Potter Deformation Sequence Caused by 17q12 Deletion: A Lethal Constellation.

17q12 deletion syndrome causes developmental abnormalities of the kidneys, pancreas, genital tract, and neurodevelopment, and it has a wide range of phenotypes ranging from fetal demise to normal adulthood with minimal renal impairment. Here we describe a rare case of 17q12 deletion diagnosed prenatally, complicated by anhydramnios and Potter sequence. The baby was born but necessitated life-saving interventions due to pulmonary and renal insufficiency and ultimately succumbed to multi-organ failure. We present full autopsy results describing findings linked to 17q12 deletion, including severe bilateral multicystic renal dysplasia, pancreatic hypoplasia, and cysts adjacent to the Fallopian tubes. We also describe pulmonary hypoplasia and Potter facies as consequences of anhydramnios. We correlate these findings to our current understanding of molecular signals altered by 17q12 deletion, notably affecting HNF1B and LHX1 genes, which are known to mediate renal and genitourinary tract development.

Cytogenomic aberrations in isolated multicystic dysplastic kidney in children.

BACKGROUND: Multicystic dysplastic kidney (MCDK) is a common form of congenital kidney anomaly. The cause of MCDK is unknown. We investigated whether MCDK in children is linked to cytogenomic aberrations. METHODS: We conducted array comparative genomic hybridization (aCGH) in ten unrelated children with MCDK. The pattern of inheritance was determined by real-time PCR in patients and their biological parents. RESULTS: Pathogenic aberrations were detected in three patients: a deletion at 7p14.3 with a size of 2.07 Mb housing 12 genes, including BBS9 (Bardet-Biedl syndrome 9) and BMPER (BMP binding endothelial regulator); a duplication at 16p13.11p12.3 with a size of 3.28 Mb that included >20 genes; and monosomy X for a female patient. The deletion at 7p14.3 was inherited from the patient's father, while the duplication at 16p13.11p12.3 was derived from the patient's mother. CONCLUSIONS: Up to 30% of patients with MCDK possess cytogenomic aberrations. BBS9 and BMPER variants have been reported to result in cystic kidney dysplasia, suggesting a possible pathogenic function for the deletion at 7p14.3 in children with MCDK. The duplication at 16p13.11p12.3 was not reported previously to associate with MCDK. Both variations were inherited from parents, indicating hereditary contributions in MCDK. Thus, aCGH is an informative tool to unravel the pathogenic mechanisms of MCDK. IMPACT: Cytogenomic aberrations are common in children with MCDK. Cytogenomic aberrations are inherited from parents, indicating hereditary contributions in MCDK. aCGH is a valuable tool to reveal pathogenic mechanisms of MCDK.

[Enlarged multicystic dysplastic kidneys with oligohydramnios during infancy caused by NPHP3 gene mutation].

OBJECTIVE: To explore the clinical features and genomic abnorm ality of a fetus enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation. METHODS: The fetuse was found to have multicystic dysplastic kidneys with oligohydramnios upon ultrasonography during the second trimester. Following induced abortion, fetal tissue was collected for the extraction of DNA, chromosomal microarray analysis (CMA) and whole exome sequencing (WES). Sanger sequencing was used to verify the suspected variants in the family. RESULTS: Antenatal ultrasound examination at 19 weeks showed "polycystic" kidneys with Oligohydramnios. Delivery was by induced labour because of the critically low amniotic fluid volume. Testing of CMA was normal. WES showed a compound heterozygous mutation of c.1817G>A, p.W606X; c.432dupA, p.E145Rfs*18 mutations are novel mutations in this study. CONCLUSION: The research may further expand the NPHP3 gene mutation spectrum. Enlarged multicystic dysplastic kidneys with oligohydramnios caused by NPHP3 gene mutation at least include one or two splice site mutation, frameshift mutation or nonsense mutation foetal poor prognosis.

Sequence variants in the renin-angiotensin system genes are associated with isolated multicystic dysplastic kidney in children.

