Other entities represented in this entry:
SNOMEDCT: 95844003; ICD10CM: E88.02; ORPHA: 722; DO: 0111592;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q26 | Plasminogen deficiency, type I | 217090 | Autosomal recessive | 3 | PLG | 173350 |
| 6q26 | Dysplasminogenemia | 217090 | Autosomal recessive | 3 | PLG | 173350 |
A number sign (#) is used with this entry because of evidence that type I plasminogen deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding plasminogen (PLG; 173350) on chromosome 6q26. Ligneous conjunctivitis is usually the initial and most common manifestation of type I congenital plasminogen deficiency.
Congenital plasminogen deficiency is a rare autosomal recessive disorder characterized clinically by chronic mucosal pseudomembranous lesions consisting of subepithelial fibrin deposition and inflammation. The most common clinical manifestation is ligneous ('wood-like') conjunctivitis, a redness and subsequent formation of pseudomembranes mostly on the palpebral surfaces of the eye that progress to white, yellow-white, or red thick masses with a wood-like 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 often occur in the mouth, nasopharynx, trachea, and female genital tract. Some affected children also have congenital occlusive hydrocephalus. A slightly increased female:male ratio has been observed (1.4:1 to 2:1) (Schuster and Seregard, 2003; Tefs et al., 2006).
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 reduced antigen levels. Patients with type II deficiency are usually asymptomatic. Ligneous conjunctivitis and pseudomembranous formation has only been associated with type I plasminogen deficiency. Presumably, normal amounts of plasminogen antigen with decreased activity, as seen in type II, is sufficient for normal wound healing (Schuster and Seregard, 2003).
Bateman et al. (1986) reported a brother and sister with ligneous conjunctivitis. The authors found reports of 9 other sets of affected sibs, suggesting autosomal recessive inheritance, although no parental consanguinity was observed. In 1 of the patients reported by Bateman et al. (1986), Cohen (1990) observed laryngeal and tracheobronchial involvement resulting in voice change and obstructive pulmonary disease.
Mingers et al. (1997) described 3 unrelated females with ligneous conjunctivitis and additional pseudomembranous lesions of other mucous membranes associated with plasminogen deficiency. The disease was characterized by massive fibrin deposition within mucous membranes due to the absence 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 2 unrelated girls of Turkish extraction who had ligneous conjunctivitis and occlusive hydrocephalus. One patient first developed chronic bilateral conjunctivitis at the age of 4 months. Enlargement of the head was noted at 2 years of age. At the age of 25 months, the child suddenly became comatose and exhibited generalized hypotonia. She was found to have occlusive internal hydrocephalus; a ventriculoatrial shunt was placed. Pseudomembranous lesions of both conjunctivae and gingival hyperplasia were present at that time. At 3 years of age and on several occasions thereafter, pseudomembranes were surgically removed from both eyes. At age 8, local treatment with hyaluronidase-containing eyedrops was highly beneficial. Genetic analysis revealed that both girls had a homozygous mutation in the plasminogen gene (see 173350.0004 and 173350.0005).
Schott et al. (1998) reported a child, born of consanguineous Turkish parents, with plasminogen deficiency. Prenatal ultrasound examination demonstrated progressive internal hydrocephalus, and the child was delivered by elective cesarean section at 35 weeks' gestation. 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 2 weeks, a thick, yellowish-white, fibrous, woody pseudomembranous layer of conjunctival proliferation had developed, spreading from the inner side of the upper and lower eyelids and completely closing both eyes. The pseudomembranes were removed surgically several times but regrew rapidly. Imaging studies demonstrated Dandy-Walker malformation, hypoplasia of the cerebellum, and hypoplastic corpus callosum. There was also hyperviscosity of tracheobronchial and nasopharyngeal secretions and impaired wound healing. Replacement therapy with lysine-conjugated plasminogen led to rapid regression of the pseudomembranes and normalization of respiratory tract secretions and wound healing. Molecular analysis identified a homozygous mutation in the PLG gene (173350.0006). A healthy brother and the unaffected parents were heterozygous for the mutation.
Schuster et al. (1999) provided follow-up of the sibs 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 repeatedly, necessitating surgical removal on 18 different occasions. The rate of conjunctival membrane formation had decreased in recent years. At 5 years of age, she developed hoarseness and was noted to have a ligneous membrane in the vocal cords. She also showed asthma-like symptoms. At the age of 8 years, she developed pneumomediastinum and had her first of 20 bronchoscopies to remove thickened membranes from her laryngotracheobronchial tree. At 16 years of age, she developed an abscess of the left lung, necessitating bronchoscopic drainage. Other features included gingival membranes and nodular, calcified masses in the renal collecting system, demonstrable by ultrasound and pyelography. Treatment with multiple eyedrops, corticosteroids, local heparin, and multiple courses of various antibiotics had been ineffective. The 14-year-old brother had developed conjunctivitis at 9 months of age, which became severe at 4 years of age. He had required surgery for ligneous conjunctival membranes on 15 occasions, beginning at the age of 5 years. He also had had gingival membranes associated with intermittent bleeding, geographic tongue, and sinusitis, as well as membrane formation in the pharynx and in the renal collecting system. Duodenal ulceration and an eosinophilic gastric infiltration were also observed.
