Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

Correlation of Cerebrospinal Fluid Total Protein and Serum Neutrophil-to-Lymphocyte Ratio with Clinical Outcomes of Guillain-Barre Syndrome Variants.

OBJECTIVE: To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and electrophysiological variants of Guillain-Barre syndrome. STUDY DESIGN: Cross-sectional study. Place and Duration of the Study: Department of Neurology, Mayo Hospital and King Edward Medical University, Lahore, Pakistan, from November 2022 to April 2023. METHODOLOGY: Fourty-six Guillain-Barre syndrome patients, aged 12-70 years, were included in the study diagnosed by using the Brighton's criteria. Functional disability and respiratory insufficiency were assessed by using the modified Hughes disability score and the Erasmus Guillain-Barre syndrome respiratory insufficiency score, respectively. Serum neutrophil-to-lymphocyte ratio and cerebrospinal fluid total protein were calculated for each patient at the time of admission. RESULTS: Axonal variants had a higher mean neutrophil-to-lymphocyte ratio (5.29 ± 4.38) than demyelinating variants (4.71 ± 3.4) and Miller-Fischer syndrome (3 ± 2.828). This ratio was positively correlated with the modified Hughes's disability score (r = 0.790, p = 0.001) and the Erasmus Guillain-Barre syndrome respiratory insufficiency score (r = 0.936, p = 0.002). Mean cerebrospinal fluid total protein was higher for demyelinating (218 ± 136 mg/dl) than axonal variants (86 ± 56 mg/dl) and Miller-Fischer syndrome (34 ± 21 mg/dl). However, higher modified Hughes disability score (4-6) (r = 0.020, p = 0.117) and a high Erasmus Guillain-Barre syndrome respiratory insufficiency score (5-7) (r = 0.115, p = 0.302) did not significantly affect mean cerebrospinal fluid total proteins. CONCLUSION: Serum neutrophil-to-lymphocyte ratio can be regarded as a reliable biomarker to assess disease severity and clinical outcome in Guillain-Barre syndrome. Cerebrospinal fluid total protein is a poor predictor of the prognosis and severity of Guillain-Barre syndrome. KEY WORDS: Guillain-Barre syndrome (GBS), Clinical outcome, Cerebrospinal fluid total protein (CSF-TP), Neutrophil-to-lymphocytic ratio (NLR), Prognostic biomarker.

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.

Epidemiology of PAX6 Gene Pathogenic Variants and Expected Prevalence of PAX6-Associated Congenital Aniridia across the Russian Federation: A Nationwide Study.

This study investigates the distribution of PAX6-associated congenital aniridia (AN) and WAGR syndrome across Russian Federation (RF) districts while characterizing PAX6 gene variants. We contribute novel PAX6 pathogenic variants and 11p13 chromosome region rearrangements to international databases based on a cohort of 379 AN patients (295 families, 295 probands) in Russia. We detail 100 newly characterized families (129 patients) recruited from clinical practice and specialized screening studies. Our methodology involves multiplex ligase-dependent probe amplification (MLPA) analysis of the 11p13 chromosome, PAX6 gene Sanger sequencing, and karyotype analysis. We report novel findings on PAX6 gene variations, including 67 intragenic PAX6 variants and 33 chromosome deletions in the 100 newly characterized families. Our expanded sample of 295 AN families with 379 patients reveals a consistent global PAX6 variant spectrum, including CNVs (copy number variants) of the 11p13 chromosome (31%), complex rearrangements (1.4%), nonsense (25%), frameshift (18%), and splicing variants (15%). No genetic cause of AN is defined in 10 patients. The distribution of patients across the Russian Federation varies, likely due to sample completeness. This study offers the first AN epidemiological data for the RF, providing a comprehensive PAX6 variants spectrum. Based on earlier assessment of AN prevalence in the RF (1:98,943) we have revealed unexamined patients ranging from 55% to 87%, that emphases the need for increased awareness and comprehensive diagnostics in AN patient care in Russia.

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.

Multiple Perianal Epidermal Cysts Found in a Case of Lowe Syndrome: A Case Report and Review of the Literature.

BACKGROUND Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare genetic condition caused by an X-linked mutation of the OCRL1 gene, with an estimated prevalence in the general population of approximately 1 in 500 000. It is a multisystem disorder most commonly affecting the eyes, central nervous system, and kidneys. These commonly manifest as congenital cataracts, intellectual disability, and proximal renal dysfunction (Fanconi-type). Epidermal lesions are an uncommon manifestation of this condition, and the association is not completely understood. CASE REPORT Here we present a case of a 9-year-old boy with Lowe syndrome who presented with multiple cystic masses found in the perianal region. An excision was then performed to remove the masses and found that the lesions were epidermal cysts, which are infrequently found in Lowe syndrome. After excision, the patient recovered uneventfully without complications. CONCLUSIONS While epidermal cysts are an uncommon manifestation that have been documented, our case remains unique given the location and associated symptoms of the lesions. At presentation, the constellation of pain and perianal masses was concerning for a malignant etiology. However, after diagnostic imaging was performed, these lesions were found to be epidermal cysts, an infrequent manifestation of Lowe syndrome. Few previous case reports described cystic lesions in association with Lowe syndrome, and none, to our knowledge, have described multiple symptomatic perianal lesions. This case is important to consider because epidermal cystic lesions can be found with this presentation and should be considered on differential diagnoses for dermatologic findings in Lowe syndrome patients.

