WT1-related disorders: more than Denys-Drash syndrome.

Historically, specific mutations in WT1 gene have been associated with distinct syndromes based on phenotypic characteristics, including Denys-Drash syndrome (DDS), Frasier syndrome (FS), Meacham syndrome, and WAGR syndrome. DDS is classically defined by the triad of steroid-resistant nephrotic syndrome (SRNS) onset in the first year of life, disorders of sex development (DSD), and a predisposition to Wilms tumor (WT). Currently, a paradigm shift acknowledges a diverse spectrum of presentations beyond traditional syndromic definitions. Consequently, the concept of WT1-related disorders becomes more precise. A genotype-phenotype correlation has been established, emphasizing that the location and type of WT1 mutations significantly influence the clinical presentation, the condition severity, and the chronology of patient manifestations. Individuals presenting with persistent proteinuria, with or without nephrotic syndrome, and varying degrees of kidney dysfunction accompanied by genital malformations should prompt suspicion of WT1 mutations. Recent genetic advances enable a more accurate estimation of malignancy risk in these patients, facilitating a conservative nephron-sparing surgery (NSS) approach in select cases, with a focus on preserving residual kidney function and delaying nephrectomies. Other key management strategies include kidney transplantation and addressing DSD and gonadoblastoma. In summary, recent genetic insights underscore the imperative to implement individualized, integrated, and multidisciplinary management strategies for WT1-related disorders. This approach is pivotal in optimizing patient outcomes and addressing the complexities associated with these diverse clinical manifestations.

Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants.

BACKGROUND: Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. METHODS: Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory and pathologic levels. RESULTS: Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate to severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. CONCLUSIONS: Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.

BACKGROUND: Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes. METHODS: We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1. RESULTS: We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients. CONCLUSIONS: Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.

Image guided SBRT for multiple liver metastases with ExacTrac® Adaptive Gating.

AIM: To report the outcome and toxicity of sequential stereotactic body radiotherapy (SBRT) for multiple liver metastases in patients treated with ExacTrac Adaptive Gating. BACKGROUND: In selected patients with a limited number of liver metastases, SBRT has been evaluated as a safe and effective treatment, with minimal toxicity and high rates of local control. MATERIALS AND METHODS: From April 2008 to October 2013, 21 patients with multiple (3-14) liver metastases (n = 101) were treated sequentially with SBRT at our institution. Maximum tumor diameter was 7.5 cm. Prior to treatment, internal markers were placed inside or near the tumor. CT or PET-CT simulation was used for the definition of gross tumor volume (GTV). Median planning target volume was 32.3 cc (3.6-139.3 cc). Treatment consisted of 3 fractions (12-20 Gy/fraction) or 5 fractions (10 Gy/fraction), prescribed to the 90-95% of the PTV volume. Daily intra-fraction image guidance was performed with ExacTrac Adaptive Gating. Regular follow-up included CT or PET-CT imaging. RESULTS: After a median of 23.2 months, the estimated local control rate was 94.4%, 80.6%, 65% and 65% after 1, 2, 3 and 4 years; the median overall survival was 62 months (95% CI 49.12-74.87) and the actuarial survival reached at 60 months was 57.6%. The univariate data analysis revealed that only primary histology other than colorectal adenocarcinoma was shown as an independent significant prognostic factor for local control (p = 0.022). Number of treated metastases did not modify significantly the overall survival (p = 0.51). No toxicity higher than G3 (1 patient with chest wall pain) and no radiation-induced liver disease were observed. CONCLUSIONS: Sequential SBRT with ExacTrac Adaptive Gating for multiple liver metastases can be considered an effective, safe therapeutic option, with a low treatment-related toxicity. Excellent rates of local control and survival were obtained.

Prospective study on stereotactic body radiotherapy for small pancreatic neuroendocrine tumors: tolerance and effectiveness analysis.

