Hyperimmunoglobulin M syndromes

INTRODUCTION — The hyperimmunoglobulin M (hyper-IgM or HIGM) syndromes include a heterogeneous group of conditions characterized by defective class-switch recombination (CSR), resulting in normal or increased levels of serum IgM associated with deficiency of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) and poor antibody function [1]. Hyper-IgM syndrome includes several genetically determined diseases [2,3] but may also be secondary to congenital rubella syndrome [4], use of phenytoin, T cell leukemia, or lymphomas [1]. This topic review discusses in detail only genetically determined forms of hyper-IgM syndrome. (See "Congenital rubella".)

EPIDEMIOLOGY — All forms of hyper-IgM syndrome are rare. The estimated frequency of CD40 ligand (CD40L) deficiency is 2:1,000,000 males [5]. Although no data are available on the frequency of activation-induced cytidine deaminase (AID) deficiency, this disorder is estimated to affect fewer than 1:1,000,000 individuals. In contrast, there are only a few reported cases of CD40 [6-9] and uracil N-glycosylase (UNG) [10] deficiencies. There is parental consanguinity in several families with autosomal recessive forms of hyper-IgM syndrome. (See 'Genetics' below.)

PATHOGENESIS — Maturation of antibody responses is marked by a series of events that include (see "Immunoglobulin genetics"):

●Class-switch recombination (CSR; also called class-switching), whereby the immunoglobulin mu heavy chain is replaced by other heavy chain isotypes with distinct biologic properties, resulting in production of immunoglobulin isotypes other than IgM

●Somatic hypermutation (SHM), by which somatic mutations are introduced in the variable region of actively transcribed immunoglobulin genes, thereby allowing production of high-affinity antibodies

●Generation of memory B cells

Costimulatory signals provided by T cells play a critical role during CSR. Activated CD4+ follicular helper T cells express CD40 ligand (CD40L; or CD154) and secrete various cytokines upon antigen recognition. Cytokines released by activated CD4+ T cells bind to cognate receptors expressed on the surface of B cells and prompt CSR to specific immunoglobulin isotypes [2,11]. CD40L binds CD40 that is constitutively expressed by B cells. CD40 ligation in B cells promotes activation of tumor necrosis factor receptor-associated factor (TRAF) molecules and the nuclear factor kappa B (NFkB) signaling pathway, allowing expression of NFkB-dependent genes, such as the activation-induced cytidine deaminase (AICDA) gene [12]. Activation-induced cytidine deaminase (AID) [13] and uracil N-glycosylase (UNG) [10] are two enzymes involved in CSR. Mismatched repair (MMR) proteins, including the postmeiotic segregation increased 2 (PMS2) protein, are also involved in the process [14]. Finally, the INO80 complex is a chromatin remodeler that is involved in conformational modifications of the immunoglobulin locus required during CSR and interacts with AID [15]. Consistent with this function, autosomal recessive INO80 deficiency is characterized by reduced IgG and IgA levels and increased serum IgM [15].

AID also initiates SHM, with deamination of cytidine residues in the variable region of immunoglobulin genes [16].

All forms of hyper-IgM syndrome are characterized by defective CSR. Impaired CSR in hyper-IgM syndromes is due to intrinsic B cell abnormalities or defects that involve several types of immune cells. This difference in the pathogenesis accounts for the distinctive clinical features in the various forms of hyper-IgM syndrome. Most forms of hyper-IgM also have impairment of SHM, with production of low-affinity antibodies (table 1) [2,3].

In particular, CD40LG (encoding for CD40L) [17-21] and CD40 [6] mutations affect the interaction between activated CD4+ T cells and cell types expressing CD40 (B cells, dendritic cells, monocyte/macrophages, platelets, activated endothelial and epithelial cells). Thus, impairment of CSR in these disorders is part of a broader spectrum of immunologic abnormalities that also includes defective T cell priming and impaired antigen-specific T cell responses, resulting in a combined immunodeficiency phenotype. In contrast, AICDA (encoding for AID) [13] and UNG [10] mutations uniquely affect B cell function and hence represent the prototypes of intrinsic B cell abnormalities of CSR. AID plays a role in B cell tolerance [22]. CD40L deficiency is also known as HIGM1, AID deficiency as HIGM2, CD40 deficiency as HIGM3, and UNG deficiency as HIGM5. No specific molecular defect has been identified yet in HIGM4. Finally, a hyper-IgM phenotype may also be seen in other, more complex immunodeficiencies, such as activated PI3-kinase delta syndrome type 1 (APDS1, due to activating mutations of the PIK3CD gene) and type 2 (APDS2, due to mutations of the PIK3R1 gene).

Mutations of the IKBKG gene (encoding for IKK-gamma/NFkB essential modulator [NEMO], a regulatory component of the NFkB signaling pathway) affect the NFkB signaling pathway in a variety of cell types and are responsible for X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID), whose phenotype may also include impaired CSR [23-25]. A similar phenotype can also be seen in patients with gain-of-function mutations in the NFKBIA gene, encoding for IkB-alpha [26]. Defective CSR also occurs in patients with deficiency of PMS2 [14], a disorder characterized by an increased risk of malignancies in childhood. Finally, CSR is defective in other diseases associated with impairment of deoxyribonucleic acid (DNA) repair, such as ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) [27]. In some cases, patients with these diseases may show immunoglobulin abnormalities similar to those seen with hyper-IgM syndrome. (See 'Differential diagnosis' below and "Syndromic immunodeficiencies" and "Ataxia-telangiectasia" and "Nijmegen breakage syndrome".)

