size and nature of the chromosomal deletion and the specific genes affected determine the symptoms and findings associated with the disorder. For example, deletions (or other defects) of certain adjacent genes within the 11p13 chromosomal region are thought to result in Wilms' tumor (WT1 gene), aniridia (PAX6 gene), and possibly mental retardation. In addition, some researchers suggest that another gene closely located to the WT1 gene (designated as the GUD gene for genital dysplasia) may result in abnormalities of genitourinary development. However, others indicate that the genitourinary abnormalities seen in WAGR syndrome/11p deletion syndrome may actually be caused by deletion or other defects of the Wilms' Tumor (WT1) gene, suggesting that WT1 gene mutations may be manifested in more than one way (pleiotropy).
Some documented cases of WAGR syndrome/11p deletion syndrome have been caused by complex chromosomal rearrangements that occur sporadically during early embryonic development (de novo). In these rearrangements, segments of chromosome 11 may break off and move to another chromosomal location. Many researchers believe that, in many WAGR syndrome/11p deletion syndrome cases caused by de novo rearrangements, parts of chromosomes other than chromosome 11 may have also switched locations.
In a few documented cases of WAGR syndrome/11p deletion syndrome, one of the parents has a balanced translocation or other chromosomal abnormality. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. Because a person with a balanced translocation has all the necessary genetic material for normal development, balanced translocations usually do not affect the carrier. However, they are associated with a higher risk of abnormal chromosomal development in the carrier's offspring. Mosaic deletions, in which more than one type of chromosomal makeup is present in an individual, have also been reported.
WAGR syndrome/11p deletion syndrome is a rare genetic disorder that is thought to affect males more frequently than females. Because some affected individuals have external genitalia that strongly resembles that of the opposite sex, incorrect sex identification may occur initially
Symptoms of the following disorders can be similar to those of WAGR syndrome/11p deletion syndrome. Comparisons may be useful for a differential diagnosis:
Drash syndrome is a very rare disorder that usually appears early in life. It is characterized by the combination of abnormal kidney function (nephropathy); Wilms' Tumor; and the presence of the gonads of one sex and external genitalia resembling that of the other, making the individual's sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Some individuals may have the incomplete form of Drash syndrome, which consists of abnormal kidney function with either genital abnormalities (pseudohermaphroditism) or Wilms' tumor. Drash syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene. Drash syndrome typically occurs for no apparent reason (sporadically). However, in rare cases, it may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Drash" as your search term in the Rare Disease Database.)
Frasier syndrome is a very rare disorder characterized by kidney failure; defective development of the gonads (gonadal dysgenesis), such as underdeveloped ovaries (streak gonads); cancer of the cells that form the ovaries or testes (gonadoblastoma); and pseudohermaphroditism. Researchers have reported that some individuals who were thought to have Drash syndrome actually had what is now designated as Frasier syndrome. Frasier syndrome is caused by a point mutation (a type of mutation which causes the replacement of a single base nucleotide with another nucleotide) in the WT1 gene, which is thought to occur for no apparent reason (sporadic).
Potocki-Shaffer syndrome is a very rare disorder characterized by multiple bony lumps or spurs on the bones (multiple exostoses) and abnormally large openings in the skull (enlarged parietal foramina). Intellectual disability, malformations of the face (dysmorphism) and premature closure of the fibrous joints between the bones of the skull (craniosynostosis) may also be associated. Potocki-Shaffer syndrome is the result of a genetic deletion at 11p11.2, which is thought to occur for no apparent reason (sporadic). There have been several documented cases of individuals with overlap of Potocki-Shaffer syndrome and WAGR syndrome/11p deletion syndrome.
Beckwith Wiedemann syndrome (BWS) The cardinal features of this disorder are bulging of the eyes (exomphalos), an enlarged tongue (macroglossia) and excessive secretion of growth hormone (gigantism) in the newborn. These features, together with omphalocele or other umbilical abnormalities, permit recognition of the disorder at birth. Because many of the affected infants have very low blood sugar (hypoglycemia) in the first days of life, anticipation of this complication can prevent serious neurologic consequences. Enlargement of the abdominal organs (visceromegaly), enlargement of cells within the outer layer of the adrenal gland (adrenocortical cytomegaly), and abnormal growth or development (dysplasia) of the renal medulla are conspicuous features. BWS patients are at increased risk of developing specific tumors. These include Adrenal carcinoma, nephroblastoma (Wilms tumor), hepatoblastoma, and rhabdomyosarcoma. BWS syndrome is caused by mutation in the chromosome 11p15.5 region. Most cases occur for no apparent reason (sporadic).
