Type I plasminogen deficiency

Congenital plasminogen deficiency is a rare autosomal recessive disorder clinically characterized by chronic pseudomembranous mucosal lesions with subepithelial fibrin deposition and inflammation. Type I plasminogen deficiency is caused by a homozygous or compound heterozygous mutation in the gene encoding plasminogen(PLG gene; 173350) on chromosome 6q26.

Type I plasminogen deficiency is characterized by decreased serum plasminogen activity, decreased plasminogen antigen levels, and clinical symptoms, whereas type II plasminogen deficiency, also known as "dysplasminogenemia," is characterized by decreased plasminogen activity with normal or slightly decreased antigen levels. Patients with type II deficiency are usually asymptomatic. Ligneous conjunctivitis and pseudomembrane formation have been associated only with type I plasminogen deficiency. Presumably, normal levels of plasminogen antigen with reduced activity, as seen in type II, are sufficient for normal wound healing (Schuster et al. 2003).

A slightly increased ratio of females to males was observed (w:m= 1.4-2.0: 1) (Schuster et al. 2003; Tefs et al. 2006).

Plasminogen activators released by the cornea in the tear fluid of the normal eye (Mirshahi et al., 1996) convert plasminogen into the fibrinolytic enzyme plasmin, which rapidly clears the cornea of fibrin deposits. The absence of plasmin activity in patients with plasminogen deficiency results in the formation of fibrin-rich viscous or membranous material in ligneous conjunctivitis. An inflammatory response associated with activation of inflammatory cells in fibroblasts, accompanied by desiccation of fibrin, results in the woody appearance of conjunctival lesions. A similar reaction occurs in other affected areas of the body. Tracheobronchial fibrin deposition compromises the ciliary system of the tracheobronchial tree and promotes bacterial growth, predisposing patients to multiple sinobronchial infections. Ear involvement (Marcus et al. 1990) is due to fibrin deposition in the middle ear. The pathophysiologic mechanism of occlusive hydrocephalus may be fibrin deposits in the cerebral ventricular system leading to impaired fluid circulation in the aqueduct region (Schott et al. 1998).

Schuster et al (1997) and Schuster and Seregard (2003) found that patients with ligneous conjuncitivis and congenital plasminogen deficiency do not have intravascular thromboembolic episodes despite severe deficiency of the key enzyme of the fibrinolytic system. Furthermore, heterozygous plasminogen deficiency does not appear to be a risk factor for thrombosis (Tait et al., 1996).

The most common clinical manifestation is ligneous (woody) conjunctivitis, a redness and subsequent formation of pseudomembranes primarily on the lid surfaces of the eye that develop into white, yellow-white, or red thick masses with a woody consistency that replace the normal mucosa. The lesions may be triggered by local injury and/or infection and often recur after local excision. Pseudomembranous lesions of other mucous membranes commonly occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus.

Schuster et al (1997) and Schuster and Seregard (2003) found that patients with ligneous conjunctivitis and congenital plasminogen deficiency do not have intravascular thromboembolic episodes despite severe deficiency of the key enzyme of the fibrinolytic system. Furthermore, heterozygous plasminogen deficiency does not appear to be a risk factor for thrombosis (Tait et al., 1996).

Tefs et al. (2006) reported variable success in treating ligneous conjunctivitis in 50 patients with topical solutions containing corticosteroids, heparin, fresh frozen plasma, plasminogen, and immunosuppression. Surgical removal of pseudomembranes was often followed by relapse. Gingivectomy in patients with ligneous gingivitis was unsuccessful and resulted in loss of teeth in at least 2 patients.

Bateman et al (1986) reported on one sibling pair with ligneous conjunctivitis. The authors found reports of 9 other affected sibling pairs, suggesting autosomal recessive inheritance, although no parental consanguinity was found. In one of the patients reported by Bateman et al. (1986), Cohen (1990) observed laryngeal and tracheobronchial involvement leading to voice changes and obstructive lung disease.

Mingers et al (1997) described 3 unrelated women with ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes associated with plasminogen deficiency. The disease was characterized by massive fibrin deposition in the mucous membranes due to lack of clearance by plasmin. Infusion of plasminogen in 2 of the patients resulted in normal plasminogen activity, confirming the causative defect, although there was no significant clinical improvement.

