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Background: Prenatal diagnosis of hyperechogenic kidneys is associated with a wide range of etiologies and prognoses. The recent advances in fetal ultrasound associated with the development of next-generation sequencing for molecular analysis have enlarged the spectrum of etiologies, making antenatal diagnosis a very challenging discipline. Of the various known causes of hyperechogenic fetal kidneys, calcium and phosphate metabolism disorders represent a rare cause. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth., Methods: We report on three cases of fetal hyperechogenic kidneys corresponding to postnatal diagnosis of nephrocalcinosis. In all cases, antenatal ultrasound showed hyperechogenic kidneys of normal to large size from 22 gestational weeks, with a normal amount of amniotic fluid. Postnatal ultrasound follow-up showed nephrocalcinosis associated with hypercalcemia, hypercalciuria, elevated 1,25(OH) 2 -vitamin D, and suppressed parathyroid hormone levels., Results: Molecular genetic analysis by next-generation sequencing performed after birth in the three newborns revealed biallelic pathogenic variants in the SLC34A1 gene, encoding the sodium/phosphate cotransporter type 2 (Npt2a), confirming the diagnosis of infantile hypercalcemia., Conclusions: Nephrocalcinosis due to infantile hypercalcemia can be a cause of fetal hyperechogenic kidneys, which suggests early antenatal anomaly of calcium and phosphate metabolism. This entity should be considered in differential diagnosis. Postnatal follow-up of infants with hyperechogenic kidneys should include evaluation of calcium and phosphate metabolism.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive disease caused by mutations in the SLC7A7 gene encoding the light subunit of a cationic amino acid transporter. Symptoms mimic primary urea cycle defects but dysimmune symptoms are also described. Renal involvement in LPI was first described in the 1980s. In 2007, it appeared that it could concern as much as 75% of LPI patients and could lead to end-stage renal disease. The most common feature is proximal tubular dysfunction and nephrocalcinosis but glomerular lesions are also reported. However, very little is known regarding histological lesions associated with LPI. We gathered every kidney biopsy of LPI-proven patients in our highly specialized pediatric and adult institution. Clinical, biological, and histological information was analyzed. Five LPI patients underwent kidney biopsy in our institution between 1986 and 2015. Clinically, 4/5 presented with proximal tubular dysfunction and 3/5 with nephrotic range proteinuria. Histology showed unspecific tubulointerstitial lesions and nephrocalcinosis in 3/5 biopsies and marked peritubular capillaritis in one child. Glomerular lesions were heterogeneous: lupus-like-full house membranoproliferative glomerulonephritis (MPGN) in one child evolved towards monotypic IgG1κ MPGN sensitive to immunomodulators. One patient presented with glomerular non-AA non-AL amyloidosis. Renal biopsy is particularly relevant in LPI presenting with glomerular symptoms for which variable histological lesions can be responsible, implying specific treatment and follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown., Methods: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice., Results: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10 -14 ). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies., Conclusions: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Background: HNF1B mutation is the leading cause of isolated hyperechogenic fetal kidneys with normal or moderately large size. Although most cases have normal amniotic fluid volume, some cases present with early oligohydramnios and renal failure associated with high perinatal mortality., Case Diagnosis/treatment: Here we report on seven fetuses from six unrelated families, carrying an HNF1B mutation, and presenting with polyhydramnios during the second or third trimester of pregnancy. Polyhydramnios was transitory in two cases. None of the mothers was presenting gestational diabetes. Bilateral hyperechogenic kidneys with size between -2.5 and +2 SD was the most common renal phenotype at prenatal US. Two patients were born prematurely at 28 and 32 weeks of gestation, respectively. Both presented high urine output the first days of life with urinary salt and potassium loss requiring hydro-electrolytic compensation. All mutations were large deletions removing the whole HNF1B gene., Conclusions: In the absence of maternal diabetes, HNF1B mutation can be associated with polyhydramnios, probably due to fetal polyuria. Thus, HNF1B mutation represents a differential diagnosis of polyhydramnios associated with hyperechogenic (and sometimes enlarged) kidneys.

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS)., Study Design: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations., Results: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years., Conclusion: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: To evaluate the applicability of 3-dimensional evaluation of renal vascularization for predicting postnatal renal function in fetuses with suspected urinary obstruction., Study Design: Fetuses were evaluated by 3-dimensional power-Doppler histogram, and vascular indices were estimated. Depth between the probe and the renal cortex was also evaluated. Postnatal follow-up was obtained in all cases and the main outcome was renal impairment., Results: Twenty-three fetuses with urinary dilatation (cases) and 73 with normal renal morphology (controls) were included in the current study. Five (21.7%) cases developed renal impairment. Vascularization index and vascularization and flow index were significantly lower in fetuses that developed renal impairment compared with those with normal renal function (P = .009 and P = .036, respectively). The 3 vascular indexes correlated with depth. Percentage of depth-corrected vascularization index and vascularization flow index were lower in fetuses developing postnatal renal failure., Conclusion: Fetal renal vascularity (vascularization index and vascularization and flow index) was significantly lower in fetuses that developed renal impairment., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Background and Objectives: Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations., Design, Setting, Participants, & Measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than +3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation)., Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated., Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