WAGR syndrome/11p deletion syndrome can be diagnosed at birth, based upon a clinical evaluation, characteristic physical findings, and chromosomal studies (high-resolution karyotyping and molecular cytogenetic tests). In many cases, the partial or complete absence of the iris of the eye (aniridia) may be the only physical feature associated with WAGR Syndrome/11p deletion syndrome that is obvious at birth. In other cases, genitourinary abnormalities associated with the syndrome may also be apparent.
If a child has aniridia, chromosomal studies are necessary to determine whether the child has a genetic predisposition for the disorders associated with WAGR syndrome/11p deletion syndrome.
Treatment of WAGR syndrome/11p deletion syndrome is directed toward the specific symptoms that are apparent in each individual.
Wilms' tumor will occur in approximately 50% of children with WAGR syndrome/11p deletion syndrome whose deletion encompasses the WT1 gene. The onset of Wilms' tumor in these children is most often between the ages of 1 and 3. The majority of cases of Wilms' tumor have been detected by age 8, but rare cases have occurred in individuals with WAGR syndrome/11p deletion syndrome as late as age 25. Surveillance for the development of Wilms' tumor in children with WAGR syndrome/11p deletion syndrome should begin at birth or as soon as WAGR syndrome/11p deletion syndrome is suspected. This surveillance consists of abdominal ultrasound every 3 months until at least age 8. In addition, feeling the abdomen for signs of swelling or masses (palpation) may be done by both the pediatrician and, with instruction, the parents. (For more information on the symptoms associated with Wilms' tumor, refer to the "Symptoms" section of this report.)
Wilms' tumor can often be treated successfully depending on the stage of the tumor at detection. Treatment programs may combine surgical techniques (including kidney removal), radiation therapy, and chemotherapy. The chemotherapy regimen currently preferred to treat Wilms' tumor consists of the drugs dactinomycin and vincristine, which may be combined with doxorubicin. Cyclophosphamide may also be used with this drug regimen to treat tumors that have not responded to the first line of chemotherapy. Other regimens sometimes used to treat Wilms' tumor include a combination of the drugs cisplatin and etoposide or a regimen that combines ifosfamide and mesna. Abnormally persistent clusters of embryonal cells within the kidneys (nephrogenic rests or nephroblastomatosis) are thought to be precursors of Wilms' tumor in some cases. Serial abdominal ultrasound may be used to monitor this tissue for changes which indicate malignancy (cancer), and surgery or chemotherapy is sometimes indicated if changes are noted.
The treatment of aniridia is usually directed at preserving vision. Drugs or surgery may be helpful for glaucoma and/or cataracts. Individuals with aniridia often lack limbal cells, which serve to regenerate the cornea. For this reason, care should be taken to prevent injury to the corneas. Contact lenses should be avoided if possible, and when needed, preservative-free ocular lubricants and antibiotics should be used. In the past, cornea transplants typically failed in persons with aniridia, but simultaneous treatment with corneal limbal stem cells has been found to significantly increase the success rate.. An artificial cornea (Boston Keratoprosthesis) and several types of artificial iris implants are currently in clinical trials.
Gonadoblastoma and Genitourinary Abnormalities:
Children with WAGR Syndrome/11p deletion syndrome should be regularly evaluated to detect abnormal development of the ovaries (streak gonads) or testes. Surgical removal of abnormal gonads (gonadectomy) may be indicated to prevent the occurrence of gonadoblastoma. In cases when gonadoblastoma is actually present, surgery to remove the gonad(s) with the tumor is performed. If one gonad is cancer-free, it still may be removed since it may be at risk for developing gonadoblastoma. Individuals who have had both gonads removed are given hormone treatment to help them develop sexual characteristics that are usually manifested during puberty. Because hormone therapy may cause secondary uterine cancer to develop, the uterus may be surgically removed (if one is present) when the gonadectomy is initially performed.
In males with WAGR syndrome/11p deletion syndrome, one or both testes may fail to descend into the scrotum (cryptorchidism). If a testis does not properly descend into the scrotum on its own before the child is 1 year of age, hormone treatment may be given. If this treatment is not successful, surgery may be performed to move the undescended testis into the scrotum and attach it in a fixed position so it will not retract (orchiopexy).
