Tricho-rhino-phalangeal syndrome in a 13-year-old girl with chronic renal failure and severe growth retardation

Introduction: The tricho-rhino-phalangeal syndrome type III (TRPS III) is a rare autosomal dominantly inherited condition. The main clinical features are sparse and slow-growing hair and nails, a pear-shaped nose with a bulbous tip, elongated and flat philtrum, thin upper lip, cone-shaped epiphyses of the phalanges, and short stature. All patients have a point mutation in the TRPS1 gene. Case report: In this paper, we present a 13-year-old female with the typical clinical features of TRPS III, extreme growth retardation, severe deformities of both proximal radii resulting in limited extension of the elbows, and chronic renal failure (CRF) in addition. Molecular diagnostics revealed a missense mutation in exon 6 of TRPS1 that she inherited from her father who is also affected with TRPS III, but does not have CRF. In the index patient, the CRF was found to be due to bilateral renal hypodysplasia (RHD). Conclusion: Beside the renal dysplasia, the girl had severe deformities of the proximal radii – findings which have not been reported so far in TRPS III.     

Atypical presentation of distal renal tubular acidosis in two siblings

Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis. We report two male siblings who presented with severe hyperchloremic metabolic acidosis, high urinary pH, nephrocalcinosis, growth retardation, sensorineural hearing loss, and hypokalemic paralysis. Laboratory investigations revealed proximal tubular dysfunction (low molecular weight proteinuria, generalized hyperaminoaciduria, hypophosphatemia with hyperphosphaturia, and hypouricemia with hyperuricosuria). There was significant hyperoxaluria and laboratory evidence for mild rhabdomyolysis. Under potassium and alkali therapy, proximal tubular abnormalities, muscular enzymes, and oxaluria normalized. A homozygous mutation in the ATP6V1B1 gene, which is responsible for dRTA with early hearing loss, was detected in both siblings. In conclusion, proximal tubular dysfunction and hyperoxaluria may be found in children with dRTA and are reversible under appropriate therapy.     

Contractile reserve assessed by dobutamine test identifies super-responders to cardiac resynchronization therapy

Introduction

In this study, we sought to determine whether myocardial contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) can identify patients who experience nearly complete normalization of left ventricular (LV) function after the implantation of a cardiac resynchronization therapy (CRT) pacemaker.

Material and methods

The study group consisted of 55 consecutive patients with non-ischemic dilated cardiomyopathy, LV ejection fraction (LVEF) < 35%, and prolonged QRS complex duration, who were scheduled for CRT pacemaker implantation. The DSE (20 µg/kg/min) was performed in all patients. The CR assessment was based on a change in the wall motion score index (ΔWMSI) and ΔLVEF during DSE. Super-response was defined as an increase in LVEF to > 50% and reduction in left ventricular end-systolic dimension to < 40 mm 12 months following the CRT implantation.

Results

A total of 7 patients (12.7%) were identified as super-responders to CRT. When compared to non-super-responders, these patients had significantly higher values of the dobutamine-induced change in ΔWMSI (1.031 ±0.120 vs. 0.49 ±0.371, p < 0.01), and ΔEF (17.9 ±2.2 vs. 8.8 ±6.2, p < 0.01). Receiver operating characteristic analysis showed that dobutamine-induced changes in ΔWMSI ≥ 0.7 and ≥ 14% for ΔEF are the best discriminators for a super-response. Patients with ΔWMSI ≥ 0.7 and ΔEF ≥ 14% are significantly less often hospitalized (p < 0.01) for worsening of heart failure during 28.5 ±3.0 months of the follow-up.

Conclusions

Contractile reserve assessed by DSE can identify patients with dilated cardiomyopathy who are likely to experience near normalization of LV function following CRT.     

3Alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate as blood-brain barrier permeator

The aim of the study was to test the efficacy of 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate as a blood-brain barrier (BBB) permeator by examining its effect on quinine uptake into the central nervous system in rats, analgesic action of morphine, and on the sleeping time induced by pentobarbital. The obtained results indicate that sodium 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanate can be considered as modifier of BBB permeability, as it exhibited a promoting effect in all three tests. In the test of quinine uptake, methyl ester of 3alpha,7alpha-dihydroxy-12-oxo-5beta-cholanoic acid (included in the study for comparison) did not show a promoting effect, which can suggest its specific action.     