Tefs et al. (2006) reported 50 patients from 44 families with severe congenital plasminogen deficiency. The parents were consanguineous in 21 cases. The median age of first clinical manifestation was 9.75 months, but ranged up to 61 years. The most common manifestation was ligneous conjunctivitis (80% of patients), followed by ligneous gingivitis (34%), and involvement of the upper and lower respiratory tract (30%), including the ears, sinus, larynx, bronchi, and lungs. Other less commonly involved areas included the female genital tract (8%), gastrointestinal tract, and skin. Four patients had congenital occlusive hydrocephalus and 2 had Dandy-Walker malformation with cerebellar hypoplasia. Venous thrombosis did not occur in 45 patients; the thrombosis history was unknown in 5 patients.
Results of treatment of ligneous conjunctivitis with hyaluronidase eye drops, corticosteroids, cyclosporine, and antiviral agents have been generally disappointing. Surgical treatment often causes accelerated recurrence of pseudomembranes. Schott et al. (1998) reported dramatic results with purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency.
Among 50 patients, Tefs et al. (2006) reported variable success of treatment of ligneous conjunctivitis with topical solutions containing corticosteroids, heparin, fresh frozen plasma, plasminogen, and immunosuppression. Surgical excision of pseudomembranes was often followed by relapse. Gingivectomy in patients with ligneous gingivitis was unsuccessful and followed by loss of teeth in at least 2 patients.
In 2 unrelated Turkish girls with plasminogen deficiency, Schuster et al. (1997) identified 2 different homozygous mutations in the PLG gene (173350.0004; 173350.0005).
In 2 sibs with plasminogen deficiency originally reported by Bateman et al. (1986), Schuster et al. (1999) identified compound heterozygosity for 2 mutations in the PLG gene (173350.0008; 173350.0009).
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 and in mice with targeted disruption of the plasminogen gene (Drew et al., 1998; Kao et al., 1998). An inflammatory reaction combined with activation of inflammatory cells in fibroblasts, with a drying out of the fibrin, results in the wood-like appearance of the conjunctival lesions. A similar reaction occurs in other affected areas of the body. Tracheobronchial fibrin deposits impair the ciliary system of the tracheobronchial tree and support bacterial growth, predisposing patients to multiple sinobronchial infections. Involvement of the ear (Marcus et al., 1990) is attributable to fibrin deposition in the middle ear. The pathophysiologic mechanism of occlusive hydrocephalus may be fibrin deposition in the cerebral ventricular system, causing impaired circulation of the fluid in the aqueduct region (Schott et al., 1998).
Schuster et al. (1997) and Schuster and Seregard (2003) noted that patients with ligneous conjuncitivis and congenital plasminogen deficiency do not experience intravascular thromboembolic episodes despite a severe deficiency of the key zymogen of the fibrinolytic system. In addition, heterozygous plasminogen deficiency does not appear to be a risk factor for thrombosis (Tait et al., 1996; Shigekiyo et al., 1992), despite several earlier reports to the contrary (Aoki et al., 1978; Dolan et al., 1988).
Schuster and Seregard (2003) provided a detailed history of ligneous conjunctivitis and plasminogen deficiency. The authors stated that ligneous conjunctivitis was first described in a 46-year-old man by Bouisson (1847). Borel (1934) was the first to describe the familial occurrence of the disorder, which he termed 'ligneous conjunctivitis.'
Ligneous conjunctivitis has been described in different animal species, including Doberman pinschers (Ramsey et al., 1996).
Aoki, N., Morio, M., Sakata, Y., Yoshida, N. Abnormal plasminogen: a hereditary molecular abnormality found in a patient with recurrent thrombosis. J. Clin. Invest. 61: 1186-1195, 1978. [PubMed: 659588] [Full Text: https://doi.org/10.1172/JCI109034]
Bateman, J. B., Pettit, T. H., Isenberg, S. J., Simons, K. B. Ligneous conjunctivitis: an autosomal recessive disorder. J. Pediat. Ophthal. Strabismus 23: 137-140, 1986. [PubMed: 3723296] [Full Text: https://doi.org/10.3928/0191-3913-19860501-09]
Borel, G. Un nouveau syndrome oculo-palpebral. Ann. Ocul. (Paris) 171: 207-222, 1934.
Bouisson, M. Ophthalmie sur-aigue avec formation de pseudomembranes a la surface de la conjonctive. Ann. Ocul. (Paris) 17: 100-104, 1847.