Schuster et al (1997) reported on two unrelated girls of Turkish descent who had ligneous conjunctivitis and occlusive hydrocephalus. One patient first developed chronic bilateral conjunctivitis at 4 months of age. At 2 years of age, enlargement of the head was noted. At 25 months of age, the child suddenly became comatose and showed generalized hypotonia. Occlusive hydrocephalus was noted; a ventriculoatrial shunt was placed. At this time, pseudomembranous lesions of both conjunctivae and gingival hyperplasia appeared. At 3 years of age and several times thereafter, the pseudomembranes in both eyes were surgically removed. At the age of 8 years, local treatment with eye drops containing hyaluronidase proved to be extremely beneficial. Genetic analysis revealed that both girls had a homozygous mutation in the plasminogen gene.

Schott et al (1998) reported a child with plasminogen deficiency born to consanguineous Turkish parents. Prenatal ultrasonography revealed progressive hydrocephalus, and the child was born at 35 weeks' gestation. A bulging fontanel and macrocephalus were the only findings at that time. Three days after birth, she developed bilateral inflammation of the palpebral portion of the conjunctiva with hypersecretion and formation of pseudomembranes. Within two weeks, a thick, yellowish-white, fibrous, woody pseudomembrane layer of conjunctival growths had developed, spreading from the inner surface of the upper and lower eyelids and completely occluding both eyes. The pseudomembranes were surgically removed several times but quickly regrew. Imaging studies revealed a Dandy-Walker malformation, hypoplasia of the cerebellum, and a hypoplastic corpus callosum.

There was also hyperviscosity of tracheobronchial and nasopharyngeal secretions and impaired wound healing. Substitution therapy with lysine-conjugated plasminogen resulted in rapid regression of pseudomembranes and normalization of airway secretions and wound healing. Molecular analysis revealed a homozygous mutation in the PLG gene (173350.0006). A healthy brother and unaffected parents were heterozygous for this mutation.

Schuster et al (1999) performed a follow-up of the siblings reported by Bateman et al (1986). The 19-year-old sister first developed conjunctivitis at 3 weeks of age. At 3 years of age, she developed bilateral conjunctival pseudomembranes and was diagnosed with ligneous conjunctivitis. These membranes recurred, requiring surgical removal 18 times. The incidence of conjunctival membrane formation had decreased in recent years. At the age of 5 years, she developed hoarseness and was found to have ligamentous membranes in her vocal cords. She also presented with asthma-like symptoms. At age 8, she developed pneumomediastinum and had her first of 20 bronchoscopies to remove thickened membranes from her laryngotracheobronchial tree. At age 16, she developed an abscess in her left lung that required bronchoscopic drainage. Other features included gingival membranes and nodular, calcified masses in the renal pelvis. The 14-year-old brother had developed conjunctivitis at 9 months of age, which worsened at 4 years of age. Since age 5, he had to undergo 15 surgeries for ligneous conjunctival membranes. He also had gingival membranes associated with intermittent bleeding, lingua geographica, and sinusitis, as well as membrane formation in the pharynx and renal pelvic system. Duodenal ulcers and eosinophilic mucositis of the stomach were also observed.

1. Bateman JB et al.(1986) Ligneous conjunctivitis: an autosomal recessive disorder. J Pediat Ophthal Strabismus 23: 137-140.
2. Bouisson M (1847) Ophthalmie sur-aigue avec formation de pseudomembranes a la surface de la conjonctive. Ann Ocul (Paris) 17: 100-104.
3. Cohen SR (1990) Ligneous conjunctivitis: an ophthalmic disease with potentially fatal tracheobronchial obstruction. Laryngeal and tracheobronchial features. Ann Otol Rhinol Laryng 99: 509-512.
4. Kao WW et al (1998) Healing of corneal epithelial defects in plasminogen- and fibrinogen-deficient mice. Invest Ophthal Vis Sci 39: 502-508.
5. Marcus DM et al (1990) Ligneous conjunctivitis with ear involvement. Arch Ophthal 108: 514-519.
6. Mingers A-M et al (1997) Homozygous type I plasminogen deficiency. Semin Thromb Hemost 23: 259-269.
7. Schott D et al (1998) Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. New Eng J Med 339: 1679-1686.
8. Schuster V et al.(1997) Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 90: 958-966.
9. Schuster V et al. (1999) Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood 93: 3457-3466.
10. Schuster V et al (2003) Ligneous conjunctivitis. Surv. Ophthal. 48: 369-388.
11. Tait RC et al (1996) Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb Haemost 76: 1004-1008.
12. Tefs K et al (2006) Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood 108: 3021-3026.