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Mutations of the UMOD gene, encoding uromodulin, have been associated with medullary cystic kidney disease 2, familial juvenile hyperuricemic nephropathy, and glomerulocystic kidney disease. We report on a 13-year-old boy presenting with chronic reduced kidney function, hyperuricemia, and impairment in urine-concentrating ability. His father was affected by an undefined nephropathy that required transplantation. The boy's renal ultrasonography showed reduced bilateral kidney volumes and cortical hyperechogenicity, with 2 tiny cysts in the left kidney. Renal biopsy showed up to 60% of glomeruli featuring an enlargement of Bowman space (glomerular cysts), with mild interstitial fibrosis (alpha-smooth muscle actin [alphaSMA] positive), inflammatory infiltrate, and focal tubular atrophy at the cortical level. At the corticomedullary junction, immature tubules (some dilated) with cytokeratin- and paired box gene 2 (PAX2)-positive immunostaining were seen, surrounded by vimentin-positive mesenchymal tissue. Unlike previously reported cases, no uromodulin-positive globular aggregates within the cytoplasm of tubular cells were observed. Uromodulin urinary excretion was absent. Genetic analysis showed a novel heterozygous sequence change in the UMOD gene (NM_003361.2:c.149G-->C; p.Cys50Ser) involving the first epidermal growth factor-like domain of the protein in both the boy and his father. This novel UMOD sequence variant, which is associated with an immunohistochemical pattern different from previous reports and a histological picture characterized by immature renal structures, suggests a possible role for UMOD in renal development. [ABSTRACT FROM AUTHOR]

A patient with Angelman syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q11: q11-->pter) karyotype and a patient with Prader-Willi syndrome and a 46,XY/47,XY,+inv dup(15)(pter-->q12: q12-->pter) karyotype were investigated with molecular markers along chromosome 15. Paternal uniparental isodisomy was found for all informative markers in the first case which indicates that this, rather than the presence of the extra chromosome, is the cause of the Angelman syndrome phenotype. Similarly, the PWS patient showed maternal uniparental distomy with absence of PWS region material on the inv dup(15) chromosome. If (1) marker chromosomes are an occasional by product of 'rescuing' a trisomic fertilisation, or (2) if duplication of the normal homologue in a zygote which has inherited a marker in place of the normal corresponding chromosome 'rescues' an aneuploid fertilisation, or (3) if the presence or formation of a marker chromosome increases the probability of non-disjunction, then uniparental disomy might be found occasionally in other subjects with de novo marker chromosomes. [ABSTRACT FROM PUBLISHER]

Background: Mutations in human SIX1 gene cause branchiootorenal or branchiootic syndrome. Six1 deficient mice exhibit uni- or bilateral renal hypoplasia or kidney agenesis. Furthermore a lack of Six1 gene in the ureter leads to hydroureter and hydronephrosis. These murine malformations resemble human kidney and urinary tract congenital anomalies (CAKUT), a group of diseases with a diverse anatomical spectrum which includes duplex collecting system as much as urethra kidney and ureteropelvic anomalies. Our study focuses on whether mutations or deletion of this gene may be associated with nonsyndromic CAKUT., Methods: Fifty unrelated patients (13-21 years) with nonsyndromic CAKUT were retrospectively recruited for SIX1 sequence variations analysis, and compared to three subjects without malformative nephrouropathies (controls). SIX1 coding sequence was screened by high resolution melt analysis (HRMA) and by Sanger direct sequencing. A quantitative comparative real-time polymerase chain reaction (PCR) was later performed in order to detect the presence of SIX1 gene deletion., Results: We did not find significant differences in the HRMA melting curves for each of the SIX1 coding exons between patients and controls, as also confirmed by Sanger direct sequencing. Moreover quantitative comparative real-time PCR for SIX1 and data normalization excluded total SIX1 gene deletion in our patients., Conclusions: We did not find sequence variations in SIX1 coding regions or complete gene deletion in our CAKUT population. These results suggest that alterations in these sequences are unlikely to be a major cause of nonsyndromic CAKUT. Nevertheless, further studies are necessary to understand if altered SIX1 expression may play a role in human development of kidney and urinary tract congenital anomalies.

