Complex Chromosomal Rearrangement Involving Chromosomes 10 and 11, Accompanied by Two Adjacent 11p14.1p13 and 11p13p12 Deletions, Identified in a Patient with WAGR Syndrome.

Three years ago, our patient, at that time a 16-month-old boy, was discovered to have bilateral kidney lesions with a giant tumor in the right kidney. Chemotherapy and bilateral nephron-sparing surgery (NSS) for Wilms tumor with nephroblastomatosis was carried out. The patient also had eye affection, including glaucoma, eye enlargement, megalocornea, severe corneal swelling and opacity, complete aniridia, and nystagmus. The diagnosis of WAGR syndrome was suspected. De novo complex chromosomal rearrangement with balanced translocation t(10,11)(p15;p13) and a pericentric inversion inv(11)(p13q12), accompanied by two adjacent 11p14.1p13 and 11p13p12 deletions, were identified. Deletions are raised through the complex molecular mechanism of two subsequent rearrangements affecting chromosomes 11 and 10. WAGR syndrome diagnosis was clinically and molecularly confirmed, highlighting the necessity of comprehensive genetic testing in patients with congenital aniridia and/or WAGR syndrome.

An uncommon presentation of WAGR syndrome with persistent fetal vasculature.

Aniridia is an autosomal dominant congenital malformation associated with mutations in the PAX6 gene. It can be associated with deletion in the contiguous WT1 gene, leading to WAGR syndrome, characterized by Wilm tumor, aniridia, genitourinary anomalies, and mental retardation. Persistent fetal vasculature is a developmental malformation caused by incomplete regression of hyaloid vasculature. Most cases of persistent fetal vasculature occur sporadically; however, some inherited forms are described. We report a case of genetically confirmed WAGR associated with congenital cataract and persistent fetal vasculature.

[National protocol for diagnosis and care of congenital aniridia: Summary for the attending physician]. / Protocole national de diagnostic et de soins (PNDS) de l'aniridie congénitale : synthèse pour le médecin traitant.

Congenital aniridia is a rare panocular disease defined by a national diagnostic and care protocol (PNDS) validated by the HAS. In most cases, it is due to an abnormality in the PAX6 gene, located at 11p13. Aniridia is a potentially blinding autosomal dominant disease with high penetrance. The prevalence varies from 1/40,000 births to 1/96,000 births. Approximately one third of cases are sporadic. Ocular involvement includes complete or partial absence of iris tissue, corneal opacification with neovascularization, glaucoma, cataract, foveal hypoplasia, optic disc hypoplasia and ptosis. These ocular disorders coexist to varying degrees and progress with age. Congenital aniridia manifests in the first months of life as nystagmus, visual impairment and photophobia. A syndromic form such as WAGR syndrome, WAGRO syndrome (due to the risk of renal Wilms tumor) or Gillespie syndrome (cerebellar ataxia) must be ruled out. Systemic associations may include diabetes, due to expression of the PAX6 gene in the pancreas, as well as other extraocular manifestations. Initial assessment is best carried out in a referral center specialized in rare ophthalmologic diseases, with annual follow-up. The management of progressive ocular involvement must be both proactive and responsive, with medical and surgical management. Visual impairment and photophobia result in disability, leading to difficulties in mobility, movement, communication, learning, fine motor skills, and autonomy, with consequences in personal, school, professional, socio-cultural and athletic life. Medico-socio-educational care involves a multidisciplinary team. Disability rehabilitation must be implemented to prevent and limit situations of handicap in activities of daily living, relying on the Commission for the Rights and Autonomy of People with Disabilities (CDAPH) within the Departmental House of People with Disabilities (MDPH). The general practitioner coordinates multidisciplinary medical and paramedical care.

Neuropsychological and neurophysiological features of WAGR syndrome: Detailed comprehensive evaluation of a patient with severe intellectual disability and autism spectrum disorder.

