• Germline gain-of-function mutations in STAT3 lead to lymphoproliferation and autoimmunity with prominent cytopenias.• Mutations in STAT3 cause altered regulatory T cells and cytokine signaling.Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-offunction mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as #NCT00001350. (Blood. 2015;125(4):591-599)

Background The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60-70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining hyper-IgE syndrome patients, the genetic etiology has not yet been identified. Methods We performed genome-wide single nucleotide polymorphism analysis for nine subjects with autosomal recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with twelve subjects from seven additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal recessive hyper-IgE syndrome. Findings Subtelomeric microdeletions were identified in six subjects at the terminus of chromosome 9p. In all patients the deleted interval involved DOCK8, encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of subjects without large deletions revealed 16 patients from nine unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, single exon- and micro-deletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+ T cells. Interpretation Autosomal recessive mutations in DOCK8 are responsible for many, though not all, cases of autosomal recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T cell activation and TH17 cell differentiation; and impaired eosinophil homeostasis and dysregulation of IgE.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

We describe a novel clinical phenotype associating T-and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apopto- IntroductionMonogenic disorders of the human immune system have provided important insights into the function of host defense mechanisms. 1 Despite remarkable progress in the field, many disorders remain poorly understood. 2,3 Identifying genetic mutations in patients with immunodeficiency syndromes may reveal novel insights into basic mechanisms of the human immune system.Here, we describe the first human patients with a biallelic mutation of serine threonine kinase 4 (STK4; MIM: 604965). STK4 (previously sometimes named MST1) was originally identified as a ubiquitously expressed kinase with structural homology to yeast Ste20. 4,5 STK4 and STK3 (MST2; MIM: 605030) are the mammalian homologs of the Drosphila Hpo protein, the central constituent of the highly conserved HIPPO pathway controlling cell growth, apoptosis, and tumorigenesis. 6 Mice lacking either Stk3 or Stk4 are viable, but those lacking both proteins are not. This indicates that each protein can substitute for the other in the most essential functions. 7 When both Stk3 and Stk4 are conditionally deleted, however, their respective role as growth control regulators becomes manifest, exemplified by liver-specific double-knockout mice that develop massive hepatomegaly and hepatocellular carcinoma. 8,9 STK4 has both proapoptotic and antiapoptotic functions. Earlier papers focused on the proapoptotic functions, and STK4 was described with the adjective "proapoptotic" in the title of a paper as recently as 2007. 10 The strongest evidence that STK4 delivers proapoptotic signals is that STK4 is cleaved by caspases 11,12 ; caspase activity is unambiguously proapoptotic. In resting conditions, STK4 is a cytoplasmic protein. In response to apoptotic stimuli, the 63-kDa full-length protein is cleaved by caspases and a 36-kDa N-terminal fragment translocates to the nucleus and phosphorylates histones, 13,14 suggesting that STK4 plays a proapoptotic role. STK4 is also in a proapoptotic regulatory loop with JNK. [15][16][17] Finally, the interaction between RASSF1A and STK4 was shown to promote Fas-mediated apoptosis. 18 There was also some evidence, before the generation of Stk4-deficient mice, that STK4 has antiapoptotic functions. For example, a study in Caenorhabditis elegans showed that phosphorylation of FOXO proteins by the STK4 ortholog DAF16 protects against cell death induced by oxidative stress. Furthermore, when DAF16 canno...