The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist



Interleukin-1 receptor antagonist (IL-1Ra) deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. We report the case of a 2-week-old male who presented with a swollen, erythematous left index finger and elevated serum markers of inflammation. He later developed cyclical fevers, diffuse pustular skin lesions, and thrombus formation. After not responding to broad-spectrum antimicrobial therapy and achieving only moderate success with systemic steroid therapy, he was ultimately treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement. Sequencing of his IL1RN gene revealed that the patient was compound heterozygous for a known mutation (E77X) associated with IL-1Ra deficiency and a novel mutation in exon 2 of the gene (c.140delC; p.T47TfsX4). His case highlights IL-1Ra deficiency as an autoinflammatory disease that is distinct from neonatal-onset multisystem inflammatory disease but that also responds well to anakinra. Our patient is the first reported compound heterozygote for E77X and the novel mutation in exon 2 of the gene, the latter of which adds to what will surely be a growing database of pathologic mutations in IL1RN.

Deficiency of interleukin-1 receptor antagonist (IL-1Ra) is a rare autoinflammatory disease that presents in the neonatal period and is characterized by pustulosis, periostitis, and sterile osteomyelitis. The illness arises from mutations in the IL1RN gene that result in nonfunctional IL-1Ra, causing cellular hypersensitivity to the proinflammatory cytokine IL-1 (1). IL-1Ra deficiency can cause severe morbidity and mortality in affected patients, but has shown good responsiveness to the recombinant IL-1Ra, anakinra (1, 2).

Previous reports have described patients with homozygous mutations in the IL1RN gene, specifically for the homozygous E77X “Dutch” mutation (1, 2). Here we describe the first patient with IL-1Ra deficiency who is a compound heterozygote for the Dutch mutation and a novel mutation in exon 2 of the gene.


The patient, a 14-day-old male, was transferred to our hospital with a swollen, erythematous left index finger after not responding to 2 days of oral antibiotic treatment and 1 day of broad-spectrum intravenous antibiotics. Upon admission, markers of inflammation were elevated, with a white blood cell count of 31 × 109/liter, a C-reactive protein (CRP) level of 134 mg/liter, and an erythrocyte sedimentation rate (ESR) of 115 mm/hour. Surgical debridement of the distal interphalangeal joint was performed, and aggressive antimicrobial therapy was continued; however, the finger did not improve (Figure 1A), and the patient also developed transient swelling and erythema of the left great toe (Figure 1B). During his hospital course, the patient developed fevers and spiked temperatures up to 38.5°C nightly for multiple days. His skin developed pustular lesions predominantly on the face, scalp, under the chin, and on both axillae, none of which improved after antifungal treatment (Figures 1C and D). Extensive cultures of blood, joint fluid, cerebrospinal fluid, skin, and urine on multiple occasions were all negative, with the exception of coagulase-negative Staphylococcus from 2 cultures that was believed to be a contaminant. Plain radiographs of the left hand revealed evidence of osteitis in the left index finger. His course was further complicated by acute neck swelling days after insertion of a peripherally inserted central catheter; neck imaging revealed a right internal jugular thrombus, requiring months of anticoagulation treatment.

Figure 1.

A, Swollen, erythematous distal interphalangeal joint after orthopedic incision and drainage. B, Swollen, erythematous left great toe (transient). C, Axillary ulceration and pustulosis. D, Pustular lesions on the upper chest, face, and scalp. Right-sided neck swelling is related to a thrombus in the right internal jugular vein.

After several days of negative cultures and lack of clinical improvement despite the antimicrobial therapy, we evaluated the patient for a rheumatic condition. After negative autoantibody panels on both the patient and his mother appeared to rule out an autoimmune disease, we suspected an autoinflammatory condition instead. On hospital day 9, antibiotics were discontinued in favor of initiating intravenous steroid therapy. After several days of intravenous methylprednisolone (1 mg/kg twice daily), his skin lesions and finger swelling gradually improved. He remained afebrile for the rest of his hospitalization. Upon discharge, he was transitioned to oral steroid therapy. His CRP level and ESR at discharge were 6.1 mg/liter and 36 mm/hour, respectively.

