Overactivity index: A noninvasive and objective outcome measure in overactive bladder in children.

INTRODUCTION: Reports showed that observing detrusor overactivity (DO) and maximum cystometric capacity (MCC) may guide rational pharmacotherapy. Since urodynamic studies (UDS) are challenging for both patients and the healthcare system, a non-invasive objective prognostic marker is preferable. OBJECTIVES: To investigate the value of the overactivity index (OI), a non-invasive measure calculated from the frequency-volume chart (FVC), for predicting the presence of symptoms and abnormal UDS in children with non-neurogenic OAB. STUDY DESIGN: This was a prospective interventional study on a consecutive sample of 92 children with urgency treated with anticholinergics and standard urotherapy. Data from history, physical examination, bladder diaries, kidneys and bladder ultrasonography, uroflow, urinalysis, urine culture, and UDS was collected at baseline, and after 3 and 6 months. Binary logistic regression was used to evaluate noninvasive parameters as predictors of Overactive Bladder Symptom Score (OABSS) total score >2 and DO and/or small MCC defined as <65% of expected bladder capacity (EBC) for age. OI was calculated as (1 - (median (all voided volumes in FVC in ml))/(0.65 ∗ EBC in ml)) ∗ 100. RESULTS: At baseline, 26 patients (36.1%) had DO and small MCC, while 21 patients (29.2%) only had DO. In 18 patients (25.0%) only small MCC was found. Seven patients had normal findings and 20 did not perform a urodynamic study. OI ≥ 23 returned as a single significant predictor of OABSS >2 (OR 7.97, 95% 1.97-32.22, p = 0.004) in multivariate regression (R2 = 30.8%; AUC = 0.86). OI correlated with "urgency episodes over two weeks" and MCC/EBC with medium (r = 0.45) and large effect (r = -0.56), respectively, p = 0.001. DISCUSSION: A strong correlation of OI and MCC/EBC ratio is useful, as rise in MCC is predictive of a positive outcome. Also, calculating the OI is more practical than performing UDS. This could contribute to the use of OI as a predictive marker for starting (or continuing) anticholinergic treatment (when OI ≥ 23) or for maintaining urotherapy alone (when OI < 23) in children with OAB. The limitations were lack of external validation of OI, a 37-49% drop-off rate for follow-up visits at 3 and 6 months, respectively, and not performing UDS on all participants at every follow-up visit. CONCLUSIONS: OI was found to be a significant predictor of the presence of OAB symptoms and correlated with the number of urgency episodes. It could estimate how much MCC differs from EBC.

The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2).

Hypomagnesemia, seizures, and intellectual disability (HSMR) syndrome is a rare disorder caused by mutations in the cyclin M2 (CNNM2) gene. Due to the limited number of cases, extensive phenotype analyses of these patients have not been performed, hindering early recognition of patients. In this study, we established the largest cohort of HSMR to date, aiming to improve recognition and diagnosis of this complex disorder. Eleven novel variants in CNNM2 were identified in nine single sporadic cases and in two families with suspected HSMR syndrome. 25 Mg2+ uptake assays demonstrated loss-of-function in seven out of nine variants in CNNM2. Interestingly, the pathogenic mutations resulted in decreased plasma membrane expression. The phenotype of those affected by pathogenic CNNM2 mutations was compared with five previously reported cases of HSMR. All patients suffered from hypomagnesemia (0.44-0.72 mmol/L), which could not be fully corrected by Mg2+ supplementation. The majority of patients (77%) experienced generalized seizures and exhibited mild to moderate intellectual disability and speech delay. Moreover, severe obesity was present in most patients (89%). Our data establish hypomagnesemia, seizures, intellectual disability, and obesity as hallmarks of HSMR syndrome. The assessment of these major features offers a straightforward tool for the clinical diagnosis of HSMR.

An Unusual Case of Syringohydromyelia Presenting with Neurogenic Bladder.