INTRODUCTION: Surgery is the standard treatment for pancreatic neuroendocrine tumors (pNETs), obtaining favorable results but associating high morbidity and mortality rates. This study assesses stereotactic body radiation therapy (SBRT) as a radical approach for small (< 2 cm) nonfunctioning pNETs. MATERIALS AND METHODS: From January 2017 to June 2023, 20 patients with small pNETs underwent SBRT in an IRB-approved study. Endpoints included local control, tolerance, progression-free survival, and overall survival (OS). Diagnostic assessments comprised endoscopy, CT scans, OctreScan or PET-Dotatoc, abdominal MRI, and histological confirmatory samples. RESULTS: In a 30-month follow-up of 20 patients (median age 55.5 years), SBRT was well-tolerated with no grade > 2 toxicity. 40% showed morphological response, 55% remained stable. Metabolically, 50% achieved significant improvement. With a median OS of 41.5 months, all patients were alive without local or distant progression or need for surgical resection. CONCLUSION: SBRT is a feasible and well-tolerated approach for small neuroendocrine pancreatic tumors, demonstrating effective local control. Further investigations are vital for validation and extension of these findings.

Pediatric kidney retransplantation focused on surgical outcomes.

INTRODUCTION: Despite survival rates after pediatric kidney transplantation (KT) are on the rise it is still likely that most pediatric recipients will require more than one retransplant in their lifetime. The earlier the age at the first KT the higher is the risk of repeat pediatric kidney transplantation (RPKT). OBJECTIVE: The current study aims to analyze the outcomes of repeat pediatric kidney transplantation (RPKT) among pediatric kidney transplant recipients focusing on surgical complications and compare the outcomes of second and subsequent grafts with those of the first kidney graft. MATERIALS AND METHODS: Retrospective study of RPKT (<18 years) undertaken between January 2000-2020. We analyzed primary etiology of renal disease, time to graft loss (GL), etiology of initial graft failure, history of acute rejection, previous delayed graft function, HLA-mismatches at the initial transplant, surgical complications and outcomes. Additionally, we compared the characteristics and outcomes of patients who underwent RPKT (group 1) with those who received a first kidney graft (group 2). RESULTS: Out of 229 kT, 59 patients underwent RPKT (26 females/33 males). At the time of RPKT median age was 11.37 years (SD:5.7). The most frequent primary renal disease was congenital nephrotic syndrome in 11 (18.6%). Fifty-four (91.5%) were on renal replacement therapy at the time of transplant. Fourty-one patients received their second KT (69.5%), 14 (23.7%) the third, 3 (5.1%) the fourth and 1 (1.7%) the fifth. Transplant graft nephrectomy (GN) was performed in 26 patients (44.1%) prior to retransplantation. Fifty-four (91.5%) received a cadaveric graft and 5 (8.5%) a living-related graft. An extraperitoneal approach was achieved in 53 patients (89.8%), whereas in the remaining 6 (10.2%) the graft was placed intraperitoneally. We observed 10 surgical complications (16.9%): 9 major which required reintervention and 1 minor (perirenal hematoma). No vascular complications were observed and none of the surgical complications were involved in graft loss. Graft survival at 1,3 and 5 years was 91%, 84% and 73% respectively. The most frequent cause of GL was chronic graft nephropathy in 15 (25.4%). After a mean follow-up of 9.40 years (SD: 4.7) only 2 patients died (3.4%), both with functioning grafts. DISCUSSION: Pediatric recipients of second and subsequent kidney grafts constitute a remarkable high-risk population but are becoming more frequent at reference pediatric transplant centers. CONCLUSIONS: RPKT is technically challenging but can yield good results. In our series overall the incidence of surgical complications and particularly vascular complications was low.

Linear Growth in Pediatric Kidney Transplant Population.

Introduction: Growth retardation is one of the main complications of chronic kidney disease (CKD) in children and induces a negative impact on quality of life. Materials and Methods: Retrospective analysis of all consecutive patients younger than 18 years old who received a first KT in our center between 2008 and 2018. Results: 95 first KT recipients, median age at KT of 7.83 years. At the time of KT, 65.52% of males and 54.05% females showed normal height. After transplantation, linear growth improved from -1.53 at transplant to -1.37 SDS height at the last visit. We detected a different linear growth pattern according to patient age at KT. Children younger than 3 years old exhibited the most significant growth retardation at baseline and the greatest linear growth over time (-2.29 vs. -1.82 SDS height), whereas catch-up was not observed in older patients. Multivariate analysis showed that use of corticosteroids was negatively related to SDS height at 1 year after transplantation and final SDS height only was positively associated with SDS height at KT. 44.2 and 22.1% patients received rhGH treatment before and after KT. 71.88% patients reached adulthood with normal final height. Conclusions: In our study, pediatric KT recipients exhibited a normal height in more than half of cases at KT and in more than two thirds at the final adult height. Only children younger than 6 years old presented a relevant growth catch-up after KT. Treatment with rhGH was used before and after KT with significant improvement in height.