CLASSIFICATION OF IEI — In the classification of inborn errors of immunity (IEI) by the International Union of Immunological Societies [28], activation-induced cytidine deaminase (AID), uracil N-glycosylase (UNG), INO80, and mutator S homolog 6 (MSH6) deficiencies are included among the "predominantly antibody deficiencies" category. By contrast, CD40LG and CD40 deficiency are listed among the "immunodeficiencies affecting cellular and humoral immunity" (combined immunodeficiencies) to indicate a broader defect of immunity that also affects crosstalk between T cells and cell types other than B cells (eg, monocytes, dendritic cells). Other conditions such as NFkB essential modulator (NEMO; IKBKG), I-kappa-B alpha (IKBA), and postmeiotic segregation increased 2 (PMS2) deficiency fall under the category of "combined immunodeficiencies with associated or syndromic features."

GENETICS — A list of gene defects that cause hyper-IgM syndromes is presented in the table (table 1). The most common form of hyper-IgM syndrome is inherited as an X-linked trait and is due to mutations of the CD40LG gene, also known as TNFSF5, which encodes CD40 ligand (CD40L). Carrier females of X-linked hyper-IgM syndrome (also known as hyper-IgM syndrome type 1 [HIGM1]; MIM #308230) are clinically healthy. Exceptional occurrence of the disease has been observed in females as a result of extreme lyonization [29] (see "Genetics: Glossary of terms", section on 'X-inactivation'), which may be the consequence of chromosomal translocation involving the CD40LG gene [30].

Activation-induced cytidine deaminase (AID) deficiency (also known as HIGM2; MIM #605258) is the second most common form of hyper-IgM syndrome and is inherited as an autosomal recessive trait. However, autosomal dominant inheritance has been reported in four families with a nonsense mutation in the AICDA gene that affected the C-terminus of the AID protein [31-33]. Uracil N-glycosylase (UNG) deficiency (MIM #608106) [10], CD40 deficiency (HIGM3; MIM #606843) [6], INO80 deficiency (MIM #610169) [15], and mutator S homolog 6 (MSH6) deficiency also have autosomal recessive inheritance.

In addition to these genetically defined forms, there is one variant of defective class-switch recombination (CSR) downstream from switch (S) region DNA cleavage (also known as HIGM4; MIM 608184) [34] whose molecular basis remains unknown.

CLINICAL MANIFESTATIONS — The clinical phenotypes of hyper-IgM syndromes vary depending upon the nature of the genetic defect. CD40 ligand (CD40L) and CD40 deficiencies are combined immunodeficiencies, whereas activation-induced cytidine deaminase (AID), uracil N-glycosylase (UNG), and INO80 deficiencies are humoral immunodeficiencies. (See "Combined immunodeficiencies: An overview" and "Primary humoral immunodeficiencies: An overview".)

CD40 ligand (CD40L) or CD40 deficiency — CD40L deficiency, which is inherited as an X-linked trait, is the most common form of hyper-IgM syndrome. Patients with CD40L or CD40 deficiency share similar features because these disorders affect the interaction between activated CD4+ T cells expressing CD40L and cell types expressing CD40 (B cells, dendritic cells, monocytes/macrophages, platelets, and activated endothelial and epithelial cells). Here, we will refer to reports pertaining to CD40L-deficient patients because only a few CD40-deficient patients have been described [6,7,35-38].

CD40L deficiency often presents in infancy with increased susceptibility to recurrent sinopulmonary infections (eg, pneumonia, sinusitis, and otitis media), primarily caused by encapsulated bacteria (eg, Streptococcus pneumoniae and Haemophilus influenzae) [5,39-41]. In addition, opportunistic infections, particularly with Pneumocystis, Cryptosporidium, and Histoplasma organisms, are common and may occur in the first few months of life. Pneumocystis jirovecii pneumonia, for example, is reported in approximately 40 percent of patients [5,39] and may represent the first clinical finding.

Chronic or protracted diarrhea occurs in one-third of patients [5,39,40], often beginning in infancy or early childhood, and may lead to failure to thrive. Infection with the parasite Cryptosporidium parvum is common and is associated with an increased risk of biliary tract disease. C. parvum infection was reported in 21 and 60 percent of CD40L-deficient patients who developed chronic diarrhea in the United States [5] and Europe [39], respectively. Sclerosing cholangitis may occur at any age and was reported in 6 [5] and 20 [39] percent of patients in the United States and European series, respectively. The different frequency of C. parvum infection and biliary tract disease in these series may reflect differences in the levels of Cryptosporidium oocysts in water supplies in these regions.

Liver disease in patients with CD40L deficiency may also be secondary to cytomegalovirus (CMV) infection. Cirrhosis and cholangiocarcinoma represent two frequent complications of Cryptosporidium and CMV infection in patients with CD40L deficiency and may occur at any age, including childhood [42,43].

Children and adults with CD40L deficiency are at higher risk for Cryptococcus and Toxoplasma infections that may affect the central nervous system [39,44,45]. Enteroviral meningoencephalitis and progressive multifocal leukoencephalopathy due to JC virus have also been described [5,46,47]. Among bacterial infections, cellulitis, sepsis, and osteomyelitis have been reported. Aphthous stomatitis is common.

CD40L deficiency is associated with an increased risk of malignancies, including hepatocarcinoma, cholangiocarcinoma, and peripheral neuroectodermal tumors of the gastrointestinal tract and the pancreas [5,39,42,48]. Lymphomas have also been reported [49]. These tumors may occur at any age, including childhood. (See "Malignancy in inborn errors of immunity".)

Autoimmune manifestations are observed in a minority of CD40L-deficient patients and include inflammatory bowel disease and cytopenias. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency" and "Gastrointestinal manifestations in primary immunodeficiency".)

Osteopenia, with onset in childhood, is another feature of CD40L deficiency and may lead to spontaneous fractures [50].

AID deficiency — The clinical phenotype of activation-induced cytidine deaminase (AID) deficiency is marked by recurrent sinopulmonary infections, mostly due to encapsulated bacteria [13,51,52]. Development of bronchiectasis and chronic sinusitis prior to initiation of immune globulin replacement therapy has been reported in some patients [52]. Meningitis, cellulitis, lymphadenitis, and infections of the gastrointestinal tract (especially due to viruses and to Giardia lamblia) are also reported.