One week later, the patient again presented to the hospital with symptoms of decreased oral intake, emesis, loose stools, and tachypnea. Upon admission, he became febrile to 39°C and spiked fevers for several days. Broad-spectrum antimicrobial therapy was initiated; however, as with his previous hospitalization, cultures of the blood, urine, and cerebrospinal fluid were negative, so these medications were ultimately discontinued. In the context of continued emesis, concern arose regarding the absorption of his oral steroids. Thus, he was switched to high-dose intravenous methylprednisolone, after which his fevers and tachypnea resolved and his oral intake improved. After remaining clinically stable for several days, he was transitioned back to oral steroids and discharged to home.

He continued to receive oral steroids for ∼3 weeks, but was readmitted again for low-grade fever, emesis, increased fussiness, and worsening of his pustular skin rash. A radiograph of his left leg at that time showed osteitis of the proximal left femoral metaphysis and diaphysis and cortical destruction in the proximal left tibial metaphysis, accompanied by periosteal reaction (Figure 2A). A chest radiograph showed widening of the anterior rib ends and osteitis (Figure 2C). Due to continued concern about the possibility of an autoinflammatory condition, the patient was started on the recombinant IL-1Ra, anakinra. Within hours after administration, his fever subsided and there was a noticeable change in his demeanor. His rash improved shortly thereafter as well. He was discharged from the hospital after his third dose of anakinra, with plans to taper and ultimately discontinue his oral steroids.

Figure 2.

A, Osteitis of the proximal left femoral metaphysis and diaphysis (arrows) and cortical destruction in the proximal left tibial metaphysis; both bones show accompanying periosteal reaction. B, Complete resolution of osteitis with healthy-appearing cortex in both the left femur and left tibia 3.5 months after anakinra was started. C, Osteitis in the right anterior ninth rib (arrow) and widening of the right anterior sixth and left anterior third and fourth ribs. D, Complete resolution of osteitis in the right ninth rib, with significantly decreased right sixth rib widening and normal caliber left third and fourth ribs 6 months after anakinra was started.

Over the next several months, he remained afebrile and had no recurrence of rash, joint swelling, or fussiness. His appetite improved and his weight, previously at less than the third percentile, improved to the 20th percentile at age 4.5 months. Repeat imaging ∼3.5 months after anakinra was started revealed healing of the left femur and tibia (Figure 2B). A chest radiograph performed for an unrelated cough ∼6 months after anakinra was started also showed significant improvement in the affected ribs (Figure 2D).

Weeks after anakinra was started, blood tests obtained during the patient's second hospitalization showed that the patient was compound heterozygous for the known Dutch mutation for IL-1Ra deficiency (E77X), as well as a novel 1-bp deletion in exon 2 of the IL1RN gene (c.140delC; p.T47TfsX4), introducing a frame shift in the protein sequence followed by a premature termination codon (Figure 3). The p.T47TfsX4 mutation is predicted to create a truncated protein one-third the size of the secreted wild-type protein (177 amino acids). The 2 mutations were demonstrated to have been inherited in trans, as sequencing obtained on both parents and the paternal grandparents revealed that the mother was a carrier for the E77X mutation, while the father was a carrier for the p.T47TfsX4 mutation (inherited from the paternal grandmother). These results confirmed the diagnosis of IL-1Ra deficiency.

Figure 3.

DNA sequence electropherograms demonstrating 2 mutations (named under the plots). The c.140delC mutation is represented by 2 electropherograms generated by forward (F) and reverse (R) sequencing. Arrows indicate the relevant nucleotides. WT = wild-type.


First described by Aksentijevich et al and Reddy et al in 2009, IL-1Ra deficiency is a new addition to the family of autoinflammatory disorders (1, 2). The disease does share features with neonatal-onset multisystem inflammatory disease (NOMID), including neonatal onset, systemic inflammation, and skin rash (3–5). However, lytic bone lesions and thrombosis, both of which occurred in our patient, are unique to IL-1Ra deficiency and are not found in NOMID (1, 2). Furthermore, patients with IL-1Ra deficiency present with pustular skin rash, while NOMID patients develop an urticaria-like rash (1, 2). While both conditions share an association with IL-1, IL-1Ra deficiency involves a loss of IL-1Ra, whereas NOMID involves mutations in the NLRP3 gene that ultimately result in hypersecretion of IL-1β (6–8). Although very few cases of IL-1Ra deficiency have been described, it is believed to be a more severe condition than NOMID (2). However, both illnesses respond remarkably well to anakinra, and in fact, some of the previously described patients with IL-1Ra deficiency showed clinical improvement prior to being diagnosed, because their treating physicians had initiated treatment with anakinra due to the similarities of their symptoms to those of NOMID (1, 2, 9, 10).