BACKGROUND: Multicystic dysplastic kidney (MCDK) is a common form of congenital cystic kidney disease in children. The etiology of MCDK remains unclear. Given an important role of the renin-angiotensin system in normal kidney development, we explored whether MCDK in children is associated with variants in the genes encoding renin-angiotensin system components by Sanger sequencing. METHODS: The coding regions of renin (REN), angiotensinogen (AGT), ACE, and angiotensin 1 receptor (AGTR1) genes were amplified by PCR. The effect of DNA sequence variants on protein function was predicted with PolyPhen-2 software. RESULTS: 3 novel and known AGT variants were found. 1 variant was probably damaging, 1 was possibly damaging and one was benign. Out of 7 REN variants, 4 were probably damaging and 3 were benign. Of 6 ACE variants, 3 were probably damaging and 3-benign. 3 AGTR1 variants were found. 2 variants were possibly damaging, and one was benign. CONCLUSION: We report novel associations of sequence variants in REN, AGT, ACE, or AGTR1 genes in children with isolated MCDK in the United States. Our findings suggest a recessive disease model and support the hypothesis of multiple renin-angiotensin system gene involvement in MCDK. IMPACT: Discovery of novel gene variants in renin-angiotensin genes in children with MCDK. Novel possibly damaging gene variants discovered. Multiple renin-angiotensin system gene variants are involved in MCDK.

The molecular biology of pelvi-ureteric junction obstruction.

Over recent years routine ultrasound scanning has identified increasing numbers of neonates as having hydronephrosis and pelvi-ureteric junction obstruction (PUJO). This patient group presents a diagnostic and management challenge for paediatric nephrologists and urologists. In this review we consider the known molecular mechanisms underpinning PUJO and review the potential of utilising this information to develop novel therapeutics and diagnostic biomarkers to improve the care of children with this disorder.

LDL Receptor-Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia.

Hypoplastic and/or cystic kidneys have been found in both LDL receptor-related protein 6 (Lrp6)- and ß-catenin-mutant mouse embryos, and these proteins are key molecules for Wnt signaling. However, the underlying mechanisms of Lrp6/ß-catenin signaling in renal development and cystic formation remain poorly understood. In this study, we found evidence that diminished cell proliferation and increased apoptosis occur before cystic dysplasia in the renal primordia of Lrp6-deficient mouse embryos. The expression of Ret proto-oncogene (Ret), a critical receptor for the growth factor glial cell line-derived neurotrophic factor (GDNF), which is required for early nephrogenesis, was dramatically diminished in the mutant renal primordia. The activities of other representative nephrogenic genes, including Lim1, Pax2, Pax8, GDNF, and Wnt11, were subsequently diminished in the mutant renal primordia. Molecular biology experiments demonstrated that Ret is a novel transcriptional target of Wnt/ß-catenin signaling. Wnt agonist lithium promoted Ret expression in vitro and in vivo. Furthermore, Lrp6-knockdown or lithium treatment in vitro led to downregulation or upregulation, respectively, of the phosphorylated mitogen-activated protein kinases 1 and 3, which act downstream of GDNF/Ret signaling. Mice with single and double mutations of Lrp6 and Ret were perinatal lethal and demonstrated gene dosage-dependent effects on the severity of renal hypoplasia during embryogenesis. Taken together, these results suggest that Lrp6-mediated Wnt/ß-catenin signaling modulates or interacts with a signaling network consisting of Ret cascades and related nephrogenic factors for renal development, and the disruption of these genes or signaling activities may cause a spectrum of hypoplastic and cystic kidney disorders.

Prenatal diagnosis of fetal multicystic dysplastic kidney via high-resolution whole-genome array.

BACKGROUND: Women with fetal multicystic dysplastic kidneys (MCDK) are commonly referred for genetic counseling, for which identification of the correct etiology is a prerequisite. METHODS: A total of 72 women with fetal MCDK at Guangzhou Women and Children's Medical Center were examined via invasive prenatal diagnosis from May 2010 to June 2015. Standard karyotyping analysis was provided to all fetuses, and chromosomal microarray with Affymetrix CytoSan HD arrays was offered to cases whose DNA samples were available. RESULTS: Abnormal karyotypes were detected in 3 of 72 (4.17%) fetuses. Of the 69 (95.8%, 69/72) fetuses with normal karyotypes, 30 (42%, 30/69) underwent chromosome microarray analysis (CMA) testing. The CMA identified pathogenic copy number variations in five fetuses, leading to a pathogenic detection rate of 16.7% (5/30). Well-known microdeletion or microduplication syndromes including renal cysts and diabetes (RCAD) syndrome and Williams-Beuren syndrome (WBS) were identified in three cases. Moreover, four chromosomal imbalanced regions were also identified in our MCDK fetuses: 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK. The proportions of variants of unknown significance before and after parental analysis were 13.3% (4/30) and 3.3% (1/30), respectively. CONCLUSIONS: In the present study, the frequency of chromosomal abnormalities in MCDK fetuses was 4.17% and all rearrangements were imbalanced aberrations. CMA was able to increase the pathogenic detection rate to 16.7% in MCDK fetuses with normal karyotype. Critical regions for RCAD syndrome, WBS and copy number variants of 22q11.1 duplication, 4q35.2 deletion, 22q13.33 duplication and 1p33 duplication were associated with fetal MCDK. Genes PEX26, ELN, HNF1B, ALG12, FRG1, FRG2 and CYP4A11 were possible candidates for fetal MCDK.