The median onset of symptoms is two years of age [52], but the diagnosis of an immunodeficiency is often delayed by a decade or two [51,52].

Lymphoid hyperplasia is a distinctive feature of AID deficiency not seen in CD40L deficiency that is characterized by paucity of lymphoid and tonsillar tissue [40]. Tonsillar hypertrophy is often prominent and may prompt tonsillectomy.

Autoimmune complications occur in approximately 20 percent of patients with AID deficiency and include cytopenias, hepatitis, inflammatory bowel disease, and arthritis [51,52]. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency" and "Gastrointestinal manifestations in primary immunodeficiency".)

UNG deficiency and HIGM4 — The few patients identified with uracil N-glycosylase (UNG) deficiency have a clinical phenotype that resembles that of AID deficiency [10]. Patients with hyper-IgM syndrome type 4 (HIGM4) also have clinical manifestations similar to, but slightly milder than, AID deficiency [34]. Autoimmune manifestations would also be expected in patients with UNG deficiency, but they have not yet been described in the small number of patients identified so far.

INO80 deficiency — Two unrelated patients with INO80 deficiency were reported in the literature [15]. Both patients manifested recurrent bacterial infections. Total T and B cell counts were normal, but the number of switched memory B cells was low. The rate of somatic hypermutation within the IgM isotype was normal, but stimulation of B cells with CD40L plus interleukin (IL) 4 failed to induce class switch to IgE in vitro. Molecular investigations demonstrated that the class-switch recombination (CSR) defect was associated with impaired repair at the switch regions of the immunoglobulin heavy-chain locus.

MSH6 deficiency — Mutator S homolog 6 (MSH6) deficiency is an autosomal recessive disorder characterized by partial impairment of CSR and abnormalities of somatic hypermutation (SHM) [53]. Consistent with a role of MSH6 in DNA mismatched repair (MMR), patients with MSH6 deficiency have defective DNA damage repair upon cell irradiation and are highly prone to various forms of cancer. However, they do not manifest increased susceptibility to severe bacterial infections in spite of a partial defect of CSR and mildly decreased serum IgG levels, along with elevated IgM, in some patients.

LABORATORY ABNORMALITIES — A B cell defect is seen in all forms of hyper-IgM. Patients with CD40 ligand (CD40L) deficiency also have a T cell defect, and patients with CD40 deficiency have an additional dendritic cell/monocyte defect. Laboratory abnormalities typically seen in hyper-IgM syndromes include:

●Markedly reduced serum levels of IgG, IgA, and IgE

●Normal or elevated levels of serum IgM

●Lack of antibody response to protein (tetanus, diphtheria, and Haemophilus influenzae B) and polysaccharide (S. pneumoniae) antigens [54]

●Normal number of total B cells, but markedly reduced number of memory (CD27+) B cells [55] and absence of switched memory (IgD-CD27+) B cells

These abnormalities are observed both in patients with CD40L (or CD40) deficiency and in patients with activation-induced cytidine deaminase (AID), uracil N-glycosylase (UNG), and INO80 deficiency. However, newborns and young infants (less than four months of age) may have residual levels of serum IgG of maternal origin. In addition, residual IgG production is often present in patients with hyper-IgM syndrome type 4 (HIGM4). Occasionally, patients with CD40L deficiency may have normal or even increased IgA serum levels [39], possibly as the result of CD40-independent, Toll-like receptor-dependent activation of B cells [56].

Although these disorders are collectively known as hyper-IgM syndrome, serum levels of IgM are normal or even decreased in approximately 50 percent of patients with CD40L deficiency at diagnosis [39].

Neutropenia occurs in two-thirds of CD40L-deficient patients [39,40] and may contribute to infections. It is often chronic, but recurrence of neutropenia, without defined periodicity, has also been observed. Bone marrow examination may show a maturational arrest at the promyelocyte stage [39]. Anemia is reported in 15 to 32 percent and thrombocytopenia in 4 percent of patients [5,39,57].

In addition, patients with CD40L deficiency typically present with the following immunologic abnormalities:

●Impairment of delayed-type hypersensitivity reactions in vivo to recall antigens in most patients [1,58] (see "Laboratory evaluation of the immune system", section on 'Cutaneous delayed-type hypersensitivity')

●Reduced in vitro T cell proliferation to recall antigens in approximately 60 percent of patients [39], whereas in vitro proliferation to mitogens (eg, phytohemagglutinin [PHA]) is normal (see "Laboratory evaluation of the immune system", section on 'T cell function proliferation assays')

●Reduced production of T helper cell type 1 (Th1) cytokines upon in vitro activation of peripheral blood mononuclear cells with anti-CD3 or superantigens [58-60]

●Lack of germinal centers (or presence of abortive germinal centers) in peripheral lymphoid tissue [61]

●Impaired differentiation and activation of dendritic cells in response to Candida and other intracellular pathogens [62]

●Defective killing activity and reduced oxidative burst of macrophages [63]

●Impaired respiratory burst and microbicidal activity of neutrophils [64]

The reduced antigen-specific T cell responses in vitro and in vivo and the poor production of Th1 cytokines upon T cell activation are also observed in patients with CD40 deficiency [65] and reflect defective cross-talk between activated CD4⁺ T cells and dendritic cells/macrophages [60].

In contrast, no defects in T cell responses are observed in patients with AID or UNG deficiency. In addition, expansion of germinal centers is observed in peripheral lymphoid tissue from these patients [13].

Evaluation of possible defects of somatic hypermutation (SHM) requires measurement of the affinity of antibody responses or molecular analysis of immunoglobulin transcripts. Both of these require sophisticated tests that are not readily available.

Patients with HIGM4 have residual IgG production [34].

