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WAGR Spectrum Disorder

Synonyms: WAGR Complex, WAGRO Syndrome, WAGR Syndrome

, BS, , MS, LCGC, , MS, LCGC, , BA, , MD, , BA, , BA, , BSN, RN, , MD, and , MD, PhD.

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Estimated reading time: 33 minutes

Summary

Clinical characteristics.

WAGR spectrum disorder was initially named for its classic features of Wilms tumor (WT), aniridia, genitourinary anomalies, and a range of neurodevelopmental delays. However, in recent years the phenotypic spectrum has expanded to include additional common findings (such as neurobehavioral/psychiatric issues, obesity, respiratory and gastrointestinal issues, hypotonia and scoliosis, and recurrent infections).

Diagnosis/testing.

The diagnosis of WAGR spectrum disorder is established in a proband with suggestive findings and a deletion of chromosome 11p13 that includes the genes WT1 and PAX6 identified by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care by pediatric specialists in oncology (Wilms tumor risk assessment and management), ophthalmology (complications of aniridia), early childhood development (developmental delay / intellectual disability, neurobehavioral issues), urology (genital anomalies and congenital anomalies of the kidney and urinary tract), and nephrology (kidney function), as well as other specialists to manage less common findings (e.g., obesity, respiratory issues, gastrointestinal involvement, and recurrent infections).

Surveillance: Recommendations have been published regarding routinely scheduled follow up to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Genetic counseling.

WAGR spectrum disorder is an autosomal dominant disorder typically caused by a de novo 11p13 deletion. Rarely, an unaffected parent of a proband with WAGR spectrum disorder has a predisposing chromosome rearrangement. Recommended evaluations of the parents to confirm their genetic status and to allow reliable recurrence risk counseling include genomic testing (to detect the 11p13 deletion present in the proband) and chromosome testing (to detect a predisposing chromosome rearrangement). If neither parent has the 11p13 deletion identified in the proband or a predisposing chromosome rearrangement, and if parental identity testing has confirmed biological maternity and paternity, the two possibilities to be considered are the proband has a de novo deletion or the proband inherited the deletion from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a deletion that is present in the germ (gonadal) cells only.

Diagnosis

No consensus clinical diagnostic criteria for WAGR (Wilms tumor, aniridia, genitourinary problems, and range of developmental delays) spectrum disorder have been published to date.

Suggestive Findings

WAGR spectrum disorder should be suspected in probands with the following clinical findings and family history [Duffy et al 2021].

Clinical Findings

Wilms tumor and/or nephrogenic rest(s)

  • Wilms tumor, also referred to as nephroblastoma, is the most common childhood tumor of the kidney [Turner et al 2022].
  • Nephrogenic rest(s) resemble residual embryonal tissue in a developed kidney and are sometimes precursor lesions of Wilms tumors [Hennigar et al 2001].

Aniridia and/or other eye disorders. Aniridia resulting from heterozygous deletion of PAX6 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). Other ocular findings may include strabismus, microphthalmia, and Peters anomaly (see PAX6 Aniridia Syndrome) [Cronemberger et al 2024].

Note: Because individuals with WAGR spectrum disorder without aniridia have been reported, the presence of aniridia is not necessary for a diagnosis of WAGR spectrum disorder.

Genital anomalies

  • In males: undescended testes (unilateral or bilateral), hypospadias, external genital hypoplasia
  • In females: streak ovaries, bicornuate uterus, polycystic ovarian syndrome, external genital hypoplasia, gonadoblastoma (a rare, typically benign tumor of the gonads that can be seen in individuals with disorders of sex development)
  • Disorders of sex development

Congenital anomalies of the kidney and/or urinary tract (CAKUT)

  • Kidney: ectopic kidney, polycystic kidney, duplicate kidney that may or may not include the ureters, horseshoe kidney, unilateral renal agenesis
  • Urinary tract: dilated renal pelvis (hydronephrosis), ureteral duplication

Developmental delays

  • Global developmental delays
  • Cognitive impairment
  • Learning disabilities

Neurobehavioral/psychiatric issues can include

  • Obsessive-compulsive disorder
  • Autism spectrum disorder
  • Attention-deficit/hyperactivity disorder
  • Anxiety
  • Depression
  • Conduct disorder
  • Sensory integration disorder

Family History

Because WAGR spectrum disorder is typically caused by a de novo deletion, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of WAGR spectrum disorder is established in a proband with suggestive findings and a deletion of chromosome 11p13 that includes the genes WT1 and PAX6 identified by molecular genetic testing (see Table 1).

