JAK3 is a tyrosine kinase belonging to the Janus kinases family, which also includes JAK1, JAK2, TYK2. Its main function is cytokine signaling. As some cytokine receptors lack enzymatic activity, they are dependent upon the intracellular JAKs to initiate signaling upon binding with their ligands (e.g., cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). These cytokines are crucial for the function and development of immune cells. The mutated JAK3 leads to blockage of JAK3 signal pathway, thus affecting the signal transduction of the above cytokines. As JAK3 is mainly expressed in T cells and NK cells, the common immunological phenotype of JAK3-deficiency is T-B+NK−. Although there are normal number of B cells in the peripheral blood, their function is impaired, as the above cytokines are unable to work well. As a result, both humoral immunity and cellular immunity are ultimately damaged, contributing to recurrent and various infections in patients.
The clinical manifestations of our patient are atypical with school-age onset and mild symptoms, manifesting as intermittent fever and abnormal liver function. His growth and development was not affected. What is more, his immunological phenotype was T low B+NK+, and the level of immunoglobulin was normal, which was different from the classical JAK3-deficiency. The recurrent respiratory infection in his childhood is a subtle sign to imply immunodeficiency. The atypical phenotype of our patient may be due to the possibility that these mutations lead to partial function loss of the JAK3, thus signal transduction was partly blocked. Atypical JAK3-deficiency has been described previously.[4,7,8,12–14,16,18,19] Some studies suggested that specific JAK3 mutations may be hypomorphic or revertant mosaicism, thus allowing JAK3 mediated signal transduction. Siblings with the same JAK3 mutations may have greatly different clinical manifestations, one with typical PID manifestations, while the other nearly normal.[8,15,16] Some patients with JAK3 heterozygous mutation or without a JAK3 mutation still developed the classical PID phenotype seen with JAK3 insufficiency.[15,16,18]
The inconformity between genotype and phenotype brings difficulties and challenges for diagnosis. It suggests that other modified genes or some environmental factors may play a certain role on the pathogenic mechanism for JAK3-deficiency.
As life-threatening infections may occur after vaccination in JAK3-deficiency patients, early diagnosis and timely BMT can remarkably improve the prognosis. It is crucial for clinicians to make an early diagnosis. Screening is an effective way to detect the potential JAK3-deficiency patients and the main method used is T-cell receptor excision circles. Within the past decades, the NGS technology made rapid progress, thus increasing potential PID patients came to light. Clinician could take advantage of its unprecedented throughput to find out thousands of mutations simultaneously. Once recurrent or infrequent infections happened, the diagnosis of PID should be considered and targeted sequencing may be the first choice. However, manifestations of most PIDs are similar and confusing, thus NGS may be a better option in this circumstance. Nevertheless, the NGS is time-consuming as well as costing. Newborn screening with NGS is required to those with a family history of PID.
So far, some countries or regions such as Europe, the United States, Canada, New Zealand, Israel, and Taiwan have established neonatal screening for PID.[34–38] However, the mainland of China has not yet set up such screening system for PID patients. More attention is needed to pay on screening for PID patients.
EBV infection is common in children and usually results in a self-limited, transient disease and viral clearance. However, when it happens to immunocompromised individuals, it is not that simple. Some types of PID are characterized by the development of EBV-associated complications or confer predisposition to EBV infection in otherwise healthy individuals, such as X-linked inhibitor of apoptosis protein deficiency, CD27 deficiency, serine/threonine-protein kinase 4 deficiency, magnesium transporter 1 deficiency, and so on.[39,40] Several case reports demonstrated that when infected with EBV, PID patients are more likely to end up in poor outcome, such as lymphoma, fulminant infectious mononucleosis, EBV-associated hemophagocytic lymphohistiocytosis, or persistent EBV viraemia.[41–45] Unfortunately, acyclovir-related antiviral drugs for EBV can only inhibit replication but are insufficient to eliminate the latent infection. HSCT was believed to be effective to them, as Intan's investigation revealed a survival rate of 72% regarding IL2RG/JAK3 SCID. Interferon α-2a is usually used in the treatment of hepatitis viruses or malignancy for its powerful antiviral effect.[47–49] However, there have been few previous publications on the use of interferon alpha-2a in CAEBV patients. In consideration of its powerful antiviral effect and our patient's personal willingness, we administered interferon α-2a to attempt to stimulate anti-EBV responses and restrict EBV replication, thus alleviating viremia. The good results of our patient indicate that interferon α-2a may be an alternative treatment for those who are unwilling to accept HSCT like our patient.
In summary, we report a patient with novel compound heterozygous JAK3 mutations but incomplete loss of immune function (T-B+NK+) who presented with CAEBV as the initial symptom. The partial loss of function in JAK3 suggested by this phenotype explains the late onset of significant disease. We summarized the genotype, phenotype, and therapies of JAK3-deficiency in this paper as well.
We sincerely acknowledge the kind participation and cooperation of the affected family.
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