WHEN TO REFER — Children with recurrent infections are typically evaluated for an immunodeficiency. Initial screening studies, including quantitative immunoglobulins and a complete blood count with differential, can be sent by primary care clinician, but other studies are usually performed by a specialist. Abnormal results should prompt referral to a clinician who specializes in inborn errors of immunity (primary immunodeficiencies). (See "Approach to the child with recurrent infections", section on 'Laboratory evaluation' and "Laboratory evaluation of the immune system", section on 'Initial approach to the patient' and 'Laboratory abnormalities' above.)

DIAGNOSIS — The diagnosis of hyper-IgM syndrome should be suspected in patients with appropriate clinical features (see 'Clinical manifestations' above), low levels of IgG and IgA, and normal to increased levels of serum IgM. Patients with these clinical and laboratory findings should have flow cytometry for lymphocyte populations (T, B, and natural killer [NK] cell subsets) as well as determination of the numbers of B cells in various stages of development (naïve, memory, switched memory). Male patients over six months of age should also have analysis for CD40 ligand (CD40L) expression on the surface of in vitro activated T cells. Definitive confirmation of the diagnosis, both for CD40L deficiency and for other forms of hyper-IgM syndrome, requires genetic testing. A list of laboratories offering testing for hyper-IgM (including protein expression, sequence analysis, prenatal diagnosis, and carrier testing) can be found at the Genetic Testing Registry (GTR). (See 'Laboratory abnormalities' above and "Laboratory evaluation of the immune system", section on 'Flow cytometry for cell populations' and "Laboratory evaluation of the immune system", section on 'Advanced tests' and "Laboratory evaluation of the immune system", section on 'T cell function proliferation assays' and "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'Defects in B cell function'.)

CD40L deficiency — The diagnosis of X-linked hyper-IgM (CD40 ligand [CD40L] deficiency) is almost certain in males with opportunistic infections and the characteristic profile of low serum levels of IgG and normal or high serum levels of IgM. In newborns and infants younger than six months of age, the diagnosis of CD40L deficiency is primarily based upon genetic testing since reduced ability to express CD40L can occur in CD4+ lymphocytes from patients in this age group [66,67]. However, confirmatory flow cytometry-based testing should still be obtained if genetic testing is performed first. Confirmation of diagnosis in older children is based upon demonstration of impaired expression of CD40L on the surface of CD4+ T cells upon in vitro activation [5,68]. Typically, this is achieved by activating peripheral blood mononuclear cells overnight with phorbol myristate acetate (PMA) and ionomycin, followed by staining for CD40L using anti-CD40L monoclonal antibodies and gating on CD8-negative cells. (See "Flow cytometry for the diagnosis of primary immunodeficiencies", section on 'Hyperimmunoglobulin M syndrome'.)

Simultaneous staining for other T cell activation markers (CD69, CD25) must be performed to confirm proper in vitro activation. This is important when considering other conditions in the differential diagnosis, such as common variable immunodeficiency (CVID) (see 'Differential diagnosis' below). In addition, gating on CD8-negative cells is preferred over gating on CD4+ lymphocytes when assessing CD40L expression on activated lymphocytes because downregulation of CD4 expression that is typically observed upon in vitro activation might otherwise confound interpretation of the results.

In most cases, use of anti-CD40L monoclonal antibodies readily allows identification of CD40L-deficient patients. However, some mutations permit low-level cell surface expression of a nonfunctional CD40L on activated T cells [69]. Thus, patients whose clinical and immunologic phenotype is strongly suggestive for CD40L deficiency, but in whom staining with anti-CD40L monoclonal antibody is normal, should be analyzed by flow cytometry using biotinylated CD40-Ig chimeric construct (followed by reaction with fluorochrome-labeled streptavidin) or monoclonal antibodies directed against the CD40-binding epitope [69]. In addition, some CD40LG mutations affect the intracytoplasmic tail of CD40L without disturbing cell surface expression and CD40 binding; in such cases, the diagnosis is ultimately achieved by mutation analysis.

Final confirmation of CD40L deficiency requires genetic testing. A variety of missense, nonsense, splice-site mutations, insertions, and deletions throughout the CD40LG gene have been reported, with only a few mutational hotspots [57,67,69,70].

CD40 deficiency — In patients with possible CD40 deficiency (eg, clinical and immunologic presentation consistent with CD40L deficiency occurring in a female or in a male with normal CD40L), the diagnosis is confirmed by analyzing CD40 expression on the surface of B cells and monocytes [6,9]. Flow cytometry can be applied on freshly isolated peripheral blood mononuclear cells without further manipulation because these cells constitutively express CD40. Most patients described with this rare form of hyper-IgM syndrome have complete lack of CD40 expression at the cell surface; however, residual expression of a mutant molecule has been reported. Genetic testing ultimately permits definitive confirmation.

AID, UNG, or INO80 deficiencies or HIGM4 — Confirmation of the diagnosis of activation-induced cytidine deaminase (AID) deficiency (also known as hyper-IgM syndrome type 2 [HIGM2]), uracil N-glycosylase (UNG) deficiency (HIGM5), or INO80 deficiency is based upon genetic testing. The molecular basis of HIGM4 remains unknown. Thus, confirmatory testing is not available for HIGM4.

DIFFERENTIAL DIAGNOSIS — Hyper-IgM can be seen in patients with other immunodeficiencies, such as activated nuclear factor kappa B (NFkB) essential modulator (NEMO; IKBKG) deficiency, I-kappa-B alpha (IKBA) deficiency, PI3K-delta syndrome (APDS), mutations of the postmeiotic segregation increased 2 (PMS2) gene, ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS), and common variable immunodeficiency (CVID). Hypomorphic mutations in recombination-activating gene 2 (RAG2) can also cause a combined immunodeficiency that may rarely present with a clinical and immunologic phenotype similar to hyper-IgM syndrome [71]. In addition, there are rare reports of acquired forms of hyper-IgM associated with congenital rubella syndrome, phenytoin therapy, T cell leukemia, lymphoma, and nephrotic syndrome [1]. (See 'Pathogenesis' above.)

