Persistent Hydrocephalus, Shunt, and Subglottic Stenosis in a Newborn with Plasminogen Deficiency due to Delayed Treatment with Plasminogen Concentrates: A Case Report

Plasminogen deficiency (PD) is an ultra-rare disease with an incidence of approximately 1.6:1,000.000 [1] and is caused by mutations of the plasminogen (PLG) gene. The underlying pathophysiology of the disease is based on reduced plasminogen function and quantity [2]. Plasminogen is a precursor protein of plasmin, which is mainly responsible for fibrinolysis [3]. Consequently, PD may lead to pseudomembrane formation on mucous membranes, occurring spontaneously or in response to trauma, with manifestations in the respiratory, urogenital, and gastrointestinal tract, as well as ligneous conjunctivitis and occlusive hydrocephalus due to stenosis of the aquaeductus mesencephali [4].

Although the effectiveness of purified plasminogen concentrates has initially been shown in a patient in 1998 [5], there is no current therapy for PD available in Europe and most parts of the world. However, expectations are high for a new plasminogen replacement therapy (Ryplazim^®) that received US Food and Drug Administration (FDA) approval in 2021 [6]. In a recent study, this new therapy showed significant reduction of symptoms and conjunctivitis lesions in 14 patients [7]. Other therapeutic options include substitution of plasma, immunosuppression, or topical therapies [8, 9]. However, success rates have been relatively low, with patients suffering from major complications leading to blindness, deafness, or neurological impairment [1].

Here we present the case of a newborn boy born in Austria in September 2022. Sonography and a fetal magnetic resonance imaging performed at 27+4 weeks’ gestation showed hydrocephalus and aqueductal stenosis, respectively. Therefore, trio whole-exome sequencing was performed, which revealed a homozygous mutation of the PLG gene (NM_000301.5:c.1607_1610dupGTGA/NP_000292.1:p.Asp537Gulfs*2) consistent with the diagnosis of severe PD type I. The same mutation was found in heterozygous form in both parents.

Hydrocephalus remained stable during pregnancy, and first postnatal cerebral ultrasound investigation showed ventricular indices above the 97th percentile, and magnetic resonance imaging confirmed the aqueductal stenosis. Baseline plasminogen activity level was severely reduced at 12%.

Follow-up cerebral sonographies demonstrated an increasing hydrocephalus (shown in Fig. 1a). Hence, a ventriculoperitoneal (VP) shunt was implanted at 9 days of life. One day after the intervention, the patient developed inspiratory stridor. Laryngoscopy showed subglottic stenosis in terms of subglottic swelling with pseudomembrane formation. These symptoms did not improve after systemic steroid therapy or adrenaline inhalations. Furthermore, the patient developed progressive respiratory distress with tachypnea and subcostal retractions, and removal of the subglottic lesions via suspension microlaryngoscopy was performed at 16 days of life. Recovery thereafter was uneventful, ventricular indices declined, and the baby was discharged home 3 weeks after birth.

However, he was readmitted 27 days later with recurrent hydrocephalus. On the cranial ultrasound, multiple intraventricular membranes were detected as the presumed cause of the shunt dysfunction (shown in Fig. 1b). Replacement of the shunt valve alone did not resolve the dysfunction. One day later, revision with exchange of the ventricular catheter and valve was performed, but blockage reoccurred quickly. Therefore, and because of very high cerebrospinal fluid (CSF) protein levels, the shunt was changed to a subcutaneous ventricular access reservoir for repeated CSF punctures.

The vicious circle continued: repeated surgery requiring re-intubations led to another episode of life-threatening respiratory insufficiency with severe subglottic stenosis (shown in Fig. 2a, b). Acute re-intubation was almost impossible but eventually succeeded with a corticosteroid-coated tube.

To prevent restenosis, we treated the patient with systemic steroids, nonsteroidal anti-inflammatory drugs, adrenaline inhalations, and daily plasma transfusions (10 mL/kg) to reverse the tissue alterations in the subglottic area. The latter increased the plasminogen activity to steady state levels of 21–22% (shown in online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000534868). Another suspension microlaryngoscopy was performed to remove remaining subglottic pseudomembranes, and flexible laryngoscopy showed good results.

In the meantime, the persistent hydrocephalus was relieved regularly by CSF punctures via the subcutaneous reservoir. Despite these interventions and the continuous plasma transfusions, the patient unfortunately developed clinical symptoms of neurological impairment including poor intake, vomiting, and irritability.

The lack of improvement under conventional therapy made us desperate for alternative treatment options. After many efforts and due to the good will of the manufacturer, we acquired six doses of the new therapeutic plasminogen concentrate, which has not yet been approved for patient use in Europe.

