PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database.

PAX2 is a transcription factor expressed during embryogenesis in the eye, ear, CNS, and genitourinary tract, and is one of the major regulators of kidney development. Mutations in this gene are associated with papillorenal syndrome (PAPRS), a genetic condition characterized by optic nerve dysplasia and renal hypo/dysplasia. In the last 28 years, many cohort studies and case reports highlighted PAX2's involvement in a large spectrum of kidney malformations and diseases, with or without eye abnormalities, defining the phenotypes associated with PAX2 variants as "PAX2-related disorders". Here, we reported two new sequence variations and reviewed PAX2 mutations annotated on the Leiden Open Variation Database 3.0. DNA was extracted from the peripheral blood of 53 pediatric patients with congenital abnormalities of the kidney and urinary tract (CAKUT). PAX2 gene-coding exonic and flanking intronic regions were sequenced with Sanger technology. Two unrelated patients and two twins carrying one known and two unknown PAX2 variations were observed. The frequency of PAX2-related disorders in this cohort was 5.8%, considering all CAKUT phenotypes (16.7% in the PAPRS phenotype and 2.5% in non-syndromic CAKUT). Although PAX2 mutations have a higher frequency in patients with PAPRS or non-syndromic renal hypoplasia, from the review of variants reported to date in LOVD3, PAX2-related disorders are detected in pediatric patients with other CAKUT phenotypes. In our study, only one patient had a CAKUT without an ocular phenotype, but his twin had both renal and ocular involvement, confirming the extreme inter- and intrafamilial phenotypic variability.

Spectrum of fetal limb anomalies.

PURPOSE: Antenatal detection of limb anomalies is not uncommon, and pregnancies are usually terminated in view of the expected physical handicap. The aim of this retrospective observational study is to delineate the spectrum of fetal limb anomalies and provide evidence in support of complete postnatal evaluation in establishing recurrence risk. METHODS: We present 54 cases of limb malformations detected antenatally and discuss the spectrum of abnormalities, the utility of fetal autopsy, and genetic testing to establish recurrence risk in subsequent pregnancies. RESULTS: 16/54 cases were isolated radial ray anomalies. There were five cases of amniotic band syndrome, five limb body wall complex cases, three VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) associations, one case of sirenomelia, two cases of limb pelvis hypoplasia, and one case of OEIS (Omphalocele Exstrophy Imperforate anus and spinal defects). Four fetuses with non-isolated radial ray anomaly had trisomy 18. One case with bilateral radial ray defect had a mutation in the FANC-E gene confirming fanconi anemia. Twelve cases were unclassified. CONCLUSION: Autopsy is the most important investigation in fetuses with limb anomalies. We suggest chromosomal microarray (CMA) as a first-tier test after autopsy. However, in cases of bilaterally symmetrical limb anomalies, in case of previous similarly affected child, or history of consanguinity, whole exome sequencing (WES) can be offered as the primary investigation, followed by CMA if WES is normal.

Radiological and surgical correlation of pelviureteric junction obstruction in positional anomalies of the kidney in children.

Pelviureteric junction obstruction, also known as ureteropelvic junction obstruction, is a congenital narrowing of the urinary excretory tract at the junction between the renal pelvis and the ureter and is a common cause of congenital pelvicalyceal dilatation. The outcome is variable, from spontaneous resolution to renal parenchymal function loss in cases of untreated high-grade obstruction. Abnormalities in renal ascent, rotation and vascularity can be associated with pelviureteric junction obstruction and easily overlooked radiologically. In this pictorial review, we explore the anatomical, radiological and surgical correlations of pelviureteric junction obstruction in the context of a normal kidney and a spectrum of renal abnormalities, including hyper-rotation (also known as renal malrotation), failed renal ascent, fusion anomalies and accessory crossing renal vessels. For each scenario, we provide technical tips on how to identify the altered anatomy at the first ultrasound assessment and correlation with scintigraphic, cross-sectional and postoperative imaging where appropriate. A detailed ultrasound protocol specifically to assess and characterise pelviureteric junction obstruction in paediatric patients is also offered.

Non-papillary prone percutaneous nephrolithotomy for renal abnormalities: single-institution experience.