Note: (1) Although larger deletions extending beyond the 11p13 region (e.g., 11p14.3-p12) have been reported [Delplancq et al 2022], deletions that specifically include WT1 and PAX6 are known to cause the classic features of WAGR spectrum disorder. (2) Deletions causing WAGR spectrum disorder may extend to encompass other genes, including ALX4 and EXT2, the genes known to cause Potocki-Shaffer syndrome [Yaga et al 2023]. (3) For information on clinical features reported in individuals with deletions spanning additional genes (e.g., ALX4, EXT2, and/or BDNF), see Molecular Genetics.

Comprehensive genomic testing methods comprise copy number detection and analysis including chromosomal microarray (CMA), genome sequencing, targeted deletion/duplication methods, or exome sequencing with copy number variant (CNV) calling.

Note: 11p13 chromosomal deletions associated with WAGR spectrum disorder require high-resolution methods and therefore may not be reliably identified by routine G-band karyotyping or other conventional cytogenetic banding techniques.

  • CMA using oligonucleotide arrays or SNP genotyping arrays can detect the deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 11p13 region.
    Note: (1) Most individuals with an 11p13 deletion are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or multiple congenital anomalies. (2) Prior to 2007 many CMA platforms were not used clinically for detecting deletions like the 11p13 deletion [Lu et al 2007].
  • Targeted deletion/duplication analysis methods such as multiplex-ligation dependent probe amplification (MLPA) and fluorescent in situ hybridization (FISH) methods designed specifically to detect deletions within the 11p13 chromosomal region can be used to establish a diagnosis of WAGR spectrum disorder [Fischbach et al 2005, Redeker et al 2008].
  • Exome and genome sequencing are comprehensive next-generation sequencing technologies that generate DNA sequence either for all coding regions (exome) or the entire genome. CNV-calling algorithms need to be utilized to reliably detect the 11p13 deletion. Genome sequencing can detect CNVs (including chromosomal deletions) more reliably than exome sequencing [Austin-Tse et al 2022].
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

WAGR Spectrum Disorder: Molecular Genetic Testing

Deletion 1MethodProportion of 11p13 Deletions 2 Identified by Method
11p13 chromosomal region incl PAX6-WT1 intervalCMA 3, 4100%
Targeted deletion/duplication analysis 5100%
Exome or genome sequencing 6Varies by method
1.
2.

See Molecular Genetics for information on this chromosomal deletion

3.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including of the 11p13 chromosomal region) that may not be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 11p13 region. CMA designs in current clinical use target the 11p13 region.

4.

Prior to 2007 many CMA platforms were not used clinically for detecting deletions like the 11p13 deletion [Lu et al 2007]. Translocations resulting in a deletion of the region have also been reported [Fischbach et al 2005] that may not be detected by CMA analysis.

5.

Targeted deletion/duplication analysis methods including fluorescent in situ hybridization (FISH) analysis, multiplex ligation-dependent probe amplification (MLPA), or other targeted quantitative methods may be used to detect the recurrent 11p13 deletion.

6.

Exome and genome sequencing methods with copy number variant (CNV) calling may be used to detect the 11p13 deletion.

Clinical Characteristics

Clinical Description

WAGR spectrum disorder is named for its characteristic features of Wilms tumor, aniridia, genitourinary anomalies, and a range of neurodevelopmental delays. Since first described by Miller et al [1964], more recent studies suggest that additional systems are involved.

To date, more than 142 individuals have been enrolled in the International WAGR Syndrome Association WAGR Spectrum Patient Registry. The following description of the phenotypic features associated with WAGR spectrum disorder is based on self-reported information from 91 individuals participating in the Duffy et al [2021] WAGR Spectrum Patient Registry, as well as the many other publications cited in this section.

