Molecular characterization of cystinuria in south-eastern European countries.

Cystinuria is an autosomal recessive disorder caused by defective transport of cystine and dibasic amino acids in the proximal renal tubules and small intestine. So far, more than 128 mutations in SLC3A1 gene, and 93 in SLC7A9 gene have been described as a cause of cystinuria. We present a molecular characterization of the cystinuria in 47 unrelated south-east European families. The molecular methodology included direct sequencing, single strand conformational polymorphism, and restriction fragment length polymorphism. A total of 93 (94.9 %) out of 98 unrelated cystinuric chromosomes have been characterized. Mutations in SLC3A1 gene account for 64.3 % and in SLC7A9 gene for 30.6 % of the cystinuric chromosomes. Ten different mutations in SLC3A1 gene were found, and two of them were novel (C242R and L573X), while in SLC7A9 gene seven mutations were found, of which three were novel (G73R, V375I and c.1048_1051delACTC). The most common mutations in this study were T216M (24.5 %), M467T (16.3 %) and R365L (11.2 %) in SLC3A1 and G105R (21.4 %) in SLC7A9 gene. A population specificity of cystinuria mutations was observed; T216M mutation was the only mutation present among Gypsies, G105R was the most common mutation among Albanians and Macedonians, and R365L among Serbs. The results of this study allowed introduction of rapid, simple and cost-effective genetic diagnosis of cystinuria that enables an early preventive care of affected patients and a prenatal diagnosis in affected families.

Self-reported adherence behavior in adolescent hypertensive patients: the role of illness representations and personality.

OBJECTIVE: This exploratory study examined the role that illness representations and personality play in the various adherence behaviors of adolescents diagnosed with essential hypertension. METHODS: The participants were 97 hypertensive adolescents. They completed self-report questionnaires pertaining to (1) demographic and medical data, (2) adherence, (3) illness representations, and (4) personality. Medical charts were also assessed. RESULTS: The hierarchical regression analyses indicated that: (1) conscientiousness, agreeableness, and perception of treatment effectiveness account for a significant amount of variance in general adherence; (2) perception of treatment effectiveness is predictive of overall specific adherence; and (3) for adherence to most of the individual specific regimen recommendations, illness representations are more predictive compared to personality dimensions. CONCLUSIONS: The personality domains of conscientiousness, extraversion, agreeableness, and illness representation dimensions (treatment control, concern, and emotional burden) were shown to predict adherence behaviors in adolescent hypertensive patients differentially. Study implications and limitations are discussed.

Metabolic syndrome in the pediatric population: a short overview.

The metabolic syndrome (MS) in adults is defined as a concurrence of obesity, disturbed glucose and insulin metabolism, hypertension and dyslipidemia, and is associated with increased morbidity and mortality from cardiovascular diseases and type 2 diabetes. Studies now indicate that many of its components are also present in children and adolescents. Moreover, the clustering of these risk factors has been documented in some children, who are at increased cardiovascular risk in adulthood. The MS is highly prevalent among overweight children and adolescents. Identifying these children is important for early prevention and treatment of different components of the syndrome. The first-line treatment comprises lifestyle modification consisting of diet and exercise. The most effective tool for prevention of the MS is to stop the development of childhood obesity. The first attempt at consensus-based pediatric diagnostic criteria was published in 2007 by the International Diabetes Federation. Nevertheless, national prevalence data, based on uniform pediatric definition, protocols for prevention, early recognition and effective treatment of pediatric MS are still needed.The aim of this article is to provide a short overview of the diagnosis and treatment options of childhood MS, as well as to present the relationships between MS and its individual components.

Polymorphisms in four candidate genes in young patients with essential hypertension.