We report the case of a 4-year-old boy who first presented with acute pyelonephritis at the age of 6 months. Diagnostic workup revealed high-grade bilateral vesicourethral reflux (VUR). At the age of 18 months, a bulking agent was used to treat bilateral VUR. Since the VUR persisted, an open bilateral Lich-Gregoir procedure was done at the age of 3 years. Immediately after surgery, he developed acute urinary retention with hydronephrosis that resolved with the placement of dwelling urinary catheter. After removal of the catheter urinary retention relapsed so placement of suprapubic urinary catheter was indicated since he did not have sensory loss. He was started with tamsulosin (α - 1-blocker) and prophylactic antibiotics. Urodynamics were performed and suggested bladder outlet obstruction. On the basis of previous urethroscopy and the absence of neurological sequelae, the differential diagnosis of Hinman syndrome was made. After removal of the suprapubic catheter, clean intermittent catheterization was started and α-blocker continued. However, magnetic resonance imaging of the brain and the spinal cord revealed syringohydromyelia extending from thoracic spine (Th5) to conus medullaris with 6 to 7 mm in diameter. Electromyoneurogram was normal. After a follow-up of 3 years, the hydronephrosis has resolved. The patient is on clean intermittent catherization and has no urinary tract infections.

Autosomal recessive Alport syndrome caused by a novel COL4A4 splice site mutation: a case report.

Alport syndrome (AS) is a genetically heterogenic, structural disorder of the glomerular basement membrane (GBM) due to the mutation of COL4A3, COL4A4, or COL4A5 genes, which clinically presents as progressive hematuric nephritis with ultrastructural changes of the GBM, high tone sensorineural hearing loss, and ocular lesions. About 15% of AS cases have autosomal mutations of COL4A3 and COL4A4 genes, including homozygous and compound heterozygous mutations. Here, we present a case of a two-year-old boy with autosomal recessive Alport syndrome (ARAS) caused by a novel c.193-2A>C COL4A4 mutation. The patient had a delayed motor and sensory development coupled with speech and language delay, megalencephaly, hematuria and proteinuria, and normal tonal audiogram and ophthalmology exam. Extensive genetic, metabolic, and neurologic workup performed at the age of 10 months was unremarkable and patient's megalencephaly was described as familial benign megalencephaly. Kidney biopsy analysis showed characteristic signs of AS. Mutations screening with use of Illumina MiSeq platform revealed that the patient was homozygous for a newly discovered splice acceptor pathogenic variant c.193-2A>C found in COL4A4 at the genomic position chr2:227985866 and both parents were heterozygous carriers. The genetic heterogeneity of AS makes the diagnostic process challenging. Although renal biopsy provides information about the characteristic GBM changes and the degree of renal parenchyma damage (interstitial fibrosis and tubular atrophy ratio), genetic testing is a more sensitive and specific method that also gives insight into potential disease severity and clinical course, and provides the basis for genetic counseling.

[HYPOKALEMIC METABOLIC ALKALOSIS ­ A REPORT OF SIX CASES].

In this article six patients with hypokalemic metabolic alkalosis, classified as Bartter or Gitelman syndrome are presented. Both syndromes result from different gene mutation inducing impaired function of the transporters involved in sodium, chloride and potassium reapsorption in thick ascending limb of the loop of Henle and distal convoluted tubules. These syndromes typically present with hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism without hypertension, polyuria and muscle weakness. Other clinical characteristics may vary considerably, depending on the gene expression. Correct diagnosis is only possible using expensive and not-routinely available genetic testing. Routine laboratory tests, especially those considering serum and urine electrolytes, can help in recognizing these syndromes and therefore in timely beginning of treatment. The most important distinctive laboratory findings are serum magnesium concentration and urine calcium excretion. In Bartter syndrome typically there is hypercalciuria with or without hypomagnesemia, while in Gitelman syndrome typical findings are hypocalciuria and hypomagnesemia. Recognizing and treating these patients is important due to possible increased morbidity and mortality induced by severe electrolyte imbalance.

The importance of ambulatory blood pressure monitoring in children and adolescents.

