Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

IgA Deficiency and Membranoproliferative Glomerulonephritis: A Case Report.

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common form of primary immunodeficiency in western countries. It can be associated with the development of autoimmune diseases both in adults and in children even though the exact pathophysiology is not fully defined. CASE PRESENTATION: We report here a case of a young patient who developed nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with the incidental finding of IgAD. We began corticosteroid therapy and angiotensin-converting enzyme inhibitor, and we observed partial remission of the nephrotic syndrome after about nine months; nonetheless, in the following follow-up visits, a progressive decline of renal function was found. CONCLUSION: Our case extends the spectrum of hitherto described glomerulonephritides associated with IgAD which were described until now.

[Extra-hepatic manifestations associated with Hepatitis and virus infection].

Hepatitis E virus (HEV) is a significant public health problem that affects almost 20 million individuals annually and cause acute liver injury in 3,5 million. Hepatitis E virus can cause acute, fulminant and chronic hepatitis and has been associated with a range of extrahepatic manifestation. The spectrum of these manifestation is still emerging. Acute pancreatitis and neurological, renal, hematologic, and muscoloskeletal manifestations have been described. Renal injury include membranoproliferative glomerulonephritis with or without cryoglobulinemia, membranous glomerulonephritis and tubular necrosis. The etiopathogenesis of extrahepatic manifestation is only supposed. It could be caused by a direct tossic effect of HEV or by an autoimmune process. We report a case of a 46 years old man who presented with acute hepatitis E. He was diagnosed to have acute severe renal failure and severe pancreatitis due to hepatitis E. Few cases have been reported in the literature concerning patients suffering from hepatitis E and severe extraepatic manifestations with a benign course and complete recovery.

[Therapy of glucocorticoid induced osteoporosis]. / Terapia dell'osteoporosi da glucocorticoidi.

Glucocorticoid-induced osteoporosis (GIO) is a major cause of secondary osteoporosis that starts early after the beginning of therapy even for low drug doses. Glucocorticoids are used for the treatment of immunologic nephropathies and in the setting of kidney transplant. In clinical practice, a number of algorithms are available; they allow us to estimate the long-term risk of major osteoporotic fracture; but none of them is specific for GIO. To date, the therapeutic approach comprises both general measures aimed at correcting calcium and vitamin D intake, and drugs (bisphosphonates, teriparatide, hormone replacement therapy, denosumab) that ameliorate bone mineral density and patient outcomes.

[Severe neutropenia during treatment with amoxicillin/clavulanic acid in a patient on regular hemodialysis treatment]. / Severa neutropenia durante trattamento con amoxicillina/acido clavulanico in un paziente in trattamento emodialitico regolare.

Beta-lactams are one of the most widely used antibiotics in respiratory diseases, both in adults and in the pediatric population. Their widespread use is also linked to the elevated tolerability and low risk of side effects that are generally not severe. We present here the case of a patient on regular haemodialysis pertaining to our Center who, after a seven-day treatment period with amoxicillin/clavulanic acid antibiotic therapy (medication originator), developed a framework of severe neutropenia (neutrophils till 10/mmc) resulting in hospitalization and the beginning of a specific diagnostic and therapeutic work-up. Our case is characterised, differently from other reports in the literature, for the onset of neutropenia after a short course of antibiotics, with a drug already used in the past without any side effects. During hospitalization, use of immunostimulant therapy led to the rapid recovery of a normal white blood cell count and resolution of severe neutropenia.