PURPOSE: To evaluate the effectiveness and safety of non-papillary prone PCNL for the treatment of patients with renal abnormalities. METHODS: An observational retrospective cohort study including PCNL cases of patients with renal abnormalities was performed. The following inclusion criteria were applied: renal stones > 1.5 cm with maximal diameter, anatomical malformations of affected kidney (malrotated kidneys, horseshoe kidneys and kidneys with complete duplicated systems, medullary sponge kidney), patients treated with standard (30Fr) PCNL or mini-PCNL (22Fr). The lithotripsy was performed using the Lithoclast Master or the Lithoclast® Trilogy (EMS Medical, Nyon, Switzerland). RESULTS: Overall, 57 patients, 35 males, and 22 females with any renal malformation underwent non-papillary prone PCNL. Our study included 25 patients with horseshoe kidneys, 21 with malrotated kidneys, 9 with kidneys with duplicated pelvicalyceal systems and 2 with medullary sponge kidneys. The mean cumulative stone size was 36 ± 1.4 mm and most of the stones were in the lower calyceal group (36.9%) and in the pelvis (27.2%). The stone-free rate (SFR) was 84.2% and the mean hospitalization time was 2.7 ± 0.7 days. In total, postoperative complications were developed in six patients (10.5%), half of them presenting fever and the other half requiring blood transfusion (Grade II). CONCLUSION: The PCNL is the method of choice for treating large stones in anomalous kidneys. The generally accepted panacea that only a papillary puncture is safe is questioned by our results. Based on our experience, a non-papillary puncture proved to be a safe and effective procedure.

Hnf1b renal expression directed by a distal enhancer responsive to Pax8.

Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.

Fetal Therapy for Renal Anhydramnios.

The most severe forms of congenital anomalies of the kidney and urinary tract present in fetal life with early pregnancy renal anhydramnios and are considered lethal due to pulmonary hypoplasia without fetal therapy. Due to the high rate of additional structural anomalies, genetic abnormalities, and associated syndromes, detailed anatomic survey and genetic testing are imperative when stratifying which pregnancies are appropriate for fetal intervention. Restoring amniotic fluid around the fetus is the principal goal of prenatal treatment. The ongoing multi-center Renal Anhydramnios Fetal Therapy (RAFT) trial is assessing the safety and efficacy of serial amnioinfusions to prevent pulmonary hypoplasia so that the underlying renal disease can be addressed.

Renal-hepatic-pancreatic dysplasia-1 with a novel NPHP3 genotype: a case report and review of the literature.

BACKGROUND: Renal-hepatic-pancreatic dysplasia type 1 (RHPD1) is a rare sporadic and autosomal recessive disorder with unknown incidence. RHPD1 is caused by biallelic pathogenic variants in NPHP3, which encode nephrocystin, an important component of the ciliary protein complex. CASE PRESENTATION: In this case report, we describe a male newborn who was confirmed by ultrasound to have renal enlargement with multiple cysts, pancreatic enlargement with cysts, and increased liver echogenicity, leading to the clinical diagnosis of RHPD. In addition, a compound heterozygous pathogenic variant, namely, NPHP3 c.1761G > A (p. W587*) and the c.69delC (p. Gly24Ala24*11) variant, was detected by WES. The patient was clinically and genetically diagnosed with RHPD1. At 34 h of life, the infant died of respiratory insufficiency. CONCLUSION: This is the first published case of RHPD1 in China. This study broadens the known range of RHPD1 due to NPHP3 pathogenic variants.

Successful Surgical Treatment of a Recurrent Pelvic Solitary Fibrous Tumor of Uterine Origin Accompanied by Doege-Potter Syndrome: A Case Report.

BACKGROUND Solitary fibrous tumors (SFT), rare soft-tissue neoplasms, are usually found in the thoracic cavity, and a uterine origin is extremely rare. SFTs with insulin-like growth factor-II (IGF-II) production induce non-islet cell tumor-induced hypoglycemia (NICTH), referred to as Doege-Potter syndrome. CASE REPORT A 70-year-old woman presented with urinary retention, and imaging revealed a huge mass occupying almost the entire pelvic space. She had a history of hysterectomy for leiomyoma of the uterus 7 years earlier. In her present course, she developed hypoglycemia, and NICTH was suspected. Her previous uterine specimen was reexamined, and immunohistochemistry (IHC) revealed the specimen to be CD34-positive and alpha-smooth muscle actin-negative, indicating that the uterine specimen was not leiomyoma but SFT. Therefore, the present pelvic tumor was considered to be a recurrence of SFT with NICTH, namely Doege-Potter syndrome. Surgical resection was performed, and the pathological examination showed the same histologic features as the previous uterine specimen, while IHC revealed the present specimen to be positive for CD34, signal transducers and activator of transcription 6, and IGF-II, consistent with the diagnosis of recurrent SFT with IGF-II production. The patient's hypoglycemia improved after tumor resection. To confirm the IGF-II secretion from the SFT, we conducted immunoblotting of the patient's perioperative serum, with results showing that the strong band of IGF-II in the preoperative serum disappeared after surgery. CONCLUSIONS Because SFTs, especially those with Doege-Potter syndrome, often recur, sometimes with a very long interval, long-term cautious surveillance is required, even after complete tumor resection.