Classic Findings

Wilms tumor. Some individuals with WAGR spectrum disorder only develop nephrogenic rests, lesions that are a precursor to Wilms tumor, but never develop Wilms tumor. Typically, individuals with WAGR spectrum disorder who develop Wilms tumor develop their initial tumor before age five years. In some individuals, nephroblastomatosis is also described, which can be a precursor to Wilms tumor. However, multiple reports describe development of Wilms tumor after age seven to eight years, with the oldest reported age being 25 years [Breslow et al 2003, Fischbach et al 2005, Takada et al 2017, Hol et al 2021].

Aniridia is a pan ocular disorder characterized by varying degrees of iris hypoplasia, nystagmus, foveal hypoplasia, and reduced visual acuity. Aniridia is nearly always present in individuals with WAGR spectrum disorder. In addition to aniridia, other commonly reported ocular findings are cataract(s), glaucoma, optic nerve hypoplasia, foveal/macular hypoplasia, amblyopia, strabismus, corneal keratopathy/pannus, Peters anomaly, and retinal detachment.

Genital abnormalities include a range of both internal and external anomalies that are like the findings seen in WT1 disorder. Females may have streak ovaries, bicornuate uterus, external genital hypoplasia, and gonadoblastoma.

Males may have cryptorchidism, hypospadias, and micropenis.

Disorders of sex development have also been reported. Craver et al [2023] reported an individual with WAGR spectrum disorder who had female external genitalia and an XY karyotype. Andrade et al [2008] reported an individual with WAGR spectrum disorder who had an XY karyotype and absent testes. Le Caignec et al [2007] reported an individual with an XY karyotype with normal female external genitalia but absence of ovaries.

Congenital anomalies of the kidney and/or urinary tract (CAKUT). More recent publications have reported a clear association between WAGR spectrum disorder and CAKUT [Duffy et al 2021] that previously may have been underrecognized. In the WAGR Spectrum Patient Registry cohort, 38.5% of individuals reported having CAKUT [Duffy et al 2021]. Additionally, more than half of the cohort reported having some kidney findings, including polycystic kidney, ectopic kidney, duplicate kidney, horseshoe kidney, renal agenesis, ureteral duplication, and dilated renal pelvis [Duffy et al 2021]. Both males and females may have difficulty emptying their bladder.

More than half of the WAGR Spectrum Patient Registry cohort reported having some functional kidney issues such as chronic kidney disease (CKD), including proteinuria, kidney stones, end-stage kidney disease (ESKD), and focal segmental glomerulosclerosis (FSGS) [Duffy et al 2021]. Although kidney failure has been primarily studied in the context of Wilms tumor survivors, CKD in WAGR spectrum disorder is thought to be multifactorial [Tracy et al 2024]. Recent research has shown that individuals with WAGR spectrum disorder and Wilms tumor were more likely to develop CKD than those without Wilms tumor [Tracy et al 2024], likely due to treatment of Wilms tumor involving nephrectomy and oncologic pharmacotherapy. Cardiometabolic features as well as a history of Wilms tumor or nephrogenic rest development are correlated with the severity of CKD and ESKD.

Range of neurodevelopmental issues. In early childhood, neurodevelopmental issues may present as delayed developmental milestones. Global developmental delay and learning disabilities in math and reading were reported in Duffy et al [2021]. Delays in communication and speech may also present and include speech (expressive) delay and language (receptive) delay. Some children may be minimally verbal or nonverbal [Duffy et al 2021].

Note: Aniridia accompanied by significant visual impairment or blindness can affect both the perception and assessment of developmental progress in children.

Other Common Features

Neurobehavioral/psychiatric issues can include obsessive-compulsive disorder (OCD), autism spectrum disorder, and attention-deficit/hyperactivity disorder (ADHD) [Duffy et al 2021]. Although Duffy et al [2021] reported 29% of individuals with anxiety, 27% with OCD, and 26% with ADHD, it is unknown how often these findings occur collectively or concurrently with each other.

Obesity was estimated to occur in 53% of individuals [Duffy et al 2021]. Typically, onset of obesity is by age ten years. Individuals with deletion of BDNF likely exhibit hyperphagia and childhood-onset obesity [Han et al 2008], whereas individuals who do not have deletion of BDNF less commonly exhibit obesity.

Individuals with WAGR spectrum disorder may also experience cardiometabolic features such as hypertension and hyperlipidemia. Although less common, some may develop diabetes mellitus and abnormal thyroid function [Fischbach et al 2005, Duffy et al 2021, Hol et al 2021].

