Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency. IntroductionPlasminogen (PLG) plays an important role in intra-and extravascular fibrinolysis, wound healing, cell migration, angiogenesis, and embryogenesis. 1 Plg is primarily synthesized by liver tissue. 2 However, other minor sources identified in mice include adrenal gland, kidney, brain, testis, heart, lung, uterus, spleen, thymus, and gut tissue. 3 In humans, the cornea has been described as an extrahepatic site of PLG synthesis. 4 Inherited PLG deficiency in humans can be divided into 2 types: true PLG deficiency (type I, or hypoplasminogenemia) and dysplasminogenemia (type II). In the former, both immunoreactive PLG level and functional activity are reduced, while the latter shows a normal or slightly reduced level of immunoreactive PLG while functional activity is significantly decreased. It has been shown by several authors since 1995 that homozygous or compound-heterozygous type I PLG deficiency is a major cause of a rare inflammatory disease affecting mainly mucous membranes in different body sites. 5,6 The most common clinical manifestation is ligneous conjunctivitis, characterized by development of fibrin-rich, woodlike ("ligneous") pseudomembranous lesions. Involvement of the cornea may result in blindness. Other, less common manifestations are ligneous gingivitis, otitis media, ligneous bronchitis and pneumonia, involvement of the gastrointestinal or female genital tract, juvenile colloid milium of the skin, and congenital occlusive hydrocephalus. 6 In severely affected patients, prognosis is poor and treatment options are few. Worldwide, more than 150 patients with this disease have been reported since 1847, the date of first description. 6,7 From the Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; For personal use o...

Summary.  Plasminogen (plg) deficiency has been classified as (i) hypoplasminogenemia or ‘true’ type I plg deficiency, and (ii) dysplasminogenemia, also called type II plg deficiency. Both forms, severe hypoplasminogenemia and dysplasminogenemia, are not causally linked to venous thrombosis. Dysplasminogenemia does not lead to a specific clinical manifestation and probably represents only a polymorphic variation in the general population, mainly in Asian countries. Severe hypoplasminogenemia is associated with compromised extracellular fibrin clearance during wound healing, leading to pseudomembraneous (ligneous) lesions on affected mucous membranes (eye, middle ear, mouth, pharynx, duodenum, upper and lower respiratory tract and female genital tract). Ligneous conjunctivitis is by far the most common clinical manifestation. More than 12% of patients with severe hypoplasminogenemia exhibit congenital occlusive hydrocephalus. In milder cases of ligneous conjunctivitis, topical application of plg‐containing eye drops, fresh frozen plasma, heparin, corticosteroids or certain immunosuppressive agents (such as azathioprine) may be more or less effective. Oral treatment with sex hormones was successful in two female patients with ligneous conjunctivitis. In severe cases with possibly life‐threatening multi‐organ involvement, true therapeutic options are not available at present. The plg‐knockout mouse is a useful tool to study the many different properties of plg in a variety of settings, such as wound healing, tissue repair and tissue remodeling, virulence and invasiveness of certain bacteria in the human host, tumor growth and dissemination, as well as arteriosclerosis.

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.

This is the third reported family with chromosome 19q13 rapid-onset dystonia-parkinsonism. Psychiatric morbidity appeared common in affected members of this family and may be part of the RDP phenotype.