Acute Encephalopathy with Unilateral Cortical-Subcortical Lesions in Two Unrelated Kindreds Treated with Glucocorticoids Prenatally for Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Established Facts and Novel Insight

Background: Prenatal glucocorticoid (GC) treatment of the female fetus with 21-hydroxylase deficiency (21-OHD) may prevent genital virilization and androgen effects on the brain, but prenatal GC therapy is controversial because of possible adverse effects on fetal programming, the cardiovascular system and the brain. Case Reports: We report 2 patients with congenital adrenal hyperplasia (CAH) due to 21-OHD who were treated prenatally with dexamethasone, suffered from an acute encephalopathy and showed focal and multifocal cortical and subcortical diffusion restrictions in early MRI and signs of permanent alterations in the follow-up neuroimaging studies. Both patients recovered from the acute episode. Whereas the first patient recovered without neurological sequelae the second patient showed hemianopsia and spastic hemiplegia in the neurological follow-up examination. Conclusion: These are 2 children with CAH, both treated prenatally with high doses of dexamethasone to prevent virilization. The question arises whether prenatal high-dose GC treatment in patients with CAH might represent a risk factor for brain lesions in later life. Adverse effects/events should be reported systematically in patients undergoing prenatal GC treatment and long-term follow-up studies involving risk factors for cerebrovascular disease should be performed.

Novel mutations in the human sucrase-isomaltase gene (SI) that cause congenital carbohydrate malabsorption

Disaccharide intolerance I or congenital sucrase-isomaltase deficiency (CSID) is a disorder leading to maldigestion of disaccharides, which is autosomal recessively inherited. Here we analyzed the sucrase-isomaltase (SI) gene from 11 patients of Hungarian origin with congenital sucrase-isomaltase deficiency. Variants in the SI gene had previously been described in CSID patients, which cause amino acid exchanges that affect the transport, the processing, or the function of the SI protein. None of our patients had known mutations for CSID. Our analyses revealed 43 SI variants in total, 15 within exons and one at a splice site. Eight of the exonic mutations lead to amino acid exchanges, causing hypomorph or null alleles. One new variation affects a splice site, which is also predicted to result in a null allele. All potential pathological alterations were present on one allele only. In six out of the 11 patients the phenotype of CSID could be explained by compound heterozygosity.

Ocular manifestations in congenital toxoplasmosis

BACKGROUND: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function. METHODS: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed. RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis. CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.

Insertion of double bicanalicular silicone tubes after endonasal dacryocystorhinostomy in lacrimal canalicular stenosis: a 10-year experience

To assess the long-term results of double bicanalicular silicone tubes in canalicular (presaccal) stenosis of the nasolacrimal duct system, a retrospective follow-up was performed on patients operated between 1992 and 2002. Forty-five patients were included in the study, 44 of whom had eyes with canalicular stenosis (primary dacryocystorhinostomy), 4 with congenital agenesis of the lacrimal duct system, and 3 cases after primary external dacryocystorhinostomy. Double bicanalicular silicone tubes were inserted, fixed in the vestibulum nasi, and left in place as long-term space holders. Of the 51 endonasal primary dacryocystorhinostomies with canalicular stenosis, 32 (63%) became symptom-free after one procedure. Nineteen (37%) patients had a relapse. Double silicone bicanalicular tube insertion as long-term spacers in canalicular stenoses has a number of advantages, but canalicular stenoses still remain a challenging area.

