Lymphoproliferative Syndrome, X-Linked, 2

A number sign (#) is used with this entry because of evidence that X-linked lymphoproliferative syndrome-2 (XLP2) is caused by mutation in the gene encoding the X-linked inhibitor of apoptosis (XIAP; 300079) on chromosome Xq25.

Description

XLP2 is an X-linked primary immune deficiency with symptom onset usually in the first years of life, although later onset may occur. Features are compatible with immune dysregulation and include hemophagocytic lymphohistiocytosis (HLH), often associated with chronic Epstein-Barr virus (EBV) infection, splenomegaly, fever, colitis or inflammatory bowel disease (IBD), and recurrent infections. Laboratory abnormalities are variable, but can include hypogammaglobulinemia, cytopenias, and low levels of a particular subset of T cells known as NKT (or iNKT) cells. Functional studies show increased sensitivity of T cells to apoptosis (activation-induced cell death, AICD), impaired cytokine production, including of TNF-alpha (TNFA; 191160), and general dysregulation of the immune pathway, such as increased levels of IL18 (600953). However, circulating levels of lymphocytes and NK cells are usually normal. Many patients die from fulminant HLH, and the only curative treatment is a hematopoietic stem cell transplant, although this procedure has been associated with a poor prognosis. Female mutation carriers are usually asymptomatic, although some female carriers may have less severe manifestations, which appears to depend on X-inactivation patterns (summary by Yang et al., 2012; review by Latour and Aguilar, 2015).

Latour and Aguilar (2015) provided a detailed review of XIAP deficiency, including clinical features, molecular genetics, and pathophysiology.

For a general phenotypic description and a discussion of genetic heterogeneity of X-linked lymphoproliferative syndrome, see XLP1 (308240).

Clinical Features

Rigaud et al. (2006) reported 12 male patients from 3 unrelated families with XLP2. Eight patients from 2 unrelated families were diagnosed in the first years of life. In the third family, 2 brothers were diagnosed at ages 20 years and 0.5 years, and they both died of HLH at diagnosis; their nephew was diagnosed at age 22 years. Eleven of 12 patients had hemophagocytic lymphohistiocytosis, which was associated with Epstein-Barr virus (EBV) infection in 8 patients. Four patients had hypogammaglobulinemia, 2 developed inflammatory bowel disease (IBD), and 9 patients had hepatosplenomegaly. There was no gross abnormality in lymphocyte cell population in these patients, although flow cytometry studies showed that the patients had low levels of NKT cells, and patient lymphocytes were more susceptible to apoptotic stimuli, which could be rescued by expression of XIAP. In all, 4 patients died at ages 6 months, 11 years, 20 years, and 41 years, respectively. Female carriers were unaffected. Rigaud et al. (2006) noted that the clinical phenotype of patients with XLP2 was similar to that observed in patients with XLP1, although patients with XLP2 often had splenomegaly, which was the first clinical manifestation of their condition.

Worthey et al. (2011) reported a boy who presented at 15 months of age with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistula, consistent with a Crohn disease (see 266600)-like illness. The age and severity suggested an underlying immune defect, but despite comprehensive clinical evaluation a definitive diagnosis was not obtained. Whole-exome sequencing identified a cys-to-tyr substitution at a highly conserved cysteine residue in the XIAP gene (300079.0004). This protein was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD (605980) signaling pathway. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At more than 42 days posttransplant the child was able to eat and drink and there had been no recurrence of gastrointestinal disease, suggesting that the mutation also drove the gastrointestinal disease.

