NORD gratefully acknowledges Volker Schuster, MD, PhD, Professor of Pediatrics, Hospital for Children and Adolescents, University of Leipzig, Medical Faculty, Leipzig, Germany, for assistance in the preparation of this report.
Congenital plasminogen deficiency type I is a rare genetic disorder. Individuals lack an enzyme called plasminogen. They develop thick growths, sometimes referred to as lesions, on the mucous membranes of the body. The mucous membranes are a moist layer of tissue that serves as a protective barrier that keeps the inside of the body from drying out. The mucous membrane that lines the inside of the eyelids and the front of the eye (called the conjunctiva) and mucous membrane that lines the inside of the mouth are most often affected. Other mucous membranes can be affected including those lining the nose, the middle ear, the stomach and intestines (gastrointestinal tract), and the respiratory tract. Abnormal growths form on these mucous membranes and without treatment can potentially cause significant complications in certain areas. The growths may resemble a membrane and are sometimes called pseudomembranes. They are described as having a ‘woody’ texture. The growths usually recur if they are removed. The overall severity of the disorder can vary greatly from one person to another depending where the growths occur. The disorder is caused by alterations in the PGL gene, which leads to a deficiency in the plasminogen.
Two types of the disorder have been described in the medical literature. Congenital plasminogen deficiency type I, also called hypoplasminogenemia, - if transmitted from both parents - is a severe disorder and primarily discussed in this report. Congenital plasminogen deficiency type II, also called dysplasminogenemia, is not believed to be associated with any symptoms.
The signs and symptoms of plasminogen deficiency type I can vary from one person to another, even among members of the same family. Initial signs may be present in infants or young children. However, in other people, no signs of the disorder may be apparent until well into adulthood. Growths may develop spontaneously, or they be ‘triggered’ by infection, trauma, or injury.
The most common symptom is ligneous conjunctivitis. Conjunctivitis refers to inflammation of the conjunctiva, the membrane the lines the eyes. Ligneous is a term that means ‘resembling wood’. People with ligneous conjunctivitis have growths or lesions on the conjunctiva that are yellow, white or red and have a texture that resemble wood. These growths most often appear on the inside of the eyelid. These growths may be preceded by redness of the conjunctiva. Sometimes, the cornea (the thin, transparent membrane that covers the front of the eye) may become involved. The growth can tear the cornea and cause scarring. Ultimately, a loss of vision can occur.
Sometimes ligneous growths may appear on the gums. They are usually not painful. Inflammation of the gums, called gingivitis, can occur. Sometimes this can lead to a loss of teeth. These growths can also form in the mucous membranes of the middle ear, nose, throat, larynx, vocal cords, and along the stomach and intestines (gastrointestinal tract), the respiratory tract, and the female genital tract. Growths in the middle ear can lead to chronic middle ear infection (otitis media) and hearing loss. When growths affect the skin the condition is called juvenile colloid milium and is characterized by small, translucent, yellow-brown bumps (papules). These growths usually occur on areas of the skin that are most exposed to the sun.
Growths in the respiratory tract can lead to serious complications including recurrent pneumonia and obstruction of the airways. Growths in the gastrointestinal tract may result in ulcers. Growths in the windpipe can potentially cause life-threatening obstruction, particularly in small children.
Some children with congenital plasminogen deficiency can develop a condition called occlusive hydrocephalus. This refers to the accumulation of cerebrospinal fluid (CSF) in the skull because the fluid cannot drain properly. This causes pressure on the tissues of the brain.
In earlier reports in the medical literature, physicians speculated that affected individuals were at risk for the development of blood clots (thrombosis). However, most evidence suggests that both forms of congenital plasminogen deficiency, in and of themselves, do not increase the risk of developing a blood clot.
Congenital plasminogen deficiency is caused by an alteration in the plasminogen (PLG) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The PLG gene contains instructions for creating the protein plasminogen. An alteration in the PLG gene may result in deficient levels of plasminogen (plasminogen deficiency type I). Plasminogen is broken down by other enzymes into plasmin. Plasmin has several functions in the body. For example, plasmin breaks down another protein called fibrin. Fibrin is an important protein in the clotting of blood and wound healing (fibrinolysis). Because of the lack of plasminogen, fibrin abnormally accumulates in the body, causing inflammation and the ligneous growths that characterize congenital plasminogen deficiency type I.
Congenital plasminogen deficiency is inherited in an autosomal recessive manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Congenital plasminogen deficiency is a rare disorder that occurs worldwide. Slightly more females have been identified than males. The exact incidence or prevalence of the disorder is unknown, but one estimate places the incidence at 1.6 people per 1,000,000 in the general population. Incidence is the rate of new or newly diagnosed people with a disorder. Prevalence is the overall number of people who have the disorder at a given time. Rare disorders, including congenital plasminogen deficiency, often go unrecognized or misdiagnosed making it difficult to determine the true frequency in the general population.
