Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

Novel DNA mutation in the GATA3 gene in an Emirati boy with HDR syndrome and hypomagnesemia.

We report the case of a young Emirati boy with HDR (Hypoparathyroidism, sensorineural Deafness, and Renal hypoplasia) syndrome due to the novel heterozygous deletion of two nucleotides (c.35_36delGC ) in exon 2 of the GATA3 gene. The patient developed hypocalcemia and hypomagnesemia at 3 weeks of age with high fractional excretion of magnesium, indicating renal magnesium loss. This is the first published report of hypomagnesemia in association with HDR syndrome.

Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy.

INTRODUCTION: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN. METHODS: We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined. RESULTS: Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls. CONCLUSIONS: Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.

Unusual Presentation of Polyautoimmunity and Renal Tubular Acidosis in an Adolescent With Hashimoto's Thyroiditis and Central Pontine Myelinolysis.

Background: Hashimoto's thyroiditis is frequently associated with other autoimmune diseases and may include renal involvement. Case description: A 17-year-old female with previously diagnosed Hashimoto's thyroiditis and vitiligo was admitted to a pediatric intensive care unit with hypokalemic paralysis and acidosis, after having suffered from recurrent muscular weakness for approximately one year. A few days later she developed central pontine myelinolysis. After initial stabilization she was also diagnosed with distal renal tubular acidosis (dRTA) and tubular proteinuria which can occur in Sjögren's syndrome. Extended screening for autoimmune diseases additionally revealed celiac disease. Treatment with Prednisone and substitution of potassium quickly lead to the resolution of proteinuria and dRTA, but unilateral paralysis of the sixth nerve as a result of central pontine myelinolysis was irreversible. Conclusions: This is the rare case of polyautoimmunity including autoimmune thyroiditis, Sjögren's syndrome, vitiligo and celiac disease in an adolescent with few disease-specific symptoms. The diagnoses were made via a complicating nephritis causing dRTA and proteinuria. Delay in diagnosis lead to permanent neurological damage. This case highlights the need for pediatricians to be aware of rare accompanying diseases and their complications in "common" pediatric autoimmune diseases like Hashimoto's thyroiditis and celiac disease.

Uric acid excretion in rotavirus gastro-enteritis.

BACKGROUND: Urate urolithiasis in children has been reported in Japan in association with rotavirus (RV) gastro-enteritis (GE). AIMS: To test the hypothesis that children with RV GE have an increased risk of hyperuricosuria compared with GE presumably caused by other viruses. OBJECTIVES: Prospective analytic cohort study of urinary uric acid excretion in children presenting with GE between 1 January 2011 and 31 May 2012. METHODS: Two groups were compared: group R (RV GE) and group N (with presumed other viral causes of GE). Serum urea, creatinine (Scr), uric acid (Sur) and urinary uric acid were compared with creatinine (Uur/Ucr) ratio, fractional excretion of uric acid (FEur) and uric acid for creatinine clearance between the two groups. RESULTS: A total of 87 Emirati children were enrolled in the study. Group R included 46 children (mean age 25 months) and group N 41 children (mean age 43 months). There was no significant difference between the two groups in the blood levels of urea, creatinine, uric acid, nor in urinary pH and specific gravity. Urinary uric acid excretion measured by Uur/Ucr ratio, uric acid for creatinine clearance and FEur was not significantly different between the two groups. CONCLUSION: There was no significant difference in uric acid levels and uric acid excretion between patients with RV GE and those with other presumed viral causes of GE. Further studies with larger sample sizes including children with more severe dehydration and a prolonged course of GE are needed.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC): report of three cases with a novel mutation in CLDN19 gene.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is caused by mutation in the genes coding for tight junction proteins Claudin-16 and Claudin-19. Affected individuals usually develop nephrocalcinosis and progressive renal failure; some of them may have ophthalmologic involvement as well. Phenotypic description of three affected individuals from the same Middle Eastern kindred (two sisters and their cousin) is presented. This includes both clinical and laboratory findings upon initial presentation and subsequent follow-up. Molecular analysis of the CLDN19 gene was performed on the three cases and one set of parents. A novel homozygous missense mutation in CLDN19 (c.241C>T, p.Arg81Cys) was detected in all three affected children. The parents were heterozygous. Clinical and laboratory data in the three children with renal and ocular manifestations of FHHNC are described. Genetic analysis revealed a novel mutation in the CLDN19 gene. FHHNC is a rare cause of nephrocalcinosis, and we believe that it should be considered in the presence of nephrocalcinosis with hypercalcuria and hypermagnesuria.

