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Wilms tumor, aniridia, genitourinary anomalies, intellectual disability, and obesity syndrome(WAGRO)

MedGen UID:
382718
Concept ID:
C2675904
Disease or Syndrome
Synonyms: CHROMOSOME 11p13-p12 DELETION SYNDROME; WAGR SYNDROME WITH OBESITY; WAGRO; WAGRO SYNDROME; Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity syndrome
 
Monarch Initiative: MONDO:0012913
OMIM®: 612469

Definition

For a detailed discussion of the WAGR syndrome, see 194072. In a subgroup of individuals with the WAGR syndrome, obesity develops. The phenotype in this subset is associated with haploinsufficiency for the BDNF gene. [from OMIM]

Additional description

From MedlinePlus Genetics
Other signs and symptoms of WAGR syndrome can include ongoing constipation, inflammation of the pancreas (pancreatitis), kidney failure, breathing problems, and allergies. Some affected children have obesity. When WAGR syndrome includes childhood-onset obesity, it is often referred to as WAGRO syndrome.

Intellectual disability and other developmental delays are also common in people with WAGR syndrome. Affected individuals often have difficulty processing, learning, and properly responding to information. Many affected individuals have difficulty speaking or understanding language. Some individuals with WAGR syndrome also have psychiatric or behavioral problems such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), or a developmental disorder called autism spectrum disorder that affects communication and social interaction.

Abnormalities of the genitalia and urinary tract (genitourinary anomalies) are seen more frequently in males with WAGR syndrome than in affected females. The most common genitourinary abnormality in affected males is undescended testes (cryptorchidism). Affected females may not have functional ovaries and may instead have undeveloped clumps of tissue called streak gonads. Females with WAGR syndrome may also have a heart-shaped (bicornate) uterus, which makes it difficult to carry a pregnancy to term.

Most people with WAGR syndrome have aniridia, an absence of the colored part of the eye (the iris). This can reduce the sharpness of a person's vision (visual acuity) and increase sensitivity to light (photophobia). Aniridia is typically the first noticeable sign of WAGR syndrome. Other eye problems may also develop, such as clouding of the lens of the eyes (cataracts), increased pressure in the eyes (glaucoma), and involuntary eye movements (nystagmus).

People with WAGR syndrome have a 45 to 60 percent chance of developing Wilms tumor, a rare form of kidney cancer. This type of cancer is most often diagnosed in children but is sometimes seen in adults. Some people with WAGR syndrome develop nephrogenic rests, which are abnormal clumps of cells in the kidneys. These can lead to Wilms tumor, but some people with nephrogenic rests never develop Wilms tumor.

WAGR syndrome is a disorder that affects many body systems and is named for its main features: Wilms tumor, aniridia, genitourinary anomalies, and a range of developmental delays.  https://medlineplus.gov/genetics/condition/wagr-syndrome

