PMC9503826_01
VZV reactivation (A, B) and vulvar ulcers (C, D) of the patient.
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At the age of 8 years, the patient experienced the metameric appearance of vesicles on the whole left upper limb up to the back, with interruption at midline level, suggestive of VZV reactivation ( Figure 1 ). Peripheral blood type I interferon signature was elevated ( Supplementary Figure 1 ). At the age of 13, after about 3 years of wellbeing, recurrent multiple vulvar ulcers appeared ( Figure 1C ). Therefore, treatment with etanercept at a dosage of 0.8 mg/kg/week was proposed to the parents and finally accepted, which resulted in a quick resolution of skin lesions ( Figure 1D ) and absence of subsequent relapses of genital ulcers.
C-reactive protein (CRP) values, dosage of steroidal treatment (prednisone equivalent), and immunoglobulin infusions in the patient during the follow-up period.
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Due to the suspicion of an immunological defect characterized by an aberrant response to viral infections, high-dose IVIG (2 g/kg every month) was started, which allowed to control both the clinical sympotms and the inflammatory markers and therfore to reduce steroidal treatment ( Figure 2 ).
Enzymatic activity of ADA2 in the patient and a healthy donor performed by semiquantitative assay. Activity was assessed in primary monocytes, which were then cultured in PBS in the presence of exogenous adenosine (15 microM), with or without the ADA1 inhibitor EHNA (30 microM). After 4 h of incubation, supernatants were collected, and the activity was evaluated through the measurement of the adenosine-derived products (inosine and hypoxanthine) in high-performance liquid chromatography. The "Ratio" on the y-axis is given by the ratio of inosine and hypoxanthine found in the supernatant to the remaining adenosine. The result is again divided by the amount of protein obtained from the cell lysate in order to normalize the result and make it independent from monocyte counts.
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PBMCs, revealing a complete loss of ADA2 activity ( Figure 3 ). Plasma ADA2 enzymatic activity was 5.6 mU/g protein (control range 58-271) when measured in extracts of dried plasma spots by the Hershfield lab at Duke University, as described by Ben Ami et al..