Factor Xiii, A Subunit, Deficiency Of

A number sign (#) is used with this entry because deficiency of factor XIII (F13) subunit A is caused by mutation in the F13A gene (134570) on chromosome 6p.

See also deficiency of factor XIII subunit B (613235), caused by mutation in the F13B gene (134580) on chromosome 1p.

Description

Factor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (Kangsadalampai et al., 1999).

Ichinose et al. (1996, 2000) proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2.

Clinical Features

Duckert et al. (1960) first described factor XIII deficiency as a congenital hemorrhagic diathesis probably due to deficiency of fibrin stabilizing factor.

Aguercif et al. (1971) described a 7-year-old French girl with factor XIII deficiency who had ecchymoses and muscular hematomas following minor trauma. Immunodiffusion showed a protein with antigenicity of factor XIII.

Kitchens and Newcomb (1979) found about 100 reported cases. Homozygotes showed umbilical stump bleeding, a high frequency of fetal wastage, soft tissue hemorrhage, and intracranial hemorrhage. The authors noted that affected males had oligospermia and small testes. Because of the long half-life of infused factor XIII and the small amounts necessary for normal hemostasis, both replacement therapy and prophylaxis were simple, effective, and relatively inexpensive.

Frydman et al. (1986) found 7 homozygotes for factor XIII deficiency in a large inbred Arab kindred. Two affected men and 1 probably affected man had children, 2 of whom were also affected. Paternity was confirmed by special tests. An affected woman had early abortions.

Standen and Bowen (1993) reported a woman with factor XIII deficiency. The patient, who was born in 1953, had a history of profuse umbilical bleeding at birth and severe hemorrhage after tonsillectomy and dental extractions in childhood. In adult life, she had suffered recurrent muscle hematomas, retroperitoneal bleeding and hemarthroses, and in 1988, had an intracranial hemorrhage which responded to fresh frozen plasma. Two pregnancies terminated in spontaneous abortion but 2 further pregnancies covered with fresh frozen plasma resulted in live offspring. For 5 years she had received factor XIII concentrate on a monthly basis and had remained well.

Kangsadalampai et al. (1999) reported a male infant, born of a consanguineous family of Syrian descent with factor XIII deficiency. He was diagnosed at age 17 months. He had a history of oozing from the umbilical cord, life-threatening retroperitoneal bleeding after urologic surgery, and a large extradural hematoma after head injury. Treatment with fresh frozen plasma and factor XIII concentrate resulted in no further bleeding episodes. Genetic analysis identified a homozygous mutation in the F13A1 gene (R260H; 134570.0009).

Birben et al. (2002) reported a consanguineous Turkish family with factor XIII deficiency. The proband was a 5-year-old girl who had bled from the umbilical cord at birth and experienced recurrent musculoskeletal hematomas. Three sibs with a history of prolonged umbilical cord bleeding at birth had died in infancy. Genetic analysis identified a homozygous truncating mutation in the F13A1 gene (134570.0014).

Souri et al. (2001) reported an Italian man with factor XIII deficiency due to mutation in the F13A1 gene (134570.0013). The patient developed a post-traumatic hematoma in the right buttock at age 9 years that required surgical drainage. A large hematoma of the right thigh developed at age 16 years, requiring repeated surgical drainage and transfusion of packed red cells and plasma several times. Plasma studies showed less than 2% of normal plasma transamidase activity, and less than 5% and 38% of normal XIIIA and XIIIB antigens, respectively. His brother also developed severe bleeding after post-traumatic splenectomy at age 21 years. His plasma had less than 2% of normal transamidase activity, and less than 5% and 41% of normal XIIIA and XIIIB antigen levels, respectively. Their parents, who were not related, were deceased.

Anwar and Langlois (2009) reported a 13-year-old boy of Canadian origin with factor XIII deficiency. He had umbilical bleeding shortly after birth. Laboratory studies showed complete lack of subunit A and reduced levels of subunit B. Genetic analysis found compound heterozygosity for 2 mutations in the F13A1 gene (134570.0015 and 134570.0016).

Acquired Factor XIII Deficiency

Lorand et al. (1988) discussed severe bleeding due to autoimmune antibody against factor XIII. Reaction to penicillin or to isoniazid were mentioned as causes.

