Persistent Left Superior Vena Cava in Cardiac Congenital Surgery

Persistent left superior vena cava (LSVC) is a relatively frequent finding in congenital cardiac malformation. The scope of the study was to analyze the timing of diagnosis of persistent LSVC, the timing of diagnosis of associated anomalies of the coronary sinus, and the global impact on morbidity and mortality of persistent LSVC in children with congenital heart disease after cardiac surgery. Retrospective analysis of a cohort of children after cardiac surgery on bypass for congenital heart disease. Three hundred seventy-one patients were included in the study, and their median age was 2.75 years (IQR 0.65-6.63). Forty-seven children had persistent LSVC (12.7 %), and persistent LSVC was identified on echocardiography before surgery in 39 patients (83 %). In three patients (6.4 %) with persistent LSVC, significant inflow obstruction of the left ventricle developed after surgery leading to low output syndrome or secondary pulmonary hypertension. In eight patients (17 %), persistent LSVC was associated with a partially or completely unroofed coronary sinus and in two cases (4 %) with coronary sinus ostial atresia. Duration of mechanical ventilation was significantly shorter in the control group (1.2 vs. 3.0 days, p = 0.04), whereas length of stay in intensive care did not differ. Mortality was also significantly lower in the control group (2.5 vs. 10.6 %, p = 0.004). The results of study show that persistent LSVC in association with congenital cardiac malformation increases the risk of mortality in children with cardiac surgery on cardiopulmonary bypass. Recognition of a persistent LSVC and its associated anomalies is mandatory to avoid complications during or after cardiac surgery.

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.

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.

Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4)

BACKGROUND: Isolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds. RESULTS: We confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families. CONCLUSION: We confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly.

Analysis and mapping of CACNB4, CHRNA1, KCNJ3, SCN2A and SPG4, physiological candidate genes for porcine congenital progressive ataxia and spastic paresis

The cause of porcine congenital progressive ataxia and spastic paresis (CPA) is unknown. This severe neuropathy manifests shortly after birth and is lethal. The disease is inherited as a single autosomal recessive allele, designated cpa. In a previous study, we demonstrated close linkage of cpa to microsatellite SW902 on porcine chromosome 3 (SSC3), which corresponds syntenically to human chromosome 2. This latter chromosome contains ion channel genes (Ca(2+), K(+) and Na(+)), a cholinergic receptor gene and the spastin (SPG4) gene, which cause human epilepsy and ataxia when mutated. We mapped porcine CACNB4, KCNJ3, SCN2A and CHRNA1 to SSC15 and SPG4 to SSC3 with the INRA-Minnesota porcine radiation hybrid panel (IMpRH) and we sequenced the entire open reading frames of CACNB4 and SPG4 without finding any differences between healthy and affected piglets. An anti-epileptic drug treatment with ethosuximide did not change the severity of the disease, and pigs with CPA did not exhibit the corticospinal tract axonal degeneration found in humans suffering from hereditary spastic paraplegia, which is associated with mutations in SPG4. For all these reasons, the hypothesis that CACNB4, CHRNA1, KCNJ3, SCN2A or SPG4 are identical with the CPA gene was rejected.

Hepatic encephalomyelopathy in a calf with congenital portosystemic shunt (CPSS)

A 4-month-old female Holstein Friesian calf was referred to the Veterinary Teaching Hospital, University of Berne, Switzerland for evaluation of ataxia, weakness, apathy and stunted growth. Clinical examination revealed generalized ataxia, propioceptive deficits, decreased menace response and sensibility. Postmortem examination did not reveal macroscopic changes of major organs. Histologically, the brain and the spinal cord lesions were characterized by polymicrocavitation, preferentially affecting the white matter fibers at the junction of grey and white matter and by the presence of Alzheimer type II cells. The liver revealed lesions consistent with a congenital portosystemic shunt, characterized by increased numbers of arteriolar profiles and hypoplasia to absence of portal veins. The pathological investigations along with the animal history and clinical signs indicated a hepatic encephalomyelopathy due to a congenital portosystemic shunt.