Papillorenal syndrome also known as renal-coloboma syndrome (OMIM 120330) is an autosomal dominant condition comprising optic nerve anomaly and renal oligomeganephronic hypoplasia. This reduced number of nephron generations with compensatory glomerular hypertrophy leads towards chronic insufficiency with renal failure. We report on two fetuses with PAX2 mutations presenting at 24 and 18 weeks' gestation, respectively, born into two different sibships. In our first patient, termination of pregnancy was elected for anhydramnios and suspicion of renal agenesis in the healthy couple with an unremarkable previous clinical history. This fetus had bilateral asymmetric kidney anomalies including a small multicystic left kidney, and an extremely hypoplastic right kidney. Histology showed dysplastic lesions in the left kidney, contrasting with rather normal organization in the hypoplastic right kidney. Ocular examination disclosed bilateral optic nerve coloboma. The association of these anomalies, highly suggestive of the papillorenal syndrome, led us to perform the molecular study of the PAX2 gene. Direct sequencing of the PAX2 coding sequence identified a de novo single G deletion of nucleotide 935 in exon 3 of the PAX2 resulting in a frameshift mutation (c.392delG, p.Ser131Thrfs*28). In the second family, the presence of a maternally inherited PAX2 mutation led to a decision for termination of pregnancy. The 18-week gestation fetus presented the papillorenal syndrome including hypoplastic kidneys and optic nerve coloboma. In order to address the PAX2 involvement in isolated renal "disease," 18 fetuses fulfilling criteria were screened: 10/18 had uni- or bilateral agenesis, 6/18 had bilateral multicystic dysplasia with enlarged kidneys, and 2/18 presented bilateral severe hypodysplasia confirmed on fetopathological examination. To the best of our knowledge, our first patient represents an unreported fetal diagnosis of papillorenal syndrome, and another example of the impact of oriented fetopathological examination in genetic counseling of the parents., ((c) 2010 Wiley-Liss, Inc.)

Objective: To characterize the ocular features of renal coloboma syndrome., Design: Prospective, observational case series., Participants: Twelve patients referred by the pediatric nephrology clinic and the ophthalmic records of five additional patients., Methods: For each patient, age at the time of examination, gender, renal function, and presence of a mutation in the PAX2 gene were noted. All patients underwent measurement of visual acuity and anterior and posterior segment examination with fundus photography. Goldmann visual fields were tested in four cases., Main Outcome Measures: Visual acuity, optic disc abnormalities, and mutation in the PAX2 gene., Results: Mean age was 21.5 years. Renal failure was mild in 6 patients and severe in 11 patients. A mutation in the PAX2 gene was identified in nine patients, without correlation to the ocular phenotype. Ocular features could be divided into five groups: optic disc dysplasia limited to an unusual pattern of retinal vessels without functional consequence; optic disc pit with normal visual acuity and blind spot enlargement; large optic disc coloboma; large coloboma of the optic disc and adjacent retina; morning glory anomaly (these last three conditions were accompanied by poor visual acuity). Fundus abnormalities were symmetrical in most cases and unrelated to renal status., Conclusions: Ophthalmic and renal characteristics of the renal coloboma syndrome are highly variable. The need for dialysis or renal transplantation can occur early in life or several years later. A wide range of ocular abnormalities located in the posterior segment can be observed. Mild optic disc dysplasia or pit have no functional consequence and can be underdiagnosed. More severe colobomas or related abnormalities, such as morning glory anomaly, often lead to poor visual acuity. Molecular biology allows detection of the mutations in the PAX2 gene, but can be negative in approximately 50% of cases. The observation of an optic disc coloboma or related abnormality stimulates the ophthalmologist to propose simple nephrologic investigations to check for renal hypoplasia, a potentially life-threatening disease. Conversely, renal hypoplasia stimulates the nephrologist to ask for a fundus examination to confirm the diagnosis and check for complications such as retinal detachment.

Background: Oligomeganephronia (OMN) is a rare congenital and usually sporadic anomaly. It is characterized by bilateral renal hypoplasia, with a reduced number of enlarged nephrons. The mechanisms involved in this deficient nephrogenesis are unknown. The paired box transcription factor PAX2 plays a fundamental role in renal development. Heterozygous Pax2 mutants in mice are characterized by renal hypoplasia and retinal defects, and in humans, PAX2 mutations have been described in the renal-coloboma syndrome., Methods: To assess whether OMN could be related to PAX2, we searched for PAX2 mutations in nine patients presenting with sporadic and apparently isolated OMN., Results: Heterozygous PAX2 mutations were found in three patients. A limited optic nerve coloboma was secondarily detected in two cases and a very mild optic disk dysplasia in one patient. None of these patients had visual impairment., Conclusions: Ocular anomaly and PAX2 mutations should be sought in all patients with OMN.

Hennekam syndrome is a rare autosomal recessive syndrome which was described for the first time in 1989. Here, we present a girl with intestinal lymphangiectasia, severe lymphedema of limbs, seizures, mild mental retardation, and facial anomalies consistent with the diagnosis of Hennekam syndrome. In addition, she had an ectopic kidney and craniosynostosis of the coronal suture, 2 manifestations not previously reported in this syndrome. While the molecular basis of Hennekam syndrome remains, as yet, unknown, this report illustrates its variable clinical expression.