Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome

Abstract

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity.

Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants.

Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3.

Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate.

Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

Keywords: STAT3; autoimmunity; cytopenia; gain of function; immune dysregulation; immunodeficiency; lymphoproliferation; precision medicine.

FIG 1.

Country of origin for each STAT3 GOF patient. Thirty-seven percent of patients were from the United States, 46% from Europe, and 17% from the rest of the world.

FIG 2.

STAT3 GOF mutations. Seventy-two unique STAT3 variants spanned all domains of the STAT3 molecule. Red dots indicate novel patients; black dots, previously published patients. A, Alanine (Ala); C, cysteine (Cys); D, aspartic acid (Asp); E, glutamic acid (Glu); F, phenylalanine (Phe); G, glycine (Gly); H, histidine (His); I, isoleucine (Ile); K, lysine (Lys); L, leucine (Leu); M, methionine (Met); N, asparagine (Asn); P, prolie (Pro); Q, glutamine (Gln); R, arginine (Arg); S, serine (Ser); T, threonine (Thr); V, valine (Val); W, tryptophan (Trp); Y, tyrosine (Tyr).

FIG 3.

Clinical manifestations of STAT3 GOF patients. Percentage is shown of each clinical manifestation within the cohort of 191 patients.

FIG 4.

Clinical images of STAT3 GOF patients. (A) Characteristic facial appearance includes round face, prominent forehead, cupped ears, and smooth philtrum. (B) Interstitial infiltrate demonstrates nodules in right upper lung, bronchiectasis, and airspace disease (patient 57). (C) Same patient as (B) after treatment with tofacitinib for 5 years showing resolution of ground-glass opacities and pulmonary nodules. (D) Rectosigmoid biopsy sample reveals mild eosinophilia in the lamina propria and chronic changes in the form of Paneth cell metaplasia (patient 61). (E) Lung biopsy of right lower lobe reveals nodular and linear septal inflammation, predominantly by lymphocytes and histiocytes, without interstitial fibrosis (patient 61) (hematoxylin and eosin, original magnification 100 ×). (F) Chronic ischemic lesion is in the white matter of the middle frontal gyrus and right semioval center, and extensive leukoencephalopathy is evident of probable microvascular origin (patient 152). (G) Subcortical and cortical enhancing lesions are in the presylvian regions, anterior temporal lobes, and pons (patient 110).

FIG 4.

Clinical images of STAT3 GOF patients. (A) Characteristic facial appearance includes round face, prominent forehead, cupped ears, and smooth philtrum. (B) Interstitial infiltrate demonstrates nodules in right upper lung, bronchiectasis, and airspace disease (patient 57). (C) Same patient as (B) after treatment with tofacitinib for 5 years showing resolution of ground-glass opacities and pulmonary nodules. (D) Rectosigmoid biopsy sample reveals mild eosinophilia in the lamina propria and chronic changes in the form of Paneth cell metaplasia (patient 61). (E) Lung biopsy of right lower lobe reveals nodular and linear septal inflammation, predominantly by lymphocytes and histiocytes, without interstitial fibrosis (patient 61) (hematoxylin and eosin, original magnification 100 ×). (F) Chronic ischemic lesion is in the white matter of the middle frontal gyrus and right semioval center, and extensive leukoencephalopathy is evident of probable microvascular origin (patient 152). (G) Subcortical and cortical enhancing lesions are in the presylvian regions, anterior temporal lobes, and pons (patient 110).

FIG 5.

Treatment provided to STAT3 GOF patients. Data were available from 164 patients. (A) Percentage of each treatment provided to patients. (B) Percentage of patients receiving 1, 2, 3, 4, or 5 or more treatments.

FIG 6.

Survival curves of STAT3 GOF patients. (A) OS of STAT3 GOF patients. (B) OS of STAT3 GOF patients based on variant domain. Purple, CCD; blue, DBD; brown, N-terminal domain; red, SH2; green, TAD; P = .0677.

FIG 7.

Survival according to clinical manifestations. Survival is significantly affected by oxygen dependance (A), enteropathy (B), autoimmune hepatitis (C), and total parenteral nutrition (TPN) dependance (D). Green, present; blue, not present.