Zelal Bircan

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell’s apical H+-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in “sporadic” cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation

Objectives To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria. Methods The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a subgroup of 280 cases (128 difficult cases, 152 randomly selected) enabling expert diagnostic verification. Step 3: Ankara 2008 Consensus Conference and statistical evaluation (sensitivity, specificity, area under the curve, κ-agreement) using as ‘gold standard’ the final consensus classification or original treating physician diagnosis. Results A total of 1183/1398 (85%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a κ-agreement of 0.96 for HSP (95% CI 0.84 to 1), 0.88 for c-WG (95% CI 0.76 to 0.99), 0.84 for c-TA (95% CI 0.73 to 0.96) and 0.73 for c-PAN (95% CI 0.62 to 0.84), with an overall κ of 0.79 (95% CI 0.73 to 0.84). Conclusion EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

Background Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCɛ1) have been recently described in patients with early onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. Method In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutational analysis was performed in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid resistant NS presenting at a median age of 23.0 months (range 0–373). Results Homozygous or compound heterozygous mutations were identified in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype–phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. Conclusion PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.

Intravenous cyclophosphamide is the drug of choice for steroid dependent nephrotic syndrome

Abstract Background : Steroid dependency is a major problem seen after therapy for idiopathic nephrotic syndrome in childhood. Although there is consensus about the usage of cyclophosphamide (CYC) in frequent relapsers, there is still a controversy concerning its usage in steroid‐dependent nephrotic syndrome (SDNS).

Childhood idiopathic nephrotic syndrome in Turkey

Background : It has been reported that there are racial and regional differences in peak incidence age, histopathological features and response to steroid therapy in childhood idiopathic nephrotic syndrome.

Does albumin and furosemide therapy affect plasma volume in nephrotic children

Abstract Albumin infusions transiently increase plasma volume (PV) and oncotic pressure, and may restore diuretic responsiveness in nephrotic edema. To determine if albumin and furosemide therapy have an effect on PV in nephrotic children, 14 severely edematous children with minimal change nephrotic syndrome were evaluated with standard clinical parameters (heart rate, blood pressure, body weight, pretibial edema, abdominal circumference) and echocardiography [inferior vena cava index (IVCI), inferior vena cava collapsibility index (IVCCI)] before, 1 h and 24 h after albumin (20%, 0.5 g/kg, 1 h) and furosemide (2 mg/kg, IV) therapy. An increase in IVCI (P<0.05), decrease in IVCCI (P<0.05), edema (P<0.005), and hematocrit (P<0.005) were statistically significant 1 h after albumin and furosemide therapy, with a transient effect 24 h later. Body weight (P<0.005), abdominal circumference (P<0.05), and edema (P<0.005) decreased significantly at 24 h. It is concluded that albumin and furosemide therapy increases PV transiently in nephrotic edema, returning to baseline values at 24 h with a decrease in body weight, abdominal circumference, and edema.

A case of aquaporin 2 R85X mutation in a boy with congenital nephrogenic diabetes insipidus

Autosomal recessive nephrogenic diabetes insipidus (ARNDI) is a rare disease usually seen in patients with consanguineous parents. We report on a case of ARNDI in a patient with non-consanguineous parents who presented with recurrent febrile attacks. The differential diagnosis of ARNDI was made by desmopressin infusion test. A homozygous mutation, R85X, was detected in the aquaporin 2 gene (AQP2) of our patient, which has been described only once previously. This case is presented to stress that even male patients with non-consanguineous parents could have ARNDI with a AQP2 gene defect, and the desmopressin infusion test is useful for differential diagnosis.

Protracted familial mediterranean fever arthritis presenting as septic arthritis

In Familial Mediterranean Fever (FMF), arthritis is the initial symptom in 25% of patients. Although FMF arthritis is acute and self-limited, in 5% of cases protracted arthritis usually affecting large joints such as knee may occur. In this report, two cases are presented who were initially diagnosed as septic arthritis, first of which had four and the second had two synovectomy operations with the diagnosis of septic arthritis. Later on they were diagnosed as FMF with detailed history. We aimed to emphasize the importance of diagnosis of FMF, which is based mainly on history and clinical features in order to prevent unnecessary operations and suffering of the patient.

Protracted febrile myalgia mimicking polyarteritis nodosa.

An insidious onset of unexplained fever, weight loss, skin lesions, abdominal pain, and musculoskeletal pain should suggest the diagnosis of polyarteritis nodosa (PAN). However, familial Mediterranean fever (FMF) with protracted febrile myalgia (PFM) should be kept in mind in the differential diagnosis. In this report, 6 cases of PFM mimicking PAN are described. Patients presented with severe muscle and abdominal pain lasting longer than 4 weeks. Their common medical history included recurrent febrile abdominal pain or arthritis. Physical examination revealed hypertension together with severe muscle tenderness. Laboratory examination revealed high acute phase reactants, negative p-ANCA, normal creatine kinase, and complement levels. Duplex abdominal ultrasonography was normal. Four of 6 patients were hospitalized with initial diagnoses of PAN. Renal and mesenteric angiography performed in 1 patient was normal. Steroid therapy controlled all the severe symptoms including hypertension in all of the cases.FMF with PFM is important in the differential diagnosis of patients with suspected vasculitis especially when myalgia is present. Hypertension may be present as a result of sympathetic discharge because of severe myalgia. Because PFM rapidly responds to a short course of corticosteroids, a rapid diagnosis of PFM in FMF patients can reduce unnecessary workup and decrease the time patients have to suffer.

Deletion of exons 2–4 in the BSND gene causes severe antenatal Bartter syndrome

BSND gene mutations usually cause severe forms of antenatal Bartter syndrome and sensorineural deafness (SND). Chronic renal failure and transient hypercalciuria are reported as controversial symptoms of this syndrome. All twelve reported BSND mutations cause SND, whereas only two of the mutations give rise to normal glomerular filtration rate (GFR) and two other mutations cause hypercalciuria. The case we report here, where the patient presented with severe clinical symptoms and deletion on exons 2–4 of the BSND gene, has not been reported previously. Decreased GFR, along with hypercalciuria and difficulties in managing fluid and electrolyte requirements, are the reasons why this patient was brought to attention.