A diagnosis of congenital plasminogen deficiency is based upon identification of characteristic symptoms, a family account of their medical history (anamnesis), a detailed patient history, and a thorough clinical evaluation. Specific laboratory tests can confirm a diagnosis specifically tests that measure the activity of plasminogen, which will be severely deficient in individuals with plasminogen deficiency type I. Antigen testing which measures the reactivity of plasminogen to a certain antigen may also be used. These tests are available in most clinical coagulation laboratories.
Molecular genetic testing can confirm a diagnosis of congenital plasminogen deficiency. Molecular genetic testing can detect alterations in the PLG gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients.
The only effective therapies reported in the medical literature are systemic and topical plasminogen concentrates (i.e. replacing the deficient plasminogen in the body) that have led to an improvement in symptoms and prevented recurrence in some people. This includes eye drops that contain plasminogen, which have been effective in treating ligneous conjunctivitis. Plasminogen eye drops, however, are not readily available. Researchers are currently investigating replacement plasminogen to see whether such therapy will clear up existing symptoms and prevent recurrence.
Various therapies have been tried to treat individuals with congenital plasminogen deficiency. Surgical removal of the growths may be beneficial initially, but the growths usually recur. Several medications have been tried including high-dose intravenous corticosteroid treatment, heparin, cyclosporine, azathioprine and hyaluronidase. There is a report of oral contraceptives leading to an increase of plasminogen level in one woman. These therapies have shown no or only limited benefit, or have only been reported in a single person.
Some children with hydrocephalus may require surgical implantation of a shunt to drain away excess cerebrospinal fluid. Additional therapy is symptomatic and supportive. Treatment may require the coordinated efforts of a team of specialists depending upon the specific organ system involved. For example, pediatricians, ophthalmologists, dental specialists, lung specialists (pulmonologists), and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
As of May 2016, a phase 2/3 clinical trial to study plasminogen IV infusions is recruiting individuals with congenital plasminogen deficiency. The ongoing clinical trials into this treatment are seeking to determine the safe, tolerability and optimal dose of the drug for people with this disorder. The Food and Drug Administration (FDA) has granted accelerated approval for this drug. This program is designed to allow for earlier approval for drugs that treat serious conditions or fill unmet medical needs.
For more information of these studies:
Safety & Efficacy of Human Plasma Derived Plasminogen Ophthalmic Drops for Treatment of Ligneous Conjunctivitis: Report of Phase 2/3 Clinical Trial (http://www.bloodjournal.org/content/126/23/2288)
Pharmacokinetics of Intravenous Infusion of Glu-Plasminogen Concentrate in Patients with Hypoplasminogenemia (http://www.bloodjournal.org/content/126/23/3498)
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Pons V, Olivera P, Garcia-Consuegra R, et al. Beyond hemostasis: the challenge of treating plasminogen deficiency. A report of three cases. J Thromb Thrombolysis. 2016;41:544-547. http://www.ncbi.nlm.nih.gov/pubmed/26036227
Suzuki T, Ikewaki J, Iwata H, Ohashi Y, Ichinose A. The first two Japanese cases of several type I congenital plasminogen deficiency with ligneous conjunctivitis: successful treatment with direct thrombin inhibitor and fresh plasma. Am J Hematol. 2009;84:363-365. http://www.ncbi.nlm.nih.gov/pubmed/19373890
Mehta R, Shapiro AD. Plasminogen deficiency. Haemophilia. 2008;14:1261-1268. http://www.ncbi.nlm.nih.gov/pubmed/19141167
Weinzierl MR, Collmann H, Korinth MC, Gilsbach JM, Rohde V. Management of hydrocephalus in children with plasminogen deficiency. Eur J Pediatr Surg. 2007;17:124-128.
Schuster V, Hugle B, Tefs K. Plasminogen deficiency. J Thromb Haemost. 2007;5:2315-2322. http://www.ncbi.nlm.nih.gov/pubmed/17900274
Tefs K, Gueorguieva M, Klammt J, et al. Molecular and clinical spectrum of type I plasminogen deficiency: a series of 50 patients. Blood. 2006;108:3021-3026. http://www.ncbi.nlm.nih.gov/pubmed/16849641
Genetics Home Reference. Congenital Plasminogen Deficiency. February 7, 2006. Available at: https://ghr.nlm.nih.gov/condition/congenital-plasminogen-deficiency Accessed On: May 17, 2016.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:217090; Last Update:04/19/2016. Available at: http://omim.org/entry/217090 Accessed on: May 17, 2016.
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