SUMMARY
1. STAT5b deficiency is an autosomal recessive disorder characterized by T cell immunodeficiency as well as short stature due to impaired growth hormone (GH) signaling. Additional clinical features include facial dysmorphisms (prominent forehead, saddle nose) and a high-pitched voice.
2. Affected patients present with short stature and recurrent pulmonary infections. Bacterial pneumonias as well as opportunistic Infections (hemorrhagic Varicella, herpes zoster and Pneumocystis jiroveci) have been reported in patients.
3. Immunologic testing of affected patients has shown modest T cell lymphopenia and decreased T cell proliferation to mitogens. NK cell numbers and gamma-delta T cell numbers were also reduced. B cell numbers, total immunoglobulin levels and vaccine responses were normal.
4. The immunologic defects in this disease stem from the involvement of STAT5b in the intracellular signaling cascade of IL-2 and IFN-gamma.
5. STAT5b is also involved in GH induced signaling. As a result, patients with STAT5b deficiency exhibit GH insensitivity.
6. Affected patients have normal or elevated GH levels and low levels of Insulin-like growth factor (which is normally secreted in response to GH) even in response to exogenous GH administration. Growth hormone binding protein levels were normal in all patients. Markedly elevated prolactin levels have been described.
7. STAT5b deficient patients also exhibit evidence of immune dysregulation including eczema, chronic diarrhea, and lymphocytic interstitial pneumonitis. IL-2 signaling by STAT5b is required to sustain FOXP3 expression in T regulatory cells.
8. Aggressive management of infections is the mainstay of therapy. Patients with significant T cell dysfunction may benefit from trimethoprim-sulfamethoxazole prophylaxis to prevent Pneumocystis infections. At this time there is not enough data to recommend the routine use of HSCT.
OVERVIEW
STAT5b deficiency is an autosomal recessive disorder characterized by T cell immunodeficiency as well as short stature due to impaired growth hormone (GH) signaling. Additional clinical features include facial dysmorphisms (prominent forehead, saddle nose) and a high-pitched voice. To date, 5 patients with this disease have been reported in the literature.
Affected patients present with short stature and recurrent pulmonary infections. Bacterial pneumonias as well as opportunistic Infections (hemorrhagic Varicella, herpes zoster and Pneumocystis jiroveci) have been reported.
Immunologic testing of affected patients has shown modest T cell lymphopenia and decreased T cell proliferation to mitogens. NK cell numbers and gamma-delta T cell numbers were also reduced. B cell numbers, total immunoglobulin levels and vaccine responses were normal.
Affected patients have normal or elevated GH levels and low levels of Insulin-like growth factor (which is normally secreted in response to GH) even in response to exogenous GH administration. Growth hormone binding protein levels were normal in all patients. Markedly elevated prolactin levels have also been described.
PATHOGENESIS
The immunologic defects in this disease stem from the involvement of STAT5b in the intracellular signaling cascade of IL-2 and IFN-gamma. IL-2 is a key cytokine involved in T cell activation and development. IFN-gamma is a key innate immunity cytokine involved in macrophage and NK cell activation as well as upregulation of MHC class I expression.
STAT5b (as well as STAT 1, 3 and 5a) is also involved in GH induced signaling. As a result, patients with STAT5b deficiency exhibit GH insensitivity.
STAT5b deficient patients also exhibit evidence of immune dysregulation including eczema, chronic diarrhea, and lymphocytic interstitial pneumonitis. IL-2 signaling by STAT5b is required to sustain FOXP3 expression in T regulatory cells. Murine models of STAT5b deficiency demonstrate decreased T regulatory cell numbers and increased numbers of autoreactive T cells.
EVALUATION
STAT5b deficiency should be considered in patients with short stature and T cell immunodeficiency resulting in opportunistic infections such as Pneumocystis jiroveci pneumonia and severe Varicella infections as well as bacterial pneumonia. Additionally, a family history of consanguinity should raise suspicion for this autosomal recessive disease.
STEP 1: Endocrine Evaluation
-Growth Hormone (GH) levels
-Insulin-like growth factor 1 (IGF-1) levels
-Growth hormone binding protein (GH-BP) levels
-Prolactin levels
-STAT5b deficient patients have normal or elevated GH levels.
-IGF-1 levels are low due to impaired GH signaling. These levels remain low even with exogenous GH administration.
-GH-BP levels have been normal in all reported patients.
-Elevated prolactin levels have been reported in patients.
STEP 2: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-T-cell proliferation to Mitogens
-IgG, IgA, IgM levels
-Specific Antibody levels
-The absolute lymphocyte count (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage). The ALC may be decreased due to T cell lymphopenia
-Low T cell numbers (CD4 and CD8) and low NK cell numbers have been described. B cell numbers are normal.
-Low T-cell proliferation to mitogens may be present.
-Total immunoglobulin levels and specific vaccine responses are normal.
STEP 3: Protein Expression and Gene Sequencing
-STAT5b protein expression and STAT5B phosphorylation
-STAT5b gene sequencing
-STAT5b protein levels may be decreased with certain mutations but some mutations allow for expression of non-functional protein. STAT5b phosphorylation and activation can be greatly impaired.
-STAT5b sequencing can confirm the diagnosis and is commercially available (Seattle Children's)
MANAGEMENT
Aggressive management of infections is the mainstay of therapy. Patients with significant T cell dysfunction may benefit from trimethoprim-sulfamethoxazole prophylaxis (4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week) to prevent Pneumocystis jiroveci infections.
At this time there is not enough data to recommend the routine use of HSCT. HSCT could correct the immunodeficiency but it would not be expected to correct the growth deficiency in this syndrome.
RESOURCES
Diagnostic Resources
1. STAT5B Sequencing - Seattle Children's
Literature Resources
1. Bernasconi 2006
Characterization of immunodeficiency in a patient with STAT5b deficiency
2. Kofoed 2003
STAT5b deficiency and growth hormone insensitivity