Congenital malformations of the urinary tract: progression to chronic renal disease. / Malformaciones congénitas del tracto urinario (CAKUT): evolución a enfermedad renal crónica.

INTRODUCTION: Congenital nephrourological abnormalities (CAKUT) are a particularly relevant group of diseases due to their high prevalence and the fact they are the main cause of chronic renal disease (CRD) in the pediatric population. Our objective was to determine the characteristics and prevalence of CAKUT in our setting, while identifying the factors associated with the occurrence of renal damage. MATERIALS AND METHODS: A retrospective, descriptive, analytical, cross-sectional study of patients seen in the Pediatric Nephrology Department of a third-level hospital from January 1 to December 31, 2018 was carried out. Epidemiological, clinical, and analytical variables were assessed, and potential risk factors associated with CRD were searched for. RESULTS: The study involved 685 patients with 827 kidney units affected by CAKUT with a mean age of 9.98 ± 5.12 years. 62.2% were male, and the mean follow-up period after diagnosis was 9.95 ± 5.09 years. 58.8% were non-obstructive dilations, followed by renal dysplasia, obstructive dilations, and number and position abnormalities. The most frequent malformation was vesicoureteral reflux (VUR). The most commonly affected side was the left (47.5%). 55% of the diagnoses were prenatal. 172 patients underwent surgery. The initially chosen treatment for VUR was endourological. Overall re-intervention rate was 20%. Of the total number of patients, glomerular filtration rate was analyzed in 383, 95 (24.8%) of whom had CRD (86% in stage 2). Male sex, bilaterality, and proteinuria were risk factors associated with CRD. CONCLUSIONS: Knowledge of the epidemiological and clinical characteristics of children with CAKUT and the factors associated with CRD helps to individualize the clinical follow-up of these patients, thus customizing diagnostic tests and healthcare resources.

INTRODUCCION: Las anomalías nefrourológicas congénitas (CAKUT), constituyen un grupo de enfermedades de gran relevancia por su alta prevalencia y por ser la principal causa de enfermedad renal crónica (ERC) en la población pediátrica. Nuestro objetivo es conocer las características y la prevalencia de CAKUT en nuestro medio, identificando los factores asociados a la aparición de daño renal. MATERIAL Y METODOS: Estudio retrospectivo, descriptivo, analítico y transversal, que incluyó los pacientes atendidos en la consulta de Nefrología Pediátrica de un hospital de tercer nivel desde el 1 de enero al 31 de diciembre de 2018. Se analizaron variables epidemiológicas, clínicas y analíticas, y se buscaron posibles factores de riesgo asociados a ERC. RESULTADOS: Se incluyeron 685 pacientes con 827 unidades renales con CAKUT con una edad media de 9,98 ± 5,12 años. El 62,2% fueron varones y el seguimiento medio desde el diagnóstico fue de 9,95 ± 5,09 años. El 58,8% fueron dilataciones no obstructivas, seguido por displasia renal, dilataciones obstructivas y anomalías de número y posición. La malformación más frecuente fue el reflujo vesicoureteral (RVU). El lado más afectado fue el izquierdo (47,5%). El 55% de los diagnósticos fueron prenatales. Fueron intervenidos 172 pacientes. El tratamiento inicial de elección en el RVU fue endourológico. La tasa de reintervención global alcanzó el 20%. Del total de pacientes, se pudo analizar el filtrado glomerular en 383 pacientes, de los cuales 95 (24,8%) tenían ERC (86% en estadio 2). El sexo masculino, la bilateralidad y la proteinuria fueron factores de riesgo asociados a la ERC. CONCLUSIONES: El conocimiento de las características epidemiológicas y clínicas de los niños con CAKUT y de los factores asociados a la ERC ayuda a individualizar el seguimiento clínico de estos pacientes adecuando las pruebas diagnósticas y los recursos sanitarios.

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract American Journal of Medical Genetics Part C.

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%-20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.

Clinical and genetic approach in the characterization of newborns with anorectal malformation.

