Primary immunodeficiency: IPEX-syndrome. Literature review and clinical case




infants, primary immunodeficiency, IPEX-syndrome, FOXP3 gene mutations, autoimmune enteropathy, diagnosis


IPEX-syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is a severe inherited X-linked disease from the group of primary immunodeficiencies associated with mutations in the FOXP3 gene, which encodes a key transcription factor for T-regulatory lymphocytes. In the pathogenesis of the disease the main role plays disorder of maturation of CD25 + CD4 + -T-regulatory lymphocytes (TR), which carry out negative selection of autoreactive clones of T- and B-lymphocytes, resulting in loss of autotolerance and early development of multiorgan autoimmune pathology in combination with severe violation of antiviral and antibacterial immunity. The typical clinical picture of IPEX-syndrome is a triad: autoimmune enteropathy, endocrinopathy (diabetes mellitus type 1, autoimmune thyroiditis), skin and/or mucosal lesions, but any combination of autoimmune pathology or isolated organ damage is possible. At the same time, intestinal lesions (autoimmune enteropathy) are found in almost 100% of patients. Laboratory immunological markers of IPEX-syndrome are absent (the disease can be detected only by genetic testing - panel sequencing of genes), which, along with the variability of clinical manifestations, creates significant diagnostic difficulties.

The article presents a clinical case of IPEX-syndrome, the clinical features of which were isolated enteropathy without clinical and laboratory signs of autoimmune damage to other organs, as well as severe lesions of the small intestinal mucosa (total villi atrophy) and rapid disease progression despite late onset (during second year of life). Although immunologists associate the late onset with «soft» mutations in the gene, easier course and more favorable prognosis. Laboratory features of this case were: negative serological markers of autoimmune intestinal lesions and elevated levels of T-regulatory lymphocytes CD4 + CD25 + CD127low +, although IPEX-syndrome is characterized by a decrease or absence of T-regulatory cells.

IPEX-syndrome in this patient was confirmed by genetic research - sequencing of the FOXP3 gene revealed a pathogenic mutation с. 736-2А>Т (Splice acceptor).

The research was carried out in accordance with the principles of the Helsinki declaration. The informed consent of the patient was obtained for conducting the studies.

No conflict of interests was declared by the authors.


AWMF. (2019). Therapie primärer Antikörpermangelerkrankungen (2019). URL:

Bacchetta R, Barzaghi F, Roncarolo MG. (2018, Apr). From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann N Y Acad Sci. 1417 (1): 5-22.; PMid:26918796

Bae KW, Kim BE, Choi J-H, Lee JH, Park YS, Kim G-H et al. (2011). A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. European Journal of Pediatrics. 170 (12): 1611-1615.; PMid:21979562

Barzaghi F, Passerini L, Bacchetta R. (2012). Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodefi ciency with Autoimmunity. Frontiers in Immunology. 3: 211.; PMid:23060872 PMCid:PMC3459184

Barzaghi F, Passerini L. (2021, Feb 22). IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis. Front Pediatr. 9: 612760.; PMid:33692972 PMCid:PMC7937806

Ben-Skowronek I. (2021, Feb 24). IPEX Syndrome: Genetics and Treatment Options. Genes (Basel). 12 (3): 323.; PMid:33668198 PMCid:PMC7995986

Carneiro-Sampaio M, Moreira-Filho CA, Bando SY, Demengeot J, Coutinho A. (2020, Nov 20). Intrauterine IPEX. Front Pediatr. 8: 599283.; PMid:33330291 PMCid:PMC7714920

Chubarova AI, Shumilov PV, Kostomarova EA, Hamatvaleeva GR, Dmitrieva YuA. (2016). Klinicheskiy sluchay sindroma immunnoy disregulyatsii, poliendokrinopatii (IPEX-sindroma) s izolirovannyim porazheniem kishechnika. Pediatriya. 95 (6): 187-192.

Consonni F, Ciullini Mannurita S, Gambineri E. (2021, Feb 5). Atypical Presentations of IPEX: Expect the Unexpected. Front Pediatr. 9: 643094.; PMid:33614561 PMCid:PMC7892580

De Benedetti F, Insalaco A, Diamanti A et al. (2006). Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome. Clin Gastroenterol Hepatol. 4: 653-659.; PMid:16630773

Gentile NM, Murray JA, Pardi DS. (2012). Autoimmune enteropathy: a review and update of clinical management. Gastroenterol. Rep. 14 (5): 380-385.; PMid:22810979 PMCid:PMC3912565

Hannibal MC, Torgerson T, Pagon RA, Adam MP et al. (2004, Oct 19). IPEX syndrome. Gene Reviews. Seattle (WA): University of Washington, Seattle, 1993-2015. Initial Posting. URL:

Kobayashi I, Kubota M, Yamada M, Tanaka H et al. (2011). Autoantibodies to villin occur frequently in IPEX, a severe immune dysregulation, syndrome caused by mutation of FOXP3. Clinical Immunology. 141 (1): 83-89.; PMid:21741320

Mailer RK. (2020, Oct 21). IPEX as a Consequence of Alternatively Spliced FOXP3. Front Pediatr. 8: 594375. eCollection 2020.; PMid:33194927 PMCid:PMC7609600

Moes N, Rieux-Laucat F, Begue B et al. (2010). Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology. 139 (3): 770-778.; PMid:20537998

Montalto M, D'Onofrio F, Santoro L et al. (2009). Autoimmune enteropathy in children and adults. Scand. J Gastroenterol. 44 (9): 1029-1036.; PMid:19255930

MOZ Ukrainy. (2021). Pervynni imunodefitsyty. Klinichna nastanova, zasnovana na dokazakh. Kyiv. URL:

MOZ Ukrainy. (2021). Standarty nadannia medychnoi dopomohy «Diahnostyka ta likuvannia pervynnykh imunodefitsytiv». URL:

Park JH, Lee KH, Jeon B, Ochs HD et al. (2020, Jun). Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review. Autoimmun Rev. 19 (6): 102526. Epub 2020 Mar 29.; PMid:32234571

Rubio-Cabezas O, Minton JAL, Caswell R, Shield JP et al. (2009). Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes. Diabetes Care. 32 (1): 111-116.; PMid:18931102 PMCid:PMC2606841

Sherman PM, Mitchell DJ, Cutz E. (2004). Invited Review: Neonatal Enteropathies: Defining the Causes of Protracted Diarrhea of Infancy. Journal of Pediatric Gastroenterology and Nutrition. 38: 16-26.; PMid:14676590

Tihonovich YuV, Petryaykina EE, Ryibkina IG, Garyaeva IV, Tyulpakov AN. (2014). H-stseplennaya immunnaya disregulyatsiya, poliendokrinopatiya i enteropatiya (IPEX-sindrom): opisanie klinicheskogo sluchaya i kratkiy obzor literaturyi. Problemyi endokrinologii. 5: 29-33.

Turkunova ME, Ditkovskaya LV, Suspitsyin EN, Tyirtova LV, Zhelenina LA, Guseva MN. (2017). Neonatalnyiy saharnyiy diabet v strukture IPEX-sindroma. Pediatr. 8 (2): 99-104.

Xavier-da-Silva MM, Moreira-Filho CA, Suzuki E, Рatricio F et al. (2015). Fetal-onset IPEX: report of two families and review of literature. Clin Immunol. 156 (2): 131-140.; PMid:25546394