Copy number variations in multicystic dysplastic kidney: update for prenatal diagnosis and genetic counseling.

OBJECTIVE: To assess the clinical implication of chromosomal microarray analysis (CMA) in prenatal diagnosis of MCDK. METHODS: Thirty-seven cases with MCDKs detected by prenatal ultrasound were enrolled in the study; 33 cases were isolated MCDKs and four cases were non-isolated MCDKs. CMA was performed on the Affymetrix CytoScan HD platform. The frequencies of the detected CNVs were compared with 461 cases that underwent CMA for anomalies unrelated to congenital anomalies of kidney and urinary tract (CAKUT) or 124 healthy newborns as controls. All of the annotated CNVs were validated by MLPA or qPCR. RESULTS: Pathogenic CNVs were detected in 13.5% (5/37) of MCDKs. Two 17q12 deletions, one untypical 22q11.2 deletion, and one 22q11.2 duplication were detected in four isolated MCDK cases. Duplication of 1q31.3q44 was identified in a non-isolated MCDK case. Three of the five pathogenic CNVs were inherited. We also validated eight CNVs of uncertain significance only detected in MCDKs and five CNVs with higher frequency in MCDKs. CONCLUSION: A substantial proportion of MCDKs were associated with pathogenic CNVs. Family members with the same CNV were asymptomatic or of different kind of renal malformations. It may be reasonable to perform CMA when MCDKs are identified prenatally. © 2016 John Wiley & Sons, Ltd.

[Application of chromosome microarray analysis for fetuses with multicystic dysplastic kidney].

OBJECTIVE: To explore the genetic etiology of fetuses with multicystic dysplastic kidney (MCDK) by chromosome microarray analysis (CMA). METHODS: Seventy-two fetuses with MCDK were analyzed with conventional cytogenetic technique, among which 30 fetuses with a normal karyotype were subjected to CMA analysis with Affymetrix CytoScan HD arrays by following the manufacturer's protocol. The data was analyzed with ChAS software. RESULTS: Conventional cytogenetic technique has revealed three fetuses (4.2%) with identifiable chromosomal aberrations. CMA analysis has detected pathogenic CNVs in 5 fetuses (16.7%), which included two well-known microdeletion or microduplication syndromes, i.e., 17q12 microdeletion syndrome and Williams-Beuren syndrome (WBS) and three submicroscopic imbalances at 4q35.2, 22q13.33, and 1p33. PEX26, FKBP6, TUBGCP6, ALG12, and CYP4A11 are likely the causative genes. CONCLUSION: CMA can identify the submicroscopic imbalances unidentifiable by conventional cytogenetic technique, and therefore has a significant role in prenatal diagnosis and genetic counseling. The detection rate of pathogenic CNVs in fetuses with MCDK was 16.7% by CMA. 17q12 microdeletion syndrome and WBS are associated with MCDK. Mutations of PEX26, FKBP6, TUBGCP6, ALG12, and CYP4A11 genes may be the causes for MCDK.

Severe neonatal presentation of Kleefstra syndrome in a patient with hypoplastic left heart syndrome and 9q34.3 microdeletion.

