Search Results (43)

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks’ gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices. Full article

Background and clinical significance: Ectopic ureters are a rare urinary tract malformation, typically diagnosed in childhood and infrequently in adulthood. The prenatal detection by ultrasound and magnetic resonance imaging (MRI) of this clinical entity has scarcely been reported. Careful foetal scanning during the late second and third trimester might provide clues and lead to prenatal detection. However, even the postnatal diagnosis is challenging, and often delayed towards adulthood, since the condition may present with nonspecific symptoms, leading to underdiagnosis or misdiagnosis. In female patients, approximately 25% of ectopic ureters open into the vagina. Due to the high risk of recurrent urinary tract infections and the potential development of uretero-hydronephrosis, timely diagnosis is essential, and prompt surgical correction is mandated. Case presentation: We report the case of a 33-year-old GII PI patient diagnosed with cystic dysplasia of the left foetal kidney at the 16 WG (weeks of gestation) scan. The malformation was consistent at 21 WG when karyotyping by amniocentesis identified a normal female molecular karyotype. MRI performed at 28 weeks confirmed the left renal dysplasia and raised the suspicion of an abnormal insertion of the left ureter into the vagina. After delivery, the vaginal ureteral ectopy was confirmed at 3 weeks postpartum via cystoscopy. Postpartum whole exome sequencing identified a variant of uncertain significance (VUS) mutation in the SOX 13 gene (SRY-box transcription factor 13). Renal scintigraphy performed 7 months postnatally identified a hypo/afunctional left kidney which led to the indication of nephrectomy by the paediatric urologist. The surgical intervention was performed at 8 months postpartum with a favourable outcome. Conclusions: Ectopic ureters are a pathology generating life-long morbidity and discomfort of the offspring and young adult. Awareness to this pathology must be raised among clinicians, especially regarding the potential detection by minute prenatal ultrasound examinations, followed by MRI to refine diagnosis. Postnatally, the persistence of suspicious yet unspecific symptoms, in both males and females, must trigger thorough imaging/cystoscopic examination to reach diagnosis and provide correct management. Full article

Background: The glucocorticoid receptor (GR) regulates the transcription of thousands of genes. In cancer, both oncogenic and tumor suppressive roles of GR have been proposed. Methods: A tissue microarray containing 18,527 samples from 147 tumor (sub-)types and 608 samples from 76 normal tissue types was analyzed for GR expression by immunohistochemistry. Results: GR positivity was found in 76.4% of 14,349 interpretable cancers, including 18.5% with weak, 19.6% with moderate, and 38.3% with strong positivity. GR positivity appeared in all 147 tumor types, with at least one strongly positive tumor in 136 types. Of out tumor entities, 77 of the 147 showed GR positivity in 100% of the cases analyzed. Only six tumor types had less than 50% GR-positive cases, including adenomas with low-/high-grade dysplasia (32.5%/21.7%), adenocarcinomas (17%) and neuroendocrine carcinomas (45.5%) of the colorectum, endometrial carcinomas (25.6%), and rhabdoid tumors (25%). Reduced GR staining was associated with grade progression in pTa (p < 0.0001) and with nodal metastasis in pT2-4 (p = 0.0051) urothelial bladder carcinoma, advanced pT stage (p = 0.0006) in breast carcinomas of no special type (NST), and high grade (p = 0.0066), advanced pT stage (p < 0.0001), and distant metastasis (p = 0.0081) in clear cell renal cell carcinoma. GR expression was unrelated to clinico-pathological parameters in gastric, pancreatic, and colorectal adenocarcinoma, and in serous high-grade carcinoma of the ovary. Conclusions: GR expression is frequent across all cancer types. Associations between reduced GR expression and unfavorable tumor features in certain cancers suggest that the functional importance of GR-regulated genes in cancer progression depends on the cell of tumor origin. Full article

Sensenbrenner syndrome, or cranioectodermal dysplasia (CED), is a rare autosomal recessive ciliopathy characterized by craniofacial, skeletal, ectodermal, and renal abnormalities. Ocular involvement, though infrequent, can include retinal dystrophy with early-onset visual impairment. We report a case of a 2-year-old boy with classic clinical features of CED and significant ocular findings. Genetic testing revealed two novel compound heterozygous variants in the WDR19 gene—c.1778G>T and c.3536T>G—expanding the known mutational spectrum associated with this condition. Ophthalmologic evaluation demonstrated bilateral optic nerve hypoplasia, high hyperopia, and severely reduced ERG responses, consistent with global retinal dysfunction. Fundoscopy revealed optic disk pallor, vessel attenuation, and peripheral pigment changes. Multisystem findings included postaxial polydactyly, brachydactyly, short stature, hypotonia, and stage 2 chronic kidney disease. This case highlights the importance of early ophthalmologic screening in suspected CED and underscores the utility of ERG in detecting early retinal involvement. The identification of two previously undescribed WDR19 variants contributes to genotype–phenotype correlation in CED and emphasizes the need for ongoing documentation to guide diagnosis, management, and genetic counseling. Full article

