Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis

Homozygous type I plasminogen deficiency has been identified as a cause of ligneous conjunctivitis. In this study, 5 additional patients with ligneous conjunctivitis are examined. Three unrelated patients (1 boy, 1 elderly woman, and 1 man) had plasminogen antigen levels of less than 0.4, less than 0.4, and 2.4 mg/dL, respectively, but had plasminogen functional residual activity of 17%, 18%, and 17%, respectively. These subjects were compound-heterozygotes for different missense mutations in the plasminogen gene: Lys19 --> Glu/Arg513 --> His, Lys19 --> Glu/Arg216 --> His, and Lys19 --> Glu/Leu128 --> Pro, respectively. The other 2 patients, a 14-year-old boy and his 19-year-old sister, who both presented with a severe course of the disease, exhibited plasminogen antigen and functional activity levels below the detection limit (<0.4 mg/dL and <5%, respectively). These subjects were compound-heterozygotes for a deletion mutation (del Lys212) and a splice site mutation in intron Q (Ex17 + 1del-g) in the plasminogen gene. These findings show that certain compound-heterozygous mutations in the plasminogen gene may be associated with ligneous conjunctivitis. Our findings also suggest that the severity of clinical symptoms of ligneous conjunctivitis and its associated complications may depend on the amount of plasminogen functional residual activity

Human homozygous type I plasminogen deficiency and ligneous conjunctivitis

On the basis of a questionnaire sent to the ophthalmology departments of hospitals throughout Germany, 10 patients with ligneous conjunctivitis or pseudomembranous disease, ranging in age from 1 to 71 years were identified. All 10 patients had severely reduced plasminogen levels. Genetic analysis revealed homozygous type I plasminogen deficiency (which had not previously been described in humans) in 7 patients and compound heterozygous plasminogen deficiency in 1 patient. Clear differentiation was not possible in 2 patients. Most of the parents had heterozygous plasminogen deficiency. None of the patients had experienced any episodes of thrombosis. Additionally, the following observations were made: 1) Levels of polymorphonuclear (PMN)-elastase protein were markedly elevated in 6 of 6 patients and 10 of 11 parents tested, and levels were higher in homozygotes than in heterozygotes. 2) Hereditary factor XII deficiency was found in 3 of 6 patients tested. 3) C1-inhibitor was elevated in 2 of 4 patients, prekallikrein was elevated in 1 of 4 patients, and plasminogen activator inhibitor type 1 was elevated in 1 of 4 patients. Infusions of lys-plasminogen concentrate induced pronounced fibrinolytic activity as indicated by high levels of D-dimer, increases in plasmin-antiplasmin complex and decreases in polymorphonuclear elastase. C1-inhibitor, prekallikrein and PAI-1 normalized after repeated infusions of lys-plasminogen. In contrast to dysplasminogenemia, severe type I plasminogen deficiency might be seen as a problem of extravascular space, in particular of the mucous membranes, possibly triggered by mechanically induced or inflammatory lesions of the vessels supplying the tissue

Polymophonuclear elastase in patients with homozygous type I plasminogen deficiency and ligneous conjunctivitis

Laboratory studies were performed on six female patients (ranging in age from 1 to 31 years) with ligneous conjunctivitis, which we regard as a systemic condition consisting of ligneous conjunctivitis and other pseudomembranous lesions. Plasminogen levels were severely reduced in all six patients; five patients were homozygous, and one patient was double heterozygous for type I plasminogen deficiency. Of family members tested, 11 of 12 parents and two of six siblings tested were diagnosed as heterozygous. No thrombotic episodes had occurred in any of the patients. Polymorphonuclear (PMN) elastase protein levels were markedly elevated in all, significantly more so in the homozygous patients (range 88 to 335 ng/mL; normal range, 20+/-10 ng/mL) than in the heterozygous patient (58 ng/mL). Of 11 parents examined, only 1 mother had normal PMN elastase (27 ng/mL, with plasminogen antigen 60% and plasminogen functional activity 86%), whereas values were moderately elevated (range 42 to 110 ng/mL) in the other 10 parents examined. After plasminogen substitution, PMN elastase levels consistently decreased but did not reach normal values. We interpret our findings as indicating that non-plasmin-induced fibrinolytic processes, possibly mediated via elastase, may be intensified in patients with plasminogen deficiency

Homozygous type I plasminogen deficiency

Homozygous type I plasminogen (Plg) deficiency has not been described in human subjects so far. Ligneous conjunctivitis is a rare and unusual form of chronic pseudomembranous conjunctivitis of unknoen etiology. Here we report for the first time on homozygous type I Plg deficiency in three unrelated female patients who suffered from ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes. The disease is caused by massive fibrin depositions within the "extravascular space" of mucous membranes because of absent clearence by plasmin. Infusions of albumin, frech frozen plasma, or Lys-plasminogen (Lys-Plg) into two of the three patients revealed normal Plg activation capacity in these patients. The absence of fibrinolytic activity could therefore be shown to be due to Plg deficiency. Similar studies in the third patients have not been completed. In the two patients studied so far, infusions of Lys-Plg resulted in pronpt and adequate Plg recovery with a short half-life and high amounst of plasmin-antiplasmin complexes and D-dimer. One patient additionally revealed and inherited partial factor XII deficiency. Functionally, this factor XII deficiency did not interfere with Plg activation. However, there may be a pathway of Plg activation in this patient via the prekallikrein C1-INH system