The NPHS2 gene encodes podocin, a membrane protein that acts as the structural scaffold in podocyte foot processes. NPHS2 mutations are associated with steroid-resistant nephrotic syndrome (SRNS), with the pathologic variant being focal and segmental glomerulosclerosis (FSGS), an emerging cause of end-stage renal disease in children. We describe a novel NPHS2 sequence variant in a girl with SRNS. Onset occurred at the age of seven years, with edema, hypo-proteinemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia and nephrotic proteinuria. Renal function was normal and autoimmunity markers were negative. Proteinuria failed to decrease after standard steroid therapy. Renal biopsy showed FSGS. Cyclosporine therapy was instituted, but no remission of proteinuria was achieved and chronic renal failure developed. Molecular analysis of the NPHS2 gene revealed a homozygous nucleotide substitution in position c.451+3A>T in intron 3-4. This nucleotide substitution has not been reported in the literature till date. The effect of the detected substitution on podocin protein was demonstrated by renal biopsy RNA extraction and cDNA amplification analysis. This technique had never been applied to a NPHS2 mutation. Based on these results, immunosuppressive drugs were discontinued and conservative therapy was undertaken.

We evaluated the association between MCP-1, CCR2, RANTES, and CCR5 gene polymorphisms and upper urinary tract infection in 273 children recruited in Northeast Italy. Statistical analysis of RANTES-403 G>A genotype frequencies showed that children carrying the RANTES-403 G allele are at higher risk for urinary tract infection, irrespective of vesicoureteral reflux., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Pediatric hydronephrosis may correspond to very different clinical situations, ranging from fully benign reversible dilatation to severe obstructive nephropathy. The genetic research is difficult, mainly because the condition is probably polygenic and the embryology of the urinary system is very complex and depends on a multifaceted interaction of genetic and environmental factors. Molecular biology has gained new insights in the complicated urinary system and in the mechanisms of obstructive nephropathy. Some mediators (tumor growth factor, tumor necrosis factor, renin angiotensin system, etc.) could be considered molecular markers of obstruction and it has been proposed to introduce them in clinical decision making, in order to make an accurate selection of patients needing surgical correction. Scintigraphy has been a standard procedure in the management of pediatric hydronephrosis for decades and has been used in many clinical studies designed to evaluate the role of selected molecular markers in clinical settings. The relationships between scintigraphic parameters and molecular mediators seems promising, in particular for the evaluation of the Reanin Angiotensin System, which plays many roles in the natural history of pediatric hydronephrosis. Angiotensin up-regulation is a turning point in many pediatric hydronephrosis and can be unveiled by captopril scintigraphy, which allows a timely diagnosis of obstruction, before irreversible parenchymal injury and loss of renal function.

Background and Objectives: Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally., Design, Setting, Participants, & Measurements: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development., Results: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.-45G>C and c.-27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[-45G>C; -27+18G>A] complex allele, and the others had the c.-27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene., Conclusions: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

Background and Objectives: Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported., Design, Setting, Participants, & Measurements: Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools., Results: Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c.1208G>A in WT1 exon 9 was identified in all of the affected members of the family., Conclusions: The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function.

Background: The main cause of reduced long-term graft survival is chronic allograft injury. Cardiovascular risk factors such as hyperhomocysteinaemia, accumulation of asymmetric dimethylarginine, increased oxidative stress and decreased production of nitric oxide seem to play an important role. Functional polymorphisms of the endothelial isoform of nitric oxide synthase (NOS) gene cause an alteration in nitric oxide production. Nitric oxide levels, and thus oxidative stress, are also influenced by hyperhomocysteinaemia., Methods: We carried out a genetic analysis of endothelial nitric oxide synthase (eNOS) 894G>T, methionine synthase (MTR) 2756A>G and methylenetetrahydrofolate reductase (MTHFR) 677C>T/1298A>C in 268 renal allograft recipient/donor (D/R) matches, with respect to long-term graft survival., Results: While MTHFR 677C>T/1298A>G and MTR 2756A>G polymorphism distribution in both recipients (R) and donors (D) showed no significant difference between matches with loss of graft function and those with long-term graft survival, the frequency of the eNOS 894TT genotype of donors was significantly increased (P = 0.040) in matches with better graft survival. The multivariate analysis identified the eNOS 894 genotype and clinically acute rejection episodes as independent risk factors for graft loss (P = 0.0406 and P = 0.0093, respectively)., Conclusions: The association between eNOS 894G>T polymorphism of donors and graft survival seems to suggest a role for this gene in chronic allograft injury; however, further studies are needed to confirm this hypothesis.

