Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome

Eleonora Gambineri, Sara Ciullini Mannurita, David Hagin, Marina Vignoli, Stephanie Anover-Sombke, Stacey DeBoer, Gesmar R S Segundo, Eric J Allenspach, Claudio Favre, Hans D Ochs, Troy R Torgerson, Eleonora Gambineri, Sara Ciullini Mannurita, David Hagin, Marina Vignoli, Stephanie Anover-Sombke, Stacey DeBoer, Gesmar R S Segundo, Eric J Allenspach, Claudio Favre, Hans D Ochs, Troy R Torgerson

Abstract

Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.

Keywords: FOXP3; IPEX-like; X-linked (IPEX); enteropathy; immune dysregulation; immune regulatory genes; polyendocrinopathy; regulatory T cells.

Figures

Figure 1
Figure 1
FOXP3 mutations identified in our cohort of IPEX patients. Schematic representation of FOXP3 mRNA and protein showing the location and sizes of the predicted structural domains. Numbers along the top line indicate amino acid number (1–431). The position of the identified mutations along the mRNA is reported with different shape for each type of variation. Each symbol represents a single kindred. ZF, zinc finger; LZ, leucine zipper; FKH, forkhead box domain; N, amino terminus; C, carboxy terminus; PolyA, polyadenylation sequence.
Figure 2
Figure 2
(A)FOXP3 mutations in IPEX (symbols in yellow) in forkhead box domain. Amino acid sequence of FOXP3 protein aligned with other FOX proteins. Shows conserved residues (blue) and highly conservative residues (green). (B)FOXP3 mutations in IPEX (symbols in yellow) in the leucine zipper domain. Amino acid sequence of FOXP3 protein aligned with c-myc and v-myc leucine zippers (known to be highly conserved). Shows highly conserved residues (blue) and highly conservative residues (green).
Figure 3
Figure 3
(A) CD25+FOXP3+ expression in IPEX, IPEX-like patients and control subjects. (B) IPEX patients differ according to the type of FOXP3 mutations. Deletion = in frame deletion; frameshift = deletion with frameshift. Values are expressed as percentage of CD4 cells, median and 5–95 percentile are shown, circles, triangles, and cones represent singles patients out of 5–95 percentile (circles = IPEX patients, triangles = IPEX-like patients, cones = control subjects) (**p < 0.001; ***p < 0.0001).
Figure 4
Figure 4
CD25+FOXP3+ expression in IPEX-like patients differed by the type of mutated genes identified and control subjects. Values are expressed as percentage of CD4 cells, mean and SD are shown.
Figure 5
Figure 5
Clinical manifestations in the IPEX and IPEX-like cohorts (A). IPEX patient stratified for type of mutation showing classical triad of symptoms (B).
Figure 6
Figure 6
Heat map showing frequencies of clinical manifestations in our cohort of patients with LRBA, CTLA4, STAT1 GOF, STAT3 GOF, STAT5b, and IL2RA mutations.
Figure 7
Figure 7
IgE levels in IPEX and IPEX-like patients. Mean and SD are shown (****p < 0.0001).
Figure 8
Figure 8
Kaplan-Meier survival curve for overall survival of patients. (A) The overall survival in the whole cohort of patient is evaluated (n = 163); (B) IPEX (n = 85) vs. IPEX-like (n = 78) patients are compared; (C) IPEX patients stratified for type of mutation: frameshift (FS) n = 6, in frame deletion (IFD) n = 11, missense (MS) n = 43, splicing mutations (SP) n = 14 and mutations in polyadenylation site (POLA) n = 11 are compared; (D) IPEX-like without mutations (NA= not available) n = 57 and IPEX-like with mutation (Mut) n = 21 are compared; (E) IPEX patient stratified whether (n = 39) or not (n = 46) they underwent HSCT and (F) IPEX-like patient stratified whether (n = 10) or not (n = 68) they underwent HSCT.
Figure 9
Figure 9
Flow chart suggesting molecular analysis strategy based on patients' clinical phenotype and immunological markers.

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