Loss of Planar Cell Polarity Effector Fuzzy Causes Renal Hypoplasia by Disrupting Several Signaling Pathways

In vertebrates, the planar cell polarity (PCP) pathway regulates tissue morphogenesis during organogenesis, including the kidney. Mutations in human PCP effector proteins have been associated with severe syndromic ciliopathies. Importantly, renal hypoplasia has been reported in some patients. However, the developmental disturbance that causes renal hypoplasia is unknown. Here, we describe the early onset of profound renal hypoplasia in mice homozygous for null mutation of the PCP effector gene, Fuzzy. We found that this phenotype is caused by defective branching morphogenesis of the ureteric bud (UB) in the absence of defects in nephron progenitor specification or in early steps of nephrogenesis. By using various experimental approaches, we show that the loss of Fuzzy affects multiple signaling pathways. Specifically, we found mild involvement of GDNF/c-Ret pathway that drives UB branching. We noted the deficient expression of molecules belonging to the Bmp, Fgf and Shh pathways. Analysis of the primary cilia in the UB structures revealed a significant decrease in ciliary length. We conclude that renal hypoplasia in the mouse Fuzzy mutants is caused by defective UB branching associated with dysregulation of ciliary and non-ciliary signaling pathways. Our work suggests a PCP effector-dependent pathogenetic mechanism that contributes to renal hypoplasia in mice and humans.

Clinical, Genetic and Orthopedic Characteristics of Desbuquois Dysplasia

Introduction. Desbuquois dysplasia is a rare skeletal dysplasia with an autosomal recessive inheritance, resembling to the group of multiple joint dislocations. The disease is caused by mutations in the CANT1 and XYLT1 genes, the protein products of which are involved in the degradation of proteoglycans, which play an important role in endochondral ossification. The polymorphism of clinical and radiological characteristics and the genetic heterogeneity of Desbuquois dysplasia necessitate the description of the phenotypic characteristics of patients with various types of mutations, which optimize diagnosis. Objective description of the clinical and radiological characteristics of three Russian patients with Desbuquois dysplasia of types 1 and 2 with remarkable orthopedic manifestation, caused by mutations in the CANT1 and XYLT1 genes. Materials and Methods. Genealogical, clinical, radiographic and genetic data of three unrelated Russian patients aged 2 to 8 years was carried out. Genetic testing was carried out using clinical exome sequencing and methyl-sensitive PCR. Results. Two patients were diagnosed with type 1 disease due to a previously described homozygous mutation in the CANT1 gene: c.898CT (p.Arg300Cys), and one type 2 due to heterozygous mutations in the XYLT1 gene. One mutation: c.1651CT (p.Arg551Cys) was detected during exome sequencing, and the second mutation: expansion of GGC repeats in the promoter region of the gene, revealed by methyl-sensitive PCR of the first exon of the gene. The main clinical signs of the disease were micromelic dwarfism, hypermobility in the joints and specific facial dysmorphisms, radiographic analysis revealed characteristic monkey wrench appearance of the proximal femur in all 3 patients, additional ossification center of the second metacarpal, advanced bone age and multiple dislocations in the joints. The patients also had extra-skeletal manifestations (congenital glaucoma, obstructive bronchitis, renal hypoplasia and congenital heart malformations). Conclusion. Genetic heterogeneity and the presence of polymorphism of clinical manifestations make it possible to consider sequencing of the clinical exome as the optimal method for diagnosing Desbuquois dysplasia types 1 and 2. Analysis of the literature and the results of our molecular genetic data indicate the possibility of expansion of the GGC repeat in the XYLT1 gene in patients with clinical manifestations of type 2 Desbuquois dysplasia.

Case Report: Candidate Genes Associated With Prenatal Ultrasound Anomalies in a Fetus With Prenatally Detected 1q23.3q31.2 Deletion

Background: Patients with deletions involving the long arm of chromosome 1 are rare, and the main aim of this study was to refine the genotype-phenotype correlation.Case Report: In this report, a 28-year-old pregnant woman, gravida 2 para 1, at 25+4 weeks of gestation underwent ultrasound examination in our institute. The ultrasonographic findings of the fetus were as follows: (1) fetal growth restriction; (2) cleft lip and palate; (3) bilateral renal hypoplasia; (4) lateral ventriculomegaly; (5) single umbilical artery; (6) absent stomach; (7) coronary sinus dilatation with persistent left superior vena cava, ventricular septal defect and unroofed coronary sinus syndrome. Chromosomal microarray analysis of amniotic fluid from the fetus revealed a 28.025 Mb deletion in 1q23.3q31.2, spanning from position 164,559,675 to 192,584,768 (hg19).Conclusion: Genotype-phenotype correlation might improve prenatal diagnosis of fetuses with chromosome 1q deletion. PBX1 could be a candidate gene for fetal growth restriction, renal hypoplasia and congenital heart disease. Fetal growth restriction was accompanied by decreased renal volume in the fetus. Combined with ultrasonic examination, the application of chromosomal microarray analysis will provide accurate prenatal diagnosis.