NEMO deleted exon 5 autoinflammatory syndrome (NDAS) — Germline mutations in the IKBKG gene that result in overexpression of a mutant isoform of NEMO lacking the domain encoded by exon 5 were reported in three males with an autoinflammatory phenotype [72]. The exon 5-deleted NEMO isoform failed to associate with TANK-binding kinase 1 (TBK1), causing impaired NFkB activation in fibroblasts in response to Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I) like receptor stimulation. By contrast, T cells, monocytes, and macrophages expressed a strong interferon (IFN) gamma and NFkB signature, with excess type I IFN production. The mechanism underlying this exaggerated inflammatory response was represented by increased stabilization of the inducible IKK protein (IKKi) kinase by the exon 5-deleted NEMO protein. Clinical manifestations included recurrent fevers, nodular skin rash evolving to panniculitis, optic neuritis, central nervous system bleeding, and hepatosplenomegaly.

I-kappa-B alpha (IKBA) deficiency — Heterozygous, gain-of-function mutations in IKBA cause a phenotype similar to NEMO deficiency, with increased susceptibility to infections, ectodermal dystrophy, and colitis [26,73-75]. (See "Syndromic immunodeficiencies".)

APDS/PASLI and APDS2 — Phosphatidylinositol 3-kinase (PI3K, also called phosphoinositide 3-kinase) activates mammalian (mechanistic) target of rapamycin (mTOR) and AKT (a murine thymoma viral oncogene homolog and protein kinase) signaling pathways that control T cell metabolism, proliferation, and effector function [76]. Activated PI3K-delta syndrome (APDS) or PASLI disease (p110-delta-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency; MIM #615513) is due to heterozygous gain-of-function mutations of the phosphatidylinositol 3-kinase, catalytic, delta (PIK3CD) gene that encodes the p100-delta subunit of PI3K [77-80]. A similar disorder is observed in families with heterozygous splice-site mutation of the phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1) gene that encodes the p85-alpha negative regulatory subunit of PI3K, termed APDS2 [81,82]. These syndromes have autosomal dominant inheritance, although sporadic occurrence due to de novo mutations is also possible in both conditions.

These defects cause increased PI3K signaling, altered intracellular metabolism, and activation of mTOR and AKT intracellular signaling pathways involved in regulation of the cell cycle [83]. Most patients with APDS have low IgA and IgG levels (particularly IgG2), high IgM levels, low specific antibody titers, decreased circulating T and B cells, and impaired CD8+T and NK cell cytotoxicity [77-80]. The proportion of transitional B cells (CD21^low CD38^hi) is increased, and there are reduced numbers of memory B cells (CD27+), especially those that are class switched due to defective class-switch recombination (CSR). The number of naïve CD4+ and CD8+ T cells is reduced, and there is an increased proportion of effector memory T cells and of T cells expressing markers of senescence (CD57+). In addition, there is increased activation-induced cell death of T cells. In vitro T and B cell proliferation is impaired. Elevated levels of serum IgM and reduced proportion of switched memory B cells are features that are shared by APDS and hyper-IgM syndromes. However, demonstration of an increased proportion of memory T cells (CD45RO+), many of which express markers of senescence, and association with severe and progressive lung disease are typical features of APDS that may help in differentiating APDS from hyper-IgM syndromes.

Patients with APDS disease have recurrent sinopulmonary infections with progressive airway damage and bronchiectasis, lymphadenopathy, nodular lymphoid hyperplasia in mucosal tissues, increased incidence of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) viremia and EBV-related lymphoma, progressive lymphopenia, elevated serum IgM, and impaired antibody responses [77-79,81,82]. Skin and oral abscesses, splenomegaly, and herpes group virus infections have also been reported [77,84]. Primary sclerosing cholangitis was reported in two adult patients [85]. A similar phenotype is observed in patients with APDS2 [81,82]. Some patients identified with APDS were previously diagnosed with hyperimmunoglobulin M syndrome (HIGM). Both APDS and APDS2 are categorized as forms of common variable immunodeficiency (CVID) by the International Union of Immunological Societies (IUIS) [86]. (See "Pathogenesis of common variable immunodeficiency", section on 'Genetics'.)

Both leniolisib, an oral small molecule that blocks the active binding site of PI3K-delta, and sirolimus (rapamycin), an mTOR inhibitor that can partially restore natural killer (NK) cell cytotoxicity, are first-line options for treatment of APDS. There are no high-quality randomized trials or studies that have compared these two different treatments directly, but limited low-quality data and clinical experience suggest that both drugs improve clinical outcomes. Drug availability and tolerability (including monitoring of side effects and drug-related toxicity) may favor one or the other line of treatment in individual patients. Immune globulin replacement therapy, antimicrobial prophylaxis, surveillance of CMV and EBV viremia, and use of anti-CMV drugs and of rituximab, when indicated, are also part of the mainstays of treatment. Hematopoietic cell transplantation (HCT) is typically reserved for patients with treatment-refractory APDS and in those with serious complications (eg, lymphoma, life-threatening infection).

A targeted therapy, leniolisib, was approved by the US Food and Drug Administration in 2023 for patients ≥12 years of age with APDS [87]. In a phase-III trial of 31 patients aged 12 to 54 years with APDS who were randomly assigned 2:1 to leniolisib 70 mg twice daily or placebo for 12 weeks, patients on leniolisib had a greater decrease in size of the index lymph nodes, a proxy for immune dysregulation, and increase in percentage of naïve B cells, a proxy for immunodeficiency compared with placebo (difference in adjusted mean change -0.25, 95% CI -0.38 to -0.12 and 37.30, 95% CI 24.06-50.54, respectively) [88]. A greater reduction in spleen volume and improvement in other immune cell subsets was also seen in the leniolisib group compared with placebo. Adverse events, including headache, nausea, and sinusitis, were common but mostly mild in both groups. Mild, transient neutropenia was reported in four patients on leniolisib. No longer-term data are available.

Patients with APDS or with APDS2 may also benefit from treatment with sirolimus, which was associated with partial restoration NK cell function, nearly full restoration of T cell function, and improvement the clinical course in case series [78,80].

