Clinical and Pathologic Manifestations of IPEX

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The first description of IPEX was provided in 1982 when a large family with multiple affected males in a five-generation pedigree was reported with early onset of polyen-docrinopathy, enteropathy, dermatitis/eczema, and premature death (Powell et al. 1982). Following the discovery of the genetic defect in IPEX (Bennett et al. 2001b; Wildin et al. 2001), more than 60 unrelated families with FOXP3 mutations have been identified. In addition to patients with the classic triad of severe diarrhea and failure to thrive, dermatitis/eczema, and early onset diabetes, patients with milder phenotypes were observed, often with delayed onset, which were not readily recognized as IPEX. The oldest patient in our series was 24 years of age when the diagnosis of IPEX was considered and subsequently confirmed by mutation analysis. The clinical findings and laboratory abnormalities observed in a cohort of 50 IPEX patients with identified FOXP3 mutations are summarized in Table 1.

2.1. Gastrointestinal Symptoms and Failure to Thrive

Severe diarrhea associated with villous atrophy and extensive lymphocytic infiltrates of the small bowel mucosa is the most prominent clinical finding in patients with the IPEX phenotype. With one exception, all patients in our series presented with gastrointestinal symptoms of watery or mucoid-bloody diarrhea with poor response to dietary

Table 1. Clinical and laboratory abnormalities in IPEX patients with FOXP3 mutations

Clinical features (n = 51)

No. affected

Percent

Enteropathy

49

98

Skin pathology

47

94

Endocrinopathy

37

74

Diabetes (type 1)

27

54

Thyroid disease

16

32

Cytopenia

24

48

(RBC, neutrophils, and platelets)

Nephropathy

15

30

Hepatitis

11

22

Neurological diseases

11

22

Serious infections

31

62

Lymphadenopathy

4

8

Arthritis/vasculitis

4

8

Laboratory features

Elevated IgE (n = 27)

25

93

Elevated IgA (n = 30)

20

67

Outcome

Alive

28

56

BMTransplantation

12

24

manipulation. Total parenteral nutrition (TPN) is frequently a life-saving intervention. Treatment with immunosuppressive drugs may improve gastrointestinal symptoms in some patients (Bindl et al. 2005).

2.2. Autoimmune Endocrinopathy

The second most common complication of IPEX is autoimmune endocrinopathy. Early onset (sometimes present at birth) insulin-dependent type I diabetes is almost a pathog-nomonic finding originally reported by Powell et al. (1982). The diabetes is difficult to control, and affected males often have anti-islet cell autoantibodies. At autopsy, the pancreas shows chronic interstitial inflammation with lymphocytic infiltrates and absence of islet cells (Wildin et al. 2002). Thyroid disease, initially presenting as either hypo- or hyper-thyroidism, is a common complication (Powell et al. 1982; Nieves et al. 2004), and may be associated with elevated thyroid stimulation hormone levels or anti-thyroid microsomal antibodies (Wildin et al. 2002).

2.3. Autoimmune Hematologic Disorders

Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, or neutropenia with early or late onset are frequently observed complications (Powell et al. 1982; Wildin et al. 2002; Nieves et al. 2004); anti-red blood cell, anti-platelet, and anti-neutrophil autoantibodies can be frequently demonstrated.

2.4. Dermatologic Abnormalities

Lesions of the skin are common clinical findings (Powell et al. 1982; Nieves et al. 2004). During infancy, the lesions may be erythematous involving the entire body. Older patients often develop chronic eczema or localized psoriasiform dermatitis. His-tologically, the psoriasiform lesions show irregular hyperplasia of the epidermis with overlying parakeratosis and lymphocytic infiltrates (Nieves et al. 2004). Alopecia universalis has been observed in several patients. Treatment with steroid ointment often improves the skin lesions.

2.5. Infections

The increased susceptibility to infections may be a direct function of the genetic defect, as was postulated by Powell et al. (1982), or it may be secondary to the decreased barrier function of the skin and gut or iatrogenic due to prolonged immuno-suppressive therapy. In our series of over 100 patients with the IPEX phenotype, approximately one half had serious infections including sepsis, meningitis, pneumonia, and osteomyelitis. These infections were observed in many cases prior to the initiation of immunosuppressive therapy. Sepsis as a direct result of line infections is a common complication. Neutropenia, if present, may contribute to susceptibility to bacterial infections. The most common pathogens identified in our series of IPEX patients were Enterococcus and Staphylococcus species, cytomegalovirus, and Candida (Gambineri et al. 2003).

2.6. Other Clinical Manifestations

Renal disease, often described as glomerulonephropathy or interstitial nephritis, has been reported (Powell et al. 1982). In our own series of IPEX patients, more than 50% with demonstrated FOXP3 mutations had renal abnormalities. In some instance, renal disease might be directly caused or worsened by treatment with cyclosprin A or FK506. Renal disease, however, has been described in IPEX patients not receiving immunosuppressive drugs. Splenomegaly and lymphadenopathy due to extensive lymphocytic infiltrates have been reported in patients at autopsy (Wildin et al. 2002). Unexpectedly, almost half of the IPEX patients in our own series had neurologic problems including seizures and mental retardation.

2.7. Laboratory Findings and Histopathology

The immunologic evaluation of IPEX patients is unremarkable except for elevated serum levels of IgE and IgA and marked eosinophilia. Functional analysis of the immune system is difficult, since most patients are on systemic immunosuppressive therapy at the time of testing. The presence of autoantibodies is a hallmark of the syndrome. Most patients with insulin-dependent diabetes have autoantibodies against pancreatic islet cells (Baud et al. 2001; Wildin et al. 2002). Circulating autoantibodies against human intestinal enterocytes and an autoantibody specific for a 75-kDa gut and kidney-specific antigen (AIE-75) have been observed (Kobayashi et al. 1998). Circulating lymphocytes expressing CD4 and CD25 markers are present in IPEX patients with FOXP3 mutations, but none of these cells express the FOXP3 protein.

The intestinal tract abnormalities are characterized by a loss of villi in the small bowel associated with mucosal erosions and lymphocytic infiltrates in the lamina propria and submucosa. Lymphocytic infiltrates may also be present in the colon. The pancreas of infants with insulin-dependant diabetes shows lymphocytic infiltrates and loss of Langerhans cells. The thyroid, if affected, demonstrates extensive lymphocytic infiltrates (Wildin et al. 2002). Microscopic evaluations of skin biopsies are consistent with eczema; some lesions resemble psoriasiform dermatitis, showing hyperplasia of the epidermis and parakeratosis. The dermis may contain large numbers of infiltrating lymphocytes that consist predominantly of CD4+ and CD8+ T cells (Nieves et al. 2004). Spleen, liver, and lymph nodes often show lymphocytic infiltrates (Wildin et al. 2002). A hypotrophic thymus, often observed at autopsy, may be the result of chronic illness or prolonged immunosuppressive therapy. Renal abnormalities include interstitial nephritis, focal tubular atrophy, membranous glomerulopathy, and lymphocytic infiltrates.

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