Cohen, S. R. Ligneous conjunctivitis: an ophthalmic disease with potentially fatal tracheobronchial obstruction. Laryngeal and tracheobronchial features. Ann. Otol. Rhinol. Laryng. 99: 509-512, 1990. [PubMed: 2195957] [Full Text: https://doi.org/10.1177/000348949009900702]
Dolan, G., Greaves, M., Cooper, P., Preston, F. E. Thrombovascular disease and familial plasminogen deficiency: a report of three kindreds. Brit. J. Haemat. 70: 417-421, 1988. [PubMed: 3219292] [Full Text: https://doi.org/10.1111/j.1365-2141.1988.tb02510.x]
Drew, A. F., Kaufman, A. H., Kombrinck, K. W., Danton, M. J., Daugherty, C. C., Degen, J. L., Bugge, T. H. Ligneous conjunctivitis in plasminogen-deficient mice. Blood 91: 1616-1624, 1998. [PubMed: 9473227]
Kao, W. W., Kao, C. W., Kaufman, A. H., Kombrinck, K. W., Converse, R. L., Good, W. V., Bugge, T. H., Degen, J. L. Healing of corneal epithelial defects in plasminogen- and fibrinogen-deficient mice. Invest. Ophthal. Vis. Sci. 39: 502-508, 1998. [PubMed: 9501859]
Marcus, D. M., Walton, D., Donshik, P., Choo, L., Newman, R. A., Albert, D. M. Ligneous conjunctivitis with ear involvement. Arch. Ophthal. 108: 514-519, 1990. [PubMed: 2138884] [Full Text: https://doi.org/10.1001/archopht.1990.01070060062050]
Mingers, A.-M., Heimburger, N., Zeitler, P., Kreth, H. W., Schuster, V. Homozygous type I plasminogen deficiency. Semin. Thromb. Hemost. 23: 259-269, 1997. [PubMed: 9255907] [Full Text: https://doi.org/10.1055/s-2007-996099]
Mirshahi, S., Soria, J., Nelles, L., Soria, C., Faure, J. P., Pouliguen, Y., Mirshahi, M. Plasminogen activators in human corneal fibroblasts: secretion, cellular localization, and regulation. Fibrinolysis 10: 255-262, 1996.
Nussgens, Z., Roggenkamper, P. Ligneous conjunctivitis: ten years follow-up. Ophthalmic Paediat. Genet. 14: 137-140, 1993. [PubMed: 8115121] [Full Text: https://doi.org/10.3109/13816819309087630]
Ramsey, D. T., Ketring, K. L., Glaze, M. B., Knight, B., Render, J. A. Ligneous conjunctivitis in four Doberman pinschers. J. Am. Anim. Hosp. Assoc. 32: 439-447, 1996. [PubMed: 8875361] [Full Text: https://doi.org/10.5326/15473317-32-5-439]
Schott, D., Dempfle, C.-E., Beck, P., Liermann, A., Mohr-Pennert, A., Goldner, M., Mehlem, P., Azuma, H., Schuster, V., Mingers, A.-M., Schwarz, H. P., Kramer, M. D. Therapy with a purified plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen deficiency. New Eng. J. Med. 339: 1679-1686, 1998. [PubMed: 9834305] [Full Text: https://doi.org/10.1056/NEJM199812033392305]
Schuster, V., Mingers, A.-M., Seidenspinner, S., Nussgens, Z., Pukrop, T., Kreth, H. W. Homozygous mutations in the plasminogen gene of two unrelated girls with ligneous conjunctivitis. Blood 90: 958-966, 1997. [PubMed: 9242524]
Schuster, V., Seidenspinner, S., Zeitler, P., Escher, C., Pleyer, U., Bernauer, W., Stiehm, E. R., Isenberg, S., Seregard, S., Olsson, T., Mingers, A.-M., Schambeck, C., Kreth, H. W. Compound-heterozygous mutations in the plasminogen gene predispose to the development of ligneous conjunctivitis. Blood 93: 3457-3466, 1999. [PubMed: 10233898]
Schuster, V., Seregard, S. Ligneous conjunctivitis. Surv. Ophthal. 48: 369-388, 2003. [PubMed: 12850227] [Full Text: https://doi.org/10.1016/s0039-6257(03)00056-0]
Shigekiyo, T., Uno, Y., Tomonari, A., Satoh, K., Hondo, H., Ueda, S., Saito, S. Type I congenital plasminogen deficiency is not a risk factor for thrombosis. Thromb. Haemost. 67: 189-192, 1992. [PubMed: 1621238]
Tait, R. C., Walker, I. D., Conkie, J. A., Islam, S. I., McCall, F. Isolated familial plasminogen deficiency may not be a risk factor for thrombosis. Thromb. Haemost. 76: 1004-1008, 1996. [PubMed: 8972025]
Tefs, K., Gueorguieva, M., Klammt, J., Allen, C. M., Aktas, D., Anlar, F. Y., Aydogdu, S. D., Brown, D., Ciftci, E., Contarini, P., Dempfle, C.-E., Dostalek, M., and 21 others. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood 108: 3021-3026, 2006. [PubMed: 16849641] [Full Text: https://doi.org/10.1182/blood-2006-04-017350]