1/13. Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases.Mutations in the Wilms' tumor suppressor gene (WT1) are linked with denys-drash syndrome (DDS), a rare childhood disease characterized by diffuse mesangial sclerosis and renal failure of early onset, XY pseudohermaphroditism, and high risk of Wilms' tumor. KTS (lysine-threonine-serine) splice site mutations in WT1 intron 9 have been described in patients with frasier syndrome, another rare syndrome defined by focal and segmental glomerulosclerosis (FSGS), XY pseudohermaphroditism, and frequent occurrence of gonadoblastoma. Cases of frasier syndrome raise the question whether splice site mutations may also be found in XX females with isolated FSGS. A girl (index case) presented with the nephrotic syndrome at 9 mo of age. The diagnosis of DDS was based on the finding of diffuse mesangial sclerosis in the kidney biopsy and of a XY karyotype. The index case's mother had had proteinuria since she was 6 years of age. A renal biopsy was performed when she was 28 and disclosed FSGS. The same splice site mutation in intron 9 (WT1 1228 5 G-->A) involving one allele was found in the child and in her mother, but not in other members of the kindred (including the parents, the two brothers, and the two sisters of the index case's mother) who were free of renal symptoms. Quantification of WT1 KTS/-KTS isoforms in the index case's father and one index case's maternal uncle showed a normal KTS/-KTS ratio of 1.50. In contrast, the index case and her mother had a low ratio (0.40 and 0.34, respectively), within the range reported in frasier syndrome. In conclusion, this study shows that the KTS splice site mutation is not specific for frasier syndrome, but that it can also be found in DDS and in a normal female (XX) with FSGS, a woman who achieved normal pregnancy. It is suggested that WT1 splice site mutations should be sought in phenotypically normal females who present with FSGS or with related glomerulopathies of early onset.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
2/13. Renal asymmetry in children with autosomal dominant polycystic kidney disease.Although for decades autosomal dominant polycystic kidney disease (ADPKD) was considered a disease of adults, our recent longitudinal studies on children from ADPKD families have shown that the disease is evident by ultrasound imaging in approximately 75% of children who are carriers of the ADPKD1 gene, the most common form of ADPKD. Here we report that, in contrast to adults, the disease appears to be unilateral initially in approximately 17% of children. Asymmetric enlargement of the kidneys is also frequently observed. This renal asymmetry can be extreme and lead to diagnostic confusion. We present 2 unusual cases of asymmetric renal involvement that we have observed during the last 10 years. The first is a 14-year-old boy who was scheduled for a nephrectomy to relieve pain and whose family requested a second opinion. The second is a 10-year-old girl who was diagnosed with ADPKD in utero by prenatal ultrasound. After birth, 1 kidney progressively developed cysts and enlarged, whereas the other had only a few tiny cysts and remained normal in size. A review of the literature shows that presentations like these often lead to a nephrectomy or surgical biopsy. A carefully obtained family history and examination of both parents with ultrasound can help to avoid unnecessary invasive procedures. If pain is a prominent symptom, it can be treated by cyst aspiration if there are only a few cysts or a single dominant cyst. The molecular mechanism for extremely asymmetric renal disease remains to be elucidated.- - - - - - - - - - ranking = 1147.4608503564keywords = polycystic kidney disease, polycystic kidney, kidney disease, polycystic, kidney (Clic here for more details about this article) |
3/13. Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: report of five infants.Five infants (two girls and three boys) from four families all had severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
4/13. Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis c.Chronic hepatitis c virus (HCV) infection may induce immunological disorders in the host such as the presence of cryoglobulinemia or serum autoantibodies. The pathogenesis of these phenomena remains unclear but may reflect the host's genetic predispositions. The aim of this study was to evaluate the association between these immunological manifestations and human leukocyte antigen (HLA) expression in Chinese patients with chronic hepatitis c. The presence of serum cryoglobulin and autoantibodies (antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, antiliver-kidney-microsomal antibody) was determined in 122 Chinese patients with chronic hepatitis c. HLA class I and class II antigens were measured by microlymphocytotoxicity assay or by dna typing in 122 chronic hepatitis c patients and 228 healthy controls. Of the 122 patients with chronic hepatitis c, 52 (43%) had cryoglobulinemia and 48 (39%) had serum autoantibodies. A significant difference in HLA frequency was noted for DR3, which was found in 36.5% of patients with cryoglobulinemia compared with 8.6% of patients without cryoglobulinemia and 11.3% of healthy controls. A significant difference in HLA frequency was also noted for DR4, which was found in 45.8% of patients with serum autoantibodies compared with 17.6% of patients without serum autoantibodies and 19% of healthy controls. Our results suggest the existence of HLA-linked susceptibility genes (DR3 or DR4) for the development of cryoglobulinemia or serum autoantibodies in Chinese patients with chronic hepatitis c.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
5/13. Familial hemophagocytic lymphohistiocytosis: an autopsy study.We describe four classical cases of familial hemophagocytic lymphohistiocytosis (FHL), a macrophage-related, autosomal recessive fatal disorder. Parental consanguinity was present in three cases. All patients presented with fever, neurological involvement of varying degrees, hepatosplenomegaly, cytopenias, deranged liver function tests, and coagulogram, hypofibrinogenemia (three cases), and hyperlipidemia (one case). An antemortem diagnosis could not be made, although it was suspected in one case. Necropsy (done in three cases and postmortem liver biopsy in one case) revealed classical features of FHL. Florid lymphohistiocytic infiltrate exhibiting hemophagocytosis was seen in the bone marrow, liver, spleen, lymph nodes and brain (examined in two case). In addition to this, focal infiltrates were seen in the kidneys, lung, pancreas, testes, adrenals, and skin. Marked lymphoid depletion was seen in one case in the lymph nodes and spleen.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
