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Vol. 63, No. 12, December 2011, pp 4018–4022
DOI 10.1002/art.30565
© 2011, American College of Rheumatology
The First Reported Case of Compound Heterozygous IL1RN Mutations Causing
Deficiency of the Interleukin-1 Receptor Antagonist
Matthew Stenerson,1 Kevin Dufendach,1 Ivona Aksentijevich,2 Jillian Brady,2 Jared Austin,3 and Ann M. Reed1
ity 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.
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.
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
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 hypersensitiv1
Matthew Stenerson, MD, Kevin Dufendach, MD, Ann M.
Reed, MD: Mayo Clinic, Rochester, Minnesota; 2Ivona Aksentijevich,
MD, Jillian Brady, BA: National Human Genome Research Institute,
NIH, Bethesda, Maryland; 3Jared Austin, MD: Oregon Health and
Science University, Portland.
Address correspondence to Ann M. Reed, MD, Mayo Clinic,
Department of Pediatric and Adolescent Medicine, Division of Rheumatology, 200 First Street SW, Rochester, MN 55905. E-mail:
[email protected]
Submitted for publication March 17, 2011; accepted in revised
form July 19, 2011.
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.
revealed a right internal jugular thrombus, requiring
months of anticoagulation treatment.
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
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.
after his third dose of anakinra, with plans to taper and
ultimately discontinue his oral steroids.
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
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.
grandmother). These results confirmed the diagnosis of
IL-1Ra deficiency.
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 urticarialike 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-1␤ (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.
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An autoinflammatory disease due to homozygous deletion of the
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