Genetic investigation confirmed the clinical phenotype of congenital chloride diarrhea in a Hungarian patient: a case report.

BACKGROUND: Congenital chloride diarrhea (CCD, OMIM 214700) is a rare autosomal recessively inherited condition characterized by watery diarrhea, hypochloremia and metabolic alkalosis. Mutations of the solute carrier family 26, member 3 (SLC26A3, OMIM 126650) gene are responsible for the disease. The gene encodes a transmembrane protein, which is essential for intestinal chloride absorption. CASE PRESENTATION: Here we report a Hungarian boy, presenting the clinical phenotype of CCD. The patient born at 32 weeks of gestation and underwent surgery for abdominal distension and intestinal obstruction related to malrotation. After recovery, electrolyte replacement therapy was necessary due to several periods of diarrhea. After exclusion of other possible causes, increased chloride concentration in the feces supported the diagnosis of CCD. The diagnosis was confirmed by molecular genetic testing. Direct sequencing revealed compound-heterozygosity for a frameshift mutation c.1295delT (p.Leu432Argfs*11) and the known Polish founder mutation c.2024_2026dupTCA (p.Ile675_Arg676insLeu). CONCLUSIONS: Here we present the clinical symptoms of the first patient in Hungary diagnosed with CCD. Based on the clinical symptoms, stool analysis and genetic testing, the diagnosis of CCD was established. Our study provides expansion for the mutation spectrum of the SLC26A3 gene and the genetic background of CCD.

Hormonal and biochemical parameters correlated with bone densitometric markers in prepubertal Hungarian children.

BACKGROUND: The conditions that define bone development in prepuberty profoundly influence bone health later in life. We aimed to reveal important determinants of bone mass in Tanner stage I. METHODS: We studied 84 healthy children (43 girls and 41 boys) aged 7 to 11 years. Serum estradiol (E2), 25-hydroxyvitamin D3-vitamin [25(OH)D3], intact parathyroid hormone (PTHi), osteocalcin (OC) and ß-crosslaps (CTXs) were longitudinally analyzed (Roche Diagnostics System). Total and spine bone mineral content (tBMC and LBMC) and density (tBMD and LBMD) were assessed, and total fat body mass index (FBMi) was calculated (DXA Lunar Prodigy). RESULTS: The serum PTHi, OC and LBMD values were significantly higher in girls than in boys. The mean 25(OH)D3 level was lower but not significantly in girls compared to boys. Significant negative correlation was found between PTHi and 25(OH)D3 levels (r=-0.28; p=0.011) when tested in all subjects, but no correlation was detected when the gender groups were separately tested. There was a trend for higher E2 levels in girls. Significant positive correlation (r=0.32; p=0.042) was detected between FBMi and E2 concentration in girls only. A significant negative correlation was found between E2 and 25(OH)D3 levels (r=-0.37, p<0.05) in girls with elevated (>3.6pmol/l) PTHi and with suboptimal (<75nmol/l) 25(OH)D3 levels. Furthermore, positive correlations were noted between E2 and CTXs and OC (r=0.54, p<0.01 and r=0.39, p<0.03) and a marginally significant positive correlation (r=0.33; p=0.06) was detected between OC and PTHi levels in girls. However, we detected no correlations when these markers were analyzed in boys. There was a significant correlation between E2 and all BMC and LBMD values in both genders. The tBMD, LBMD and tBMC values showed weak, but significant negative associations with 25OHD3 levels (ß=-0.44 to -0.55; p<0.001) in girls only. All BMD and BMC values were positively predicted by OC levels, but not by CTXs, in both genders. Among the biochemical markers, E2 was the only factor correlating with all dependent variables (BMCs and BMDs) in both genders. Among all parameters analyzed, FBMi (ß=0.64) showed the strongest influence on tBMC characteristically in girls only. CONCLUSIONS: Our results support that 1.) E2 levels play a key role in defining bone turnover and bone mass in both genders already in prepuberty; 2.) high PTHi levels in childhood should be evaluated with caution, because the normal range for serum PTHi in different Tanner stage groups is not well established; and 3.) the negative correlation between 25(OH)D and E2 and the positive correlation between PTHi and OC suggest that estrogens regulate PTHi indirectly and cause lower circulating 25(OH)D3 levels. We propose that the decreased levels of 25(OH)D3 reflect not the real vitamin supply, but may rather be the result of E2 regulation. Therefore, the actual serum 25OHD levels may underestimate the availability of factors supporting bone formation.