Respiratory issues such as asthma and obstructive sleep apnea are common [Duffy et al 2021]. Children with WAGR spectrum disorder who are age seven to ten years have high rates of sleep disturbance and manifestations of sleep-disordered breathing [Kalish-Schur et al 2025] that may require specific management (see Management, Treatment of Manifestations).

Gastrointestinal (GI) issues commonly include problems with oral intake, gastroesophageal reflux disease (GERD), and abnormal bowel movements, specifically chronic diarrhea and chronic constipation [Fischbach et al 2005, Dahan et al 2007, Duffy et al 2021, Hol et al 2021]. Less common but more severe GI issues include congenital anomalies such as diaphragmatic hernia and intestinal malrotation and functional issues such as acute and chronic pancreatitis, gallstones, and peptic ulcers [Fischbach et al 2005, Diacono et al 2012, Duffy et al 2021].

Musculoskeletal. Hypotonia and scoliosis are common [Duffy et al 2021].

Neurologic findings are not well characterized; however, there are some reports of epilepsy and seizures as well as imaging findings such as agenesis of the corpus callosum and mild brain atrophy [Brémond-Gignac et al 2005, Dahan et al 2007, Duffy et al 2021, Devaraj et al 2023].

Individuals with PAX6 aniridia syndrome have also been reported to exhibit a reduced, hypoplastic pineal gland. Pineal gland abnormalities in individuals with PAX6 aniridia syndrome appear to be associated with reduced melatonin secretion and increased sleep disturbances [Hanish et al 2016, Grant et al 2017]. Sisodiya et al [2001] reported that individuals with PAX6 aniridia syndrome often experience higher levels of hyposmia associated with decreased olfactory bulb size and function.

Individuals with deletions inclusive of BDNF exhibit a distinct phenotype of reduced pain sensitivity [Sapio et al 2019]. This altered pain perception manifests as a blunted response to acute stimuli in quantitative sensory testing and is supported by parental reports of reduced pain-related behaviors from typically painful injuries, medical procedures, or acute illness [Sapio et al 2019].

Immunologic. Individuals with WAGR spectrum disorder may have recurrent infections, particularly of the ear, upper respiratory tract, and urinary tract [Dahan et al 2007, Duffy et al 2021]. Recurrent bouts of pneumonia have been reported as part of the WAGR Discovery Cohort [Fischbach et al 2005, Duffy et al 2021].

Cardiac involvement does not appear to be common. Reported mild structural cardiac defects include atrial septal defect, patent foramen ovale, and ventricular septal defect [Fischbach et al 2005, Duffy et al 2021, Hol et al 2021]. Two individuals had tetralogy of Fallot [Fischbach et al 2005, Demir et al 2011]. Duffy et al [2021] also reported cardiometabolic issues including hypertension in more than one third of individuals, and 12% of individuals met criteria for potential metabolic syndrome including obesity and at least two of three other findings (hypertension, hyperlipidemia, glucose intolerance).

Linear growth. Poor linear growth or short stature was reported in 48% of individuals, as well as obesity and short stature, which were commonly reported together, resulting in body mass index (BMI) percentiles that may be abnormal [Duffy et al 2021].

A range of non-specific craniofacial features may be present including low-set ears, downslanting palpebral fissures, and micrognathia [Duffy et al 2021] (full text; see Figure 1).

Hearing loss. Auditory processing disorder has been reported in 22% of individuals [Duffy et al 2021], and hearing loss requiring use of hearing aids has been reported in 5% to 10% of individuals [Duffy et al 2021, Obst et al 2025].

Other findings. For information on clinical features reported in individuals with larger deletions encompassing WT1, PAX6, and additional genes (e.g., ALX4, EXT2, and/or BDNF), see Molecular Genetics.

Prognosis. Life expectancy in WAGR spectrum disorder has not been formally studied to date. However, the International WAGR Syndrome Association reports several individuals with WAGR spectrum disorder in their 40s and 50s, demonstrating that survival into adulthood is expected. The oldest individual with molecularly confirmed WAGR spectrum disorder reported in the literature was age 48 years [Prasher et al 2012]. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations with the reported causative 11p13 deletions have been identified.

