STAT5b Deficiency: An Unsuspected Cause of Growth Failure, Immunodeficiency, and Severe Pulmonary Disease

Over the past 20 years, more than 150 new genetic disorders related to primary immunodeficiencies have been described, most of which initially present in the pediatric population. 1 Pediatric researchers and medical personnel should be cognizant of signs and symptoms associated with diseases related to immunodeficiency. STAT5b deficiency is a recently identified disease entity that involves both severe growth hormone‐resistant growth failure and severe immunodeficiency. Due to the early growth failure and the key role of STAT5b in growth hormone (GH) action, most of the cases have been published in the endocrinology literature until now. However, the identification of rare, human STAT5Bmutations has highlighted the distinct and critical role of STAT5b in both growth and immunity. 2-5 The possibility of a STAT5b disorder in children should be considered by the general pediatrician when chronic infection and/or unexplained pulmonary disease are concomitant with growth failure. The aim of this review is to provide updated information toward recognition of possible STAT5b deficiencies and to help provide an appropriate workup to mitigate symptoms associated with the disease. In this way, careful monitoring, timely therapy, frequent health care visits, and prophylactic medicines can be initiated. The molecular etiology and clinical consequences of STAT5b deficiencies will be described. First Cases of STAT5b Deficiency The cardinal feature of GH insensitivity (GHI) is severe growth failure, associated with elevated serum concentrations of GH, resulting in a clinical phenotype that is essentially indistinguishable from that of congenital GH deficiency. The phenotype of GHI has been attributed to more than 70 mutations in the GHR gene, encoding the GH receptor (GHR). 7 GHI in the presence of normal GHR, in contrast to classic GHI, has remained largely uninvestigated. The molecular basis has been determined in only a few cases, including three reports of homozygous mutations in the IGF-I (insulin growth factor-I) gene. 3-5 Beginning in 2003, a series of GHI cases with normal GHR were identified 3-5 and found to be associated with mutations in the STAT5B gene. 3 The first STAT5B mutation was a homozygous autosomal recessive missense mutation identified in a female patient with extremely short stature (‐7.5 SD) and who had serum IGF-I levels less than 15% of normal, despite elevated serum GH concentrations.Shortly thereafter, several additional cases, each harboring novel mutations of STAT5B, were reported. All of these cases were characterized by severe growth failure and GHI. Together, these cases convincingly implicated STAT5B mutations as potential etiologies of the GHI syndrome and pointed to STAT5b playing an important role in normal postnatal human growth. The first cases of identified STAT5b deficiency, 3-5 distinct from GHI caused by mutations in the GHR or IGF1 genes, were also found to be associated with symptoms of severe infection, autoimmune diatheses, and lymphocytic interstitial pneumonitis. The combination of severe GH-resistant growth failure and chronic infection led to evaluation of potential disorders of cytokine receptor signaling. In the first described case, the patient, 3 with a missense mutation (p.A630P) in the STATB gene, had lymphocytic interstitial pneumonitis, chronic lung disease, hemorrhagic varicella, atopy, and autoimmune disease diagnosed at a young age. More detailed evaluations indicated that the patient had decreased numbers of regulatory CD4+CD25hi T cells (Treg). 8