Yang et al. (2012) reported 9 Japanese boys from 6 unrelated families with XLP2 confirmed by genetic analysis. Three of the patients had previously been reported (Pachlopnik Schmid et al., 2011; Zhao et al., 2010). Eight of the patients presented between 2 months and 2 years of age with disease symptoms. Five had recurrent HLH, fever, splenomegaly, and cytopenia. EBV infection was found in 4 patients, all of whom had HLH, and hypogammaglobulinemia was found in 2 patients. Other common features included fever, cytopenia, and splenomegaly. Most patients with HLH were treated with corticosteroids with or without cyclosporin A to prevent a rapidly fatal disease course. Two patients presented with colitis; one of these was the maternal uncle of the family's proband, and died at age 4 before the diagnosis of XLP2. There was some variability: 1 patient (patient 4) was a 15-year-old boy with recurrent infections and hypogammaglobulinemia without additional symptoms, whereas another patient (patient 3.2) was asymptomatic at age 17 years, although his brother presented at age 2 months and had EBV-associated recurrent HLH and most features of the disorder. None of the patients developed lymphoma. The patients had decreased levels of a specific type of NKT cells within the CD3+ T cell compartment that express an invariantly rearranged T-cell receptor consisting of TCRV-alpha-24 and TCRV-beta-11 chains (iNKT cells).

In a follow-up study of Yang et al. (2012), Nishida et al. (2015) identified 8 additional patients with XLP2 from 6 Japanese families. Six patients from 4 families had typical features of the disorder, including recurrent HLH (5 patients), splenomegaly (2 patients), and/or colitis (2 patients). The onset of symptoms was highly variable, ranging from 1 month to 12 years; at the time of the report, the ages of the patients ranged from 2 to 47 years. Including the previously reported patients, Nishida et al. (2015) found that 3 had reduced numbers of CD19+ switched B cells. Patient cells showed increased AICD of T lymphocytes compared to controls.

Dziadzio et al. (2015) reported a large Caucasian family with XLP2, including 6 affected males. There was wide phenotypic variability. Four males had colitis with onset ranging from infancy to age 12, 5 had skin involvement, including boils and erythema nodosum (EN), and 3 had recurrent infections (V.20, V.22, and V.24), mainly respiratory. Only 2 patients (V.22 and V.25) had features consistent with HLH, and 3 were positive for EBV (V.20, V.22, and V.24). Three boys died at ages 2, 12, and 16 years (V.25, V.24, and V.19, respectively), including 1 who died after a bone marrow transplant. The least severely affected male (V.22) was a 30-year-old man who had 1 episode of an unusual febrile illness at age 15 and had recurrent respiratory infections, chronic acne, and folliculitis. Six of 7 female carriers were affected to varying degrees with erythema nodosum (EN) and/or variable bowel symptoms, including IBD and irritable bowel syndrome.

Yang et al. (2015) reported a Japanese family in which 3 sibs, 2 boys and a girl, had manifestations of XLP2. The boys were more severely affected, but all 3 had pancytopenia, fever, and evidence of EBV infection. The boys had splenomegaly. The boys developed HLH in infancy and at age 5 years, respectively, whereas the girl presented at age 7 years with pancytopenia but did not completely fulfill the criteria for HLH, and was considered to have 'incomplete HLH.' None had hypogammaglobulinemia. Genetic studies showed that the boys were hemizygous for a truncating mutation in the XIAP gene, and the mother and daughter were heterozygous for the mutation. X-chromosome inactivation studies in the daughter showed a highly skewed pattern, with preferential expression of the mutant allele and nonrandom inactivation of the paternal wildtype allele in peripheral blood and hair root cells. The asymptomatic mother, who was heterozygous for the mutation, had a random pattern of X-inactivation. Cells from all 3 affected sibs showed decreased XIAP protein expression, impaired NOD2 (605956) signaling with decreased production of TNF-alpha (TNFA; 191160), and augmented AICD of peripheral blood mononuclear cells (PBMC). The patients also had marked elevation of serum IL18 (600953).

