Multifocal Recurrent Osteomyelitis and Hemophagocytic Lymphohistiocytosis in a Boy with Partial Dominant IFN-γR1 Deficiency: Case Report and Review of the Literature

Abstract

Mutations in the genes coding for cytokines, receptors, second messengers, and transcription factors of interferon gamma (IFN-γ) immunity cause Mendelian susceptibility to mycobacterial disease (MSMD). We report the case of a 7-year-old male patient with partial dominant (PD) IFN-γ receptor 1 deficiency who had suffered from multifocal osteomyelitis attributable to bacille Calmette-Guérin vaccination since the age of 18 months. He developed hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory complication, and died with multiorgan dysfunction, despite having been diagnosed and treated relatively early. Patients with PD IFN-γR1 deficiency usually have good prognosis and might respond to human recombinant subcutaneous IFN-γ. Several monogenic congenital defects have been linked to HLH, a catastrophic "cytokine storm" that is usually ascribed to lymphocyte dysfunction and thought to be triggered by interferon gamma. This is the sixth patient with both MSMD and HLH of whom we are aware. The fact that patients with macrophages that cannot respond to IFN-γ still develop HLH, bring these assumptions into question.

Keywords: Mendelian susceptibility to mycobacterial disease; bacille Calmette–Guérin vaccine; hemophagocytic lymphohistiocytosis; human recombinant interferon gamma; interferon gamma receptor 1 deficiency; macrophage activation syndrome; multiorgan dysfunction; osteomyelitis.

Figure 1

(A) Anteroposterior X-ray film revealing metaphyseal osteolytic lesions in femurs (arrowheads). Contrast with panel (B). Radiological improvement after 1 year of antimycobacterial drug treatment, with femoral remodeling. (C) CT scan, sagittal view, showing presacral mass and osteolytic lesions of the S3–S4 vertebral bodies (arrowheads). Contrast with panel (D). Improvement after 1 year of treatment, with vertebral remodeling and decreased antesacral mass.

Figure 2

Clinical relapse with upper arm abscess, and new lytic lesions in parietal bone (left panels) and left humerus (right panels). (A) X-ray of skull, lateral view. (B) Posteroanterior view, showing osteolytic lesions (arrows). (C) Swelling of left shoulder over abscess. (D) X-ray of left humerus showing osteolytic lesions (arrow).

Figure 3

Electropherogram showing a heterozygous four-nucleotide deletion in the patient, as contrasted with a healthy control and the patient’s parents.

Figure 4

Third relapse with CT scans showing left psoas abscess and multiple osteolytic lesions. (A) Fistulized multifocal pneumonia and left psoas abscess. (B) Bone marrow aspirate (Hematoxylin and eosin staining, 40×) showed histiocytes phagocytizing three blood cell lineages. (C,D) CT scan, coronal view, showing lumbar vertebral osteolytic lesions (panel C, arrows) and left psoas abscess (panel D, arrow). (E,F) Gross appearance of chest wall and lung specimen at autopsy, confirming multifocal fistulized pneumonia.