Multinodular goiter in children: treatment controversies.

BACKGROUND: Multinodular goiter (MG) is very common in adults. MG may occur in children in some exceptional circumstances. The objective of this study was to examine two cases of MG in children who relapsed soon after surgery and to discuss the treatment options in pediatric ages. METHODS: Two girls consulted for euthyroid colloid goiter, uninodular goiter and bilateral MG. They were intervened by hemithyroidectomy and total thyroidectomy, respectively, due to the existence of local symptoms. RESULTS: Goiters reappeared 3 years after intervention in both cases. They already appeared as bilaterally MG, and patients underwent a total thyroidectomy, in one case after 1 year of treatment with levothyroxine (LT4). CONCLUSIONS: MG treatment remains controversial. There is an increasing trend to a more radical surgery decreasing recurrence risk. Treatment with LT4 may be tested but it is rarely effective. Regardless of the therapeutic option, these children should be followed up and they should know about the possibility of goiter regeneration and the need for reintervention.

Distribution and genetic variation of hymenolepidid cestodes in murid rodents on the Canary Islands (Spain).

BACKGROUND: In the Canary Islands there are no previous data about tapeworms (Cestoda) of rodents. In order to identify the hymenolepidid species present in these hosts, a survey of 1,017 murine (349 Rattus rattus, 13 Rattus norvegicus and 655 Mus musculus domesticus) was carried out in the whole Archipelago. Molecular studies based on nuclear ITS1 and mitochondrial COI loci were performed to confirm the identifications and to analyse the levels of genetic variation and differentiation. RESULTS: Three species of hymenolepidids were identified: Hymenolepis diminuta, Rodentolepis microstoma and Rodentolepis fraterna. Hymenolepis diminuta (in rats) and R. microstoma (in mice) showed a widespread distribution in the Archipelago, and R. fraterna was the least spread species, appearing only on five of the islands. The hymenolepidids found on Fuerteventura, Lanzarote and La Graciosa were restricted to one area. The COI network of H. diminuta showed that the haplotypes from Lanzarote and Fuerteventura are the most distant with respect to the other islands, but clearly related among them. CONCLUSIONS: Founder effects and biotic and abiotic factors could have played important role in the presence/absence of the hymenolepidid species in determined locations. The haplotypes from the eastern islands (Fuerteventura and Lanzarote) seem to have shared an ancestral haplotype very distant from the most frequent one that was found in the rest of the islands. Two colonization events or a single event with subsequent isolation and reduced gene flow between western-central and eastern islands, have taken place in the Archipelago. The three tapeworms detected are zoonotic species, and their presence among rodents from this Archipelago suggests a potential health risk to human via environmental contamination in high risk areas. However, the relatively low prevalence of infestations detected and the focal distribution of some of these species on certain islands reduce the general transmission risk to human.

Finding of Parastrongylus cantonensis (Chen, 1935) in Rattus rattus in Tenerife, Canary Islands (Spain).

Parastrongylus cantonensis is a parasite of murid rodents that can infect humans and cause health problems as eosinophilic meningitis. Although it is endemic in south Asia, the Pacific islands, Australia, USA, and a few Caribbean islands, it has been extended to new geographical regions. In the Canary Islands (Spain) a survey of helminths of Rattus rattus, Rattus norvegicus and Mus musculus domesticus was carried out. Furthermore, five species of molluscs were examined for nematode larvae to determine whether they are potential intermediate hosts of P. cantonensis. Nematodes were found in the lungs of 15% of 67 R. rattus examined in Tenerife, one of the four studied islands, with a prevalence of 20% in the highest focus of infection. Based on morphological and molecular analysis, with the complete internal transcribed spacer 2 (ITS-2) and a fragment of the small subunit ribosomal RNA (SSU rRNA) nucleotide sequences, nematodes were identified as P. cantonensis. Larval nematodes found from snails and slugs were identified as third-stage (L(3)) Metastrongyloidea, but the molecular study showed that they did not belong to P. cantonensis. This is the first finding of angiostrongyliasis in rats in the Canary Islands (Spain). New molecular data for this species and Parastrongylus dujardini are reported. The presence of P. cantonensis in Tenerife could be of importance from the public health point of view. Further studies are required in order to look for other potential foci of infections in the Canary Islands.