Differential Diagnosis
IPEX syndrome is classified by the International Union of Immunological Societies (IUIS) as an inborn error of immunity that results in immune dysregulation due to absent or defective regulatory T cells (Treg) . Autoimmunity is the primary clinical manifestation. Among the ten unique disorders with Treg dysfunction, LRBA deficiency, CTLA4 haploinsufficiency, CD25 deficiency, FERMT1 deficiency, BACH2 deficiency, IKAROS GOF (gain of function), and CD122 deficiency have the most clinical overlap with IPEX syndrome . Other inborn errors of immunity without Treg dysfunction, including immune dysregulation with colitis, can also mimic IPEX syndrome . In addition to immune dysregulation disorders, monogenic forms of neonatal diabetes that are clinically evident soon after birth can present similarly to IPEX syndrome. These conditions are most commonly associated with pancreatic defects and lack autoimmune manifestations . Similarly, intrinsic defects of the intestinal microvilli have clinical presentations consistent with enteropathy with malabsorption and diarrhea but are not immune mediated . See for these and other considerations in the differential diagnosis. Table 2. Syndromes of Known Genetic Cause to Consider in the Differential Diagnosis of IPEX Syndrome
Gene(s)/ Genetic Mechanism | Disorder | MOI | Additional Key Features |
|---|
BACH2 | BACH2-related immunodeficiency autoimmunity2 | AD | Enteropathy, chronic variable immunodeficiency |
CTLA4 | CTLA4 haploinsufficiency (autoimmune lymphoproliferative syndrome, type V) (OMIM 616100) | AD | Enteropathy, autoimmune cytopenias, autoimmune thyroiditis |
FERMT1 | FERMT1 deficiency | AR | Gingivitis, periodontitis, mucosal inflammation |
IKZF1 | IKAROS GOF (OMIM 616873) | AD | Low Treg numbers, immune deficiency, autoimmune disease; Distinguished from IPEX syndrome by low B cell numbers3 |
IL2RA | CD25 deficiency (OMIM 606367) | AR | Identified in 3 persons w/IPEX syndrome-like clinical phenotype. |
Source: GeneReviews — "IPEX Syndrome"
