Immunodeficiency 31c

A number sign (#) is used with this entry because immunodeficiency-31C (IMD31C) is caused by heterozygous mutation in the STAT1 gene (600555) on chromosome 2q32.

Immunodeficiency-31A (IMD31A; 614892), an autosomal dominant disorder, and immunodeficiency-31B (IMD31B; 613796), an autosomal recessive disorder, are allelic.

Description

IMD31C is disorder of immunologic dysregulation with highly variable manifestations resulting from autosomal dominant gain-of-function mutations in STAT1 (600555). Most patients present in infancy or early childhood with chronic mucocutaneous candidiasis (CMC). Other highly variable features include recurrent bacterial, viral, fungal, and mycoplasmal infections, disseminated dimorphic fungal infections, enteropathy with villous atrophy, and autoimmune disorders, such as hypothyroidism or diabetes mellitus. A subset of patients show apparently nonimmunologic features, including osteopenia, delayed puberty, and intracranial aneurysms. Laboratory studies show increased activation of gamma-interferon (IFNG; 147570)-mediated inflammation. (summary by Uzel et al., 2013 and Sampaio et al., 2013).

Clinical Features

Van de Veerdonk et al. (2011) evaluated 14 patients from 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis. Mononuclear cells from the affected patients were characterized by poor production of IFNG (147570), IL17 (IL17A; 603149), and IL22 (605330). In addition to candidiasis, the 67-year-old father of one of the Dutch families had autoimmune hepatitis, and his 38-year-old daughter had autoimmune hemolytic anemia and anti-phospholipid antibodies; his 37-year-old son had candidiasis but no autoimmune phenomena. The father and daughter also suffered from chest infections, and the daughter had pulmonary embolism and Pneumocystis jirovecii pneumonia with symptomatic cytomegalovirus infection. None of the other families exhibited autoimmune disease, but members of 2 of the British families also suffered from chest infections. One member of the second Dutch family, as well as her deceased mother, and members of 2 British families had esophageal or oral carcinoma. Members of all 3 British families also had hypothyroidism.

Uzel et al. (2013) reported 5 unrelated children with IMD31C. Three patients presented with mucocutaneous candidiasis between 3 and 8 months of age. Another 4-year-old patient presented in infancy with recurrent infections and dermatitis and was later found to have enteropathy; this patient did not develop candidal infection. The last patient, who presented in early childhood with hypothyroidism and growth delay, was later found to have enteropathy with villous atrophy, and had 1 episode of mild candidiasis. Three patients developed insulin-dependent diabetes mellitus later in childhood. Other variable autoimmune disorders included hypothyroidism, hemolytic anemia, thrombocytopenia purpura, and autoimmune enteropathy. These features were reminiscent of the complex immune disorder known as X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX; 304790), but none of the patients had mutations in the FOXP3 gene (300292). The patients had evidence of immunodeficiency, with recurrent bacterial, viral (RSV, HSV, VSV), and mycobacterial infections and a progressive decrease in T- and B-cell numbers and immunoglobulin levels, although these laboratory features were variable. Two patients showed early developmental delay. Additional features included eczema, poor growth with delayed secondary sexual characteristics, and poor bone growth; 2 patients had intracranial aneurysms. Two patients died in childhood. Immunologic workup showed decreased CD4+ (186940) IL17-producing T cells, but regulatory CD4+ T cells were normal. The first 3 patients were identified from a cohort of 5 patients with chronic mucocutaneous candidiasis and additional features who underwent STAT1 sequencing, and the 2 remaining patients were identified from a cohort of 35 patients with an IPEX-like phenotype who underwent STAT1 sequencing.

Sampaio et al. (2013) reported 5 unrelated patients with severe disseminated dimorphic fungal infections due to IMD31C. A Hispanic girl from Arizona presented at age 15 years with extensive Trichophyton tonsurans infection and later developed disseminated coccidioidomycosis. Another girl from Arizona, who was Caucasian, presented at age 9.5 years with disseminated coccidioidomycosis that eventually involved the central nervous system, resulting in death at age 17. Three additional patients had disseminated histoplasmosis beginning at 12, 17, and 7 years of age, respectively. One patient had a lifetime history of bone fractures and recurrent infections, including candidal thrush in early infancy; another had oral candidiasis, progressive multifocal leukoencephalopathy caused by the JC virus, and Pseudomonas sepsis resulting in death at age 31 years.

Molecular Genetics

In 2 Dutch and 3 British families with autosomal dominant chronic mucocutaneous candidiasis, van de Veerdonk et al. (2011) identified 2 heterozygous mutations in exon 10 of the STAT1 gene. Both mutations, arg274 to trp (R274W; 600555.0008) and ala267 to val (A267V; 600555.0009), occurred in the coiled-coil domain of STAT1 and resulted in defective responses in Th1 and Th17 cells, characterized by poor production of IFNG, IL17, and IL22 (605330).

