Discussion
STAT5B mutation is an uncommon cause of ILD. It has been reported to be associated with GHI, immunodeficiency and autoimmunity (1,2). There are 12 case reports of STAT5B mutation or deficiency till now(2–4). Most of these cases had growth failure secondary to GHI and immunodeficiency due to defects in regulatory T (Treg) cells. Eczema, thrombocytopenic purpura, and/or autoimmune disease like juvenile idiopathic arthritis, autoimmune thyroiditis or celiac disease were present in almost all cases (2–4). Severe pulmonary disease presenting in early childhood was characteristic feature of most of the cases except in 1 case (5). Similarly, our case also manifested the features of GHI, autoimmunity (celiac disease), immunodeficiency (CD8 cell deficiency) and ILD.
Pulmonary involvement in STAT5B mutation has been hypothesized due to decreased numbers of Treg and attenuated effector T cell (Teff) function or associated autoimmune phenomenon (1,2). Lung involvement has shown varied manifestations in the form of recurrent pulmonary infections, LIP, progressive pulmonary fibrosis and respiratory failure (2,4). On the basis of clinical and radiological findings, we made the diagnosis of fibrosing ILD in contrast to previously reported findings of LIP. However, we couldn’t perform lung biopsy for characterization of ILD.
Most of the previous case reports had lymphopenia with reduced CD4 and CD8 T cells, NK cells, Treg cells and function (2,3). We found reduction in total CD3 and naïve CD8 cells with normal CD4 and NK cells. This could be explained because of variable phenotypic expression of STAT5B mutation. We could not perform functional assays of T cells because of logistic issues. Though B cells are rarely affected in this disorder, these patients have been reported to have hypergammaglobulinemia similar to our case, low IgM memory B-cells, and increased switched memory B-cell counts (6).
Growth failure in STAT5B mutation has been associated with normal baseline and stimulated GH levels and reduced IGF-1 levels indicating GHI as its cause (1). These patients usually do not respond to recombinant human GH administration (2). Our case did not receive such therapy.
The novel mutation p.Val669Gly in STAT5B gene in our case seems to selectively affecting respiratory system and growth more than leading to immune dysregulation as compared to previous reports as the autoimmunity was less well established in our case.
This case highlights STAT5B mutation as a novel cause of ILD in children. This condition may be thought of in any child with unexplained pulmonary manifestations or childhood ILD of unknown etiology associated GHI, autoimmune conditions and immunodeficiency particularly lymphopenia.