Hypomagnesemia with hypercalciuria and nephrocalcinosis: case report and a family study

A 7-month-old male infant was referred for investigation after a documented febrile urinary tract infection. His past medical history was characterized by episodes of unexplained fever and mild dehydration. The ultrasound examination of his kidneys demonstrated bilateral diffuse medullary nephrocalcinosis. His serum and urine biochemistry revealed hypomagnesemia (0.4 mmol/l), hyperuricaemia (506 µmol/l), mildly increased iPTH (71 pg/ml) and hypercalciuria (16.0 mg/kg/day). The diagnosis of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) was confirmed by mutational analysis of the CLDN16 gene, encoding paracellin-1. Sequencing displayed a homozygous Leu151Phe exchange affecting the first extracellular loop of paracellin-1. There were eight family relatives who underwent biochemical analysis, renal ultrasound and genetic investigation for CLDN16 mutations. Five of them were found to be heterozygous for the Leu151Phe mutation. Two heterozygotes (the mother and the maternal grandfather) presented with hypercalciuria. The grandfather had a history of recurrent passage of calculi. These findings point to the role of heterozygous CLDN16 gene mutations in renal pathophysiology. In conclusion, patients suspected of having FHHNC should be screened for CLDN16 mutations, especially with respect to genetic counseling. In addition, heterozygotes at risk should be clinically assessed in order to prevent renal complications of hypercalciuria.     

Significance of confirming Epstein-Barr virus nuclear antibody as tumor marker

BACKGROUNND/AIM: Study of the association between Epstein-Barr virus (EBV) and the tumors of the nasopharynx renders an opportunity to introduce causal treatment Already have been proven the anti-EBV (anti-Epstein-Barr nucleus antigene) antibodies in the blood serum of the patients infected with EBV, while over 91% of the patients with nasopharyngeal malignant tumors also have a detectable anti-EBV marker. The aim of this research was to determine if there were anti-EBV antibodies in the serum of the patients with the already verified nasopharyngeal malignant tumors, and, if there were, to determine the quantitative ratio to the values in the serum of the healthy controls. METHODS: The study involved 74 individuals in the period from 1994-2001 divided into four groups: group A counting 11 patients with undifferentiated carcinome of nasopharyngeal type (UCNT); group B counting 25 patients with UCNT X-ray treated at least three years before the onset of the study; group C including 28 healthy subjecets (blood donors), and the group D with 10 patients with planocellular nasopharyngeal carcinoma. Serologic diagnostics of the patients serum was performed using the techniques of Reedman and Klein for the detection of anti-EBV antibodies in the serum. RESULTS: The presence of the statistically significantly higher values of the mean geometric titer (MGT) of the anti-EBNA antibodies was determined in 36 patients with histologically verified UCNT as compared with the control groups including 10 patients with planocellular carcinomas of the nasopharynx and 28 blood donors. Presented were anti-EBNA titers with 95% confidence interval for any participants according to the Hoo clinical classification of nasopharyngeal tumors, as well as according to the fact if they had been radiotreated within the previous three years. CONCLUSION: The results of this study confirm the conclusions of the recent literature on the possible etiopathogenesis of nasopharyngeal tumors and the use of viral anti-EBNA antibodies as viral markers in the diagnostics of UCNT diseases.     

ATM prevents unattended DNA double strand breaks on site and in generations to come

Ataxia telangiectasia (A-T) is a disorder characterized by cerebellar degeneration, immunodeficiency, genomic instability and genetic predisposition to lymphoid malignancies with translocations involving antigen receptor loci. The Ataxia Telangiectasia Mutated gene encodes the ATM kinase, a central transducer of DNA damage signals. Until recently, the etiology of the lymphoid phenotype in A-T patients and the mechanisms by which ATM ensures normal repair of DNA double strand break (DSB) intermediates during antigen receptor diversification reactions remained poorly understood. Last year, Bredemeyer et al. (Nature 2006; 442:466-70) demonstrated that ATM stabilizes chromosomal V(D)J recombination DSB intermediates, facilitates DNA end joining and prevents broken DNA ends from participating in chromosome deletions, inversions and translocations. A more recent study by Callen et al. (Cell 2007; 130:63-75) highlighted the importance of ATM-mediated checkpoints in blocking the long-term persistence and transmission of un-repaired DSBs in developing lymphocytes. Collectively, these results have provided complementary mechanistic insights into ATM functions in V(D)J recombination that can account for the lymphoid tumor-prone phenotype associated with A-T.     

Recessive CHRM5 variant as a potential cause of neurogenic bladder

Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.