6/13. Malignancy risk in patient with neurofibromatosis and autosomal dominant polycystic kidney disease.Cancer appearance in some inherited diseases depends on the interactions with other genes. lung cancer is rare in neurofibromatosis and has not been reported in Caucasian population. In this paper, we present the case of lung adenocarcinoma in a patient with neurofibromatosis, pseudoarthrosis of tibia, and autosomal dominant polycystic kidney disease. cytogenetic analysis of the pleural effusion showed chaotic cleavage and constitutional inversion of chromosome 9, transmitted from the mother. family investigation revealed two autosomal dominant diseases, neurofibromatosis and polycystic kidney disease in the same family. These findings suggest that the second autosomal dominant disease in the family and inversion of chromosome 9 contributed to the severity of neurofibromatosis and patient's risk to malignancies.- - - - - - - - - - ranking = 1374.5530204277keywords = polycystic kidney disease, polycystic kidney, kidney disease, polycystic, kidney (Clic here for more details about this article) |
7/13. Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: a new autosomal recessive syndrome?We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non-autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function. The phenotype observed in the two sibs was identical. Although a combination of liver, kidney, and pancreatic involvement has been described in Ivemark syndrome (hepato-renal-pancreatic syndrome), the coexistence of NDM, CH, and glaucoma in both sibs suggests the possibility that this combination of manifestations describes a new autosomal recessive syndrome. mutation analysis for several candidate genes is warranted.- - - - - - - - - - ranking = 285.13755744159keywords = polycystic kidney, polycystic, kidney (Clic here for more details about this article) |
8/13. Homozygous and double heterozygous factor v Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss.Prospective and controlled data about the individual risk profile in asymptomatic children with homozygous or double heterozygous risk genotypes for factor v Leiden (FVL) and factor II (FII) G20210A are currently unavailable. The systematic and prospective observational study presented here was designed to determine the impact of the homozygous and double heterozygous FVL and FII G20210A genotypes on the prenatal and postnatal risk profiles of affected children. risk infants and heterozygous controls were identified by screening of 85,304 neonates. Follow-up included the comparison of prenatal and postnatal development, ultrasonography of brain and kidneys, and a panel of independent determinants of thrombophilia. The numbers of identified or expected FVL homozygotes and double heterozygotes did not differ significantly (FVL: 116 versus 91, p=0.08; FVL/FII: 94 versus 76, p=0.17), indicating the absence of a prenatal disadvantage. A prenatal advantage was suggested in FII homozygotes, whose identified number far exceeded the expected (19 versus 4, p=0.002). Clinical and/or imaging abnormalities indicated spontaneous thromboembolic events in 4 of 129 risk infants (3%) but in none of the 178 controls (p=0.02). Physical and neurological development was normal in both groups during the first 2 years of life. The risk genotypes appear to confer a significant predisposition for spontaneous thromboembolic events in infancy without impeding development within the first two years of life. Foetal risk genotypes do not cause an increased foetal loss rate. Moreover, homozygous FII G20210A appears to be associated with a prenatal advantage.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
9/13. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma.Hereditary paraganglioma syndrome has recently been shown to be caused by germline heterozygous mutations in three (SDHB, SDHC, and SDHD) of the four genes that encode mitochondrial succinate dehydrogenase. Extraparaganglial component neoplasias have never been previously documented. In a population-based registry of symptomatic presentations of phaeochromocytoma/paraganglioma comprising 352 registrants, among whom 16 unrelated registrants were SDHB mutation positive, one family with germline SDHB mutation c.847-50delTCTC had two members with renal cell carcinoma (RCC), of solid histology, at ages 24 and 26 years. Both also had paraganglioma. A registry of early-onset RCCs revealed a family comprising a son with clear-cell RCC and his mother with a cardiac tumor, both with the germline SDHB R27X mutation. The cardiac tumor proved to be a paraganglioma. All RCCs showed loss of the remaining wild-type allele. Our observations suggest that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas and carry implications for medical surveillance.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
10/13. Linking human genetics with molecular medicine: will hereditary renal cancer play a major role?An inherited or familial predisposition to form kidney tumors represents less than 4% of all renal malignancies. However, hereditary renal cancer (HRC) syndromes offer important opportunities for gene discovery and function. Basic and clinical HRC investigation often provides unique insight into regulation of cell growth, cell proliferation, tumor invasion and metastasis. The genetics, biochemistry and physiology of renal tumorigenesis has been directly impacted and significantly expanded by HRC research over the last ten years. Mutations have been identified in several genes tightly linked to increased risk for development of renal cancer. Inheritance of these mutated genes causes specific hereditary syndromes often associated with clinically significant nonrenal manifestations. Molecular and biochemical alterations of most HRC gene products are also detected in sporadic renal cancer emphasizing the importance of HRC gene function in nonhereditary carcinogenesis. Despite these important molecular findings, the clinical contribution of HRC research has generally been limited to genetic screening and prognostic assessment. HRC patients and their physicians continue to face difficult decisions regarding cancer control and quality of life despite advances in minimally invasive surgical and radiological techniques. The ultimate challenge for clinicians and scientists will be translation of molecular and genetic research into clinical tools that impact diagnosis, treatment and prevention. This bench to bedside report describes the diagnosis, genetics, pathophysiology and current cancer treatment options available for HRC syndromes.- - - - - - - - - - ranking = 1keywords = kidney (Clic here for more details about this article) |
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