A new family with congenital factor XIII deficiency showing a deficit of both subunit A and B. Type I factor XIII deficiency

In this study we present a new case of Factor XIII deficiency. The proposita, a 34 year old woman, showed a deficiency of both subunit a and subunit b, and a moderate bleeding tendency. Because of the concomitant decrease of subunits a and b the proposita is considered to be an example of Type I disease. Factor XIII levels were less than 10% both as activity and antigen. Several family members showed intermediate levels of both subunit a and b and were asymptomatic. They were considered to be heterozygotes. The hereditary pattern is autosomal incompletely recessive. Type I disease appears much less frequent than Type II.     

Glanzmann's thrombasthenia associated with a transient deficiency of factor XIII

A three-year-old girl suffering from ecchymoses developed severe epistaxis. The diagnosis of thrombasthenia was made on the basis of platelet aggregation studies, flow cytometric analysis with monoclonal antibodies and gel electrophoretic analysis. In addition, coagulation studies at the time of epistaxis repeatedly showed a transient deficiency of factor XIII activity and antigen.     

Characterisation of connective tissue cells containing factor XIII subunit a.

Paraffin embedded sections of human liver, lymph node, and placenta showed that certain connective tissue cells were positive for factor XIII subunit a. These cells were further characterised by double immunofluorescence labelling and by combined immunofluorescence and enzyme cytochemical staining on frozen sections. They were labelled by the monoclonal antibodies RFD7 and anti-Leu M3 (markers of the macrophage cell line) but gave a negative reaction for the fibroblast marker IIG10 and showed no alkaline phosphatase activity. Immunoblotting detected factor XIII subunit a in macrophages isolated from placenta but not in human fibroblasts. At lower dilutions, the commercially available antibody against the b subunit of factor XIII also positively reacted with the same cell population. The facts that immunoblotting showed that the antiserum crossreacted with the a subunit and that placental macrophages did not stain strongly for the b subunit also indicate that this antigen is not present in adult connective tissue cells.     

Fibrin cross-linking in congenital factor XIII deficiency.

Homozygous patients with factor XIII deficiency are devoid of immunologically identifiable A protein, the active enzymatic component. Quantitative studies of transamidase activity of the factor are available in only a few cases, and the fibrin cross-linking pattern is not well known. The present paper deals with the quantitative estimation of factor XIII transamidase activity (dansylcadaverine system), factor XIII molecular subunits, and the corresponding fibrin cross-linking pattern in seven homozygous patients with factor XIII deficiency. The results indicate that transamidase activity was present in all patients, and the range was 0.5-1.7%. The pattern of fibrin stabiisation showed an absence of cross-linking in two patients, the presence of gamma-gamma-dimers (traces) in four, and gamma-gamma-dimers plus incomplete alpha-polymers (traces) in one patient. In conclusion, the homozygous patients reported here were not completely devoid of functioning factor XIII.     

Congenital factor XIII deficiency in the south of Tunisia

Factor XIII deficiency is a rare autosomal recessive congenital disorder of haemostasis characterised by a plasmatic factor XIII level less than 1% in homozygote and bleeding as of the youth. We report a study about ten patients with congenital factor XIII deficiency from seven south-Tunisian families, there are seven females. Umbilical bleeding was common and only two patients had intracranial bleeding. The standard screening tests are normal. Factor XIII activity was less than 1% in all patients. A sub-unit A deficit was detected for the ten patients. Out hemorrhagic context, five patients receive regular prophylactic transfusion with fresh frozen plasma.     

Characterization of a large deletion that leads to congenital factor XIII deficiency

Congenital factor XIII deficiency is a rare bleeding disorder that is inherited in an autosomal recessive manner with a frequency of 1 per 2 million individuals in the human population. In Japan, 53 cases of factor XIII deficiency were registered in the national survey for blood coagulation disorders in 2006. One hundred twenty-three cases were listed in the international Factor XIII Registry (http://www.f13-database.de/) by October 2007. The most frequent genomic abnormalities among the registered cases are point mutations; nucleotide deletions have been identified in only 16 cases. Most deletions are less than 20 bp; only 2 large deletions have been reported. However, detailed studies in either of these 2 cases have not been performed. We analyzed a case of congenital factor XIII deficiency. The patient is Japanese born to consanguineous parents, and his factor XIII A antigen and activity levels are both less than 10% of normal. The LA-PCR product for exons 4-6 of the factor XIII gene was 5 kb smaller than expected. The deletion is exactly 5984 bp long, including the entire exon 5. This finding suggests that the deletion caused a frameshift that produced a premature termination codon in exon 6. Deletions usually occur in repetitive sequences, but repetitive sequences were not found around this deletion. The semiquantified F13A1 mRNA level in the patient sample was only 1% of normal, and suggests that the mRNA surveillance system (nonsense-mediated mRNA decay) may be involved.     

Congenital factor XIII deficiency. A family report.

