Osteomyelitis, Sterile Multifocal, With Periostitis And Pustulosis

A number sign (#) is used with this entry because of evidence that sterile multifocal osteomyelitis with periostitis and pustulosis (OMPP) is caused by homozygous mutation in the IL1RN gene (147679) on chromosome 2q14.

Clinical Features

Leung and Lee (1985) reported a Hispanic female infant with the clinical, radiologic, and histologic presentation of infantile cortical hyperostosis (see Caffey disease, 114000) who also developed cutaneous pustulosis. The bone lesions developed at 3 weeks of age, accompanied by a low-grade fever. At 3 months of age, she was noted to have a papular rash that gradually developed into pustular vesicles, then into plaques, and finally into desquamation. Skin biopsies showed subcorneal pustular dermatitis or pustular psoriasis, and the skin lesions responded to local and systemic steroids. Repeat skeletal survey at 5.5 months of age showed resolution of subperiosteal thickening of all the previously involved bones, and radiolucent lesions that had been seen in both proximal tibiae had almost completely disappeared.

Ivker et al. (1993) reported a Hispanic male infant who had poor feeding, recurrent fevers, leukocytosis, thrombocytosis, and a small pustule on his chest. The infant presented at 2.5 weeks of age with Staphylococcus epidermidis sepsis and meningitis and was found to have multiple sterile lytic bone lesions. The bone lesions improved on prednisone, but as the corticosteroid was being tapered at 3 months of age, he developed generalized psoriatic pustulosis. Skin biopsy demonstrated epidermal hyperplasia, subcorneal pustules, spongiform pustules, and dilated tortuous papillary blood vessels. The skin lesions were only minimally responsive to treatment with topical corticosteroids, thus systemic methotrexate and then etretinate were administered, but the latter had to be discontinued due to severe dryness of the mucous membranes and skin fragility. The patient subsequently died of staphylococcal and pseudomonal septicemia. Citing similarities between this patient's bone lesions and chronic recurrent multifocal osteomyelitis (CRMO; 259680), Ivker et al. (1993) noted that approximately 20% of patients with CRMO develop pustulosis palmaris and plantaris (Sofman and Prose, 1990).

Aksentijevich et al. (2009) described 9 children from 6 unrelated families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. All patients presented by 2.5 weeks of age; the common manifesting features included fetal distress, pustular rash, joint swelling, oral mucosal lesions, and pain with movement. Over time, cutaneous pustulosis developed, ranging from discrete crops of pustules to generalized severe pustulosis or ichthyosiform lesions. Biopsies of skin lesions from 2 patients showed extensive infiltration of epidermis and dermis by neutrophils, pustule formation along hair follicles, acanthosis, and hyperkeratosis. Histopathologic evidence of vasculitis was observed in the connective and fat tissue adjacent to bone in 1 patient. Nail changes were seen in 4 children, 2 of whom had separation of the nail and nail bed similar to the onychomadesis seen in psoriasis. Three patients underwent cervical vertebral fusion secondary to collapsing vertebral osteolytic lesions. Cerebral vasculitis or vasculopathy was seen on MRI in 1 patient. Two of the children died of multiorgan failure secondary to the inflammatory response syndrome, at 2 months and 21 months of age, respectively; a third child died at 9.5 years of age due to complications of pulmonary hemosiderosis with progressive interstitial fibrosis. Empiric treatment with the recombinant interleukin-1 receptor antagonist anakinra led to a response in 1 patient; other patients subsequently treated with anakinra showed a rapid response.

Reddy et al. (2009) reported an 18-month-old male infant who had neonatal onset of pustular rash, marked osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis. Because of worsening respiratory distress and similarities of the case to NOMID (neonatal-onset multisystem inflammatory disease; 607115), anakinra was administered, with rapid and sustained resolution of the skin lesions and respiratory distress.

Molecular Genetics

In patients with neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis, Aksentijevich et al. (2009) identified homozygosity for a 2-bp deletion (147679.0004) and nonsense mutations (147679.0002 and 147679.0003) in the IL1RN gene. Another patient whose parents originated from an isolated population in the northwestern part of Puerto Rico was homozygous for a 175-kb deletion (147679.0005) on chromosome 2q13 that encompassed the IL1RN gene. Heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro; patients treated with anakinra responded rapidly.

In an 18-month-old male infant with neonatal onset of pustular rash, osteopenia, lytic bone lesions, respiratory insufficiency, and thrombosis, Reddy et al. (2009) identified homozygosity for the 175-kb deletion.

Population Genetics

Aksentijevich et al. (2009) estimated the allele frequency of the IL1RN 2-bp deletion to be 0.2% in Newfoundland. In a geographically matched population from the northwestern part of Puerto Rico, the 175-kb deletion had an allele frequency of 1.3%, the authors suggested that the incidence of DIRA in some regions of Puerto Rico may be as high as 1 in 6,300 births.

Nomenclature

Aksentijevich et al. (2009) proposed the acronym DIRA for deficiency of interleukin-1 receptor antagonist.