Bradycardia following oral corticosteroid use: case report and literature review.

INTRODUCTION: Corticosteroids are used in various clinical conditions that include many immune-mediated inflammatory diseases. Different side effects were described including cardiac arrhythmias. Most of those arrhythmias were in the form of bradycardia which usually occurs with high intravenous steroid doses. More significant arrhythmias and cardiac arrest were also described. In this report we describe a case of bradycardia that developed after the use of oral corticosteroids. CASE REPORT: We report a case of bradycardia that developed in a 14 year-old male after receiving oral prednisone. The patient had steroid-sensitive nephrotic syndrome and presented with anasarca that started to develop few days prior to hospitalization. He had no underlying heart disease. Vitals was normal. Investigations confirmed a new nephrotic relapse. Oral prednisone 80 mg / day divided into three doses was started. Albumin infusions were initially given with intravenous furosemide to control the edema. Seven days after hospitalization, he developed bradycardia with a pulse rate of 50-60 per minute, which was less than 50% of the baseline heart rate. He didn't develop significant symptoms and he had no other apparent corticosteroids side effects. Cardiac evaluation and echocardiography were normal. Electrocardiogram revealed only sinus bradycardia.The bradycardia recovered after decreasing the dose of steroids to 60 mg PO every other day and he was discharged in stable condition a few days later. CONCLUSION: Cardiac arrhythmias may develop with all forms of steroids including oral prednisone. Bradyarrhythmias can occur even with standard doses of oral prednisone.

Systemic lupus erythematosus with severe nephritis that mimicked Henoch-Schoenlein purpura.

INTRODUCTION: Systemic lupus erythematosus (SLE) belongs to a family of related autoimmune rheumatic disorders that are capable of affecting multiple organs, and they are all associated with a variety of autoantibodies. Henoch Schoenlein purpura (HSP) is a sort of systemic vasculitis that is not associated with auto-antibodies and can affect different organs including the kidneys. CASE REPORT: A 12 year-old girl presented with abdominal pain, low grade fever, swollen and tender feet and left hand, skin rash on the lower extremities, and high blood pressure. Initial laboratory tests revealed severe proteinuria, microscopic hematuria and low C3 level. Renal biopsy showed diffuse proliferative glomerulonephritis with IgA, fibrinogen and C3 deposits. The case was accordingly diagnosed as HSP with severe IgA nephropathy. Treatment was started with mycophenolate mofetil (MMF) and pulse methylprednisolone followed by prednisolone. The patient improved and treatment was discontinued after 5.5 months. One month after withdrawal of her medications, the patient presented again with serositis and recurrent proteinuria. Both antinuclear antibodies (ANA) and anti dsDNA were positive. At this point she was diagnosed to have SLE disease and immunosuppressive treatment was restarted. Following this, symptoms disappeared, proteinuria regressed and anti-dsDNA titer dropped. CONCLUSION: This case presented with features of HSP and was later-on diagnosed to have SLE. This kind of clinical overlapping has not been reported in the literature to the best of our knowledge.

Lupus cystitis in an Omani girl.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organs involvement. Bladder involvement (Lupus cystitis) is a rare manifestation of SLE, and occurs in association with gastrointestinal manifestations. We report a case of lupus interstitial cystitis with bladder irritation and bilateral hydroureteronephrosis in an adolescent female who was treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone and mycofenolate mofetil (MMF). Her symptoms ameliorated, and the hydroureteronephrosis improved. She was presented again with systemic flare up of the disease together with hydrouretronephrosis, but without bladder irritation symptoms. The diagnosis of lupus cystitis was confirmed by radiographic abnormalities, cystoscopy and bladder biopsy.