Four sisters born to consanguineous muslim parents with a bleeding disorder since birth are presented. They also had prolonged umbilical cord bleeding and history of delayed wound healing. Since childhood, they have been developing spontaneous ecchymotic spots. Three out of four sisters had Factor XIII deficiency. Their mother's sisters, who have been developing ecchymotic spots were found to have normal clot stability and Factor XIII levels. Family study indicates autosomal recessive mode of inheritance of the congenital Factor XIII deficiency.     

六个成骨不全家系的临床表型分析及基因变异检测

目的分析6个成骨不全家系的临床表型并明确其致病变异,为遗传咨询及产前诊断提供依据。方法收集6个家系的临床资料以及外周血或引产组织样本,应用二代测序(next generation sequencing,NGS)技术对先证者的全部基因进行检测,用PCR反应扩增检出的变异位点,之后进行Sanger测序。在6个家系的所有成员以及100名健康对照中对检测到的变异位点进行验证。结果家系1的先证者及其女儿携带COL1A1基因c.1976G>C杂合变异,家系2~6的先证者分别携带COL1A2基因c.2224G>A、COL1A1基因c.2533G>A、COL1A2基因c.2845G>A、COL1A1基因c.2532_2540delCGGACCCGC以及COL1A2基因c.1847G>A杂合变异。先证者的双亲均未携带相应变异,在100名健康对照中均未检测到上述变异。结论6个成骨不全家系的致病原因可能均为COL1A1/2基因的变异。新发现的变异丰富了成骨不全症的表现型-基因型数据库,并为这些家系的遗传咨询及产前诊断提供了依据。     

Combined occurrence of von Willebrand's disease and factor XIII deficiency: a case report

We report the case of a three year old female child with combined occurrence of von Willebrand's disease and factor XIII deficiency, an extremely rare combination. The patient presented with prolonged bleeding following cuts and wounds. Clot solubility test using 5M urea was positive. Platelet aggregation using ristocetin was reduced, which corrected on adding normal plasma. Aggregation with other agonists was normal. We discuss the clinico- hematological profile of the case. Only one such case has been reported in literature in the past to the best of our knowledge.     

Ornithine carbamoyltransferase deficiency: molecular characterization of 29 families

Ornithine carbamoyltransferase deficiency is the most common inherited defect of the urea cycle. We examined 28 male and 9 female patients from 29 families and identified 25 distinct mutations in OTC, 14 of which were novel. Three novel missense mutations (p.Ala102Pro, p.Pro158Ser, p.Lys210Glu) and a novel deletion of the Leu43 are not directly involved either in the enzyme active site or in the intersubunit interactions; however, the mutations include conserved residues involved in intramolecular interaction network essential for the function of the enzyme. Three novel large deletions – a 444 kb deletion affecting RPGR, OTC and TSPAN7, a 10 kb‐deletion encompassing OTC exons 5 and 6 and a 24.5 kb‐deletion encompassing OTC exons 9 and 10 – have probably been initiated by double strand breaks at recombination‐promoting motifs with subsequent non‐homologous end joining repair. Finally, we present a manifesting heterozygote carrying a hypomorphic mutation p.Arg129His in combination with unfavorably skewed X‐inactivation in three peripheral tissues.     

Genetic heterogeneity of the B subunit of coagulation factor XIII: resolution of type 2

An apparent discrepancy in phenotyping the genetic polymorphism at the FXIII B locus by electrophoresis or isoelectric focusing has been investigated. The data indicate that the product of the type 2 allele, which can be detected by agarose electrophoresis, is not resolved from the product of the type 1 allele by isoelectric focusing. The understanding of this problem has previously been confused by the absence or very low frequency of the type 2 allele in Japanese populations studied by isoelectric focusing and electrophoresis.
An alternative enzyme-linked immunoblotting technique is described which substantially improves the method for phenotyping products of the FXIII B locus after electrophoresis.     

Molecular characterization of Complement Factor I deficiency in two Spanish families

Complement Factor I (CFI) is a regulator of the classical and alternative pathways. CFI has enzymatic activity and is able to cleave C3b and C4b. Homozygous Factor I deficiency is associated with infectious and/or autoimmune diseases.

Here we describe the biochemical and genetic characterization in two Spanish families with complete Factor I deficiency. In Family 1, the propositus suffered from several episodes of meningitis for more than a year. Biochemical complement studies showed undetectable Factor I levels in the propositus and in her sister, while their parents and a brother had partial Factor I deficiency and were healthy. In Family 2, three out of five children were homozygous for Factor I deficiency, two of whom suffered from meningitis and the third one from several infections. The parents and the other two siblings were healthy and heterozygous for Factor I deficiency.

Molecular studies showed that the two families had different mutations at exon 5 of the Factor I gene, which codifies for module LDLr1. One mutation corresponds to a 772G>A change at the donor splice site that was originally found in a family from Northern England. The second is a new missense mutation 739T>G, that generates a Cys to Gly change.