Oculocerebrorenal syndrome of Lowe protein controls cytoskeletal reorganisation during human platelet spreading.

Lowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.

Unusual Presentation in WAGR Syndrome: Expanding the Phenotypic and Genotypic Spectrum of the Diseases.

The deletion of chromosome 11p13 involving the WT1 and PAX6 genes has been shown to cause WAGR syndrome (OMIM #194072), a rare genetic disorder that features Wilms' tumor, aniridia, genitourinary anomalies, as well as mental retardation. In this study, we expand the genotypic and phenotypic spectrum of WAGR syndrome by reporting on six patients from six unrelated families with different de novo deletions located on chromosome 11p13. Very rare phenotypes of lens automated absorption and lens thinning were detected in four of the six patients. We assessed the involvement of the ARL14EP gene in patients with and without severe lens abnormalities and found that its deletion may worsen the lens abnormalities in these patients.

[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.

The Largest Germline Heterozygous Deletion Encompassing Potocki-Shaffer and WAGR Syndromes Loci to Date: A Case Report.

Potocki-Schaffer syndrome includes multiple exostoses, parietal foramina, and variable developmental delay/intellectual disability. It is associated with a heterozygous deletion of the 11p12p11.2 region. In some cases, the deletion extends to the WAGR locus (11p13p12). We describe here a 9-month-old girl harboring the largest germline heterozygous deletion characterized so far. Oligohydramnios and parietal foramina were noticed during pregnancy. No patient has been diagnosed before with concomitance of these two syndromes during the prenatal period. Cytogenetic diagnosis was anticipated on basis of clinical and radiological signs. Postnatal conventional karyotype confirmed an interstitial 11p deletion: 46,XX,del(11)(p11.2p15.1). Array-comparative genomic hybridization characterized a 29.6 Mb deletion. Our case illustrates the interest of high-resolution genomic approaches to correlate adequately clinical phenotypes with specific genes in suspected contiguous gene deletion syndromes.

Genetics and epidemiology of aniridia: Updated guidelines for genetic study.

Aniridia is a panocular disease characterized by iris hypoplasia, accompanied by other ocular manifestations, with a high clinical variability and overlapping with different abnormalities of the anterior and posterior segment. This review focuses on the genetic features of this autosomal dominant pathology, which is caused by the haploinsufficiency of the PAX6 gene. Mutations causing premature stop codons are the most frequent among the wider mutational spectrum of PAX6, with more than 600 different mutations identified so far. Recent advances in next-generation sequencing (NGS) have increased the diagnostic yield in aniridia and contributed to elucidate new etiopathogenic mechanisms leading to PAX6 haploinsufficiency. Here, we also update good practices and recommendations to improve genetic testing and clinical management of aniridia using more cost-effective NGS analysis. Those new approaches also allow studying simultaneously both structural variants and point-mutations in PAX6 as well as other genes for differential diagnosis, simultaneously. Some patients with atypical phenotypes might present mutations in FOXC1 and PITX2, both genes causing a wide spectrum of anterior segment dysgenesis, or in ITPR1, which is responsible for a distinctive form of circumpupillary iris aplasia present in Gillespie syndrome, or other mutations in minor genes. Since aniridia can also associate extraocular anomalies, as it occurs in carriers of PAX6 and WT1 microdeletions leading to WAGR syndrome, genetic studies are crucial to assure a correct diagnosis and clinical management, besides allowing prenatal and preimplantational genetic testing in families.

Pediatric Delayed Union in the Presence of WAGR Syndrome.

In this study, we present the management of an intra-articular fracture in a 13-year-old boy with WAGR syndrome, an extremely rare genetic disorder. The goal of this study was to provide possible solutions to the complex pain management requirements presenting in the setting of trauma to the right lower extremity. Given the scarcity of literature available with regard to this condition, we aim to not only increase awareness of the disease but also provide insight into trauma management and expected outcomes.

Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience.

BACKGROUND: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. METHODS: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death. RESULTS: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). CONCLUSIONS: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. LAY SUMMARY: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.

Preferentially Paternal Origin of De Novo 11p13 Chromosome Deletions Revealed in Patients with Congenital Aniridia and WAGR Syndrome.

The frequency of pathogenic large chromosome rearrangements detected in patients with different Mendelian diseases is truly diverse and can be remarkably high. Chromosome breaks could arise through different known mechanisms. Congenital PAX6-associated aniridia is a hereditary eye disorder caused by mutations or chromosome rearrangements involving the PAX6 gene. In our recent study, we identified 11p13 chromosome deletions in 30 out of 91 probands with congenital aniridia or WAGR syndrome (characterized by Wilms' tumor, Aniridia, and Genitourinary abnormalities as well as mental Retardation). The loss of heterozygosity analysis (LOH) was performed in 10 families with de novo chromosome deletion in proband. In 7 out of 8 informative families, the analysis revealed that deletions occurred at the paternal allele. If paternal origin is not random, chromosome breaks could arise either (i) during spermiogenesis, which is possible due to specific male chromatin epigenetic program and its vulnerability to the breakage-causing factors, or (ii) in early zygotes at a time when chromosomes transmitted from different parents still carry epigenetic marks of the origin, which is also possible due to diverse and asymmetric epigenetic reprogramming occurring in male and female pronuclei. Some new data is needed to make a well-considered conclusion on the reasons for preferential paternal origin of 11p13 deletions.

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.