Liu et al. (2011) identified 12 missense mutations in exons 6 through 10 of the STAT1 gene in 36 patients from 20 kindreds with autosomal dominant chronic mucocutaneous candidiasis. All 12 mutations affected a cluster of residues in a specific pocket of the STAT1 coiled-coil domain, near residues essential for dephosphorylation. Extensive functional characterization revealed that at least 11 of the 12 candidiasis-associated STAT1 mutations were gain of function, with enhanced induction of GAS binding in response to IFNG, IFNA (147660), or IL27 (608273). Studies with the arg274-to-gln (R274Q; 600555.0010) and asp165-to-gly (D165G; 600555.0014) mutations showed that the gain-of-function mechanism involved increased phosphorylation of tyr701 of STAT1 due to impaired nuclear dephosphorylation. Patients with STAT1 gain-of-function mutations had lower proportions of circulating IL17A- and IL22-producing T cells and lower secretion of IL17A, IL17F (606496), and IL22 compared with healthy controls and patients with STAT1 loss-of-function alleles, such as leu706 to ser (L706S; 600555.0001). Liu et al. (2011) concluded that patients with familial or sporadic autosomal dominant chronic mucocutaneous candidiasis and mutations affecting the coiled-coil domain of STAT1 produce lower amounts of IL17, which renders them susceptible to extracellular fungal disease.

By cloning and transfection experiments, Smeekens et al. (2011) found that the R274Q mutation underlying chronic mucocutaneous candidiasis inhibited IL12R (see 601604)/IL23R (607562) signaling, likely due to STAT1 hyperphosphorylation. Inhibition of IL12R/IL23R signaling led to diminished Th1/Th17 responses and increased susceptibility to fungal infections.

Soltesz et al. (2013) described the genetic, immunologic, and clinical findings in 9 patients with chronic mucocutaneous candidiasis from the Czech Republic, Hungary, Russia, and Ukraine who ranged in age from 9 to 48 years. Using whole-exome sequencing, they identified heterozygous missense mutations in the STAT1 gene in all 9 patients, including 2 novel mutations affecting the coiled-coil domain, asn179 to lys (N179K; 600555.0020) and gln285 to arg (Q285R; 600555.0021), and a mutation affecting the DNA-binding domain, thr385 to met (T385M; 600555.0022). The N179K and Q285R mutations resulted in STAT1 gain of function for GAF-dependent responses. The T385M mutation in the DNA-binding domain, as well as the frequent R274W mutation in the coiled-coil domain, led to increased STAT1 phosphorylation due to loss of dephosphorylation.

In 5 unrelated children with IMD31C, Uzel et al. (2013) identified 4 different heterozygous missense mutations in the STAT1 gene (see, e.g., T385M, 600555.0022). In vitro functional expression studies showed that all the mutations resulted in increased STAT1 phosphorylation, activation, and increased DNA binding in response to IFNG stimulation, consistent with a gain of function. Transfected cells also showed decreased STAT1 dephosphorylation compared to wildtype, indicating prolonged activation. Flow cytometric analysis of patient lymphocytes confirmed increased IFNG-induced STAT1 hyperphosphorylation.

In 5 unrelated patients with disseminated infection with dimorphic fungi, including coccidioidomycosis and histoplasmosis, Sampaio et al. (2013) identified 4 different heterozygous missense mutations in the STAT1 gene (see, e.g., A267V, 600555.0009; T385M, 600555.0022; and R274G, 600555.0025). Four of the mutations were demonstrated to occur de novo; parental samples from the fifth patient were not available. In vitro functional expression studies indicated that the mutations resulted in enhanced IFNG-induced STAT1 phosphorylation and increased DNA binding in B cells compared to wildtype, consistent with a gain of function. However, the initial hyperresponsiveness to IFNG was impaired upon restimulation, suggesting that the IFNG tachyphylaxis may be central to the immunologic defect in this disorder. Knockdown of PIAS1 (603566) resulted in near normalization of STAT1 gene expression after restimulation, and treatment of transfected cells or patient cells with a methyl donor resulted in enhanced methyl-associated STAT1, decreased STAT1/PIAS1 interaction, and decreased IFNG-induced STAT1 phosphorylation, suggesting a potential therapeutic use.

Yamazaki et al. (2014) identified 2 novel gain-of-function STAT1 mutations, lys278 to glu (K278E; 600555.0026) in the coiled-coil domain and gly384 to asp (G384D; 600555.0027) in the DNA-binding domain, in 3 Japanese patients with chronic mucocutaneous candidiasis disease. Ectopic expression of the STAT1 mutants in HeLa cells was associated with increased phosphorylation of both mutant and wildtype STAT1 due to impaired dephosphorylation, indicating that heterodimers of mutant and wildtype STAT1 or homodimers of mutant STAT1 had reduced dephosphorylation function. Anti-CD3D (186790)/anti-CD28 (186760) or Candida stimulation of peripheral blood mononuclear cells and CD4-positive T cells resulted in significantly reduced production of IL17A and IL22, but not IL17F, in 4 patients with STAT1 gain-of-function mutations, including the 3 patients with K278E or G384D mutations and 1 patient with the R274Q mutation. Only anti-IL17F autoantibody was detected in sera from 11 of 17 patients with STAT1 gain-of-function mutations. Yamazaki et al. (2014) concluded that impaired production of IL17A and IL22, but not IL17F, is associated with development of chronic mucocutaneous candidiasis disease.