Heart failure in two West Highland white terriers caused by congenital angiomatous cardiac anomaly

The paper describes the clinical and pathological characteristics of an unusual cystic congenital cardiac anomaly that caused clinical signs of congestive heart failure, respiratory distress and cardiac arrhythmias in two West Highland white terrier puppies. In both dogs a definitive diagnosis was made postmortem.

Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies

Context and Objective: Most cases of goitrous congenital hypothyroidism (CH) from thyroid dyshormonogenesis 1) follow a recessive mode of inheritance and 2) are due to mutations in the thyroid peroxidase gene (TPO). We report the genetic mechanism underlying the apparently dominant inheritance of goitrous CH in a nonconsanguineous family of French Canadian origin. Design, Setting, and Participants: Two brothers identified by newborn TSH screening had severe hypothyroidism and a goiter with increased (99m)Tc uptake. The mother was euthyroid, but the father and two paternal uncles had also been diagnosed with goitrous CH. After having excluded PAX8 gene mutations, we hypothesized that the underlying defect could be TPO mutations. Results: Both compound heterozygous siblings had inherited a mutant TPO allele carried by their mother (c.1496delC; p.Pro499Argfs2X), and from their father, one brother had inherited a missense mutation (c.1978C-->G; p.Gln660Glu) and the other an insertion (c.1955insT; p.Phe653Valfs15X). The thyroid gland of one uncle who is a compound heterozygote for TPO mutations (p.Phe653Valfs15X/p.Gln660Glu) was removed because of concurrent multiple endocrine neoplasia type 2A. Immunohistochemistry revealed normal TPO staining, implying that Gln660Glu TPO is expressed properly. Modeling of this mutant in silico suggests that its three-dimensional structure is conserved, whereas the electrostatic binding energy between the Gln660Glu TPO and its heme group becomes repulsive. Conclusion: We report a pedigree presenting with pseudodominant goitrous CH due to segregation of three different TPO mutations. Although goitrous CH generally follows a recessive mode of inheritance, the high frequency of TPO mutations carriers may lead to pseudodominant inheritance.

rFVIIa in the treatment of persistent hemorrhage in pediatric patients on ECMO following surgery for congenital heart disease

BACKGROUND: Patients who require extracorporeal membrane oxygenation (ECMO) postsurgery for congenital heart disease (CHD) frequently experience severe bleeding episodes. Whereas recombinant-activated factor VII (rFVIIa) has proven efficacy in counteracting intractable hemorrhage in various scenarios, its use in patients on ECMO is limited by the increased risk for thrombotic events. METHODS: Between December 2004 and January 2006, ECMO was used in 10 pediatric patients following cardiac surgery, of whom seven were treated with rFVIIa because of intractable hemorrhage. Their medical records were reviewed with respect to variations in chest tube output and transfusion requirements, occlusion of or thrombus formation in the ECMO circuit and the occurrence of thromboembolic events. Outcome and rate of ECMO circuit occlusion were compared with historic controls. RESULTS: Three patients died, and four survived (none of the deaths was attributable to thrombus formation or bleeding). All patients were treated with aprotinin prior to and during rFVIIa therapy. Two patients developed an occlusion of the oxygenator, one after receiving co-medication with a FXIII concentrate, another after RBC transfusion in the ECMO system. In two patients, thrombus formation was observed in the ECMO system on inspection after discontinuation. Thromboembolic events were not observed. CONCLUSIONS: Recombinant-activated factor VII in a median dosage of 90 microg.kg(-1) was used in seven pediatric patients on ECMO. Rates of ECMO system occlusions and mortality did not differ from historic controls. Neither the reduction of chest tube output nor the blood product transfusion requirements did reach statistical significance.