The effect of terazosin on functional bladder outlet obstruction in women: a pilot study

PURPOSE: We assessed the effect of terazosin (Hytrin(R)) on functional bladder outlet obstruction in women. MATERIALS AND METHODS: Functional bladder outlet obstruction was defined as a maximum flow rate of less than 12 ml per second combined with a detrusor pressure at maximum flow rate of more than 20 cm H2O in pressure flow studies in the absence of neurological disorders or mechanical causes. In a prospective pilot study 15 women with functional bladder outlet obstruction were treated with terazosin. Terazosin was initiated at 1 mg daily and gradually increased to the maintenance dose of 5 mg daily during 2 weeks. Symptoms and urodynamic parameters were assessed before and 3 to 4 weeks after the initiation of alpha-blocker therapy. RESULTS: While on terazosin, voiding symptoms subjectively improved greater than 50% in 10 of the 15 women (p = 0.002). Median maximum urethral closure pressure at rest decreased significantly from 98 to 70 cm H2O (p = 0.001), median maximum detrusor pressure decreased from 45 to 35 cm H2O (p = 0.008), median detrusor pressure at maximum flow decreased from 34 to 27 ml per second and median post-void residual urine decreased from 120 to 40 ml (p = 0.006 and 0.002, respectively). There was a significant increase in the median maximum flow rate from 9 to 20 ml per second and in median voided volume from 300 to 340 ml (p = 0.0005 and 0.021, respectively). Storage symptoms, functional urethral length and maximum cystometric capacity did not change significantly with alpha-blocker therapy (p > 0.05). Overall terazosin resulted in a significant improvement in symptoms and urodynamic parameters in 10 of the 15 women (67%). CONCLUSIONS: Terazosin had a significant symptomatic and urodynamic effect in two-thirds of our patients. These results suggest that terazosin may be an effective treatment option in women with voiding dysfunction due to functional bladder outlet obstruction.

Ultrasound assessment of detrusor thickness in men-can it predict bladder outlet obstruction and replace pressure flow study?

PURPOSE: We estimated the diagnostic accuracy of ultrasound detrusor thickness measurement for BOO and investigated whether this method can replace PFS for the diagnosis of BOO in some patients with lower urinary tract symptoms. MATERIALS AND METHODS: Detrusor thickness was measured by linear ultrasound (7.5 MHz) at a filling volume of greater than 50% of cystometric capacity in 102 men undergoing PFS for LUTS. All patients with prior treatment for bladder outlet obstruction and those with underlying neurological disorders were excluded from analysis. Detrusor thickness was correlated with PFS data. Obstruction was defined according to the Abrams-Griffiths nomogram. RESULTS: Detrusor thickness was significantly higher (p <0.0001) in obstructed (61 cases, median detrusor thickness 2.7 mm, IQR 2.4 to 3.3) compared to unobstructed (18 cases, median detrusor thickness 1.7 mm, IQR 1.5 to 2) as well as equivocal (23 cases, median detrusor thickness 1.8 mm, IQR 1.5 to 2.2) cases. A weak to medium Spearman correlation was found between detrusor thickness and PFS parameters. For a diagnosis of BOO, detrusor thickness of 2.9 mm or greater had a positive predictive value of 100%, a negative predictive value of 54%, specificity of 100% and sensitivity of 43%. ROC analysis revealed that detrusor thickness had a high predictive value for BOO with an AUC of 0.88 (95% CI 0.81-0.94). CONCLUSIONS: In men with LUTS without prior treatment and/or neurological disorders, ultrasonographically assessed detrusor thickness 2.9 mm or greater has a high predictive value for BOO and can replace PFS for the diagnosis of BOO. However, this cutoff value needs to be validated in a larger study population.

Antegrade endopyelotomy for treatment of ureteropelvic junction obstruction in transplanted kidneys

BACKGROUND AND PURPOSE: Little is known about the incidence and treatment of ureteropelvic junction (UPJ) obstruction of renal grafts. We report on three cases treated by endopyelotomy. PATIENTS AND METHODS: Graft function declined in three patients 98, 135, and 144 days after kidney transplantation. Acute rejection was excluded by renal biopsy. Ultrasonography revealed a dilated collecting system, and a percutaneous nephrostomy tube was placed. An antegrade nephrostogram showed UPJ obstruction. Percutaneous antegrade endopyelotomy was performed with the cold-knife technique, and the area was stented for 6 weeks using a 14F/8.2F Smith endopyelotomy stent. RESULTS: No intraoperative or postoperative complications occurred. The endopyelotomies were successful, and the creatinine clearances returned to normal. CONCLUSION: Antegrade endopyelotomy in patients with UPJ obstruction of a renal graft is feasible and effective. Normal kidney function was restored after correction of the obstruction.

Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder

In 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 delG, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.

P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia

PURPOSE OF REVIEW: P450 oxidoreductase deficiency--a newly described form of congenital adrenal hyperplasia--typically presents a steroid profile suggesting combined deficiencies of steroid 21-hydroxylase and 17alpha-hydroxylase/17,20-lyase activities. These and other enzymes require electron donation from P450 oxidoreductase. The clinical spectrum of P450 oxidoreductase deficiency ranges from severely affected children with ambiguous genitalia, adrenal insufficiency and the Antley-Bixler skeletal malformation syndrome to mildly affected individuals with polycystic ovary syndrome. We review current knowledge of P450 oxidoreductase deficiency and its broader implications. RECENT FINDINGS: Since the first report in 2004, at least 21 P450 oxidoreductase mutations have been reported in over 40 patients. The often subtle manifestations of P450 oxidoreductase deficiency suggest it may be relatively common. P450 oxidoreductase deficiency, with or without Antley-Bixler syndrome, is autosomal recessive, whereas Antley-Bixler syndrome without disordered steroidogenesis is caused by autosomal dominant fibroblast growth factor receptor 2 mutations. In-vitro assays of P450 oxidoreductase missense mutations based on P450 oxidoreductase-supported P450c17 activities provide excellent genotype/phenotype correlations. The causal connection between P450 oxidoreductase deficiency and disordered bone formation remains unclear. SUMMARY: P450 oxidoreductase mutations cause combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase. Individuals with an Antley-Bixler syndrome-like phenotype presenting with sexual ambiguity or other abnormalities in steroidogenesis should be analyzed for P450 oxidoreductase deficiency.

Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.

The arterial switch operation in Europe for transposition of the great arteries: a multi-institutional study from the European Congenital Heart Surgeons Association

OBJECTIVES: This study analyzes the results of the arterial switch operation for transposition of the great arteries in member institutions of the European Congenital Heart Surgeons Association. METHODS: The records of 613 patients who underwent primary arterial switch operations in each of 19 participating institutions in the period from January 1998 through December 2000 were reviewed retrospectively. RESULTS: A ventricular septal defect was present in 186 (30%) patients. Coronary anatomy was type A in 69% of the patients, and aortic arch pathology was present in 20% of patients with ventricular septal defect. Rashkind septostomy was performed in 75% of the patients, and 69% received prostaglandin. There were 37 hospital deaths (operative mortality, 6%), 13 (3%) for patients with an intact ventricular septum and 24 (13%) for those with a ventricular septal defect (P < .001). In 36% delayed sternal closure was performed, 8% required peritoneal dialysis, and 2% required mechanical circulatory support. Median ventilation time was 58 hours, and intensive care and hospital stay were 6 and 14 days, respectively. Although of various preoperative risk factors the presence of a ventricular septal defect, arch pathology, and coronary anomalies were univariate predictors of operative mortality, only the presence of a ventricular septal defect approached statistical significance (P = .06) on multivariable analysis. Of various operative parameters, aortic crossclamp time and delayed sternal closure were also univariate predictors; however, only the latter was an independent statistically significant predictor of death. CONCLUSIONS: Results of the procedure in European centers are compatible with those in the literature. The presence of a ventricular septal defect is the clinically most important preoperative risk factor for operative death, approaching statistical significance on multivariable analysis.

Congenital hypotrichosis and partial anodontia in a crossbred beef calf

Clinical examination, skin biopsies, skull radiographs, and DNA analysis of a 2-day-old Red Angus-Charolais-Simmental cross bull calf confirmed the diagnosis of congenital hypotrichosis and anodontia defect (HAD), also called anhidrotic ectodermal dysplasia, which is a rare anomaly caused by a deletion in the bovine EDA gene on the X chromosome.