Clinical features

From HPO
Nephroblastoma
MedGen UID:
10221
Concept ID:
C0027708
Neoplastic Process
The presence of a nephroblastoma, which is a neoplasm of the kidney that primarily affects children.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Decreased testicular size
MedGen UID:
66027
Concept ID:
C0241355
Finding
Reduced volume of the testicle (the male gonad).
Hypoplastic female external genitalia
MedGen UID:
868321
Concept ID:
C4022715
Anatomical Abnormality
Underdevelopment of part or all of the female external reproductive organs (which include the mons pubis, labia majora, labia minora, Bartholin glands, and clitoris).
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
Accumulation of substantial excess body fat.
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Echolalia
MedGen UID:
8532
Concept ID:
C0013528
Mental or Behavioral Dysfunction
Echolalia is the automatic imitative repetition of sounds, words, or phrases in the absence of explicit awareness. The repeated words or phrases are typically odd or used in a non-social manner. These can be words or phrases that the affected individual has heard or invented.
Polyphagia
MedGen UID:
9369
Concept ID:
C0020505
Finding
A neurological anomaly with gross overeating associated with an abnormally strong desire or need to eat.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of extreme restlessness and excessive motor activity is associated with mental distress or a feeling of inner tension.
Emotional lability
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or disproportionate to events and circumstances.
Low frustration tolerance
MedGen UID:
108189
Concept ID:
C0548883
Mental or Behavioral Dysfunction
The feeling of frustration can be defined as an emotional reaction that occurs when a desired goal is not achieved. Frustration intolerance is defined as an age-inappropriate response to frustration, characterized by crying or temper tantrums in children, or aggressive or other undesirable behaviors.
Compulsive behaviors
MedGen UID:
109373
Concept ID:
C0600104
Mental or Behavioral Dysfunction
Behavior that consists of repetitive acts, characterized by the feeling that one "has to" perform them, while being aware that these acts are not in line with one's overall goal.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Reduced social reciprocity
MedGen UID:
868342
Concept ID:
C4022736
Finding
A reduced ability to participate in the back-and-forth flow of social interaction appropriate to culture and developmental level, which is normally characterized by an influence of the behavior of one person on the behavior of another person. This results in difficulty interacting with others through emotional, physical, or verbal communication.
Multiple congenital exostosis
MedGen UID:
4612
Concept ID:
C0015306
Congenital Abnormality
Hereditary multiple osteochondromas (HMO), previously called hereditary multiple exostoses (HME), is characterized by growths of multiple osteochondromas, benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones. Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by age 12 years. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk for malignant degeneration is low (~2%-5%).
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Malar flattening
MedGen UID:
347616
Concept ID:
C1858085
Finding
Underdevelopment of the malar prominence of the jugal bone (zygomatic bone in mammals), appreciated in profile, frontal view, and/or by palpation.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Congenital aniridia
MedGen UID:
1941
Concept ID:
C0003076
Congenital Abnormality
PAX6-related aniridia occurs either as an isolated ocular abnormality or as part of the Wilms tumor-aniridia-genital anomalies-retardation (WAGR) syndrome. Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure (resulting in glaucoma), lens (cataract and lens subluxation), fovea (foveal hypoplasia), and optic nerve (optic nerve coloboma and hypoplasia). Individuals with aniridia characteristically show nystagmus and impaired visual acuity (usually 20/100 - 20/200); however, milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur. Other ocular involvement may include strabismus and occasionally microphthalmia. Although the severity of aniridia can vary between and within families, little variability is usually observed in the two eyes of an affected individual. WAGR syndrome. The risk for Wilms tumor is 42.5%-77%; of those who develop Wilms tumor, 90% do so by age four years and 98% by age seven years. Genital anomalies in males can include cryptorchidism and hypospadias (sometimes resulting in ambiguous genitalia), urethral strictures, ureteric abnormalities, and gonadoblastoma. While females typically have normal external genitalia, they may have uterine abnormalities and streak ovaries. Intellectual disability (defined as IQ <74) is observed in 70%; behavioral abnormalities include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. Other individuals with WAGR syndrome can have normal intellect without behavioral problems.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Corneal opacity
MedGen UID:
40485
Concept ID:
C0010038
Finding
A reduction of corneal clarity.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Raised intraocular pressure
MedGen UID:
68606
Concept ID:
C0234708
Finding
Intraocular pressure that is 2 standard deviations above the population mean.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Recent clinical studies

Etiology

Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE
Cortex 2013 Nov-Dec;49(10):2700-10. Epub 2013 Feb 19 doi: 10.1016/j.cortex.2013.02.009. PMID: 23517654Free PMC Article
Rodríguez-López R, Pérez JM, Balsera AM, Rodríguez GG, Moreno TH, García de Cáceres M, Serrano MG, Freijo FC, Ruiz JR, Angueira FB, Pérez PM, Estévez MN, Gómez EG
Gene 2013 Mar 10;516(2):285-90. Epub 2012 Dec 21 doi: 10.1016/j.gene.2012.11.073. PMID: 23266638
Farooqi IS
Best Pract Res Clin Endocrinol Metab 2005 Sep;19(3):359-74. doi: 10.1016/j.beem.2005.04.004. PMID: 16150380