Nine of 26 patients in one series underwent HCT with reduced-intensity conditioning, with all but one patient eventually achieving donor engraftment despite frequent complications and initial engraftment failure in a third of patients [89]. Outcomes are better if human leukocyte antigen (HLA) matched donors are used. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

The prognosis of APDS/PASLI and of APDS2 prior to available treatments was largely determined by the severity and progression of lung disease and by the occurrence of EBV-related lymphoma. Patients can survive into adulthood. However, without treatment, most patient have persistent symptoms and life-threatening lymphoproliferation, and/or infections are common [89]. No long-term data on prognosis for patients who are on treatment or who have undergone transplantation are available.

PMS2 deficiency — Postmeiotic segregation increased 2 (PMS2) is a protein involved in mismatch DNA repair (MMR). Monoallelic PMS2 germline mutations are associated with Lynch syndrome, whereas biallelic mutations contribute to the majority of cases of constitutional mismatch repair deficiency (CMMRD), a rare condition associated with cancer in childhood [90]. MMR is involved also in CSR. Three patients with biallelic deleterious PMS2 mutations were found to have severe defects of CSR in vivo and partial, B cell-intrinsic defects of CSR in vitro [14]. These defects reflected impaired occurrence of DNA double-strand breaks in the switch regions of immunoglobulin genes and abnormal formation of switch junctions. The clinical and laboratory features of these patients included recurrent infections, café-au-lait spots on the skin, tumors in childhood (colorectal carcinoma, non-Hodgkin lymphoma), low levels of IgG and IgA, and normal to increased levels of IgM. Two of the three patients had a reduced proportion of CD27+ memory B cells. It is unclear whether this condition is also characterized by a mild defect of somatic hypermutation (SHM).

Ataxia-telangiectasia — Patients with AT may present with hyper-IgM due to the presence of monomeric IgM. Elevated alpha-fetoprotein levels and presence of typical neurologic features and telangiectasias facilitate the diagnosis of AT. (See "Ataxia-telangiectasia".)

Nijmegen breakage syndrome — Increased levels of serum IgM (possibly reflecting monomeric IgM molecules) have been reported in patients with NBS. However, these patients show unique features of microcephaly, short stature, facial dysmorphisms, and progressive decline of intellectual ability that are not seen in hyper-IgM syndrome. (See "Nijmegen breakage syndrome".)

TWEAK deficiency — Autosomal dominant tumor necrosis factor-like weak inducer of apoptosis (TWEAK; TNFSF12) deficiency was identified in patients with recurrent infections and defective antibody responses to protein and polysaccharide antigens [91]. Mutated TWEAK associated with B cell activating factor (BAFF) receptor and downregulated BAFF-mediated activation of the noncanonical NFkB pathway, causing impaired survival and proliferation of B cells in response to BAFF.

Common variable immunodeficiency — A proportion of patients with CVID have T cell activation defects and may present with a hyper-IgM-like immunologic phenotype [92,93]. CVID remains largely a diagnosis of exclusion. Accurate analysis of the immunologic phenotype and testing to rule out HIGM syndrome is important in the diagnostic approach to these patients. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Common variable immunodeficiency in children".)

It is not rare to see patients who were initially given a diagnosis of CVID but were eventually diagnosed with hyper-IgM. This occurs because CVID is much more common than any form of hyper-IgM syndrome and because there is significant clinical and immunologic overlap between these groups of disorders. Some clues that indicate a diagnosis of hyper-IgM syndrome rather than CVID and that should prompt appropriate laboratory tests include:

●Presentation at very young age (less than four years of life)

●Occurrence of opportunistic infections

●Development of severe biliary tract disease

●An obvious pattern of inheritance (X linked, autosomal recessive, autosomal dominant) since most cases of CVID are sporadic

Congenital rubella syndrome — Increased levels of IgM, with variable levels of IgG, have been reported in patients with congenital rubella infection. Deafness, cataracts, and cardiac disease, clinical features that are not found in hyper-IgM syndrome, are the classic manifestations of congenital rubella syndrome. (See "Congenital rubella", section on 'Clinical features' and "Congenital rubella", section on 'Immunologic response'.)

Malignancies — The sudden development of increased IgM levels in an adult should prompt the clinician to consider the possibility of a malignancy, in particular multiple myeloma or lymphoma. In these cases, serum levels of other immunoglobulin isotypes are not necessarily altered, at least initially.

CARRIER DETECTION — CD40 ligand (CD40L) deficiency is an X-linked disease. Random X-chromosome inactivation leads to a bimodal pattern of CD40L expression on the surface of CD8-negative (ie, CD4+) lymphocytes from female carriers of X-linked hyper-IgM syndrome [94]. However, mutation analysis is the method of choice to determine the carrier status in females of childbearing age belonging to families with CD40L deficiency and should be proposed as part of genetic counseling.

TREATMENT — Patients with hyper-IgM should be managed by an immunology specialist in addition to their primary care provider. All patients are treated with immune globulin replacement therapy. Additional therapies are indicated depending upon the type of hyper-IgM and the complications that a patient develops. Immune globulin therapy is reviewed in greater detail separately. (See "Immune globulin therapy in inborn errors of immunity".)

CD40L and CD40 deficiencies — The treatment of CD40 ligand (CD40L) or CD40 deficiency is more complex than other forms of hyper-IgM because these defects cause combined immune deficiencies. Immune globulin replacement therapy is effective in reducing the risk of recurrent sinopulmonary infections and bronchiectasis. However, patients with CD40L or CD40 deficiency are at high risk of opportunistic infections and of liver/biliary tract complications that reflect T cell or dendritic cell/monocyte defects, respectively.