Background and Clinical Significance: The incidence of persistent ductus arteriosus (PDA) in preterm infants is the highest and depends on their birth weight (BW) and respiratory condition after birth. Previously, after the unsuccessful drug treatment, surgical ligation was the primary treatment option. However, according to clinical studies, the Amplatzer Piccolo Occluder was approved for PDA closure for patients ≥700 g. In our country, percutaneous PDA embolization has not been performed yet. Case Presentation: We present three premature infants with hemodynamically significant patent ductus arteriosus (hsPDA) in whom percutaneous occlusion was performed using the Amplatzer Piccolo Occluder (APO). The average gestational week (GW) was 27 ± 1, while body weight was 1030 ± 60 g. All patients had respiratory deterioration, with dilatation of the left heart chambers, and renal failure. The second developed a severe form of broncho-pulmonary dysplasia. Transthoracic echocardiography (TTE) examinations revealed a hemodynamically significant PDA (LA/Ao 1.8–2.2) and medical closure was unsuccessfully carried out. Due to the hemodynamically significant PDA maintenance in all neonates, transvenous PDA closure was performed using the APO (APO 9-PDAP-04-02-L, 9-PDAP-04-04-L, 9-PDAP-05-054L, respectively). The entire devices, with both retention discs, are implanted within the duct. TTE pointed out adequate device position without descending aorta, left pulmonary artery obstruction, residual shunt, and reverse remodelling of the left ventricle and left atrium. The first newborn was weaned from mechanical ventilation three days after the procedure and discharged three weeks after. The second patient was extubated 2 weeks after the procedure, and even the severe BPD, X-ray showed improvement. The third patient’s renal failure completely resolved, weaned from inotropic drug support and mechanical ventilation. Conclusions: Due to a significantly lower complication rate than surgical ligation, we will strive to make percutaneous PDA occlusion a new standard for treatment in newborns, especially preterm newborns, in our country. Full article

Background and Objectives: Pathogenic variants in the PAX2 gene have been associated with a spectrum of eye and kidney disorders, ranging from papillorenal syndrome (known as renal coloboma syndrome) to isolated nephrosis without kidney morphological anomalies (focal segmental glomerulosclerosis), inherited in an autosomal dominant manner. However, due to the growing number of reports of pathogenic variants in the PAX2 gene, it is observed that genotype–phenotype correlation is not always consistent. We present patients from two unrelated families with PAX2 pathogenic variants c.685C>T and c.250G>A, highlighting the diverse phenotypic expression of PAX2-related disorders. Materials and Methods: We analyzed clinical and genetic data from two families who were tested for genomic abnormalities using targeted next-generation sequencing and Sanger sequencing for segregation analysis. Results: In Family A, a 27-year-old male presented with chronic kidney disease stage 3, proteinuria, and multicystic kidney dysplasia diagnosed at 11 years old. An ophthalmologic examination revealed bilateral optic nerve dysplasia. In Family B, a 6-year-old female and her 4-year-old sister were clinically diagnosed with renal hypoplasia, while their 36-year-old father presented with chronic kidney disease stage 3, focal segmental glomerulosclerosis, and optic disc pits. Genetic analysis identified a heterozygous PAX2 pathogenic variant c.685C>T, p.(Arg229*), in Family A and a heterozygous PAX2 pathogenic variant c.250G>A, p.(Gly84Ser) in Family B. Conclusions: The literature and our data further support that the same PAX2 variants may cause diverse kidney and ocular phenotypes among unrelated families and within the same family. Due to variable expressivity, a wide range of clinical manifestations of rare hereditary kidney diseases are still underdiagnosed, and a multidisciplinary approach is required to detect extrarenal signs of PAX2-related disorder. Full article

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1–3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003–2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77–100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a “founder mutation” in Russia. Full article

Background: Posterior urethral valves (PUVs) represent the most common cause of male congenital lower urinary tract obstruction, often responsible for renal dysplasia and chronic renal failure. Despite recent improvements in patients’ outcomes thanks to prenatal ultrasound early diagnosis, PUVs can still impact sexual function and fertility. This study aims to review the available evidence on fertility in PUV patients, examining paternity rates and semen parameters. Methods: A review was conducted of the PubMed, Cochrane, Scopus, and Embase databases. Studies focusing on fertility and paternity outcomes in PUV patients were selected, including case reports, case series, and retrospective and prospective studies. Results: A total of 15 studies met the inclusion criteria. The review revealed that PUV patients often exhibit compromised semen parameters, including low sperm count, reduced motility, and abnormal morphology, as well as alterations in seminal plasma. PUV diagnoses are common in adults exhibiting infertility and ejaculation disorders, suggesting PUVs cannot be considered only a pediatric disease. Paternity rates among PUV patients were rarely reported in extenso, hampering the correct assessment of the overall medium paternity rate and its comparison with that of healthy individuals. Lastly, seminal parameters were assessed in a minimal cohort of patients, therefore, they could not be considered representative. Conclusions: Fertility and seminal parameters in PUV patients represent an under-investigated area. PUVs can variably and non-univocally affect fatherhood, and they may be associated with compromised semen quality. Early intervention and long-term follow-up are essential to address potential fertility issues. Future research should focus on developing targeted strategies to preserve and enhance fertility in this patient population. Full article

