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.

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.

Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.

Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Sangrado de angiomiolipoma renal en paciente con síndrome de genes contiguos (TSC2/PKD1) tras 17 años de tratamiento renal sustitutivo / Renal angiomyolipoma bleeding in a patient with TSC2/PKD1 contiguous gene syndrome after 17 years of renal replacement therapy

Presentamos el caso de un varón de 32 años, con síndrome de genes contiguos TSC2/PKD1, que le ocasiona esclerosis tuberosa (ET) y poliquistosis renal autosómica dominante simultáneamente. Evolucionó a enfermedad renal terminal y se realizó trasplante renal a los 12 años. Los riñones presentaban angiomiolipomas (AML), que son tumores benignos frecuentes en pacientes con ET. A los 17 años postrasplante, presentó un cuadro de dolor abdominal, anemización y hematoma retroperitoneal. Dicho hematoma se produjo por el sangrado de los AML. Como tratamiento se realizó embolización selectiva. Nuestro paciente podría haberse beneficiado en el momento del trasplante renal del tratamiento con inhibidores de mTOR. Este fármaco actúa como inmunosupresor y reductor tumoral en la ET, al disminuir el riesgo de rotura y hemorragia. En este paciente no se administró porque cuando se trasplantó no se conocía la relación de los inhibidores de mTOR con la ET. Este caso confirma que, a pesar de tratarse de pacientes trasplantados o en diálisis, el riesgo de sangrado por los AML persiste, por lo cual se propone realizar controles periódicos de los riñones propios y valorar la nefrectomía (AU)

We report the case of a 32-year-old male diagnosed with TSC2/PKD1 contiguous gene syndrome, presenting with tuberous sclerosis (TS) and autosomal dominant polycystic kidney disease simultaneously. He progressed to end-stage renal disease and received a kidney transplant at the age of 12. The native kidneys presented angiomyolipomas (AML), which are common benign tumours in patients with TS. Seventeen years after transplantation, he presented with abdominal pain, anaemia and a retroperitoneal haematoma, the latter caused by renal AML bleeding. Selective embolisation was performed. Our patient could have benefited from the administration of mTOR inhibitors at transplant. This therapy is immunosuppressive and reduces the size of benign tumours in TS as well as the risk of rupture and bleeding. This patient did not receive mTOR inhibitors at the time of the transplant because the relationship between mTOR inhibitors and TS was unknown at that time. This case confirms the persistent risk of renal AML bleeding for both transplanted patients and patients on dialysis. As a result, we would recommend routine check-ups of native kidneys and nephrectomy assessment (AU)

Bezafibrate to prevent relapsing pancreatitis in WAGR syndrome.

Recurrent episodes of acute, severe pancreatitis are a feature of the rare WAGR congenital anomaly syndrome. Although pancreatitis is well recognised as a life-threatening association of WAGR syndrome, treatment to prevent pancreatitis is not recommended. We report the successful prevention of hypertriglyceridaemia-associated relapsing pancreatitis in a child with WAGR syndrome with Bezafibrate. In addition to dietary fat restriction, Bezafibrate may be a useful therapeutic adjunct in WAGR related relapsing pancreatitis.

WAGR syndrome with tetralogy of Fallot and hydrocephalus.

Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR) syndrome occurs sporadically due to deletion of chromosome 11p13. A variety of other abnormalities involving different systems have been reported in patients with WAGR syndrome. We report on a patient with WAGR syndrome with accompanying tetralogy of Fallot and hydrocephalus.

Aniridia: current pathology and management.

Aniridia is a rare panocular disorder affecting the cornea, anterior chamber, iris, lens, retina, macula and optic nerve. It occurs because of mutations in PAX6 on band p13 of chromosome 11. It is associated with a number of syndromes, including Wilm's tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation (WAGR) syndrome. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression. This, in addition to stem-cell deficiency, results in a fragile cornea and aniridia-associated keratopathy (AAK). It also results in abnormalities in the differentiation of the angle, resulting in glaucoma. Glaucoma may also develop as a result of progressive angle closure from synechiae. There is cataract development, and this is associated with a fragile lens capsule. The iris is deficient. The optic nerve and fovea are hypoplastic, and the retina may be prone to detachment. Aniridia is a profibrotic disorder, and as a result many interventions--including penetrating keratoplasty and filtration surgery--fail. The Boston keratoprosthesis may provide a more effective approach in the management of AAK. Guarded filtration surgery appears to be effective in glaucoma. Despite our increasing understanding of the genetics and pathology of this condition, effective treatment remains elusive.

Brain-derived neurotrophic factor and obesity in the WAGR syndrome.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF. METHODS: We studied the relationship between genotype and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization. RESULTS: Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [+/-SD] z score at 8 to 10 years of age, 2.08+/-0.45 in patients with heterozygous BDNF deletions vs. 0.88+/-1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMI > or = 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P<0.001). The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001). CONCLUSIONS: Among persons with the WAGR syndrome, BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity; thus, BDNF may be important for energy homeostasis in humans.