BACKGROUND: Kleefstra syndrome arises from haploinsufficiency of EHMT1 caused by either microdeletions at 9q34.3 or intragenic mutations. Patients with Kleefstra syndrome have multisystem involvement including intellectual disability, hypotonia, and characteristic facial features. METHODS: We report on the severe neonatal presentation of the first case of Kleefstra syndrome associated with hypoplastic left heart syndrome and multicystic renal disease in a patient with a 9q34.3 microdeletion. RESULTS: Array-CGH analysis revealed a 2.1 Mb deletion at 9q34.3, including EHMT1 and NOTCH1. CONCLUSION: Kleefstra syndrome is a multisystem disorder with a high frequency of congenital heart disease and less frequently, renal defects. Mortality has rarely been documented, particularly in infancy. Based on the present case and the extant literature, a routine echocardiogram and renal ultrasound should be ordered in all cases of Kleefstra syndrome. The cardiac changes seen in this patient could be the result of the haploinsufficiency of EHMT1, NOTCH1, or their combined effect.

Dyserythropoiesis in a child with pyruvate kinase deficiency and coexistent unilateral multicystic dysplastic kidney.

Pyruvate kinase (PK) deficiency is the commonest enzyme deficiency in the glycolytic pathway leading to hemolytic anemia secondary to decreased Adenosine Triphosphate (ATP) synthesis in the red cells. synthesis. PK deficiency due to mutations in the PKLR (1q21) gene leads to highly variable clinical presentation ranging from severe fetal anemia to well compensated anemia in adults. We describe dyserythropoiesis in the bone marrow of a child with transfusion dependent anemia and unilateral multicystic dysplastic kidney (MCDK) mimicking Congenital Dyserythropoietic Anemia type I (CDA type I). Persistently low erythrocyte PK levels and double heterozygous mutations present in the PKLR gene confirmed the diagnosis of PK deficiency.

TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia.

OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.

Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients.

AIM: The angiotensin type 2 (AT2 ) receptor takes part in the process of ureteric bud during kidney development. Therefore, the gene encoding AT2 receptor, the AGTR2 gene located in the X chromosome, is a potential candidate for genetic association with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). This study aimed to investigate whether AGTR2 gene polymorphisms are associated with CAKUT in general or even with common phenotypes of CAKUT in a Brazilian sample of paediatric patients. METHODS: We analyzed 290 paediatric patients with CAKUT and 262 healthy controls from the same geographic area. TaqMan single-nucleotide polymorphism (SNP) genotyping assays for AGTR2 gene at rs1403543, rs3736556, rs35474657, rs5193 and rs5194 were performed. The sample was in Hardy-Weinberg Equilibrium for all five SNPs. RESULTS: The presence of CAKUT in general was not significantly associated with the SNPs included in this study. However, when patients were segregated according to major phenotypes, the diagnosis of Ureteropelvic Junction Obstruction (UPJO) was significantly associated with AGTR2 gene polymorphisms at rs3736556 and at rs5194. On the other hand, the diagnoses of vesicoureteral reflux and of multicystic dysplastic kidney were not associated with AGTR2 gene polymorphisms. CONCLUSION: Our results support that the AGTR2 gene may contribute to the pathogenesis of UPJO and the genetic origin of CAKUT could vary according to phenotype expression.

Genetic and radiological aspects of pediatric renal cystic disease: A case series / Aspectos genéticos e imagenológicos de la enfermedad quística renal en pediatría: serie de casos

Renal cystic diseases are common conditions whose etiology can be highly heterogeneous. They require a correct approach for adequate diagnosis and management. We aimed to illustrate part of the spectrum of renal cystic diseases through some clinical cases managed in our service. We describe 11 clinical cases including clinical entities such as renal multicystic dysplasia, and autosomal dominant and autosomal recessive polycystic renal disease, among other pathologies. Renal cystic diseases are heterogeneous in their clinical presentation, natural history, radiological findings, and genetic and pathophysiological basis. An integral clinical approach is needed to get a clear etiological diagnosis and offer adequate individualized care and follow-up for patients.

Las enfermedades quísticas renales son condiciones frecuentes cuya etiología puede ser muy heterogénea, por lo que se requiere un adecuado abordaje para su diagnóstico y manejo. El objetivo de este trabajo fue ilustrar parte del espectro de la enfermedad renal quística por medio de casos clínicos manejados en la Fundación Valle del Lili. Se describen 11 casos clínicos que incluyen enfermedades como displasia multiquística renal, enfermedad poliquística renal autosómica dominante y autosómica recesiva, entre otras. Las enfermedades quísticas renales varían en su presentación clínica, historia natural, hallazgos imagenológicos, bases genéticas y fisiopatológicas, por consiguiente, el enfoque diagnóstico y el manejo integral se debe realizar de forma individualizada y con un abordaje multidisciplinario.

