A rare mutation causing autosomal dominant STAT1 deficiency in a South African multiplex kindred with disseminated BCG infection

The proband, a previously well, HIV uninfected, 2-year-old boy born to nonconsanguineous parents presented with chronic erythematous, papular skin lesions over the right deltoid muscle at the site of BCG vaccination and on the right side of his chest wall, and bilateral finger swelling. BCG vaccination at birth was followed by the development of a nodule at the vaccination site surrounded by a cluster of raised papules which over time coalesced to form an erythematous, non-healing plaque-like lesion without fistulation (Fig. 1a). At 18 months of age, he developed a similar cluster of papules on the right anterior chest wall, inferolateral to the right nipple. Additionally, he also developed finger swelling (Fig. 1b) around the same time. Imaging of the hands and chest revealed multiple lucencies of phalanges of both hands, the right distal humerus, both clavicles and left scapula, consistent with multifocal osteomyelitis (Fig. 1c, d). Skin biopsies of the BCG site and chest wall lesions cultured Mycobacterium tuberculosis complex, which on molecular testing was confirmed to be BCG, susceptible to both rifampicin and isoniazid. Immunological evaluation revealed raised IgG, IgM, and IgA concentrations, normal CD3, CD4, CD8, CD19 and CD16/56 cell counts, and a normal oxidative burst test (dihydrorhodamine 123 (DHR) as oxidative probe) – refer Supplementary file. He was started on four-drug antimycobacterial therapy (rifampicin, isoniazid, ethambutol, and levofloxacin), after 3 months ethambutol and levofloxacin were discontinued. Rifampicin and isoniazid were stopped after 18 months. He is currently 9 years old and has remained asymptomatic for 5 years. He has not experienced further serious illness such as salmonella or candida infection, mycobacterial infection, or hospitalization. He has a mild residual deformity of the middle finger of his left hand without any functional consequences (Fig. 1e).

Five years after the proband presented, his well-grown, HIV uninfected, 10-month-old, maternal half-brother presented with intermittent swelling and decreased range of motion of the right middle finger and the right knee. He received BCG vaccine at birth and developed ulceration at the BCG vaccination site with surrounding papule formation and swollen right axillary lymph nodes. At the time the local clinic prescribed a course of antibiotics. At presentation, he had a healing scar at the BCG vaccination site, a small single firm lymph node with soft tissue swelling in the right axilla, uniform soft tissue swelling of the right middle finger, and normal lower limbs. Radiology showed expansion of the proximal 3rd phalanx with multiple ill-defined lucencies (Fig. 2a), and expansion of the 2nd left anterior rib with ill- defined lucencies consistent with multifocal osteomyelitis. Right axillary soft tissue swelling consistent with adenopathy was demonstrated. Lung fields were clear, and there was no mediastinal adenopathy (Fig. 2b).

Blood culture yielded no organisms. There were no skin lesions or lymph nodes amenable to biopsy. Immunological evaluation included normal levels of IgG, IgM, and IgA concentrations, normal CD3, CD4, CD8, CD19 and CD16/56 cell counts, and a normal (DHR) oxidative burst test – refer Supplementary file. A presumptive diagnosis of disseminated BCG infection with multifocal osteomyelitis was made and rifampicin, isoniazid, ethambutol, and levofloxacin were commenced. After three months he was stepped down to rifampicin and isoniazid. Repeat x-ray demonstrated healing osteomyelitis (Fig. 2c). He is now 3 years old, has completed 18 months of antimycobacterial therapy, is well, and has not experienced recurrent mycobacterial infection or other serious infections.

Whole exome sequencing demonstrated a novel heterozygous substitution in the splice site between intron 13 and exon 14 of the STAT1 gene, NM_007315: c.1128-1G>A, in the proband and his mother but not in his father. The mutation was confirmed in both the proband and his mother by Sanger sequencing (Fig. 3). The identical heterozygous mutation was recently confirmed in his half-sibling. The biological father of the half-sibling was not tested and there was no other maternal offspring (Fig. 4).