See Molecular Genetics for clinical features reported in individuals with larger deletions encompassing WT1, PAX6, and additional genes (e.g., ALX4, EXT2, and/or BDNF).

Nomenclature

WAGR spectrum disorder describes the wide range of clinical manifestations associated with chromosome 11p13 haploinsufficiency. The use of the term "spectrum," first proposed by Duffy et al [2021], aims to capture the genetic and clinical variability that the historically used term "WAGR syndrome" does not fully address within its traditional framework and classic understanding. This change acknowledges the diversity of potential presentations of manifestations and supports a more comprehensive approach to diagnosis and care.

In addition to the classic term "WAGR syndrome" (which captures the feature of aniridia plus at least one of the other three classic features encompassed in the WAGR acronym), WAGR spectrum disorder has been referred to by several names clinically and in the literature.

  • AGR syndrome/triad described individuals who did not develop Wilms tumor but presented with the three other classic features.
  • WAGR plus and WAGRO ("O" stands for obesity) was intended to include obesity, another prevalent feature, in the working understanding of the disorder.
  • WAG(r) emphasized the absence of significant developmental delay in some individuals.
  • Del 11p/aniridia complex and del 11p13 were used to describe affected individuals by the genetic finding they shared rather than their clinical phenotype [Duffy et al 2021].

Prevalence

WAGR spectrum disorder is estimated to occur in 1:500,000-1,000,000 births [Duffy et al 2021].

Differential Diagnosis

The clinical findings of WT1 heterozygous pathogenic variants or PAX6 heterozygous pathogenic variants alone (without involvement of adjacent genes) include a subset of features seen in WAGR spectrum disorder (see Table 2).

Table 2.

WAGR Spectrum Disorder: Selected Disorders in the Differential Diagnosis

GeneDisorderFeatures Similar to WAGR Spectrum DisorderFeatures Distinct from WAGR Spectrum Disorder
PAX6 PAX6 aniridia syndrome AniridiaAbsence of Wilms tumor, genital anomalies, CAKUT, & ID
WT1 WT1 disorder
  • Wilms tumor
  • Genital anomalies
  • CAKUT
Absence of aniridia

CAKUT = congenital anomalies of the kidney and urinary tract; ID = intellectual disability

For other genes, loci, and syndromes associated with Wilms tumor, see Wilms Tumor Predisposition.

Management

Clinical practice guidelines for WAGR spectrum disorder have been published [Duffy et al 2021] (full text; see Figure 5).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with WAGR spectrum disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

WAGR Spectrum Disorder: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Wilms tumor ±
nephrogenic rests 		Initiate WAGR spectrum disorder screening program 1At birth or time of diagnosis, perform complete abdominal & pelvic ultrasound evaluations to examine for signs of nephrogenic rests, nephroblastomatosis, &/or Wilms tumor.
Eyes Ophthalmologic evalBy ophthalmologist familiar w/manifestations & complications of aniridia
Genital abnormalities Eval by urologist &/or gynecologist
  • Assess for internal & external genital anomalies.
  • Determine follow-up screening required.
CAKUT Kidney Refer to nephrologist if presence of kidney anomalies or signs of CKD.Evaluate baseline kidney function.
Urinary tract Refer to urologist if urinary tract anomalies identified.
Neurologic Refer to neurologist if concern for seizures or other abnormal neurologic findings.Consider MRI for brain anomalies (if not included in eval that led to diagnosis of WAGR spectrum disorder).
Neurodevelopmental
issues 		Developmental assessment
  • To include motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Musculoskeletal Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Spine for evidence of scoliosis
Neurobehavioral/
psychiatric issues 		Neuropsychiatric evalFor persons age >12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, &/or findings suggestive of ASD
Gastrointestinal/
Feeding 		Gastroenterology / nutrition / feeding team eval
  • To include eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Speech/Language Refer to speech-language therapist.As needed for persons w/delayed language milestones
Cardiometabolic health Assessment for cardiac involvement as neededRefer to cardiologist as needed.
Hearing Audiologic evalAssess for auditory processing disorder & hearing loss.
Respiratory issues Refer to sleep medicine or otolaryngology to consider need for tonsillectomy &/or adenoidectomy.Eval for obstructive sleep apnea
Genetic counseling By genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of WAGR spectrum disorder to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.
2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