AIM: To determine whether four potential genetic factors (polymorphisms in genes for alpha-adducin, beta-adducin, the G-protein beta-3 subunit and nitric oxide synthase) are important for the development of essential hypertension (EH) in Slovenian children and young adults with EH. METHODS: Both a nuclear families approach and case-control study have been performed. Genotyping of common polymorphisms in these genes using polymerase chain reaction was carried out in 104 nuclear families (an affected child, both parents) and in 200 control patients. RESULTS: Using the transmission disequilibrium test, no statistically significant differences were found between the frequencies of transmitted and non-transmitted alleles in nuclear families for all four investigated polymorphisms. In addition, the distributions of genotypes and alleles for the four polymorphisms did not differ significantly between our children and 200 healthy control patients. The allele frequencies of all polymorphisms were concordant with those observed in some other Caucasian populations. CONCLUSION: We found no association between the investigated gene variants and EH, so we conclude that they do not confer a significantly increased risk of the development of EH in the Slovenian population of hypertensive children.

Eighteen-year follow-up of a patient with partial hypoxanthine phosphoribosyltransferase deficiency and a new mutation.

Hypoxanthine phosphoribosyltransferase (HPRT) deficiency is an inherited disorder. Complete deficiency of HPRT activity is phenotypically expressed as the devastating Lesch-Nyhan syndrome. Partial HPRT deficiency usually causes hyperuricemia, precocious gout, and uric acid nephrolithiasis. We describe an 18-year follow-up of a 5-year old boy with partial HPRT deficiency and report a novel mutation in his HPRT gene. He presented with overproduction of uric acid and passage of uric acid renal stones, and without gout or neurological and behavioral abnormalities. Treatment with allopurinol, adequate hydration, urinary alkalization, and a low-purine diet was started. No subsequent nephrolithiasis has occurred. After 18-year of this therapy his physical and neuropsychological status were normal, merely his glomerular filtration rate (GFR, normal 97-137 mL min(-1)/1.73 m(2)) fell from normal to 65.1 mL min(-1). The most likely cause of initial renal impairment in our patient is uric and/or xanthine crystalluria. A missense and transition mutation 169A>G (57ATG>GTG, 57met>val) in exon 3 of the patient's HPRT gene was identified and the mother was the carrier of the mutation. As far as we are aware, the identified mutation has not previously been reported. We named the mutant HPRT Maribor.

Twenty-four-hour ambulatory blood pressure monitoring in infants and toddlers.

During the past several years, 24-hour (24-h) ambulatory blood pressure monitoring (ABPM) has become a useful tool for the diagnosis and management of children and adolescents with elevated blood pressure (BP). Some reports have also provided blood pressure nomograms for particular devices. However, there are very few reports of the use of this method in very young children. In our study we investigated the applicability of ABPM in 97 healthy infants and toddlers, aged from 2 to 30 months. A satisfactory ABPM profile was obtained in 86.6% of the children, with an average of 75.0% satisfactory BP recordings. The mean +/- SD systolic and diastolic BP of healthy infants and toddlers was 99+/-12/62+/-12 mmHg during the daytime and 95+/-11/57+/-10 mmHg during the night, with no gender difference being observed. The 24-h mean +/- SD systolic and diastolic BP, which may be a more appropriate measure of BP in this particular age group, was found to be 97+/-12/59+/-11 mmHg. We also confirmed the increase in systolic and diastolic BP with increased height (length). There was only a slight nocturnal decrease in BP. We conclude that this method is applicable for the assessment of blood pressure in very young children.

A diagnostic approach for the child with hypertension.

Hypertension during childhood is not rare, with an estimated prevalence of between 1% and 2%, although it is often an underrecognized clinical entity. Elevated blood pressure may be a sign of underlying disease or it may represent early onset of essential hypertension. In recent years the measurement of blood pressure has been emphasized as an important component of the routine pediatric physical examination that enables early detection of children with hypertension. In the evaluation of the child with documented blood pressure elevation, confirmation of truly and persistently elevated blood pressure is of the utmost importance. In addition, a thorough history and a full clinical examination are essential. These are followed by appropriate investigations, which are tailored to the age of the child and to the severity of the blood pressure elevation. Investigations should not only focus on a search for the underlying cause, but also on establishing effects on target organs, complications or additional diseases and on assessment of the total cardiovascular risk to the individual patient. An algorithm, which is a valuable diagnostic tool for the diagnosis and management of the child with hypertension, is presented. All children with confirmed hypertension need long-term follow-up, counseling and treatment. In those cases where an underlying cause of the hypertension is detected, the established diagnosis then determines the specific therapy and management.