[Association between WAGR syndrome and diaphragmatic hernia]. / Asociación entre síndrome de WAGR y hernia diafragmática.

Anomalies in WT-1 (Wilms' tumor gene), mapped to 11p13, cause Denys-Drash, Frasier and WAGR syndromes. WAGR syndrome is characterized by Wilms' tumor (W), aniridia (A), genitourinary anomalies (G) and mental retardation (R). In the early human fetus, WT-1 is expressed in the pleural and abdominal mesothelium, and consequently this gene may play a role in diaphragm development. The first report of an association between WAGR syndrome and congenital diaphragmatic hernia has recently been published. We present another infant with aniridia, left cryptorchidism with testicular dysgenesis, right-sided posterolateral diaphragmatic hernia and moderate psychomotor retardation, in whom genetic study showed a deletion of 11p13 and PAX-6, confirming the diagnosis of WAGR syndrome.

Asociación entre síndrome de WAGR y hernia diafragmática / Association between WAGR syndrome and diaphragmatic hernia

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Clinical, cytogenetic and molecular characterization of a patient with combined succinic semialdehyde dehydrogenase deficiency and incomplete WAGR syndrome with obesity.

We describe the clinical course, as well as cytogenetic and molecular findings, of a 3-year-old obese boy with psychomotor retardation who exhibited two rare conditions: succinic semialdehyde dehydrogenase deficiency (SSADH deficiency, MIM 271980), a disorder of gamma-aminobutyric acid metabolism with a heterogeneous clinical spectrum, and partial Wilms' tumor, aniridia, genital abnormalities, and mental retardation (WAGR) syndrome, an association between Wilms' tumor, aniridia, genitourinary malformations, and mental retardation due to mutations involving the short arm of chromosome 11, particularly deletions at the chromosomal region 11p13 (MIM 194072). Diagnosis of SSADH deficiency in our patient was established by demonstration of absent enzyme activity in isolated leucocytes, and was associated with a novel missense mutation (c.587G>A; p.Gly196Asp) in the SSADH coding sequence. We further confirmed an incomplete WAGR syndrome in this boy [karyotype 46, XY, del (11) (p13p14.2)] with a normal WT1 (Wilms' tumor) gene and an absence of pathology in the genitourinary tract, but with obesity (WAGR syndrome with obesity, WAGRO syndrome). The patient also exhibited distinctive cerebral anomalies such as increased signals of the globi pallidi, internal hydrocephalus and cerebellar vermian atrophy. However, treatment options for this patient are limited, including supportive treatment, physiotherapy, special educational training, and vigabatrin. In summary, we report the first patient with the exceptional rare findings of both SSADH deficiency and partial WAGR/WAGRO syndrome.

Focal segmental glomerulosclerosis in solitary kidney in WAGR syndrome.

WAGR syndrome consists of Wilms' tumour, aniridia, genitourinary malformations and mental retardation, and is associated with chromosomal microdeletion of 11p13. We report a case of young male, exhibiting several typical features of WAGR syndrome (e.g. WT, aniridia and genitourinary abnormalities), but missing some other (mental retardation and chromosomal abnormality absent). Renal biopsy performed in our patient for unexplained proteinuria showed focal segmental glomerulosclerosis, presumably of secondary origin; the decrease of proteinuria was achieved by the firm control of BP in conjunction with the reduction of body weight.

Morbid obesity and hyperphagia in the WAGR syndrome.

A 33-year-old man with WAGR syndrome is described with morbid obesity associated with hyperphagia and an apparent lack of satiety. It is possible that a gene associated with satiety is present at 11p13 although it is premature to conclude that obesity is a specific feature of WAGR syndrome.

Clinical and molecular evidence for the role of androgens and WT1 in testis descent.

Testicular maldescent is a common congenital disorder associated with testicular cancer and infertility. In this study, testis position was assessed in subjects with genital abnormalities due to AR mutations, Denys-Drash and WAGR syndromes or an unknown aetiology. Subjects with completely female genitalia and an AR mutation or an unknown aetiology had a greater proportion of maldescended testes (intra-abdominal and inguinal) than those with less severe abnormalities (P=0.00027 and P<0.000001, respectively). Whereas subjects with severe, moderate or mild abnormalities and an unknown aetiology, had similar testis positions. The Denys-Drash and WAGR syndrome group had a greater proportion of maldescended testes than the AR mutation (P=0.013) and unknown aetiology groups (P=0.00019). Androgen production and AR binding were normal in three subjects with Denys-Drash and WAGR syndromes. These findings indicate that the relationship between testis descent and genital abnormalities is a multi-factorial process with greater complexity than previously proposed.