WAGR Spectrum Disorder: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay /
Intellectual disability /
Neurobehavioral issues 		See Developmental Delay / Intellectual Disability Management Issues.
Wilms tumor ±
nephrogenic rests 		Standard treatment per pediatric oncologist
Altered pain perception Monitor for objective signs of injury or illness (e.g., swelling, limping, reduced activity) rather than relying on facial expressions or verbal complaints.
Aniridia & related ocular findings Standard treatment per ophthalmologist familiar w/aniridia & its complications
  • Use preservative-free artificial tears frequently.
  • No contact lenses unless bandage lenses
  • Encourage use of sunglasses, hats.
Low vision services
  • For infants & young children: early childhood intervention services
  • For school-age children: per IEP &/or 504 plan
  • For adults: per community-based low vision services
Genital abnormalities Consultation w/disorders of sexual development clinic & urologist
Urinary tract anomalies Per treating urologist
Kidney anomalies / CKD Per nephrologist
Gastrointestinal/
Feeding 		Feeding therapy
  • Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
  • Gastrostomy tube placement may be required for persistent feeding issues.
Cardiometabolic/
Obesity 		Multidisciplinary approach
  • Promotion of routine physical activity
  • Orthopedist, PT, &/or other exercise specialists to provide individualized intervention strategies
  • Encourage healthy diet overall & nutritional interventions if BDNF deleted &/or signs of hyperphagia.
  • Behavioral counselor & nutrition specialist may be helpful in dietary mgmt, like recommendations for Prader-Willi syndrome.
Respiratory issues Standard treatment per pulmonologist, sleep medicine specialist, or ENTSee footnotes 1 & 2.
Cancer predisposition Oncology treatment as needed
Transition to adult care Develop realistic plans for adulthood.
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of home & school environments
  • Encourage participation in community activities.

CKD = chronic kidney disease, IEP = individualized education plan; PT = physical therapist

1.

Two reports of individuals with WAGR spectrum disorder and tracheomalacia who experienced respiratory distress after general anesthesia suggest that anesthesiologists caring for individuals with WAGR spectrum disorder should be alerted to this possibility [Yanagidate et al 2001]. The percentage of individuals reporting tracheomalacia was 13% [Duffy et al 2021]. Additionally, the authors are aware of a number of young children experiencing respiratory distress after general anesthesia and/or requiring hospitalization for pneumonia [K Trout, personal observation].

2.

Anesthesiologists should consider the possibility of velopharyngeal insufficiency [Ma et al 2025].

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended [Duffy et al 2021].

Table 5.

WAGR Spectrum Disorder: Recommended Surveillance

System/ConcernEvaluationFrequency
Wilms tumor ±
nephrogenic rests 		WAGR spectrum disorder screening programDuffy et al [2021] (full text; see Figure 6)
Aniridia & other ocular findings Routine eye exam by ophthalmologist w/experience in treating aniridiaPer treating ophthalmologist
Neurodevelopment Monitor developmental progress & educational needs.At each clinic visit
Genital anomalies Urologic/gynecologic examPeriodically as affected person ages
Urinary tract anomalies Per treating urologist
Kidney anomalies / CKD WAGR spectrum screening programSee Table 6 below, adapted from Duffy et al [2021] (full text; see Figure 6)
Cardiometabolic/
Obesity 		Routine biometric screening; urine &/or blood screening as indicatedAt each clinic visit
Respiratory Monitor for obstructive sleep apnea; perform sleep study if concerns for obstructive sleep apnea.As indicated, per pulmonologist

CKD = chronic kidney disease

Table 6.