BACKGROUND: Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a contiguous gene deletion syndrome caused by a de novo deletion including the 11p13 region. Although autism spectrum disorder (ASD) is frequently observed in patients with WAGR syndrome, few reports have comprehensively described its characteristics. We herein present the detailed neuropsychological and neurophysiological findings of a patient with WAGR syndrome complicated with severe psychomotor developmental delay and ASD. CASE PRESENTATION: The patient is presently a 6-year-old boy. Microarray analysis revealed a 7.1 Mb loss at 11p14.3-p13 and a 9.3 Mb loss at 11p13-p12, which encompassed the PAX6, WT1, and PRRG4 genes. His behavioral features were characteristic even among the ASD population: severe hypoesthesia to touch, pain, and temperature in addition to remarkable sensory seeking posing a high risk of serious accident. Sensory Profile analysis objectively identified a strong preference for sensory stimulation. Furthermore, his somatosensory evoked potential (SSEP) showed a mild delay in central conduction time, suggesting partial brain stem dysfunction-induced hypoalgesia. DISCUSSION: This first attempt to characterize sensory dysfunction using Sensory Profile and SSEP in WAGR syndrome may contribute to understanding its neuropsychological features and improve the quality of rehabilitation and socioeducational support in affected children.

Identification of a 6-month-old baby with a combination of WAGR and Potocki-Shaffer contiguous deletion syndromes by SNP array testing.

WAGR 11p13 deletion syndrome is associated with abnormalities including (W) ilms tumor, (A) niridia, (G) enitourinary abnormalities, and growth and mental (R) etardation (WAGR). Potocki-Schaffer syndrome is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses, parietal foramina development delay, mental retardation, and facial dysmorphism. In some cases, males may have enlarged anterior fontanels and genital abnormalities. Each of these syndromes is very rare. Here we report a patient with both WAGR and Potocki-Shaffer syndromes who presented with aniridia, nystagmus, macular dysplasia, enlarged anterior fontanel, mental retardation, ptosis, low-set ears, micrognathia, and atrial septal defect at 6 months old. SNP array revealed a large (26.25 Mb)deletion: arr[hg19]11p15.1p11.2(18742043-44991839)× 1. Genetic testing allowed for diagnosis of this patient at a very young age. In addition to the postnatal phenotype of the patient, we found one prenatal symptom of these syndromes is oligohydramnios, which when present might indicate advanced prenatal diagnosis. This made the possibility of prenatal diagnosis for these syndromes.

[WAGR syndrome by heterozygous deletion of the WT1 gene. Pediatric case report]. / Síndrome WAGR por deleción en heterocigosis del gen WT1. Caso clínico pediátrico.

WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) is an uncommon genetic disorder due to the deletion of the 11p13 region that contains the WT1 and PAX6 genes. It involves a distinctive combination of clinical conditions, with aniridia and Wilms tumor being the most notable. We present a 17-month-old infant with microcephaly, ocular alterations (buphthalmos, leukocoria, bilateral aniridia), scrotal hypoplasia, undescended testes and neurodevelopmental delay who underwent multiplex ligation-dependent probe amplification study for WT1, showing haploinsufficiency in the probes that hybridize to the 11p13 region, compatible with an heterozygous deletion of the gene. Wilms tumor was later diagnosed. WAGR syndrome is infrequent; its report in Latin America is low. It is important to disseminate its clinical characteristics, emphasizing an interdisciplinary management focused on the early identification of both the syndrome and its possible complications.

El síndrome WAGR (tumor de Wilms, aniridia, anomalías genitourinarias y retraso mental) es un trastorno genético infrecuente debido a la deleción de la región 11p13, que contiene los genes WT1 y PAX6. Comprende una combinación distintiva de afecciones clínicas; la aniridia y el tumor de Wilms son las más notables. Se presenta a un lactante de 17 meses con microcefalia, alteraciones oculares (buftalmos, leucocoria, aniridia bilateral), hipoplasia escrotal, testículos en la región inguinal y retraso en el neurodesarrollo, a quien se le realizó el estudio de amplificación de sondas dependiente de ligandos múltiples para WT1, que mostró haploinsuficiencia en las sondas que hibridaban la región 11p13, compatible con una deleción en heterocigosis del gen. Posteriormente, se diagnosticó tumor de Wilms. Dada su baja prevalencia, es importante difundir sus características clínicas y hacer énfasis en un manejo interdisciplinario centrado en la identificación precoz del síndrome y de sus posibles complicaciones.

WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities / Síndrome WAGRO: uma condição genética rara associada à aniridia e a anormalidades oftalmológicas adicionais

ABSTRACT Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.

RESUMO A aniridia é uma doença ocular congênita com grau variável de hipoplasia ou ausência do tecido da íris. É causada pela perda de função do gene PAX6 e pode ser uma anormalidade ocular isolada ou parte de uma síndrome. WAGRO refere-se a uma condição genética rara que leva ao tumor de Wilms, aniridia, anomalias geniturinárias, déficit intelectual e obesidade e é causada por uma deleção do braço curto do cromossomo 11 (11p), onde o gene PAX6 está localizado. Aqui, nós relatamos um menino de 8 anos de idade com aniridia, catarata polar e subluxação do cristalino, além de retardo neuropsicomotor e de fala. A avaliação cariotípica revelou uma deleção intersticial envolvendo a região 11p13-p14, confirmando o diagnóstico da síndrome WAGRO. Em casos de aniridia, um diagnóstico de síndrome de WAGRO deve ser considerado.

WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities.

Aniridia is a congenital eye disorder with a variable degree of hypoplasia or absence of iris tissue. It is caused by loss of function of the PAX6 gene and may be an isolated ocular abnormality or part of a syndrome. WAGRO refers to a rare genetic condition leading to Wilms tumor, aniridia, genitourinary anomalies, mental retardation, and obesity and is caused by a deletion of the short arm of chromosome 11 (11p), where the PAX6 gene is located. Here, we report on an 8-year-old boy with aniridia, polar cataract, and lens subluxation along with neuropsychomotor and speech delays. Karyotype evaluation showed an interstitial deletion including region 11p13-p14, confirming the diagnosis of WAGRO syndrome. In cases of aniridia, a diagnosis of WAGRO syndrome should be considered.

Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations.

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

Common genetic and epigenetic syndromes.

Cytogenetic anomalies should be considered in individuals with multiple congenital anomalies. DNA methylation analysis is the most sensitive initial test in evaluating for Prader-Willi and Angelman syndromes. The timely identification of cytogenetic anomalies allows for prompt initiation of early intervention services to maximize the potential of every individual as they grow older. Although many of these conditions are rare, keeping them in mind can have a profound impact on the clinical course of affected individuals. This article reviews some of the more common genetic syndromes.

Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

A case of 9.7 Mb terminal Xp deletion including OA1 locus associated with contiguous gene syndrome.

Terminal or interstitial deletions of Xp (Xp22.2→Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea.

A Case of 9.7 Mb Terminal Xp Deletion Including OA1 Locus Associated with Contiguous Gene Syndrome

Terminal or interstitial deletions of Xp (Xp22.2-->Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea.

[Sporadic aniridia and Wilm's tumor--a case report and review of recommendation for diagnostic approach in WAGR's syndrome]. / Aniridia sporadyczna i guz Wilmsa--opis przypadku i rekomendacje postepowania diagnostycznego u chorych z zespolem WAGR.

The current paper presents a case of 14 months old girl with WAGR's syndrome. This syndrome is a genetic disorder characterized by the deletion at 11p13 locus which gives clinical presentation of aniridia, Wilms' tumor, genitourinary anomalies and mental retardation. Although WAGR's syndrome is a rare disorder, knowledge of its presentation is helpful in early diagnosis of nephroblastoma and may have impact on clinical outcome of the patient. Since aniridia may be the first symptom of WAGR's syndrome, it is recommended that all neonates with aniridia need to be screened for deletion of WT1 on chromosome 11p13. These with deletions should be monitored regularly for tumor development.