The objective of this study was to present our data on ambulatory blood pressure monitoring (ABPM) in children and adolescents referred to our Department because of casual BP elevation over the 95th percentile on at least 3 visits in primary care office. ABPM studies in 139 children, 94 boys and 45 girls, mean age 14.14 (range 4-19) years, were reviewed. A total of 107 (76.98%) children had hypertension according to the ABPM criteria. Primary hypertension (PH) was diagnosed in 89 (64.03%), secondary hypertension (SH) in 18 (12.95%) and white coat hypertension (WCH) in 32 (23.02%) children. In both PH and SH groups, hypertension was predominantly systolic (60.67% and 55.56%, respectively). There was no statistically significant difference in diurnal and nocturnal systolic and diastolic blood pressure (BP) loads between PH and SH groups. The non-dipping phenomenon was detected in 49.44%, 66.66% and 40.62% of children with PH, SH and WCH, respectively. The mean pulse pressure values were 60.41, 58.58 and 52.25 mm Hg in the PH, SH and WCH groups, respectively. A statistically significant difference was found in pulse pressure values between PH and WCH (df=55, t=6.15, P<0.01) groups and between SH and WCH groups (df=31, t=3.18, P=0.001). Target organ damage was diagnosed in 16 (17.98%) children with PH and in 5 (27.78%) children with SH. None of the children with WCH had target organ damage. ABPM is indispensable for establishing the diagnosis of hypertension in children. It is the only reliable method of WCH diagnosis.

Postnatal evaluation and outcome of infants with antenatal hydronephrosis.

This study was aimed at evaluating the clinical outcome of infants with antenatally diagnosed hydronephrosis. Our objective was also to determine whether there is a significant correlation between anterior posterior pelvic diameter (APPD) and urinary tract abnormalities detected. We retrospectively analyzed data of 145 infants collected between January 2000 and May 2010. Inclusion criteria were the presence of APPD > or = 5 mm on prenatal US scan after 20 weeks of gestation, at least 6-month follow-up and at least two postnatal US scans. Most patients underwent renal scintigraphy (n = 140, 96.6%) and micturating cystourethrography (n = 141, 97.2%). Of 145 infants, 77 (53.1%) had idiopathic or transient hydronephrosis. The second most common diagnosis was vesicoureteral reflux found in 21 (14.4%) infants, followed by ureteropelvic junction obstruction without significant kidney damage found in 18 (12.4%) infants. The relative risk of significant urologic abnormality according to the degree of antenatal hydronephrosis (ANH) was 21.25 (95% CI: 2.95-156.49) for severe ANH, 1.57 (95% CI: 0.94-2.62) for moderate ANH and 0.47 (95% CI: 0.33-0.66) for mild ANH. There was a significant increase in the riskper increasing degree of hydronephrosis. In 19 out of 145 (13.2%) infants, immediate surgery was required. These data support the need of antenatal detection and long-term postnatal follow-up of infants with ANH.

[Congenital disorders of glycosylation and project "Euroglycanet"]. / Prirodeni poremecaji glikozilacije i projekt "Euroglycanet".

Congenital disorders of glycosylation are rapidly growing group of inborn errors of metabolism caused by defects in the biosynthesis of glycoproteins. Primary disorders are due to enzyme deficiencies, resulting in defects of assembly, transfer or processing of carbohydrate side chains, leading to incomplete glycosylation of plasma proteins. They comprise disorders of N-glycosylation, O-glycosylation and combined disorders. Congenital disorders of N-glycosylation are multisystem diseases with wide variation in clinical presentation including mental retardation, severe developmental delay, seizures, malformations, structural abnormalities of central nervous system, liver fibrosis, hormonal and coagulation disorders, etc. In contrary, O-glycosylation disorders are often organ restricted and have characteristics of congenital malformations. Isoelectric focusing of serum transferrin is the accepted screening method for many of N-glycosylation disorders. In the last two years the method is available in Croatia. The aim of this article is to point out congenital disorders of glycosylation as possible causes of multisystem disorders of unknown origin, especially when central nervous system symptoms or liver fibrosis are present. "Euroglycanet" is a project set up by European medical doctors, in particular geneticists, and glycobiologists with the purpose to exchange experiences and knowledge and to improve research, diagnosis and treatment of congenital disorders of glycosylation.