WAGR Spectrum Disorder: Chronic Kidney Disease Screening and Risk Assessment

Screening CategoryKey Risk Factors / Clinical Signs in WAGR Spectrum DisorderRecommended Surveillance
Mandatory annual screening
  • Hypertension (seen in ~35%)
  • Proteinuria (indicator of glomerular damage)
  • Obesity (develops in ~67% by age 10 yrs)
Annual measurement of blood pressure (plotted on age-appropriate charts), urine albumin-to-creatinine ratio, & serum creatinine (to estimate GFR)
High-risk history requiring vigilance
  • History of Wilms tumor or nephroblastomatosis
  • History of nephrectomy (reduced nephron mass)
  • History of low birth weight (<2.6 kg, seen in ~26%)
  • Closer monitoring of blood pressure & kidney function, esp in following Wilms tumor treatment
  • Educate families on nephron-protective measures (e.g., avoiding NSAIDs)
Associated comorbidities to monitor
  • Frequent/recurrent UTIs (~21%)
  • Metabolic syndrome features (~12%)
  • Cardiovascular disease risk factors (elevated lipids)
  • Low threshold for urinalysis & culture w/febrile illnesses
  • Monitor blood glucose & lipid profiles, particularly as obesity develops.
Structural abnormalities (baseline & follow up)
  • CAKUT (~39%)
  • Kidney scarring / size disparities
  • FSGS (~19%)
  • Baseline renal ultrasound to assess for CAKUT, kidney size, & echogenicity
  • Repeat imaging based on nephrologist guidance or if clinical status changes (e.g., rising creatinine, new-onset hypertension)
Critical timelines
  • CKD onset can occur 2-13 yrs post Wilms tumor treatment.
  • ESKD risk accumulates significantly after age 12 yrs.
  • Surveillance should not be relaxed in adolescence or young adulthood.
  • Transition affected persons to adult nephrologist care w/clear summary of their lifetime risk.

CAKUT = congenital anomalies of the kidney and urinary tract; CKD = chronic kidney disease; ESKD = end-stage kidney disease; FSGS = focal segmental glomerulosclerosis; GFR = glomerular filtration rate; NSAIDs = nonsteroidal anti-inflammatory drugs; UTI = urinary tract infection

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In vitro and mouse model research that may contribute to the future understanding and management of WAGR spectrum disorder is ongoing [Justice et al 2017, Shen et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

WAGR spectrum disorder is an autosomal dominant disorder typically caused by a de novo 11p13 deletion.

Risk to Family Members

Parents of a proband

  • Most probands reported to date with WAGR spectrum disorder whose parents have undergone genomic testing have the disorder as the result of a de novo chromosome 11p13 deletion.
  • Rarely, an unaffected parent of a proband with WAGR spectrum disorder has a predisposing chromosome rearrangement.
    A reciprocal translocation, t(2;11) (p21;p15), was identified in the father of a child with an 11p14.3p12 deletion [Gimelli et al 2010].
  • Evaluation of the parents by genomic testing that will detect the 11p13 deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a predisposing chromosome rearrangement in the parents is also recommended.
  • If neither parent has the 11p13 deletion identified in the proband or a predisposing chromosome rearrangement, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If the proband represents a simplex case (i.e., a single affected family member) and neither parent has the 11p13 deletion or a predisposing chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism for the deletion.
  • If one of the parents has a predisposing chromosome rearrangement, the risk to sibs of having the 11p13 deletion is increased and depends on the specific chromosome rearrangement and the possibility of other variables.

Offspring of a proband. Individuals with WAGR spectrum disorder are not known to reproduce.

Other family members

  • Given that most probands with WAGR spectrum disorder reported to date have the disorder as the result of a de novo 11p13 deletion, the risk to other family members is presumed to be low.
  • In the rare event that a parent of the proband has a predisposing chromosome rearrangement, other family members may be at risk of being carriers of the rearrangement.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the 11p13 deletion has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Prenatal or preimplantation genetic testing using genomic testing that will detect the 11p13 deletion found in the proband may be offered when the parents do not have the 11p13 deletion but have had a child with WAGR spectrum disorder. In this instance, the recurrence risk associated with the possibility of parental gonadal mosaicism or other predisposing genetic mechanisms is probably slightly greater than that of the general population (though still presumed to be <1%).

No specific prenatal findings in WAGR spectrum disorder have been identified; however, oligohydramnios has been reported in the prenatal history of individuals diagnosed with WAGR spectrum disorder [Tezcan et al 2015, Meng et al 2020, Delplancq et al 2022].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International WAGR Syndrome Association
    Email: reachingout@wagr.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

WAGR Spectrum Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
PAX611p13Paired box protein Pax-6PAX6 databasePAX6PAX6
WT111p13Wilms tumor proteinWT1 databaseWT1WT1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for WAGR Spectrum Disorder (View All in OMIM)

194072WILMS TUMOR, ANIRIDIA, GENITOURINARY ANOMALIES, AND IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; WAGR

Molecular Pathogenesis

All reported individuals with WAGR spectrum disorder to date have deletions of chromosome 11p13 that include WT1 and PAX6.

