Secondary Logo

Journal Logo

Letters to the Editor

Chronic Recurrent Multifocal Osteomyelitis and Deficiency of Interleukin-1–receptor Antagonist

Sakran, Waheeb MD; Shalev, Stavit A MD; Sakran, Waheeb MD; Shalev, Stavit A MD; El-Shanti, Hatem MD; Uziel, Yosef MD, MSc; Uziel, Yosef MD, MSc

Author Information
The Pediatric Infectious Disease Journal: January 2013 - Volume 32 - Issue 1 - p 94
doi: 10.1097/INF.0b013e3182700cc1

To the Editors:

Deficiency of interleukin-1–receptor antagonist (DIRA) is a rare autosomal-recessive autoinflammatory disorder with onset of bone and skin inflammation in the newborn period or early infancy.1,2 The etiology of DIRA has been linked to mutations in IL1RN, the gene encoding the interleukin-1–receptor antagonist, leaving the proinflammatory cytokines interleukin-1α and interleukin-1β unopposed, constantly activating the receptor and leading to inflammation. Due to the availability of effective therapy, a prompt and accurate diagnosis is important.

CASE REPORT

A 6-year-old female patient was first hospitalized in our department at the age of 4 months because of high fever, irritability and swelling on the left side of the chest. Family history is as follows: the parents were first double cousins, and they had a daughter with chronic recurrent multifocal osteomyelitis (CRMO) who died at the age of 4 years.

On physical examination, she had signs of an upper respiratory tract infection. Except for left-sided swelling of the chest, the physical examination was normal. Initial laboratory tests showed erythrocyte sedimentation rate of 40mm/h, anemia (hemoglobin 9.8), leukocytosis (white blood cells 19,450 with left shift) and thrombocytosis (platelets 628,000). Kidney and liver enzymes were normal. Blood culture was negative. Chest radiography showed bone lesions of the left sixth rib. An isotopic bone scan revealed a lytic bone lesion on the left sixth rib. We assumed the patient had CRMO as her sister. Treatment with antibiotic therapy and nonsteroidal antiinflammatory drugs was initiated, and she improved gradually. She had no constant skin manifestations at that time, but had a transient pustular rash at the age of 2 months.

During 6 years of follow-up, the patient had multiple exacerbations of bone swelling including ribs, femur, tibia, hands and shoulders. Multiple bone lesions were seen when isotopic bone scans were performed (Fig., Supplemental Digital Content 1, https://links.lww.com/INF/B332). The child had nail anomalies—onychosis and high levels of inflammatory markers. She also had growth delay with failure to thrive and inability to bear weight upright or walk unassisted. She received treatment for CRMO, which included nonsteroidal antiinflammatory drugs, corticosteroids and intravenous bisphosphanate, with poor response.

Genetic testing for CRMO and Majeed syndrome was negative. After the first report of DIRA,1,2 sequencing of IL1RN showed that the child was homozygous for the mutation c.160C>T (Q54X). We initiated treatment with anakinra (recombinant interleukin-1–receptor antagonist), 2mg/kg/day, which resulted in an immediate response. During a year of treatment and follow-up, she had resolution of all bone lesions and nail anomalies, normalization of the inflammatory markers; she gained weight and was able to walk independently.

After the genetic diagnosis, prenatal investigation of another pregnancy revealed fetus heterozygous for the c.160C>T (Q54X) mutation. At the time when this article was written, the pregnancy was successfully ongoing.

DISCUSSION

This is the first report of DIRA from Israel, diagnosed in a child of Arab-Moslem-Lebanese origin, who lives in the Galilee, in northern Israel. The reported patient had mainly recurrent bone lesions of multiple bones, restricted growth with failure to thrive, onychosis, inability to bear weight when standing and elevated inflammatory markers. Genetic testing of the IL1RN gene revealed that the patient was homozygous for c.160C>T (Q54X), a previously reported mutation in a Lebanese family. The finding of this mutation in 2 unrelated families of Lebanese origin may suggest a founder effect. So far, 20 cases of DIRA have been reported worldwide.1–5

The main manifestations reported to date are cutaneous such as pustular rash, oral mucosal lesions, cutaneous pustulosis, acanthosis, hyperkeratosis and nail changes. Bone manifestations include pain, joint swelling, extensive epiphyseal ballooning and periosteal elevation of the long bones and the anterior rib ends and multifocal osteolytic lesions. Inflammatory markers were present in most patients.1,3

In contrast to other DIRA patients described in the literature, whose symptoms presented between birth and 1 month of age,1–5 our patient was first admitted at the age of 4 months, indicating a somewhat later onset (although a transient rash had appeared before admission). Her main manifestations along the years were inflammatory bone lesions, similar to the natural history of her sister. This CRMO-like presentation may represent a broader spectrum of the phenotype.

It is important that medical staff, especially pediatricians, and infectious diseases specialists recognize this disease and its symptoms and signs because early diagnosis and effective treatment with anakinra can induce remission, improve quality of life, prevent permanent damage to the bones and early mortality.

Waheeb Sakran, MD

Pediatric Department B

Emek Medical Center

Afula

Stavit A Shalev, MD

Waheeb Sakran, MD

The Rappaport Faculty of Medicine

Technion

Haifa

Stavit A Shalev, MD

Genetic Institute

Emek Medical Center

Afula, Israel

Hatem El-Shanti, MD

Shafallah Medical Genetic Center

Doha, Qatar

Yosef Uziel, MD, MSc

Pediatric Rheumatology Unit

Pediatric Department, Meir Medical Center

Kfar Saba

Yosef Uziel, MD, MSc

Sackler School of Medicine

Tel Aviv University

Tel Aviv, Israel

REFERENCES

1. Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360:2426–2437
2. Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360:2438–2444
3. Stenerson M, Dufendach K, Aksentijevich I, et al. The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum. 2011;63:4018–4022
4. Thacker PG, Binkovitz LA, Thomas KB. Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto-inflammatory condition that mimics multiple classic radiographic findings. Pediatr Radiol. 2012;42:495–498
5. Beck C, Girschick HJ, Morbach H, et al. Mutation screening of the IL-1 receptor antagonist gene in chronic non-bacterial osteomyelitis of childhood and adolescence. Clin Exp Rheumatol. 2011;29:1040–1043

Supplemental Digital Content

© 2013 Lippincott Williams & Wilkins, Inc.