Clinical Variability

Nishida et al. (2015) reported 3 unrelated Japanese boys with dysgammaglobulinemia associated with a specific mutation in the XIAP gene (glu349del; 300079.0005). One of the patients had previously been reported by Yang et al. (2012) (patient 4). These patients had recurrent infections and hypogammaglobulinemia without additional symptoms, specifically no HLH or colitis, although 1 developed aplastic anemia and required a hematopoietic stem cell transplant. Patient cells showed normal XIAP expression, but 2 patients had decreased numbers of CD19+ switched B cells. Patient cells did not showed increased AICD of T lymphocytes compared to controls. Microarray analysis indicated that the gene expression patterns were different in patients with the E349del mutation compared to patients with other mutations in the XIAP gene. Patients with E349del had 10-fold lower expression of a number of genes, including those involved in B cell development and Ig levels.

Inheritance

The transmission pattern of XLP2 in the families reported by Rigaud et al. (2006) and Worthey et al. (2011) was consistent with X-linked recessive inheritance.

The transmission pattern of XLP2 in the family reported by Dziadzio et al. (2015) was consistent with X-linked dominant inheritance with a less severe phenotype in females compared to males.

Molecular Genetics

In affected members, all males, of 3 families with XLP2, Rigaud et al. (2006) identified hemizygous mutations of the XIAP gene. One family carried a deletion of the cytidine at nucleotide 291 (300079.0001), one a premature termination mutation (300079.0002), and the third a deletion encompassing exon 2 (300079.0003). The mothers of affected individuals were asymptomatic heterozygous carriers. The mutations were found by linkage analysis followed by candidate gene sequencing. Patient lymphocytes showed absence of the XIAP protein.

Worthey et al. (2011) identified a missense mutation of a highly conserved cysteine in the XIAP gene (C203Y; 300079.0004) in a boy with XLP2 manifest as intractable inflammatory bowel disease. His asymptomatic mother carried the mutation; she had evidence of skewed X-inactivation in NK, B, and T helper cells. Functional assays of patient peripheral mononuclear cells showed an increased susceptibility to AICD and defective responsiveness to NOD2 (605956) ligands, consistent with loss of normal XIAP function in apoptosis and NOD2 signaling.

In 9 Japanese male patients from 6 unrelated Japanese families with XLP2, Yang et al. (2012) identified 6 different truncating mutations in the XIAP gene (see, e.g., 300079.0005-300079.0007). The mutations were found by direct screening of the XIAP gene after exclusion of mutations in the SH2D1A gene (300490). The mothers of patients from families 1 through 5 were heterozygous carriers of the mutations, whereas the mother of 2 sibs (family 6) did not carry the mutation in peripheral blood, suggesting germline mosaicism. Flow cytometric analysis of patient lymphocytes showed decreased XIAP expression in 7 of 8 patients; low-normal expression was found in a patient (patient 4) with an in-frame deletion mutation (E349del; 300079.0005) and a milder phenotype with only hypogammaglobulinemia and recurrent infections. The expression pattern of XIAP in carrier mother cells was variably reduced or showed a bimodal pattern. Western blot analysis, performed on 3 patients, showed decreased XIAP levels.

In 6 affected males from a large Caucasian family with XLP2, Dziadzio et al. (2015) identified a truncating mutation in the XIAP gene (300079.0008). There were 7 female carriers, 6 of whom were symptomatic to varying degrees. Flow cytometric analysis of peripheral cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2, with decreased TNF-alpha (191160) production. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers revealed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and EN had random X-inactivation, resulting in expression of the mutated XIAP protein in her monocytes and impaired NOD2 responses in vitro. These findings indicated that the pattern of X-inactivation can influence the phenotype in female carriers. The findings also indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased AICD of patient-derived T-cell blasts in vitro, suggesting that the mutation also affected the antiapoptotic properties of XIAP.

Population Genetics

The incidence of mutations in XIAP leading to XLP2 is estimated to be 1 to 2 cases per million live births (review by Latour and Aguilar, 2015).

Animal Model

In a review, Latour and Aguilar (2015) noted that studies have shown that certain strains of Xiap-deficient mice have compromised immunity leading to decreased survival when infected with certain pathogens, including intracellular bacteria and viruses. These infections are associated with splenomegaly and compromised innate immunity with altered cytokine production.