GATA3 gene encodes a transcription factor expressed during thymus, liver, kidney, adrenal gland, central and peripheral nervous systems, placenta and T lymphocytes embryonic development. Mutations of GATA3 cause Hypoparathyroidism, sensorineural Deafness and Renal dysplasia syndrome (HDR). We report the case of a girl with a terminal deletion of the short arm of chromosome 10 (10p12.1-pter), including both HDR locus and the DiGeorge critical region 2 (DGCR2), with HDR phenotype but not DiGeorge syndrome 2 features. The girl developed chronic renal failure during the first year of life, associated with sensorineural hearing loss, facial dysmorphic features and psychomotor development. She had hypodysplastic kidneys and bilateral grade 3-vesicoureteric reflux. Her karyotype was 46,XX,del(10)(p12.1-pter). Quantitative analysis by Real Time PCR on blood DNA confirmed the lack of one copy of GATA3 gene. She underwent renal transplantation at the age of 11. Our patient is the first case with a large deletion of the short arm of chromosome 10 - that certainly involves DGCR2 - with the HDR phenotype but without the clinical features of DGS2. This peculiarity suggests the hypothesis that the mechanisms underlying this syndrome may be more complex. It is therefore possible that DGS2 may be determined by locus heterogeneity.

The severe mental retardation and speech deficits associated with 22q13 terminal deletions have been attributed in large part to haploinsufficiency of SHANK3, which maps to all 22q13 terminal deletions, although more proximal genes are assumed to have minor effects. We report two children with interstitial deletions of 22q13 and two copies of SHANK3, but clinical features similar to the terminal 22q13 deletion syndrome, including mental retardation and severe speech delay. Both these interstitial deletions are completely contained within the largest terminal deletion, but do not overlap with the nine smallest terminal deletions. These interstitial deletions indicate that haploinsufficiency for 22q13 genes other than SHANK3 can have major effects on cognitive and language development. However, the relatively mild speech problems and normal cognitive abilities of a parent who transmitted her identical interstitial deletion to her more severely affected son suggests that the phenotype associated with this region may be more variable than terminal deletions and therefore contribute to the relative lack of correlation between clinical severity and size of terminal deletions. The phenotypic similarity between the interstitial deletions and non-overlapping small terminal 22q13 deletions emphasizes the general nonspecificity of the clinical picture of the 22q13 deletion syndrome and the importance of molecular analysis for diagnosis.

Congenital anomalies of the kidney and urinary tract, as well as primary vesico-ureteric reflux (VUR) and associated renal dysplasia, are the most relevant causes of end-stage renal failure in the pediatric population. In vivo and in vitro experimental studies have allowed the identification of several genes involved both in ureteric bud branching, ureteric elongation and insertion into the bladder, and in nephrogenesis. It has been proposed that both renal and ureteral abnormalities, as well as the associated renal hypo-dysplasia, may derive from a common mechanism as the result of a dysregulation of the normal developmental program. The large homologies between mice and the human genome suggest that the same genes could be involved both in rodent and human VUR. Furthermore, epidemiological observations suggest that not only syndromic but also isolated VUR is an inherited trait. Linkage analysis for homologous mouse genes in humans, genome-wide linkage studies in multigenerational families and association studies by polymorphisms support the hypothesis that VUR is genetically heterogeneous and is caused by a number of different genes acting with random environmental effects. The present teaching paper is an overview of the embryology and genetics of primary VUR and associated congenital reflux nephropathy.