After decrease of CSF protein levels, another VP shunt was inserted again instead of the reservoir under perioperative treatment with plasminogen concentrates. 68.8 mg were administered shortly preoperatively and four times postoperatively. One vial was kept for future emergency treatment. Peak plasminogen activity levels increased to 142%, and trough levels were above 50% (shown in online suppl. Fig. 1). Fortunately, intraoperative bronchoscopy showed no airway stenosis. Postoperative shunt function was good, hydrocephalus resolved within the following weeks, and follow-up sonographies showed remission of intraventricular pseudomembranes.

Of note, apart from the named dramatic neurological and respiratory complications, the patient also developed ligneous conjunctivitis which was initially treated by abrasion and later with plasma eye drops derived from a plasma donation.

To ensure enteral feeding, a percutaneous endoscopic gastrostomy tube was implanted before discharge. To prevent repeated pseudomembrane formation, the tube was placed successfully using laparoscopy without gastroscopy under sedoanalgesia without intubation. Additionally, we were able to increase plasminogen levels to 20–29% perioperatively with intensified plasma transfusions (15 mL/kg on three consecutive days beginning at the day of surgery).

As it is currently impossible to obtain more plasminogen concentrate, we resumed regular plasma transfusions to increase plasminogen activity. Plasma administration was reduced from three times a week to once per week over 4 weeks, leading to an increase of through plasminogen activity by 4–8% from baseline. Finally, the patient was able to be discharged to home after 5 months of inpatient care, and we keep performing weekly plasma transfusions in outpatient care.

PD is a very rare condition with limited treatment options; thus, patients as well as caregivers eagerly await new therapies. Due to the limited number of affected patients, therapeutic options have not yet been optimized, and ideal dosages for currently available therapies are unknown.

In two cases of PD resulting in congenital hydrocephalus, Weinzierl et al. [10] reported the benefit of ventriculo-cholecystic shunt after failure of VP and ventriculoatrial shunts. As seen in preterm infants with intraventricular hemorrhage, ventricular lavage might be beneficial [11, 12] if intraventricular septa already occurred. However, to our knowledge, there are no data on this treatment in patients with PD.

Substitution with regular plasma transfusions is an option [9]; however, with the consequence of volume burden that might lead to right ventricular overload and the risk of transfusion reactions in the long term. In our case, despite extensive conservative treatment, severe complications occurred.

Retrospectively, it appears that the initial decision to implant the VP shunt without perioperative plasma transfusions may not have been the most suitable choice for our patient, regarding his drastic response to any trauma. Based on our experience, we would advise caregivers in similar situations to consider perioperative plasma transfusions where plasminogen substitutes are not available. Furthermore, extraventricular drainage or Ommaya reservoir implantation are an alternative option, but to the best of our knowledge, there are no studies available showing lower rates of stenosis in comparison to VP shunts. Further trials are necessary to compare extraventricular drainage, Ommaya reservoir, and VP shunt with respect to occlusive events.

As was seen in our and other cases [13], plasminogen concentrate is very efficacious for treating PD. Our patient stabilized after receiving five doses. If he would have had access to the concentrate earlier, the complications he experienced might have been avoided. Expectations remain for positive long-term results and a better and faster availability of the concentrate for all affected patients worldwide.

We extend special thanks to Dr. Amy Shapiro (Indiana Haemophilia and Thrombosis Center) for expert advice and Dr. Roberto Crea and Mr. Aleksandar Marinkovic from Kedrion Biopharma, without whom we would not have been able to obtain plasminogen concentrate for our patient.

We also like to thank our multidisciplinary team and everyone involved in the care of this challenging case: Prof. Dr. Olga Plattner, Prof. Dr. Doris-Maria Denk-Linnert, and Dr. Imme Roesner, who contributed to the laryngological decisions and performed laryngeal microsurgery, and Dr. Katharina Thom of the pediatric coagulation team.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient’s father for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

No funding was granted for this work.

B.S.B. and C.B. wrote the initial draft and revised and approved the final draft. C.M. contributed to the hematologic case management and drafting and final review of the manuscript. J.B. (OB/GYN) performed perinatal diagnostics and reviewed the manuscript. V.K. (ENT), M.B.N. (Anesthesia), and A.R. (Neurosurgery) contributed to clinical case management. All authors reviewed the manuscript and approved the final manuscript.

All data generated or analyzed during this study are not publicly available. Further inquiries can be directed to the corresponding author. Additional data have been provided as supplementary material and can be viewed online.