Prevention of opportunistic infections — Prevention of P. jirovecii pneumonia is based upon continuous prophylaxis with trimethoprim-sulfamethoxazole (cotrimoxazole) [39]. Cryptosporidium infection represents a challenge. Nitazoxanide and azithromycin may be helpful in patients with active disease but will rarely eradicate Cryptosporidium. Azithromycin has been also proposed for prophylaxis of Cryptosporidium infection, but no data are available to support long-term efficacy. The best prophylaxis to prevent Cryptosporidium infection remains use of hygienic measures (table 2), such as avoiding baths in rivers, lakes, or nonchlorinated pools and home water supply management (eg, filter consumed water if regional water contains Cryptosporidium). (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV" and "Cryptosporidiosis: Treatment and prevention".)

Management of neutropenia — Patients with chronic, severe neutropenia and a history of severe infections may benefit from subcutaneous administration of recombinant human granulocyte-colony stimulating factor (rhG-CSF) [95]. (See "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Granulocyte colony-stimulating factor'.)

Hematopoietic cell transplantation — The only curative approach for patients with CD40L (or CD40) deficiency is allogeneic hematopoietic cell transplantation (HCT). Survival rates have improved over the years, with the 20-year survival rate now approaching 90 percent [96]. Younger age, absence of liver disease at the time of transplantation, and myeloablative conditioning are associated with better outcomes [96,97]. Early HCT may prevent liver disease [98].

In a series of 38 patients with CD40L deficiency treated by HCT from 1993 to 2002 and followed for a median of 3.4 years, overall survival was 68 percent, and disease-free survival was 58 percent [99]. The presence of lung disease and use of a mismatched, unrelated donor were associated with poorer survival rate. The chance of survival was higher in patients without liver disease than in those with preexisting liver disease (72 versus 39 percent).

Long-term survival with (n = 67) and without (n = 109) HCT was compared in a series of 176 patients from 28 sites diagnosed with CD40L deficiency between 1964 and 2013 and followed for a mean of 8.5 years [96]. Survival was similar in both groups (85 versus 80 percent, respectively). However, survivors treated with HCT had slightly better functional status (median scores of 100 versus 90, respectively on the Karnofsky-Lansky score [100 represents normal activity whereas 90 reflects minor restrictions]). Among patients who underwent HCT and who had data on conditioning regimen available, engraftment was observed in 93 percent of those who received myeloablative conditioning and 85 percent of those who received nonmyeloablative regimens. Factors that were associated with improved survival after HCT included transplant era (survival was higher in the more recent era [1993 to 2013] compared with earlier years [1964 to 1992]), age <5 years at the time of HCT, and absence of liver disease at the time of HCT. Graft-versus-host disease (GVHD) occurred in 40 percent of transplanted patients and was mostly an acute complication. Infections and transplant-related complications (venoocclusive disease and GVHD) were the main causes of death, and most deaths occurred within the first year after HCT.

Another multicenter study of 130 patients with CD40L deficiency who underwent HCT from 1993 to 2015 reported overall, event-free, and disease-free survival rates of 78, 58, and 72 percent, respectively, five years after HCT [97]. The overall survival rate was nearly 90 percent in patients who underwent HCT at <5 years of age compared with 38 percent for those transplanted at >10 years of age. A similar difference in survival was seen in those with and without preexisting organ damage (56 versus 93 percent, respectively). Sclerosing cholangitis was the most significant risk factor, whereas chronic lung disease did not influence outcomes for HCT performed in 2000 or later. Use of myeloablative conditioning regimens was also associated with better survival. Mortality after HCT was predominantly due to infection.

Reactivation of Cryptosporidium infection, even when subclinical, may occur after HCT and may lead to disseminated infection and death in patients with CD40L or CD40 deficiency [100]. For this reason, active surveillance against Cryptosporidium infection should be performed periodically by polymerase chain reaction (PCR) on stool samples. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Liver transplantation — Liver transplantation (LT) has been performed in patients with CD40L deficiency and end-stage liver disease, but mortality is high, particularly if it is performed without HCT. In a series of 13 patients who underwent LT for sclerosing cholangitis, six died, including all four who received LT alone, one of four who received LT followed by HCT, and one of five who received HCT followed by LT [101]. Mortality was associated to relapse of Cryptosporidium species infection and liver disease in all patients who underwent LT without HCT.

Recombinant CD40L replacement therapy — The safety and potential benefit of treatment with recombinant CD40 ligand (CD40L) was explored in three CD40L-deficient patients [58]. Increased secretion of T helper cell type 1 (Th1) cytokines upon in vitro activation of mononuclear cells and in vivo acquisition of the capacity to mount delayed-type hypersensitivity were demonstrated, although the latter effect ceased after recombinant human CD40L (rhCD40L) was discontinued. No variations in immunoglobulin levels and specific antibody responses were noted. Treatment with rhCD40L might be a valid treatment option for CD40L-deficient patients with biliary Cryptosporidium disease in light of the lack of effective treatment for patients with active Cryptosporidium infection and of improved T cell function following administration of hrCD40L [58].

Gene therapy — The use of gene therapy for CD40L deficiency is under study [102,103].

AID and UNG deficiencies and HIGM4 — Treatment of hyper-IgM syndrome due to activation-induced cytidine deaminase (AID) or uracil N-glycosylase (UNG) deficiency is based upon immune globulin replacement therapy that can be administered intravenously or subcutaneously. This treatment results in marked reduction in the frequency and severity of infections and may also reduce the occurrence of lymphoid hyperplasia [3,52]. Patients with hyper-IgM syndrome type 4 (HIGM4) are also treated with immune globulin replacement therapy. Immune globulin therapy is reviewed in detail separately. (See "Immune globulin therapy in inborn errors of immunity".)

Antibiotic prophylaxis is recommended in patients who have developed chronic complications, such as bronchiectasis and/or chronic or recurrent sinusitis. (See "Bronchiectasis in children without cystic fibrosis: Management", section on 'Chronic antibiotics'.)