Purpose: We performed a case-control study in children diagnosed by the first episode of upper urinary tract infection with or without vesicoureteral reflux to evaluate the association of functional polymorphism of interleukin-8 (-251A>T and +2767A>G), and its receptor CXCR1 (+2607G>C)., Materials and Methods: Genomic DNA was obtained from 265 children with a clinical and laboratory diagnosis of urinary tract infection who were recruited in northeast Italy. The children were subdivided as 173 who were dimercapto-succinic acid scan positive with positive static renal scintigraphy in acute conditions, consistent with the diagnosis of acute pyelonephritis, and 92 who were dimercapto-succinic acid scan negative. Genetic analysis for the same polymorphisms was also extended to a control population of 106 umbilical cord DNA samples., Results: Statistical analysis of genotype data showed that 1) the tested populations were in Hardy-Weinberg equilibrium, 2) there were significant differences between the dimercapto-succinic acid scan positive and negative groups (p=0.049), and the dimercapto-succinic acid scan positive group vs controls (p=0.032) in terms of interleukin-8 -251A>T polymorphism frequency, 3) there was also a significant difference in the distribution of IL-8 -251A>T and +2767A>G polymorphisms between dimercapto-succinic acid scan positive and negative children in the subgroup without vesicoureteral reflux (p=0.03 and 0.02, respectively) and 4) no significant differences were found in the frequency of the distribution of CXCR1 +2607G>C polymorphism in all groups., Conclusions: These data suggest that the gene for the proinflammatory chemokine interleukin-8 is involved in susceptibility to acute pyelonephritis during upper urinary tract infection in children with or without vesicoureteral reflux.

Dent's disease (DD) involves nephrocalcinosis, urolithiasis, hypercalciuria, LMW proteinuria, and renal failure in various combinations. Males are affected. It is caused by mutations in the chloride channel CLCN5 gene. It has been suggested that DD is underdiagnosed, occurring in less overt forms, apparently without family history. A possible approach to this problem is to search for CLCN5 mutations in patients who may have a high prevalence of mutations: end-stage renal disease (ESRD) patients with previous calcium, struvite, or radio-opaque (CSR) stones. We looked for CLCN5 mutations in 25 males with ESRD-CSR stones selected from all of the patients (1,901 individuals, of which 1,179 were males) of 15 dialysis units in the Veneto region. One DD patient had a new DD mutation (1070 G > T) in exon 7. The new polymorphism IVS11-67 C > T was detected in intron 11 in one patient and one control. We also found 28 females with ESRD and stone history, and seven more males with ESRD and non-CSR stones. The prevalence of stone formers among dialysis patients in our region was 3.2%, much lower than the prevalence observed in older studies. Struvite stones continue to play a major role in causing stone-associated ESRD .

Purpose: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype., Methods: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses., Results: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15., Conclusion: The presented and published data still do not allow any definite conclusions to be drawn concerning karyotype-phenotype correlations. Only concerted efforts to characterize molecularly the sSMCs associated or not with a clinical phenotype can yield results suitable for addressing karyotype-phenotype correlations in support of genetic counseling.

We report on a new case of FRAXE mutation identified through the screening of a population of FRAXA-negative mentally retarded individuals. The index case, a 4-year-old boy with distinct minor anomalies and mental retardation with severe verbal impairment, his older brother, referred to as normal, and the mother have undergone careful clinical and molecular evaluation. The molecular defect, characterized by standard Southern blot analysis, is represented by a hypermethylated "full mutation" in the 2 boys and by a unique, altered, presumably unmethylated, band in the mother, which is interpreted as a "premutation." The cytogenetic analysis failed to detect a folate-sensitive Xq27-28 fragile site in either "fully mutated" individual. The phenotype and intellectual performance of the 15-year-old brother of the propositus appeared completely normal. Our propositus shares some traits with previously described FRAXE-mutated subjects, suggesting an association with the Xq28 molecular defect; nevertheless, we find it difficult to reconcile the molecular identity and phenotypic difference in these mutated members of the same family. This could be a case of extreme phenotypic variability or a result of a more complicated molecular mechanism.

We report the case of a young patient with macrocephaly. After excluding the most frequent causes of macrocephaly (hereditary disorders, degenerative, osseous and metabolic diseases, neurocutaneous syndromes and cerebral malformations), the likelihood of a chromosome disorder was investigated, revealing an unbalanced de novo translocation: 46,X,der(X),t(X;7) (q13 or q13.2; q11.23 or q21.11), i.e., a partial trisomy of the long arm of chromosome 7, associated with a partial monosomy of the long arm of chromosome X. Though this chromosome disorder is relatively rare, it should be considered in the differential diagnosis of patients under one year of age presenting with macrocephaly, scoliosis and non-progressive psychomotor retardation.

