Autosomal dominant (AD) loss-of-function (LOF) variants in STAT1 are a known cause of Mendelian susceptibility to mycobacterial disease (MSMD); however, the clinical phenotype is highly heterogeneous.
We report three individuals from a single family harboring a novel heterozygous STAT1 variant (p.D92A).
A 4-year-old boy born to non-consanguineous parents with no history of recurrent infections or early neonatal deaths presented at 1 year and 10 months of age with a right mandibular mass and gait disturbance. Contrast-enhanced computed tomography revealed destructive mass lesions involving the right mandible and the vertebral bodies (Th1 and Th11). Biopsy of the Th11 lesion demonstrated CD1a-negative, CD68-positive, and factor XIIIa-positive histiocytes, but a definitive diagnosis was not established. Based on the clinical findings, systemic juvenile xanthogranuloma was suspected, and chemotherapy was initiated; however, the disease relapsed repeatedly. Subsequent genetic reevaluation identified the STAT1 p.D92A variant. Functional analyses demonstrated reduced STAT1 tyrosine phosphorylation following IFN-γ stimulation compared with wild type, and luciferase assays confirmed significantly decreased transcriptional activity, consistent with an LOF effect. Although Mycobacterium bovis Bacillus Calmette-Guérin (BCG) was not definitively detected in biopsy specimens, BCG osteomyelitis associated with MSMD was suspected. The patient achieved and maintained remission with anti-mycobacterial therapy.
The younger sister of Case 1, currently 2 years old, was identified to carry the same variant through family screening at 1 month of age, and BCG vaccination was withheld. At 2 years of age, she presented with erythema and swelling of the right ankle and bilateral knees, accompanied by fever and generalized erythematous rash. Laboratory evaluation revealed elevated C-reactive protein (CRP) and hypercytokinemia. MRI showed fasciitis and peritendinitis extending from the lower leg to the foot, without clear evidence of osteomyelitis or arthritis. She was treated with cephalexin and prednisolone for presumed bacterial tenosynovitis and an excessive immune response resembling systemic juvenile idiopathic arthritis, with good clinical improvement and no recurrence to date.
The father, who carries the same variant, remains asymptomatic.
This family demonstrates a novel N-terminal AD STAT1 LOF variant with experimentally confirmed functional impairment and marked phenotypic heterogeneity, ranging from osteomyelitis to soft tissue inflammation and an asymptomatic carrier state. Further studies are needed to elucidate the factors determining phenotypic variability.