Fraser Syndrome With Megalencephaly: A Rare Association

An outborn term neonate was referred at 12 h of life with multiple congenital anomalies. A baby was born out of consanguineous marriage to a mother with 2 previous abortions. Clinical examination showed features such as bilateral cryptophthalmos, syndactyly involving all limbs, and clitoromegaly suggestive of Fraser syndrome. Ultrasound of the abdomen showed unilateral renal hypoplasia. Echocardiography showed ostium secundum atrial septal defect, small ventricular septal defect, and patent ductus arteriosus. Magnetic resonance imaging of the brain revealed megalencephaly with polygyria. Further evaluation and surgical treatment of cryptophthalmos were advised but could not be done because of socioeconomic constraint, and the neonate was discharged and lost to follow-up. The occurrence of cerebral malformations in Fraser syndrome is highly variable and not very well described in the literature. To the best of our knowledge, association of megalencephaly with this syndrome is being reported for the first time. We also intend to educate the physicians about the antenatal clues associated with this rare syndrome, which could promote antenatal diagnosis and thereby modify the outcome.

Unilateral seminal vesicle agenesis in patient presenting with epididymo-orchitis

Seminal vesicle anomalies are rare. It includes agenesis, hypoplasia, duplication, fusion and cyst. Agenesis of seminal vesicle is usually associated with anomalies of ipsilateral kidney and can be the cause of infertility in male [1]. We report a case with seminal vesicle agenesis with ipsilateral renal hypoplasia.

A Homozygous Dab1−/− Is a Potential Novel Cause of Autosomal Recessive Congenital Anomalies of the Mice Kidney and Urinary Tract

This study aimed to explore morphology changes in the kidneys of Dab1−/− (yotari) mice, as well as expression patterns of reelin, NOTCH2, LC3B, and cleaved caspase3 (CASP3) proteins, as potential determinants of normal kidney formation and function. We assumed that Dab1 functional inactivation may cause disorder in a wide spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Animals were sacrificed at postnatal days P4, P11, and P14. Paraffin-embedded kidney tissues were sectioned and analyzed by immunohistochemistry using specific antibodies. Kidney specimens were examined by bright-field, fluorescence, and electron microscopy. Data were analyzed by two-way ANOVA and t-tests. We noticed that yotari kidneys were smaller in size with a reduced diameter of nephron segments and thinner cortex. TEM microphotographs revealed foot process effacement in the glomeruli (G) of yotari mice, whereas aberrations in the structure of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were not observed. A significant increase in reelin expression, NOTCH2, LC3B and cleaved CASP3 proteins was observed in the glomeruli of yotari mice. Renal hypoplasia in conjunction with foot process effacement and elevation in the expression of examined proteins in the glomeruli revealed CAKUT phenotype and loss of functional kidney tissue of yotari.

Renal oligohydramnios and Potter sequence with cystic kidney disease

For the first time in 1946 E.L. Potter (1901–1993) described the characteristic appearance of stillborns and deceased newborns with bilateral renal agenesis. Due to the further observations Potter distinguished the syndrome (Q60.6) – a set of characteristic external signs that are formed due to the extreme degree of oligohydramnios and intrauterine compression of the fetus. Classical Potter syndrome is diagnosed by the disfunction of both kidneys in the fetus (for example, bilateral agenesis), which leads to death. The term «Potter sequence» or oligohydramnios sequence with diverse causes has received the wide clinical use. The term «renal oligohydramnios» (ROH) is used to describe oligohydramnios resulting from a decrease or absence of fetal kidney function. The authors state that renal oligohydramnios and Potter sequence often develop in the fetus with cystic kidney disease with the formation of cysts in the parenchyma of both kidneys (autosomal recessive polycystic kidney disease, autosomal dominant polycystic kidney disease, glomerulocystic kidney disease associated with HNF1ß/TCF2 gene mutations, renal-coloboma syndrome, cystic renal hypoplasia, cystic renal dysplasia with mutations of the CEP55 gene).

Early Robotic-Assisted Laparoscopic Pyeloplasty for Infants Under 3 Months With Severe Ureteropelvic Junction Obstruction

Objective: To present our primary experience of robotic-assisted laparoscopic pyeloplasty (RALP) for severe ureteropelvis junction obstruction (UPJO) infants under 3 months.Methods: We performed a retrospective study of 9 infants under 3 months who underwent RALP for severe UPJO between April 2017 and March 2019 in our center. The severe UPJO was defined as infants with severe hydronephrosis (Society of Fetal Urology grades III or IV, anteroposterior diameter >3 cm or split renal function <40% or T 1/2 >20 min) involving bilateral, solitary kidney, or contralateral renal hypoplasia UPJO at the same time. All clinical, perioperative, and postoperative information was collected.Results: There were four bilateral UPJO cases, two solitary kidney UPJO cases and three unilateral UPJO with contralateral renal hypoplasia cases included. One single surgeon performed RALP on all of the infants. The mean age of the infants was 1.62 ± 0.54 months. The mean operative time was 109.55 ± 10.47 min. The mean estimated blood loss was 19.29 ± 3.19 ml, and the mean length of hospital stay was 5.57 ± 0.73 days. According to the ultrasonography results, all patients had a significant recovery of renal function at 12 months after the operation.Conclusions: To maximize the protection of renal function, early RALP is a safe and feasible option for the treatment of severe UPJO in infants under 3 months.