Association of lean and fat body mass, bone biomarkers and gonadal steroids with bone mass during pre- and midpuberty.

BACKGROUND/AIMS: The association of bone mass with body composition, bone turnover markers and gonadal steroids was examined in Hungarian children during pre- and midpuberty. METHODS: Two hundred and thirty-seven 7- to 16-year-old subjects (56% girls) were investigated. Bone mineral density (BMD), fat mass and total and appendicular lean mass were estimated with dual-energy X-ray absorptiometry (Lunar Prodigy). The fat mass index and appendicular lean mass index (LMI) were calculated. Serum bone markers, parathyroid hormone, estradiol and testosterone were analyzed. Associations between variables were evaluated by multiple regression analysis. RESULTS: During prepuberty, bone biomarkers, gonadal steroids and appendicular LMI were associated with bone mass in both genders (p < 0.05). During midpuberty, girls' bone turnover markers were negatively associated with bone mass (p < 0.001). In prepuberty, appendicular LMI and ß-crosslaps were predictors of bone mass in both genders. During midpuberty, appendicular LMI and gonadal steroids positively contributed to bone mass in both genders, while osteocalcin exerted a negative influence on total and L1-L4 spine BMD in girls and on L1-L4 BMD in boys (all p < 0.001). CONCLUSIONS: Predictors for bone development varied according to Tanner stage and gender. The most significant determinants of bone mass were appendicular LMI and estradiol.

Randomized trial: immunogenicity and safety of coadministered human papillomavirus-16/18 AS04-adjuvanted vaccine and combined hepatitis A and B vaccine in girls.

PURPOSE: This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone. METHODS: Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7. RESULTS: The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population. CONCLUSIONS: Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls.

[Investigation of adolescents' bone metabolism in the western part of Transdanubia]. / Serdülôk csontanyagcsere-markereinek vizsgálata a nyugat-dunántúli régióban.

UNLABELLED: Childhood reference range based on the age is not available in Hungary, therefore the diagnosis and therapy of bone metabolic diseases of childhood are subject to difficulties. The aim of this work is to provide information about the adolescents' results of bone mineral density and bone biomarkers. SUBJECTS AND METHODS: Measurements were performed in 169 healthy adolescents (98 girls, 71 boys, age: 17.0+/-1.2 years). Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine were measured using Double X-ray Absorptiometry (DXA, LUNAR, GE Health Care, USA) and Z-score values were analyzed using different reference population. In the serum, bone biomarkers osteocalcin (OC) and beta-crosslaps (beta-Cl) were measured by a fully automated, electrochemiluminescence immunoassay method (Elecsys-2010, Roche). Data were analyzed according to gender and the Tanner stage and grade system. Associations between body mass index (BMI), calcium intake, consumption of soft drinks and coke, and physical exercise were investigated. RESULTS: BMC values for both age groups were significantly elevated in boys of the Tanner stage V. (15-16 years: 62.9+/-14.3 g; 17-19 years: 69.8+/-9.3g) than in girls (58.1+/-10.4; 61.6+/-8.5 g) (p<0.001). BMD values were higher in girls, than in boys (1.17+/-0.12 g/cm 2 vs. 1.13+/-0.11 g/cm 2) (p<0.05). OC and beta-Cl levels showed negative correlation with age in both gender (p<0.01), while OC and beta-Cl levels were higher in boys, than in girls (p<0.001). Elevation of BMC and BMD values were associated with increase of BMI in both gender (p<0.05), but the biomarkers in thin girls were higher, than in overweight girls (p<0.05). Authors obtained excellent correlations between the BMD-Z-score values compared to the German standard and to their own population (girls: r=0.97, boys: 0.88), but the absolute values significantly differed from one another. 80% of adolescents are on a diet with insufficient calcium intake, while 38% of them do not play sport regularly. Excessive intake of soft drinks was determined in 60% of adolescents. In the case of insufficient calcium intake (4.7%, 6/127), low bone mass was measured using the Z-score of the German reference values. Among children with adequate calcium intake, BMD assessed by DXA was normal. CONCLUSION: These data help to determine normal reference values among healthy high school students. Further studies are needed in wider range of young population for the establishment of Hungarian reference values of bone markers.