Haploinsufficiency of WT1 is the underlying cause for the increased risk for Wilms tumor. WT1 encodes Wilms tumor protein (WT1), a transcription factor with an important role in cell differentiation in the kidneys and urinary tract as well as gonadal progenitor cells. WT1 is primarily expressed in the kidney and gonadal progenitor cells and has a tumor suppression role as well [Dong et al 2015, Wilm & Munoz-Chapuli 2016] (see WT1 Disorder).

Deletions of PAX6 cause PAX6 aniridia syndrome and associated ocular features. A member of the PAX (paired box) family of genes, PAX6 encodes a DNA-binding protein with a role in controlling organogenesis [van Heyningen & Williamson 2002] (see PAX6 aniridia syndrome.

Mechanism of disease causation. Haploinsufficiency

Genes of interest in the 11p13 chromosomal region. Although deletions of PAX6 and WT1 cause aniridia and Wilms tumor / nephrogenic rests, respectively, to date other genes of interest in the deleted region have not been identified to cause the findings that account for the broader phenotypic spectrum of WAGR spectrum disorder.

Individuals whose deletion also encompasses ALX4 and EXT2 have concomitant Potocki-Shaffer syndrome (PSS) [Delplancq et al 2022]. Common findings of PSS include enlarged parietal foramina, which are openings of parietal bones of the skull due to abnormal development [Yaga et al 2023]. Deletion of EXT2 in PSS also predisposes to hereditary multiple exostoses, more commonly known now as osteochondromas, which are benign cartilage-capped bony growths primarily originating from the growth plate or the surface of some flat bones (see Hereditary Multiple Osteochondromas). Focal bone pain is common in osteochondromas. Although 2%-5% of osteochondromas may become malignant chondrosarcomas, to date there have been no reports of such malignant transformation in WAGR spectrum disorder or PSS.

While contiguous gene deletions of PAX6 and WT1 are well established as the primary contributors of WAGR spectrum disorder, the clinical significance of haploinsufficiency of other genes in the region remains uncertain and warrants further investigation. Several genes, such as ELP4, PRRG4, and SLC1A2 [Dahan et al 2007, Duffy et al 2021], have been associated with the developmental phenotype in WAGR spectrum disorder, but due to small sample sizes and the complex, heterogenous nature of the neurodevelopmental phenotype in WAGR spectrum disorder, drawing definitive conclusions about the effects of these genes is challenging [Xu et al 2008, Yamamoto et al 2014, Addis et al 2015].

Specific laboratory technical considerations

  • Mosaicism has rarely been reported in individuals with WAGR spectrum disorder [Erez et al 2010, Huynh et al 2017]. To date, the level of mosaicism of the 11p13 contiguous gene deletion in reported individuals has been low enough to be possibly missed via standard chromosomal microarray techniques. Therefore, clinical laboratories should ensure mosaicism is considered when conducting a microarray on individuals with a strong clinical suspicion for WAGR spectrum disorder.
  • Detection of 11p13 chromosomal deletion through comprehensive sequencing methods. Exome and genome sequencing methods may be used to diagnose individuals with WAGR spectrum disorder. However, the ability of these methods to detect the deletion relies on robust copy number variant (CNV) detection and analysis with CNV calling specifically used. Due to its more uniform coverage, genome sequencing can more reliably detect small deletions/duplications, CNVs, and other structural variants than exome sequencing [Austin-Tse et al 2022].

Chapter Notes

Author Notes

Dr Jennifer Kalish at the Children's Hospital of Philadelphia is actively involved in clinical research regarding individuals with WAGR spectrum disorder.

For more information about how to participate in the research, email ude.pohc@rgaw.

If you would like to speak to a member of the clinical team regarding our clinical experience and research findings from the literature, contact ude.pohc@rgaw.

Acknowledgments

We would like to thank the board of the International WAGR Syndrome Association for their invaluable support and all patients and families for their generous participation in our research efforts.

Revision History

  • 12 March 2026 (bp) Review posted live
  • 14 October 2025 (jk) Original submission

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