OBJECTIVE: This study aimed to investigate clinical, surgical, and genetic data of neonates with anorectal malformation (ARM). STUDY DESIGN: A retrospective observational study was conducted on neonates with ARM as an isolated type (group 1), with ≤2 (group 2), and with ≥3 associated malformations (group 3), born between 2009 and 2020. Distribution of ARM, associated abnormalities and genetic testing were analyzed, and risk factors for adverse outcomes were identified. RESULTS: The 45 ARM cases (36% females) were divided as follows: 13 neonates belonging to group 1 (29%), 8 to group 2 (18%), and 24 to group 3 (53%). Cases were equally distributed over 11 years. Krickenbeck anatomy was: without fistula/imperforate anus (18%), perineal fistula (36%), rectourethral fistula (4%), rectovesical fistula (2%), vestibular fistula (4%), cloaca (4%), and rare ARMs (31%). Groups showed differences in anthropometric data, Krickenbeck anatomy, and intensive care burden. Additional major congenital abnormalities were prevalent specific of VATER/VACTERL spectrum (vertebral/anorectal/cardiac/tracheoesophageal/renal/limb defects), but also Hirschsprung disease was found in 3/20 biopsies (15%). The most frequent minor abnormality was a single umbilical artery. In group 3, we identified four de novo microdeletions at 8p23.2, 8q13.3, Xp22.31-p22.2, Xq28, four de novo microduplications at 1p36.32, 6p24.1-p23, 13q14.11, 15q11.2, one microdeletion at 9q33.1 inherited from the affected mother, one microdeletion at 7q35 inherited from the unaffected father, one structurally uncharacterized rearrangement involving 9p23-q34.3. Thus, we attributed the Xq28 deletion with inactivated FAM58A gene in one girl to the X-linked dominant STAR syndrome (toe syndactyly-telecanthus-anogenital/renal malformations). CONCLUSIONS: Despite the great physical and social burden on ARM patients and their parents, in the majority of cases, the etiology is largely unknown and attributed to be multifactorial. In females, STAR syndrome should be part of the differential diagnosis. Associated malformations of other organ systems interact in outcome parameters.

[Surgical treatment of Zinner syndrome].

Zinners syndrome (SC) is a rare congenital disease characterized by ejaculatory duct obstruction, seminal vesicle cyst in combination with ipsilateral renal agenesis. This syndrome is due to development arrest of the Wolffian duct (mesonephros). Before the onset of sexual activity, the disease is asymptomatic. The main symptoms are nonspecific, including dysuria, urinary frequency, perineal and scrotal pain after ejaculation. A clinical case with the presentation of our own experience of surgical robot-assisted treatment of a patient with Zinners syndrome is presented in the article.

Pancake kidney in a patient with chronic kidney disease: A unique presentation.

Pancake kidney is one of the least common renal fusion anomalies encountered in medical practice. Less than 30 cases of this renal variant have been reported in the medical literature. Patients are generally asymptomatic, with the diagnosis of pancake kidney usually found incidentally on imaging study or autopsy. Given the rarity of reported cases, it is difficult to establish a relationship with specific associated clinical findings. Asymptomatic patients are managed conservatively with regular follow-up. We present the case of a 69-year-old female who was found to have pancake kidney, several renal cysts, and chronic kidney disease (CKD). No other reported cases have the diagnosis of CKD.

Congenital Anomalies of the Kidneys and Urinary Tract.

Congenital anomalies of the kidneys and urinary tract (CAKUT) are some of the most common abnormalities detected on prenatal imaging assessment. It is estimated that CAKUT comprises 20% to 30% of all major birth defects. More than 200 clinical syndromes currently include CAKUT as a component of the phenotype. This chapter outlines the evaluation and management of the most common forms of CAKUT.

Evaluation of screening with urine dipsticks and renal ultrasonography for 3-year-olds in Chiba City over 30 years.

BACKGROUND: Urinary screening for 3-year-olds cannot adequately detect congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Urinary screening for 3-year-olds was investigated over 30 years. Dipsticks for proteinuria, hematuria, glycosuria, leukocyturia, and nitrite at first screening, and dipsticks, urinary sediments, and renal ultrasonography at second screening were performed. Screening results were evaluated. RESULTS: The positive rates of proteinuria, hematuria, leukocyturia, and nitrite relative to 218,831 children at the first screening were 1.0%, 4.6%, 2.3%, and 0.88%, respectively. Thirty-seven glomerular disease, 122 CAKUT, and 5 urological disease cases were found. We detected 6 stage 3-4 chronic kidney disease (CKD) and 3 end-stage kidney disease cases, including 3 CAKUT, comprising 2 bilateral renal hypoplasia and 1 vesicoureteral reflux (VUR), and 6 glomerular diseases, comprising 4 focal segmental glomerulosclerosis and 2 Alport syndrome. The positive rates relative to 218,831 children and CKD detection rates for each tentative diagnosis of mild hematuria, severe hematuria, proteinuria and hematuria, proteinuria, and suspected urinary tract infection were 1.4% and 0.67%, 0.11% and 3.7%, 0.01% and 28.6%, 0.02% and 45.0%, and 0.08% and 9.7%, respectively. Among 14 VUR cases with significant bacteriuria, 13 were found by leukocyturia, 12 had grade ≥ IV VUR, and 10 had severe renal scars. CONCLUSIONS: Nine stage 3-5 CKD cases comprising 3 CAKUT and 6 glomerular disease were found by urinary screening of 3-year-olds among 218,831 children. The combination of urine dipsticks including leukocyturia at the first screening and ultrasonography at the second screening appeared useful.