Males with cryptorchidism may also have the urinary opening on the underside of the penis (hypospadias). When hypospadias is identified in infants, routine removal of the penis's foreskin (circumcision) soon after birth should not be performed. The foreskin can be essential in aiding surgical repair later in life. Surgical correction is performed as necessary for cosmetic, reproductive, and/or psychological purposes and/or to correct problems with urination. Surgical correction is usually performed before the child is 1 year of age.
In females with WAGR syndrome/11p deletion syndrome, the ovaries may be small, or may not have developed properly (streak ovaries). Abnormal ovaries may or may not function well enough to produce adequate levels of hormones for the development of puberty and for menstruation. If abnormal ovaries are detected, surveillance for the development of gonadoblastoma is necessary. Pelvic ultrasound or MRI (magnetic resonance imaging) may be used.
Individuals with WAGR syndrome/11p deletion syndrome may have the gonads of one sex and external genitalia resembling that of the opposite sex (ambiguous genitalia), making their sexual assignment (i.e., male or female) uncertain (pseudohermaphroditism). Surgery may be performed to correct some abnormalities of the external genitalia, and hormone treatment may be instituted.
The intellectual capacity of individuals with WAGR syndrome/11p deletion syndrome may range from severe impairment (IQ of 35 or lower) to mild impairment (IQ of 70 ) to intelligence that is within normal limits (IQ of approximately 100). Most individuals with WAGR syndrome/11p deletion syndrome fall into the range of mild to moderate impairment (IQ of 35 to 70) Children with WAGR syndrome/11p deletion syndrome should be referred for Early Intervention services soon after birth or diagnosis. Physical, Occupational, and Speech therapies, as well as Special Education services can maximize normal development and can ensure that appropriate steps are taken to help affected individuals reach their potential.
Kidney (Renal) Failure:
The renal failure associated with WAGR syndrome/11p deletion syndrome often causes high blood pressure (hypertension) high blood cholesterol (hyperlipidemia) and the leakage of protein from the blood into the urine (proteinuria). Treatment consists of medications called "ACE" (angiotensin converting enzyme) inhibitors, or "ARBs" (angiotensin II receptor blockers). If given early in the course of kidney failure, these drugs may help maintain blood pressure within a normal range, reduce the loss of protein through the blood, and may prolong the function of the kidney(s). Some individuals with WAGR Ssyndrome/11p deletion syndrome and renal failure may require kidney transplant.
Genetic counseling is important for individuals withWAGR Ssyndrome/11p deletion syndrome and for their families. Chromosomal studies are necessary to determine parents' risk for WAGRsyndrome/11p deletion syndrome in subsequent children. Ongoing genetic counseling will also allow for up-to-date genetic testing and for the provision of information regarding new treatments and therapies.
The National Institutes of Health (NIH) is currently conducting a comprehensive study of WAGR Ssyndrome/11p deletion syndrome. This study is sponsored by the National Institute of Child Health and Human Development, and is open to all children and adults with WAGR Ssyndrome/11p deletion syndrome. The purpose of this study is to learn more about how the genes involved in WAGR Ssyndrome/11p deletion syndrome affect people who have this condition. Participating in the study involves sending blood samples and medical records to NIH investigators. There is no cost to participants. For more information, contact: Dr. Joan Han, Phone: (301) 435-7820. Email: firstname.lastname@example.org.
The National Wilms Tumor Study (NWTS) is currently conducting a Late Effects Study (LATE) designed to identify treatment related conditions that may develop in participants who were originally treated on one of our five clinical trials. The goals of all of our protocols have always included developing more effective and less damaging treatments for children with Wilms tumor and studying the cause of this disease. LATE is a federally funded, multi-institutional observational study that follows participants and their children throughout their lives in order to continue monitoring treatment results and possible late effects. Future clinical trial protocols will be conducted by the Children's Oncology Group (COG); click on www.childrensoncologygroup.org to learn more about this organization.
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
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about WAGR syndrome/11P deletion syndrome:
Kelly Trout, RN, BSN
International WAGR Syndrome/11p Deletion Syndrome Association
Organizations related to WAGR Syndrome/11p Deletion Syndrome
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM); http://www.ncbi.nlm.nih.gov/omim/194072 , Last update: 8/18/09, Accessed 10/10.
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