Males
IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [Ruemmele et al 2004] and neonatal polyendocrinopathy [Dotta & Vendrame 2002] found in males. In a large natural history study, 95% of individuals with IPEX syndrome had disease onset in the first year of life, with 50% by age one month [Barzaghi et al 2012]. However, atypical clinical presentation has been reported with onset later in childhood [Consonni et al 2021].
Presentation. The most common presentation of IPEX syndrome is malabsorption with severe watery diarrhea, type 1 insulin-dependent diabetes mellitus, thyroiditis, and dermatitis in males younger than age one year. This disorder is frequently accompanied by other autoimmune phenomena. Males with a somewhat milder/atypical disease phenotype can present at older ages [Ge et al 2017, Hwang et al 2018]. Fetal presentation of IPEX syndrome includes hydrops, echogenic bowel, skin desquamation, intrauterine growth deficiency, and fetal akinesia. There may be a family history of pregnancy loss [Rae et al 2015, Vasiljevic et al 2015, Xavier-da-Silva et al 2015, Reichert et al 2016, Louie et al 2017, Shehab et al 2017].
Enteropathy. The enteropathy of IPEX syndrome, often the initial symptom, is present in virtually all affected individuals. Even in those with milder disease, the diarrhea typically begins in the first six to 12 months of life. Autoimmune enteropathy results in loss of intestinal villi architecture with malabsorption and watery diarrhea, which may contain mucus and blood. Malabsorption ultimately leads to growth failure and cachexia [Bacchetta et al 2018]. Small bowel biopsy is helpful in evaluating the extent of enteropathy. Histologic findings in most individuals have shown graft-vs-host-like changes with lymphocytic infiltrates with depletion of goblet cells and anti-enterocyte antibody deposition [Patey-Mariaud de Serre et al 2009]. Exocrine pancreatic insufficiency has been observed in some individuals [Gambineri et al 2008, Scaillon et al 2009], which may worsen the diarrhea. Other gastrointestinal manifestations include colitis [Lucas et al 2007] and gastritis [Gambineri et al 2008, Scaillon et al 2009]. Food allergies and intolerance are common, which can be diagnosed based on results of immunoglobulin E (IgE) testing to specific food antigens or skin prick testing [Torgerson et al 2007].
Endocrinopathy is present in the majority of affected individuals. Type 1 insulin-dependent diabetes mellitus, often with onset in the first months of life, is the most common endocrine manifestation [Gambineri et al 2008, Rubio-Cabezas et al 2009]. Thyroid disease (thyroiditis with either hypothyroidism [more common] or hyperthyroidism) is also frequently present [Wildin et al 2002, Gambineri et al 2003, Gambineri et al 2008, Rubio-Cabezas et al 2009].
Dermatitis. The dermatitis is most frequently eczematous, but psoriasiform and ichthyosiform dermatitis have been reported as well. Other dermatologic manifestations include painful chelitis and skin lesions related to food allergies. Rare cutaneous symptoms include pemphigoid nodularis and epidermolysis bullosa acquisita [Nieves et al 2004, McGinness et al 2006, Halabi-Tawil et al 2009, Bis et al 2015].
Autoimmune disorder. Most affected individuals have other autoimmune phenomena including cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia, autoimmune neutropenia [Barzaghi et al 2018]), autoimmune hepatitis [López et al 2011], and nephropathy (membranous nephropathy, interstitial nephritis, and – rarely – minimal change nephrotic syndrome) [Park et al 2015, Sheikine et al 2015]. Lymphadenopathy and splenomegaly as a result of lymphoproliferation have been reported [Ochs &Torgerson 2007, Nademi et al 2014, Bacchetta et al 2018, Barzaghi et al 2018]. Alopecia and arthritis have also been observed [Barzaghi et al 2018], as well as interstitial lung disease related to immune dysregulation [Baris et al 2014].
Infectious complications. Infections of the gastrointestinal tract, skin, and airways occur in individuals with IPEX syndrome [Bacchetta et al 2018], and severe or invasive infections including sepsis, meningitis, pneumonia, and osteomyelitis affect a significant number of subjects [Gambineri et al 2008, Barzaghi et al 2012, Barzaghi et al 2018]. Common pathogens identified were Staphylococcus, Enterococcus, cytomegalovirus, and Candida [Halabi-Tawil et al 2009, Barzaghi et al 2012]. Some infections may be secondary to immunosuppressive therapy, malnutrition, and central venous access; however, many occur prior to the initiation of treatment. Serious infections in individuals with IPEX syndrome are not thought to be due to an intrinsic immune defect but instead are typically related to poor barrier function of the small intestines and skin [Bacchetta et al 2018].
Survival. The outcome of IPEX syndrome is universally poor. Many children die within the first or second year of life from metabolic derangements, severe malabsorption, or sepsis. Although improvements in immunosuppressive regimens have prolonged survival, long-term immunosuppression does not appear to prevent morbidity due to disease progression and side effects or complications in the majority of individuals [Barzaghi et al 2018].
Early hematopoietic stem cell transplantation (HSCT) can cure IPEX syndrome; some survivors are now more than ten years post transplant and doing well. If individuals develop diabetes or thyroiditis prior to HSCT, these aspects of the disorder usually persist, but the other signs of IPEX syndrome resolve. Survival and long-term outcomes are improved if HSCT occurs at an earlier age, prior to the individual developing irreversible organ damage related to the extensive, systemic autoimmunity present in virtually all individuals with IPEX syndrome [Rao et al 2007, Burroughs et al 2010, Kucuk et al 2016].