Vulvar cancer is one of the rarest gynecological malignancies. The development of this condition can be associated with either dysplasia linked to human papillomavirus (HPV), primarily affecting younger women, or vulvar dermatoses such as lichen sclerosus, which predominantly affect older women. Over the last decade, the incidence of vulvar cancer has risen by 0.6% annually, while the relative survival rate has declined. Although metastasis to the vulva is uncommon, it can occur, particularly from cancers in nearby organs such as the cervix, bladder, rectum, or anus. More rarely, metastases from breast cancer and renal cell carcinoma have been reported in the vulva. Vaginal metastases from clear cell renal carcinoma are especially rare. In this article, we present the case of a 56-year-old patient diagnosed with clear cell renal carcinoma, who came to our clinic with a lesion on the right labia, which was identified as a metastasis originating from the kidney. Given the rarity of genital metastases in renal cancer, such cases should be examined and discussed to encourage further research and studies. Full article

Background: Renal artery stenosis (RAS) and mid-aortic syndrome (MAS) are significant yet under-recognized causes of pediatric hypertension. RAS is characterized by the narrowing of the renal arteries, while MAS involves the stenosis of the abdominal aorta along with its associated vessels. The etiologies of RAS and MAS often involve genetic factors and acquired conditions such as fibromuscular dysplasia and Takayasu arteritis, contributing to their complex clinical presentations. Despite advancements in diagnostic imaging, challenges remain in effectively identifying these conditions. Pharmacological treatment can achieve partial blood pressure control, but it usually does not lead to complete recovery. Treatment options range from angioplasty to more definitive surgical interventions such as renal artery reimplantation and aorto-aortic bypass, tailored according to the specific pathology and extent of the disease. Methods: This review explores the diagnosis and management of RAS and MAS in children, highlighting the necessity for early detection and showcasing the evolving landscape of treatment. Conclusions: We advocate for a multidisciplinary approach that includes advanced imaging for effective diagnosis and tailored therapy. By integrating the latest research and clinical practices, this article provides valuable insights into managing complex vascular conditions in the pediatric population, ultimately aiming to enhance the quality of life for affected individuals. Full article

Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of diseases with differing mechanisms, clinical presentations, and prognoses. With an estimated prevalence of between 4 and 60 per 10,000 births, CAKUT represents a sizable number of patients for pediatric and adult nephrologists as therapies have progressed, allowing longer life spans. Many CAKUT disorders are associated with genetic mutations, and with advances in genomic sequencing, these genes are being identified at an increasing rate. Understanding these mutations provides insight into these conditions’ molecular mechanisms and pathophysiology. In this article, we discuss the epidemiology, presentation, and outcomes of CAKUT in addition to our current understanding of genetic and molecular mechanisms in these diseases. Full article

Primary cilia (PC) are microtubule-based organelles that function as cellular antennae to sense and transduce extracellular signals. Nephronophthisis 3 (NPHP3) is localized in the inversin compartment of PC. Mutations in NPHP3 are associated with renal-hepatic-pancreatic dysplasia. In this study, we investigated whether vinblastine (VBL), a microtubule destabilizer, induces anticancer drug resistance through NPHP3-associated PC formation in HeLa human cervical cancer cells. A considerable increase in PC frequency was observed in HeLa cells under serum-deprived (SD) conditions, which led to the inhibition of VBL-induced cell death. VBL-resistant cells were established by repetitive treatments with VBL and showed an increase in PC frequency. NPHP3 expression was also increased by VBL treatment under serum starvation as well as in VBL-resistant cells. NPHP3 expression and PC-associated resistance were positively correlated with apoptosis-antagonizing transcription factor (AATF) and negatively correlated with inhibition of NPHP3. In addition, AATF-mediated NPHP3 expression is associated with PC formation via the regulation of intraflagellar transport protein 88 (IFT88). VBL resistance ability was reduced by treating with ciliobrevin A, a well-known ciliogenesis inhibitor. Collectively, cancer cell survival following VBL treatment is regulated by PC formation via AATF-mediated expression of IFT88 and NPHP3. Our data suggest that the activation of AATF and IFT88 could be a novel regulator to induce anticancer drug resistance through NPHP3-associated PC formation. Full article

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine. Full article

A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband’s eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband’s sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype–phenotype correlations in cardiomyopathy. Full article