Different phenotypes of HNF1ß deletion mutants in familial multicystic dysplastic kidneys.

Multicystic dysplastic kidney (MCDK) is one of the most common congenital abnormalities of the kidney and urinary tract (CAKUT), although its pathophysiology remains unknown. Familial occurrence of MCDK suggests that mutations in genes associated with nephrogenesis are involved in the pathogenesis in at least some cases. Hepatocyte nuclear factor 1ß (HNF1ß) is a member of the homeodomain-containing super family of transcription factors, and is known to regulate tissue-specific gene expression in a number of organs including the kidneys, pancreas and liver. It has been recently postulated to be associated with CAKUT, including MCDK. We recently encountered a family with a deletion mutant of HNF1ß, of which the 2nd son, the proband, developed bilateral MCDK resulting in renal loss of function in infancy while the 1st son developed unilateral MCDK. Their father has two normal kidneys. This family confirmed that mutations in the HNF1ß gene are strongly associated with the development of MCDK. Furthermore, the fact that no clear phenotype-genotype correlation exists suggests that gene(s) other than HNF1ß are also involved in nephrogenesis and the development of MCDK.

Autosomal dominant polycystic kidney disease with ectopic unilateral multicystic dysplastic kidney.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. In most cases, ADPKD similarly affects bilateral kidneys. CASE PRESENTATION: Among the 605 ADPKD patients that were followed up by our center, we identified two male patients with unilateral ADPKD. The cases were remarkable because the patients also had ectopia and multicystic dysplasia in the contralateral kidney, which are generally sporadic disease conditions. Both patients tested positive for polycystic kidney disease 1 mutation, but negative for hepatocyte nuclear factor 1 beta mutation. Moreover, the deterioration of their kidney function seemed to be quicker than their age- and sex-matched controls and siblings. Both patients had started a long-term hemodialysis in their 40s. CONCLUSION: Anatomical and genetic abnormality in patients with ADPKD may be more frequent and complex than previously believed. The compensatory capacity in patients with ADPKD is fragile, and missing one kidney could accelerate the deterioration of renal function.

Ultrasound diagnosis of central nervous system anomalies (bifid choroid plexus, ventriculomegaly, Dandy-Walker malformation) associated with multicystic dysplastic kidney disease in a trisomy 9 fetus: case report with literature review.

Trisomy 9 is a lethal chromosomal abnormality that rarely progresses beyond the second trimester of pregnancy. Multiple central nervous system anomalies, including bifid choroid plexus, ventriculomegaly, and Dandy-Walker malformation, associated with multicystic dysplastic kidney disease in a trisomy 9 fetus are reported. The prenatal ultrasound diagnosis has been aided by novel three-dimensional ultrasound software.

Classifying and evaluating fetuses with multicystic dysplastic kidney in etiologic studies.

Multicystic dysplastic kidney (MCDK) is one of the most common fetal malformations, but its etiology remains unclear. Identification of the molecular etiology could provide a basis for prenatal diagnosis, consultation, and prognosis evaluation for MCDK fetuses. We used chromosome microarray analysis (CMA) and whole-exome sequencing (WES) to conduct genetic tests on MCDK fetuses and explore their genetic etiology. A total of 108 MCDK fetuses with or without other extrarenal abnormalities were selected. Karyotype analysis of 108 MCDK fetuses showed an abnormal karyotype in 4 (3.7%, 4/108) of the fetuses. However, CMA detected 15 abnormal copy number variations (CNVs) (14 pathogenic CNVs, and one variant of unknown significance [VUS] CNVs), in addition to four cases that were consistent with the results of karyotype analysis. Out of the 14 pathogenic CNVs cases, three were of 17q12 microdeletion, two of 22q11.21 microdeletion, 22q11.21 microduplication uniparental disomy (UPD), and one case of 4q31.3q32.2 microdeletion, 7q11.23 microduplication, 15q11.2 microdeletion, 16p11.2 microdeletion, and 17p12 microdeletion. Of the 89 MCDK fetuses with normal karyotype analysis and CMA, 15 were tested by WES. Two (13.3%, 2/15) fetuses were identified by WES as Bardet-Biedl syndrome (BBS) 1 and BBS2. Combined application of CMA-WES to detect MCDK fetuses can significantly improve the detection rate of genetic etiology, providing a basis for consultation, and prognosis evaluation.