The authors describe 7 new cases of Angelman syndrome (AS: 3 males and 4 females) diagnosed on the basis of clinical features (dysmorphic facial features, severe mental retardation with absent speech, peculiar jerky movements, ataxic gait and paroxysms of inappropriate laughter) and neurophysiological findings. Failure to detect deletion of the long arm of chromosome 15 or the absence of epileptic seizure were not considered sufficient to exclude a diagnosis of AS. Feeding problems, developmental delay and early signs of ataxia, especially tremor on handling objects and unstable posture when seated, proved effective as clinical markers for early diagnosis of AS. The EEG patterns characteristic of AS were found within the first 2 years of life (under 18 months in the majority of cases). The authors conclude that AS should be included in differential diagnosis in a child aged under 12 months having cryptogenic psychomotor retardation with prevalent language compromise. Repeat EEG recordings are needed to check for the typical trace, and cytogenetic investigations are mandatory.

This report concerns 2 unrelated patients with apparent CHARGE association and a chromosome abnormality, resulting from different unbalanced familial translocations involving chromosomes 2 and 18 in one family, and chromosomes 3 and 22 in the other. Although the identification of two different chromosome abnormalities might be due to chance, the observation of a long arm deletion of chromosome 22 in patients 2 and of the frequent coexistence of CHARGE association and DiGeorge anomaly raise the possibility of a contiguous gene syndrome in at least some CHARGE cases.

The authors report on cytogenetic results of six patients with hypomelanosis of Ito. Karyotypes from peripheral lymphocytes prometaphases and skin fibroblasts metaphases were normal. A review of the literature revealed no specific chromosomal abnormality but a close association between mosaicism and HI syndrome. The X-chromosome was involved in 53% of the abnormal cases.

Anticentromere antibody (ACA) was investigated in 116 blood relatives of 22 ACA positive patients affected with scleroderma and, for comparison, in 82 healthy subjects matched for age and sex who belonged to 25 families. No relative showed any evident scleroderma symptom although in 8 an unusual cold sensitivity of the extremities was present. ACA at a low titer (40), was found in 4 relatives (3.44%), while it was absent in control sera. The 4 ACA positive relatives were first as well as second degree relatives of probands. Two had familial disease: one idiopathic chronic hypoparathyroidism and the other mental retardation. The third had myasthenia gravis and the fourth unusual cold sensitivity and allergic dermatitis. At present we cannot explain the significance of ACA occurrence in relatives of ACA positive patients. Followup clinical and serological studies could show a possible association of low titer of ACA with subclinical scleroderma features in patients who later develop overt disease.

Proximal extra material in the long arm of chromosome 15, has been described in individuals with different phenotypes (isolated mental retardation, multiple malformations, repeated miscarriages), and with apparently normal phenotype, in which cytogenetic analysis was invariably carried out on the basis of clinical indications. The paper describes a child with mental retardation, and his father, who both had proximal extra material in 15q. Caution is advised in the study of karyotype-phenotype correlation.

Cytogenetic investigation was carried out on 231 female patients referred for suspected sex chromosome abnormality. Cases were classified into five groups according to reason for referral and chromosome abnormality frequency was estimated. The overall frequency of abnormal karyotypes was 38.5%. The rate of positive identification of chromosome abnormality ranges from 0 in patients with secondary amenorrhoea to 80% in those with Turner phenotype. Our data demonstrate that the indications for referral of female patients with suspected sex chromosome abnormality are not only primary amenorrhoea alone or short stature and primary amenorrhoea without Turner stigmata, but also short stature of unknown etiology without any additional anomaly during childhood.

Three subjects from 2 unrelated families with partial duplication of 17q, derived from a reciprocal parental translocation between chromosomes 11 and 17 with different breakpoints, are described. A female patient from one family with a 46,XX,-11,+der(11),t(11;17)(q24;q23.2)pat chromosome complement had died at 2 months of age. In the second family, a male propositus and a subsequent fetus, identified by cytogenetic prenatal diagnosis, showed a 46,XY,-11,+der(11),t(11;17)(q2505,q24.3) mat chromosome complement. Twelve other cases involving partial duplication of chromosome 17 have been reported, 11 of these derived from a balanced translocation, and 1 was a duplication. All these cases showed psychomotor and mental retardation, cranial contour anomalies, micrognathia, bulbous nose, short neck, skeletal anomalies, and CNS defects. The phenotypic and clinical observations in the three subjects of this report are compared with previously reported findings.