Unilateral macrocystic dysplasia and contralateral agenesis in a monoamniotic twin.

OBJECTIVE: We present a case report of a congenital malformation of the uropoetic tract in one of the monoamniotic twins. CASE REPORT: A 24-year-old primigravida with male monochorionic monoamniotic twins was dia-gnosed with congenital malformation in fetus A at 24 weeks of gestation. Ultrasound verified macrocystic dysplasia and contralateral renal agenesis. Planned caesarean section was performed after the observational management of the patient in the 34th gestational week. In fetus B, a physiological finding was confirmed on the postpartum ultrasonography. In fetus A, CT examination of the abdomen confirmed the finding of left kidney agenesis and polycystic degeneration of the right kidney. Exitus letalis was stated on the newborns 5th day. CONCLUSION: The occurrence of the described combination of congenital malformation in monoamniotic twins is rare. When dysplasia significantly affects the function of the parenchyma, renal agenesis with multicystic dysplasia of the other kidney is a condition incompatible with life. For the intrauterine survival of the affected fetus, the normal renal function of the twin was important and thus the normal volume of amniotic fluid was maintained. As a result, the fetus did not develop extrarenal symptoms of the Potter sequence in the described case - especially pulmonary hypoplasia and the newborn was able to ventilate spontaneously. The death was caused by the consequences of renal failure associated with anuria.

Preoperative MRI presentations of Herlyn-Werner-Wunderlich syndrome.

Herlyn-Werner-Wunderlich (HWW) syndrome is a rare complex female urogenital anomaly, with diverse anatomical presentations. Due to obstruction, most patients with HWW syndrome need to be addressed surgically. The treatment strategy should be tailored to the different anatomical variants of each patient. Therefore, a detailed and comprehensive preoperative evaluation is needed. In this review, we describe the embryology and clinical manifestations of HWW syndrome and discuss and illustrate its diverse preoperative magnetic resonance imaging presentations to guide clinical treatment.

Targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization for non-islet cell tumor hypoglycemia secondary to a liver metastatic solitary fibrous tumor: A case report and literature review.

Doege-Potter syndrome is a rare paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. Doege-Potter syndrome always presents with recurrent fasting hypoglycemia, which can occasionally be life-threatening. The best choice of treatment for Doege-Potter syndrome and solitary fibrous tumor is complete resection. However, when it is unfeasible, local-regional treatment can be used as a palliative therapy. Herein, we report a case of a 46-year-old man with Doege-Potter syndrome that occurred secondary to the liver and pancreatic metastatic solitary fibrous tumors. After he received six rounds of targeting-intratumoral-lactic-acidosis transcatheter-arterial-chemoembolization (TILA-TACE) treatment in our hospital, his hypoglycemia was clinically cured, and the liver metastatic tumor was well controlled. We suggest that TILA-TACE can be considered when curative resection is unfeasible for metastatic liver solitary fibrous tumors to help a patient obtain further surgery opportunities.

Renal cell carcinoma coexistence with ipsilateral renal duplex system: a case report.

The duplex kidney is one of the common congenital anomalies of the kidney and urinary tract. Meanwhile, renal cell carcinoma is also the most typical variant constituting more than 90% of cancers of the kidneys. However, renal cell carcinoma is rare in a duplicated collecting system, and literature regarding its association is very sparse. Herein, we present a 28-year-old male patient who presented with abdominal pain and hematuria and was diagnosed with left upper pole renal cell carcinoma coexisted with a duplicated collecting system by computed tomography scan. The patient underwent a left partial nephrectomy followed by meticulous suturing of opened pelvicalyceal system. The histopathology result showed clear cell carcinoma. The postoperative period was uneventful, and the patient was discharged without complications. In conclusion, the coexistence of the duplex system and renal cell carcinoma in the ipsilateral kidney is rare and maybe more than a coincidence, requiring a deeper insight and further elucidation.