The patients with IL-1Ra deficiency described by Aksentijevich et al and Reddy et al were all homozygous for mutations in the IL1RN gene or had parents who were respective heterozygous for these mutations (1, 2). Five of the 9 patients described by Aksentijevich et al were from 3 unrelated Dutch families and exhibited a nonsense nucleotide mutation affecting the amino acid at position 77 (E77X), resulting in a truncated IL-1Ra protein that is not secreted. Our patient was heterozygous for this E77X “Dutch” mutation, but also possessed a novel 1-bp mutation in exon 2 of the gene, which resulted in a frameshift mutation. Clearly, these mutations resulted in a sufficient alteration of the IL-1Ra protein to render it either suboptimal or completely nonfunctional. To the best of our knowledge, our patient is the first described compound heterozygote with IL-1Ra deficiency.

Each of the previously described patients with IL-1Ra deficiency presented either at birth or in the first 2.5 weeks of life, most commonly with fetal distress, a pustular rash, oral mucosal lesions, and joint swelling. Imaging demonstrated periostitis, widening of the ribs, and multifocal osteolytic lesions in almost every patient (1, 2). Our patient's clinical course was very similar, presenting with joint swelling and a pustular rash and later exhibiting similar radiographic findings. Interestingly, despite elevations in their laboratory markers of inflammation (ESR, CRP level, white blood cell count), only 1 of the previously described patients had a fever either prior to or after hospitalization. Despite receiving antibiotic therapy for a presumed septic joint, our patient developed fevers several days in a row during his first 2 hospitalizations, which prompted a full evaluation for sepsis (routine for infants younger than 2 months of age). As the evaluation was ultimately unrevealing and fevers persisted despite broad-spectrum antibiotics, it is reasonable to assume that his fevers were likely the result of a systemic inflammatory disease process itself rather than an infection; indeed, his fever resolved and he remained afebrile after anakinra was started during his third hospitalization. Of note, Ivker et al (11) and Leung and Lee (12) previously described 2 patients with pustulosis and bone lesions who did have fevers associated with their clinical course, although these patients were never diagnosed as having IL-1Ra deficiency.

As with many of the other patients with IL-1Ra deficiency who were treated with steroids earlier in their hospital course, our patient had only a partial response to steroid treatment. It was not until anakinra was started that he demonstrated significant clinical and radiographic improvement. Given cellular vulnerability to hyperstimulation from IL-1 in IL-1Ra deficiency, this suggests that while broad immunosuppression with corticosteroids can result in modest benefit, significant improvement is only achieved by increasing competitive inhibition at the IL-1R level via recombinant IL-1Ra.

IL-1Ra deficiency is a rare condition that presents during the neonatal period and may result in significant morbidity and even mortality (1, 2). Many patients present with symptoms suggestive of infection (joint swelling, pustular rash, osteomyelitis), making clinical suspicion critical in order to avoid misdiagnosis and improper management with antibiotics alone.

Although they are distinct illnesses, IL-1Ra deficiency does share some clinical features with NOMID, and both have shown excellent responsiveness to anakinra (1, 5, 9, 10). Thus, it is advisable to consider treatment with anakinra as soon as there is clinical suspicion of an autoinflammatory condition, especially since corticosteroid therapy results in only a mediocre response, and long-term steroid use is fraught with side effects that can be detrimental during infancy (as evidenced by our patient's growth inhibition that resolved after discontinuation of steroids). As diagnostic testing currently requires gene sequencing, a definitive diagnosis may be achieved long after the patient shows clinical improvement from anakinra treatment. Additional studies are needed involving the diagnosis of IL-1Ra deficiency and the consequences of long-term treatment with IL-1 inhibitors in this disorder.


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Reed had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Stenerson, Dufendach, Aksentijevich, Brady, Austin, Reed.

Acquisition of data. Stenerson, Dufendach, Aksentijevich, Brady, Austin, Reed.

Analysis and interpretation of data. Stenerson, Dufendach, Aksentijevich, Brady, Austin, Reed.