Tick-born encephalitis (TBE) vaccination in children: advantage of the rapid immunization schedule (i.e., days 0, 7, 21).

Tick-borne encephalitis (TBE) is an important, vaccine-preventable arthropod-borne disease, causing severe illness in children too. In order to evaluate the immune response to different licensed primary immunization schedules, a total of 294 children aged 1 to 11 years of age were enrolled in a randomized, controlled, multi-center trial. The subjects were vaccinated with the pediatric formulation of a TBE vaccine (Encepur children) according to the conventional schedule (Group C; N = 73, vaccination on days 0, 28 and 300), the modified conventional schedule (Group M; N = 139, vaccination on days 0, 21 and 300), or the rapid schedule (Group R; N = 82, vaccination on Days 0, 7 and 21). Antibody titers as measured by neutralization-test (NT) and ELISA were determined on Days 0, 42, 180, 300, and 321. The demographic data of the study groups were similar. Most subjects (97%-100%) reached an NT titer of at least 1:10 on Day 42. On Day 42, the highest NT geometric mean titers (GMTs) were reached in Group C. In Group C and Group M, titers declined up to Day 300. Until Day 300, the highest NT-GMTs were maintained in Group R, notably without a decline compared to Day 42. Group M reached titers similar to Group R on Day 42, but these titers declined by 50% up to Day 180. Similar to the NT, on Day 42 highest geometric mean concentrations (GMCs) as measured by ELISA across all groups were reached in Group C. In all groups, titers declined until Day 300. On Day 300, GMC ELISA of Group R was higher compared to Group C and Group M. To conclude, the rapid immunization schedule in children not only provides fast protection but also leads to stable titers as measured by NT for at least 300 days after vaccination.

Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene.

OBJECTIVE: A 5-month-old male infant presenting with recurrent respiratory tract infections, chronic diarrhea, and failure to thrive was found to be pancytopenic. Bone marrow and x-ray examinations were consistent with Shwachman-Diamond syndrome (SDS). Genomic DNA sequencing, restriction fragment analysis, and studies of the mutant proteins were performed to gain further knowledge on the molecular pathology of SDS. MATERIALS AND METHODS: Exons 1 to 5 of the SBDS gene were amplified and sequenced. COS-7 cells were transfected with expression vectors containing wild-type cDNA or mutant cDNAs generated by site-directed mutagenesis. Protein expression of SBDS variants were examined by Western blotting. Pulse-chase assay and densitometry were used to study protein stability. RESULTS: Two novel missense mutations (c.362A > C in exon 3, and c.523C > T in exon 4) of the SBDS gene were identified in the patient. These mutations result in p.N121T and p.R175W amino acid replacements and correspond to amino acid residues that are highly conserved in SBDS proteins. In vitro expression studies revealed a markedly decreased half-life of the p.R175W protein, whereas stability of the p.N121T mutant was not significantly reduced compared to that of the wild type. CONCLUSION: This is the first report of compound heterozygous missense mutations occurring in patients with SDS. These mutations may not eliminate SBDS expression but may result in impaired protein stability and protein function leading to severe disease.

[Chronic recurrent multifocal osteomyelitis]. / Krónikus rekurrens multifokális osteomyelitis.

The chronic recurrent multifocal osteomyelitis has been reported very rarely in the literature. However, its significance must be emphasized, because it is a spontaneously healing, benign disease, as compared to the classical forms of osteomyelitis. It leaves behind almost no residual symptoms, and many operations, long antimicrobial therapy may be avoided by diagnosing it. In this case report the authors provide the review of the disease through the history of a 9-year-old boy.