Treatment of autoimmune manifestations in AID deficiency requires use of immunosuppressive regimens, as in other autoimmune disorders that are not associated with immunodeficiency. Treatment is discussed in topic reviews on the specific autoimmune disorder (eg, inflammatory bowel disease). (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency" and "Gastrointestinal manifestations in primary immunodeficiency".)

MONITORING — In patients with CD40 ligand (CD40L) or CD40 deficiency, monitoring of liver status by regular assessment of liver function (preferably every four to six months unless liver dysfunction is already apparent) and by ultrasound evaluation (at least once a year), as well as polymerase chain reaction (PCR) based testing for the presence of Cryptosporidium and Microsporidium in the stool (approximately twice a year), are important to detect early signs of infection. In patients who develop infection with one of these organisms, treatment with azithromycin or nitazoxanide should be used to prevent progression of the infection, which may otherwise ultimately lead to severe biliary tract and liver complications.

Patients with activation-induced cytidine deaminase (AID) and uracil N-glycosylase (UNG) deficiency should be monitored for the development of bronchiectasis and for lymphoproliferative disease. Chest computed tomography (CT) can be used to document onset and progression of bronchiectasis, and the frequency at which it is performed is based upon the evolution of the clinical status. Lymphoproliferation can be assessed by chest and abdominal CT. Abdominal ultrasound may also be helpful, especially if repeat assessments are needed at shorter intervals.

Patients with hyper-IgM syndrome type 4 (HIGM4) should have periodic reevaluation of immune function to see if it has normalized since these patients may have spontaneous disease resolution [104].

PROGNOSIS — Severe and opportunistic infections, liver/biliary tract disease, and malignancies are the most important causes of death in CD40 ligand (CD40L) and CD40 deficiencies. In a series of 176 patients who were diagnosed with X-linked hyper-IgM between 1964 and 2013, 144 patients were living at the close of the survey [96]. The survival probability was approximately 60 percent at 20 years since diagnosis and was significantly higher in those without than in those with liver disease (probability of survival at 20 years since diagnosis: approximately 67 versus 20 percent). Survival at 20 years was nearly 90 percent in those who had undergone transplantation. (See 'Hematopoietic cell transplantation' above.)

The long-term prognosis of activation-induced cytidine deaminase (AID) and uracil N-glycosylase (UNG) deficiency is less severe. In this disease, regular use of immune globulin replacement therapy and prompt treatment of infections are effective in avoiding development of chronic lung disease and early death.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Definition – The hyperimmunoglobulin M (hyper-IgM or HIGM) syndromes include a heterogeneous group of congenital and acquired conditions characterized by defective class-switch recombination (CSR), resulting in normal or increased levels of serum immunoglobulin M (IgM) associated with deficiency of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) and poor antibody function. (See 'Introduction' above.)

●Genetics/pathogenesis – All genetically determined forms of hyper-IgM syndrome are characterized by defective CSR (table 1). Some forms also have impairment of somatic hypermutation (SHM), with production of low, rather than high, affinity antibodies. Impaired CSR in hyper-IgM syndrome is due to B cell-intrinsic abnormalities or to defects that involve several types of immune cells. This difference in the pathogenesis accounts for the distinctive clinical features in the various forms of hyper-IgM syndrome. (See 'Pathogenesis' above.)

●CD40 ligand (CD40L) and CD40 deficiencies – CD40L deficiency is the most common form of hyper-IgM syndrome. It is inherited as an X-linked trait and is a combined immunodeficiency. This disease affects the interaction between activated CD4+ T cells and cell types expressing CD40 (B cells, dendritic cells, monocyte/macrophages, platelets, activated endothelial and epithelial cells). The clinical phenotype of CD40L deficiency is marked not only by recurrent sinopulmonary infections but also by opportunistic infections and liver and biliary tract disease. CD40 deficiency affects the interaction of the same cell types as CD40L deficiency and therefore has a similar clinical presentation. (See 'Pathogenesis' above and 'Genetics' above and 'CD40 ligand (CD40L) or CD40 deficiency' above.)

●AID and UNG deficiencies – In contrast, activation-induced cytidine deaminase (AID) deficiency and uracil N-glycosylase (UNG) deficiency account for hyper-IgM syndrome due to a B cell-intrinsic defect of CSR (humoral rather than combined immunodeficiency). These patients suffer from recurrent sinopulmonary infections and enlargement of lymph nodes and tonsils and are at higher risk for autoimmune manifestations. (See 'Pathogenesis' above and 'Genetics' above and 'AID deficiency' above and 'UNG deficiency and HIGM4' above.)

●Diagnosis – The diagnosis of hyper-IgM syndrome should be suspected in patients with appropriate clinical features, low levels of IgG and IgA, and normal to increased levels of serum IgM. Genetic testing using a gene panel or whole exome sequencing is used to confirm genetically determined forms of hyper-IgM syndrome. There is one form of hyper-IgM (HIGM4) for which the molecular basis remains unknown. (See 'Diagnosis' above and 'Genetics' above.)

●Differential diagnosis – Causes of acquired forms of hyper-IgM include congenital rubella syndrome, antiseizure medications (phenytoin), and tumors (T cell leukemia, multiple myeloma, and lymphomas). These patients tend to have laboratory findings suggestive of hyper-IgM syndrome, but their clinical manifestations are distinct. (See 'Differential diagnosis' above.)

●Treatment – Patients with hyper-IgM should be managed by an immunology specialist in addition to their primary care provider. Key aspects of management include (see 'Treatment' above):

•Patients with hyper-IgM syndrome require immune globulin replacement therapy, as discussed separately. (See "Immune globulin therapy in inborn errors of immunity".)

•Patients with CD40L and with CD40 deficiency require additional measures, including prophylaxis against Pneumocystis jirovecii infection, hygienic measures to reduce the risk of Cryptosporidium infection (table 2), and regular monitoring of liver function. (See 'Prevention of opportunistic infections' above.)

•The only definitive cure for CD40L (or CD40) deficiency is hematopoietic cell transplantation (HCT). (See 'Hematopoietic cell transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.