G-protein beta3 subunit gene C825T polymorphism in patients with vesico-ureteric reflux.

The C825T polymorphism in the GNB3 gene encoding a beta3 subunit from heterotrimeric G-proteins correlates strongly with the variation in activity of the G-proteins. It has so far been associated with a variety of medical conditions, but has not been tested for association with vesico-ureteric reflux (VUR). Primary VUR is a condition of genetic origin that appears to be inherited in an autosomal dominant mode, but with reduced penetrance. The constitutional change in G-protein-mediated cell signaling associated with the C825T polymorphism might be one of the factors that participate in the development of VUR by modifying the effect of still unknown mutated gene(s). A significant difference in genotype frequencies (chi(2) = 7.38, P = 0.025, df = 2) was observed between patients with primary VUR (33 CC homozygotes, 40 CT heterozygotes, 12 TT homozygotes) and healthy controls with no medical record of reflux (114 CC homozygotes, 88 CT heterozygotes, 18 TT homozygotes). This result suggests that the C825T polymorphism of the GNB3 gene might be associated with the development of VUR.

Subterminal deletion/duplication event in an affected male due to maternal X chromosome pericentric inversion.

UNLABELLED: We report a 13-month-old male infant with an apparently normal karyotype, severe growth and developmental delay, ichthyosis, hypogonadism, limb shortness, hypoplasia of the corpus callosum and a round, flat face and thin upper lip as a consequence of a subtelomeric del/dup event of the X chromosome. The recombinant X chromosome (rec(X)), derived from crossing-over within the inversion, was identified in a family, in which the mother is a carrier of pericentric inversion of one X chromosome and pericentric inversion of the heterochromatic region of chromosome 9. The inv(X) chromosome was also analysed in her sister and daughter. The rec(X) had a duplication of the segment Xq27.3-->Xqter and deletion of the Xp22.31-->Xpter and was interpreted as Xqter-Xq27.3::Xp22.31-Xqter. The rec (X) was characterised by FISH using a number of BAC probes. There are only three published reports of chromosome rearrangements resulting in a similar subtelomeric duplication of Xq in males. The proband's phenotype corresponds to descriptions of contiguous gene syndromes due to deletion of the STS, SHOX, ARSE and KAL genes. Despite the loss of the ARSE gene there was no evidence of chondrodysplasia punctata. Additional conditions associated with duplication of the Xq28 segment, such as severe growth retardation and developmental delay, a peculiar head shape, atrophy of the cerebral hemispheres and hypoplasia of the cerebellum and corpus callosum, were observed. CONCLUSION: Fluorescent in situ hybridisation techniques using subtelomeric DNA probes are essential tools for detection of such complex submicroscopic chromosomal rearrangements as the dup/del event of the X chromosome described in our patient.

Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.

Angiotensin-converting enzyme gene polymorphism as a cardiovascular risk factor in children.

A family history of cardiovascular disease predicts cardiovascular risk in the next generation, which is either the result of inherited traits or certain living habits in some families. The aim of our study was to evaluate both variables and particularly the role of one of the possible genetic risk factors - angiotensin-converting enzyme (ACE) gene polymorphism. History and anthropometric and biochemical parameters, ACE gene polymorphism and carotid wall thickness - intima media thickness (IMT) were studied in two groups of children: in children whose parents had a stroke before the age of 45 years and in children without a positive family history. The preliminary results of the present study failed to confirm our hypothesis that ACE gene polymorphism is a cardiovascular risk factor in children of parents with premature stroke.