Biochemical Features

Lorand et al. (1970) found decreased levels of factor XIII in the fathers of 4 nonconsanguineous families with only affected males. The pattern was that of a dimeric protein. Homozygotes had a single band, while heterozygotes showed 3 bands. A fluorescent technique was used to localize transglutaminase activity after electrophoresis on thin-layer agarose gels.

Israels et al. (1973) showed that the catalytically active F13 subunit A is functionally and immunologically absent in homozygous deficient persons. The immunologically cross-reactive material consists only of the carrier (B subunit) protein.

Forman et al. (1977) gave a preliminary report of a patient that might have functionally absent, but immunologically intact, factor XIII. Francis and Todd (1979) found that patients with factor XIII deficiency lack immunologically identifiable subunit A, but have normal or reduced subunit B.

Inheritance

Fisher et al. (1966) described an affected Moroccan woman who was the offspring of an uncle-niece mating. Parents and sibs were apparently normal, suggesting autosomal recessive inheritance. Zahir (1969) observed an affected female, the offspring of a first-cousin marriage. Both parents had low factor XIII levels.

McDonagh et al. (1974) studied 2 families with only male patients; all parents of homozygotes were heterozygous. Male and female heterozygous sibs occurred with equal frequency and heterozygous males transmitted their heterozygosity to sons.

Fried et al. (1981) observed affected males and females in equal proportions and parental consanguinity.

Diagnosis

By means of a technique with enhanced sensitivity, Duckert (1964) demonstrated partial deficiency of FXIII in presumptive heterozygotes. Urea-solubility of the fibrin clot was an in vitro characteristic. All the usual clotting tests are normal, but the diagnosis could be made easily by the urea solubility test.

Butten (1967) described a patient whose parents, as well as several other relatives, were apparent heterozygous carriers on testing.

Mapping

Frydman et al. (1985) found linkage between factor XIII deficiency and HLA (see, e.g., 142800) on chromosome 6p in an Israeli-Arab kindred with factor XIII deficiency in at least 6 affected persons spanning 2 generations. The lod score was 2.51 at theta 0.10. The F13A1 gene maps to 6p.

Molecular Genetics

Board et al. (1988) defined 3 different haplotypes associated with factor XIIIA deficiency, which suggested heterogeneity in the mutations causing this disorder. No evidence of major gene deletion or rearrangement was found.

In a Japanese man with factor XIII deficiency and a lifelong bleeding tendency, Kamura et al. (1992) identified a homozygous 2-bp deletion in the F13A1 gene (210delAG; 134570.0001). He was born of consanguineous parents.

Coggan et al. (1995) identified compound heterozygosity for 2 mutations in the F13A1 gene (Y441X; 134570.0004 and N60K; 134570.0005) in a family with a bleeding disorder.

Kangsadalampai et al. (1999) identified 2 different homozygous mutations in the F13A1 gene (V414F; 134570.0008 and R260H; 134570.0009, respectively) in 2 unrelated patients with factor XIII deficiency. Functional expression studies in yeast showed that both mutations resulted in decreased catalytic activity and decreased levels of expressed enzyme.

History

Steinberg and Ratnoff (1970) found a highly significant difference in the frequency of parental consanguinity between families with only males affected and families with affected females. They advanced this as evidence for the existence of both X-linked and autosomal forms. Girolami et al. (1977) found 2 sisters born of a nonconsanguineous marriage with deficiency of subunit A and normal subunit S (now called B). By inference, they suggested that an X-linked mutation might involve the S subunit. Since the report of Ratnoff and Steinberg (1968), observations have discredited the X-linked hypothesis; with description of more cases the sex ratio is closer to unity, indicative of autosomal inheritance. Fried et al. (1981) concluded that 'there is no report of even a single family that requires the assumption of X-linked inheritance.' X-linked inheritance for both the A and the B subunits seems to have been completely excluded (Kera et al., 1981).

Animal Model

Lauer et al. (2002) generated transgenic mice with targeted deletion of exon 7 of the F13a gene. FXIII transglutaminase activity in plasma was reduced to about 50% in mice heterozygous for the mutant allele and was abolished in homozygous null mice. Homozygous mutant mice were fertile, but showed impaired reproduction with increased maternal death during gestation. Homozygous mice showed bleeding episodes, with hematothorax, hematoperitoneum, and subcutaneous hemorrhage, resulting in decreased survival. Mutant mice also showed prolonged bleeding times and impaired clot stabilization. Replacement with human plasma FXIII restored bleeding time. The phenotype in homozygous mutant mice recapitulated the key features of the human disorder.