Diagnosis

Elbaz E, Martin GC, Gabison E
Ophthalmology 2020 Feb;127(2):197. doi: 10.1016/j.ophtha.2019.10.015. PMID: 31973833
Sapio MR, Iadarola MJ, LaPaglia DM, Lehky T, Thurm AE, Danley KM, Fuhr SR, Lee MD, Huey AE, Sharp SJ, Tsao JW, Yanovski JA, Mannes AJ, Han JC
Pain 2019 May;160(5):1070-1081. doi: 10.1097/j.pain.0000000000001485. PMID: 30855519Free PMC Article
Adams DJ, Clark DA
Pediatr Clin North Am 2015 Apr;62(2):411-26. Epub 2015 Jan 22 doi: 10.1016/j.pcl.2014.11.005. PMID: 25836705
Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE
Cortex 2013 Nov-Dec;49(10):2700-10. Epub 2013 Feb 19 doi: 10.1016/j.cortex.2013.02.009. PMID: 23517654Free PMC Article
Jung R, Rauch A, Salomons GS, Verhoeven NM, Jakobs C, Michael Gibson K, Lachmann E, Sass JO, Trautmann U, Zweier C, Staatz G, Knerr I
Mol Genet Metab 2006 Jul;88(3):256-60. Epub 2006 Mar 20 doi: 10.1016/j.ymgme.2006.02.003. PMID: 16545979

Therapy

Sapio MR, Iadarola MJ, LaPaglia DM, Lehky T, Thurm AE, Danley KM, Fuhr SR, Lee MD, Huey AE, Sharp SJ, Tsao JW, Yanovski JA, Mannes AJ, Han JC
Pain 2019 May;160(5):1070-1081. doi: 10.1097/j.pain.0000000000001485. PMID: 30855519Free PMC Article
Farooqi IS
Best Pract Res Clin Endocrinol Metab 2005 Sep;19(3):359-74. doi: 10.1016/j.beem.2005.04.004. PMID: 16150380

Prognosis

Boese EA, Tollefson MR, Schnieders MJ, Darbro BW, Alward WLM, Fingert JH
Curr Eye Res 2020 Jan;45(1):91-96. Epub 2019 Aug 14 doi: 10.1080/02713683.2019.1649704. PMID: 31361967Free PMC Article
Adams DJ, Clark DA
Pediatr Clin North Am 2015 Apr;62(2):411-26. Epub 2015 Jan 22 doi: 10.1016/j.pcl.2014.11.005. PMID: 25836705
Rodríguez-López R, Pérez JM, Balsera AM, Rodríguez GG, Moreno TH, García de Cáceres M, Serrano MG, Freijo FC, Ruiz JR, Angueira FB, Pérez PM, Estévez MN, Gómez EG
Gene 2013 Mar 10;516(2):285-90. Epub 2012 Dec 21 doi: 10.1016/j.gene.2012.11.073. PMID: 23266638
Jung R, Rauch A, Salomons GS, Verhoeven NM, Jakobs C, Michael Gibson K, Lachmann E, Sass JO, Trautmann U, Zweier C, Staatz G, Knerr I
Mol Genet Metab 2006 Jul;88(3):256-60. Epub 2006 Mar 20 doi: 10.1016/j.ymgme.2006.02.003. PMID: 16545979

Clinical prediction guides

Boese EA, Tollefson MR, Schnieders MJ, Darbro BW, Alward WLM, Fingert JH
Curr Eye Res 2020 Jan;45(1):91-96. Epub 2019 Aug 14 doi: 10.1080/02713683.2019.1649704. PMID: 31361967Free PMC Article
Sapio MR, Iadarola MJ, LaPaglia DM, Lehky T, Thurm AE, Danley KM, Fuhr SR, Lee MD, Huey AE, Sharp SJ, Tsao JW, Yanovski JA, Mannes AJ, Han JC
Pain 2019 May;160(5):1070-1081. doi: 10.1097/j.pain.0000000000001485. PMID: 30855519Free PMC Article
Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE
Cortex 2013 Nov-Dec;49(10):2700-10. Epub 2013 Feb 19 doi: 10.1016/j.cortex.2013.02.009. PMID: 23517654Free PMC Article
Rodríguez-López R, Pérez JM, Balsera AM, Rodríguez GG, Moreno TH, García de Cáceres M, Serrano MG, Freijo FC, Ruiz JR, Angueira FB, Pérez PM, Estévez MN, Gómez EG
Gene 2013 Mar 10;516(2):285-90. Epub 2012 Dec 21 doi: 10.1016/j.gene.2012.11.073. PMID: 23266638
Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan FL, Uhl GR, Rennert OM, Yanovski JA
N Engl J Med 2008 Aug 28;359(9):918-27. doi: 10.1056/NEJMoa0801119. PMID: 18753648Free PMC Article

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