Hypoplasminogenemia (ORPHA:722)
A rare multi-system disease characterized by markedly impaired extracellular fibrinolysis leading to the formation of ligneous (fibrin-rich) pseudomembranes on mucosae.
Epidemiology
Whilst epidemiological data is limited, the prevalence of hypoplasminogenemia (HPG) is estimated to be in the range of 1/625,000.
Clinical description
Onset of clinical manifestations usually occurs in early infancy, but can occur at any age. Although not well understood, triggers of lesions may include microtrauma (dust, a foreign body), surgical procedures or local inflammation. The most common clinical manifestation of HPG are lesions of the conjunctivae (ligneous conjunctivitis (LC)) which initially appear as inflammation but progress to development of membranous lesions. Other sites of involvement include the oral cavity with gingival lesions (ligneous periodontitis), nose, sinuses, ears, throat and tonsils, gastrointestinal tract (duodenal ulcers, lesions in the small and large bowel), the respiratory tract (pseudomembranous laryngitis, trachea-bronchitis and consolidation or atelectasis), urinary tract, and the female genital tract (vaginitis, cervicitis, involvement of the fallopian tube, ovary and endometrium). The central nervous system (occlusive hydrocephalus, Dandy Walker malformation) and the skin (juvenile colloid milium) may also be affected, but are less common. HPG has been reported to effect wound healing. HPG is not a risk factor for thrombophilia.
Etiology
HPG is caused by homozygous or compound-heterozygous pathogenic variants in the gene PLG (6q26); encoding plasminogen (plg). In HPG, PLG mutations result in parallel reductions in both the level of immunoreactive plg and its functional activity.
Diagnostic methods
Diagnosis relies on recognition of the clinical manifestations and laboratory tests for plg activity and immunoreactive levels. Diagnosis can be confirmed by genetic testing.
Differential diagnosis
Whilst infection of the affected area is most frequently the assumed diagnosis, the differential diagnosis is extensive and dependent on the area affected and includes polyps, allergies, cholesteatoma, hearing loss, Cowden's Disease, oral fibromas, gingival hypertrophy, reactive airway disease, pneumonia, gastroesophageal reflux disease, ulcers, inflammatory bowel disease, irritable bowel syndrome, kidney stones, endometriosis, polycystic ovarian disease, primary infertility, juvenile colloid milium, Ehlers Danlos (poor wound healing) as well as amyloidosis and lipoid proteinosis.
Antenatal diagnosis
Prenatal genetic diagnosis is possible if a couple has a prior affected child and the pathogenic genetic variants in both PLG genes have been identified. Identification of compound heterozygous or homozygous hypoplasminogenemia is not necessarily predictive of the development of symptoms or severity that may be experienced.
Genetic counseling
HPG is inherited in an autosomal recessive pattern. Siblings of individuals who have hypoplasminogenemia each have a 25% risk of inheriting the condition. Genetic counseling should be offered to families with an affected individual and at-risk couples. Individuals who are heterozygous or have dysplasminogenemia (plg activity is reduced, but immunoreactive levels are normal or slightly reduced) are asymptomatic.
Management and treatment
Management depends on the site(s) of involvement. Treatment strategies have been targeted mainly towards management of LC. The plg concentrate, ryplazim, was recently approved (June 2021, USA) and is administered intravenously as a replacement therapy for plasminogen and has been shown effective in treating both eye and systemic lesions. A currently unlicensed plg ophthalmologic concentrate has been utilized with reported success for eye lesions. In the absence of plg concentrate, treatment is with fresh frozen plasma. Other attempted systemic medications have included anticoagulants, immunosuppressants, hormone therapy, antihistamines, and antibiotics. Surgical interventions have been attempted, but in the absence of plg concentrate, typically result in rapid regrowth of lesions. Occlusive hydrocephalus is treated as standard. Other topical treatments for eye lesions may be used as an adjunctive to plg replacement.
Prognosis
Where the conjunctivae is involved, the visual prognosis is typically moderate; although chronic lesions can lead to loss of vision. The prognosis for severe cases with multiorgan involvement can be quite poor.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Dr Rebecca BIALAS  - Dr Amy SHAPIRO