Pathophysiological clinical features of an infant with hypertension secondary to multicystic dysplastic kidney: a case report

Background The association of hypertension with congenital renal hypoplasia has been established. We report a case of an infant who underwent nephrectomy for hypertension. Case presentation Magnetic resonance imaging for the mother revealed fetal renal masses, and fetal multicystic dysplastic kidney was suspected. Following birth, the baby developed hypertension. Numerous investigations revealed that the left kidney was non-functional, and she was initiated on benazepril hydrochloride. However, because the drug response was poor, the left kidney was removed at the age of 7 months. Examination of the renal specimen revealed abrupt transition from normal to atrophic cortex with lobar atrophy and cysts. Tubular atrophy, marked abnormal blood vessels with wall thickening, gathered immature glomeruli, and parenchymal destruction were observed. Renin was partially localized in the proximal tubules and the parietal epithelium of the Bowman’s capsule in the immature glomeruli. We speculated that an abnormal vascular structure and irregular renin localizations may be the cause of hypertension. Serum renin and aldosterone levels gradually reduced post-surgery, reaching normal levels on the 90th postoperative day. A long follow-up is needed due to the possibility of the child developing hypertension in the future. Conclusion This is a case of an infant with MCDK, which discusses the clinicopathological features based on the pathophysiological analysis, including renin evaluation.

Renal Dysplasia in a Free-Living Giant Anteater Cub (Myrmecophaga tridactyla) - Ultrasonographic and Tomographic Aspects

Background: Renal dysplasia is a congenital disorder that occurs during differentiation of the renal parenchyma or as a consequence of a functional and/or structural obstruction of the lower urinary tract. In wild animals, this pathology has been reported in cynomolgus monkeys (Macaca fascicularis), golden hamsters (Mesocricetus auratus) and African elephants (Loxodanta africana). However, there are no reports of the disease in the giant anteater (Myrmecophaga tridactyla). Thus, this paper describes a case of renal dysplasia in a free-living giant anteater cub, which was sent to the wild animal clinic of the Federal University of Mato Grosso (UFMT) in Cuiabá, MT, Brazil. Case: The rescued animal had a good body condition score and clinical parameters within the normal range for the species. After a routine clinical evaluation, the anteater cub was subjected to radiography and ultrasound tests. Blood tests, serum tests for hepatic and renal profiles, urinalysis, urinary protein creatinine ratio, and chest X-rays did not reveal significant changes. However, the abdominal ultrasound examination revealed a volumetric loss of about 1.17 cm in length in the left kidney, and a renal length to aortic artery diameter ratio of approximately 2.8. This kidney showed irregular contours, loss of corticomedullary demarcation, with preserved echogenicity and cortical echotexture. The right kidney showed the standard size of the species, with a length of approximately 3.08 cm. In view of the suspicion of renal dysplasia, a contrast-enhanced CT scan was performed in order to assess the dynamics of uptake and excretion of the contrast medium in the affected kidney and in the ipsilateral collecting system. An examination of the tomographic images indicated that the volume of the left kidney was reduced, isodense in relation to the right kidney, with discrete and homogeneous uptake in all phases after administration of the contrast medium, no occurrence of nephrogram and pyelogram phases, or any detection of contrast in the corresponding ureter.Discussion: Giant anteaters (Myrmecophaga tridactyla) are animals classified as a species vulnerable to extinction. Today, most research involving this species focuses on its ecology, behavior, diet, morphology and parasitology, but little is known about the imaging aspects of the species or about congenital changes such as renal dysplasia. Although the definitive diagnosis of this pathology depends on a histopathological examination, the same diagnosis can be made with a wide margin of safety by assessing the epidemiological aspects and the dynamics of renal uptake of the contrast medium through computed tomography. In this analysis, both vascularization and renal filtration capacity can be assessed. Thus, based on CT imaging, it was concluded that this was a case of renal dysplasia, since the left kidney showed a discrete homogeneous uptake stable in both the arterial and venous phases, without producing any accumulation of contrast medium in the pelvic region or the collecting system, proving to be completely nonfunctional. These findings differ from cases of renal hypoplasia, which, although they reduce renal volume, do not cause structural changes in the renal parenchyma or disturbances in the filtration dynamics of contrast media. They also differ from cases of acquired chronic nephropathy, since, albeit associated with reduced renal volume and changes in renal filtration dynamics, they produce different parenchymal ultrasound changes that usually occur in elderly animals and generally produce bilateral lesions.