• thymic dysplasia : any of a group of hereditary disorders, some transmitted as an autosomal recessive trait and others as an X-linked recessive trait, characterized by faulty development of the thymus, which may be associated with
• normal serum immunoglobulin levels and impaired cell-mediated immunity (Nezelof's syndrome)
• Swiss type agammaglobulinemia and impairment of both cell-mediated and humoral immunity
• variable deficiencies of immunoglobulins, the severity being dependent on the degree of the deficiency.
• combined immunodeficiencies (T and B lymphocytes)


• severe combined immunodeficiency (SCID) / Swiss type agammaglobulinemia / "bubble boy" disease or syndrome^ref

Epidemiology : 1 in 75,000 live births (1 in 100,000 live male births). SCID gained popular culture recognition in 1984 when media attention began to focus on an affected boy, David, who lived in a “bubble” designed to protect him from exposure to pathogens.
Varieties : the genetic defects that cause SCID have been identified in > 95% of cases.  Individuals with defective repair pathways are increasingly recognized with radiosensitivity and immunodeficiency. Patients with defects in ataxia-telangiectasia mutated, nibrin, MRE11, Rad50, Artemis, DNA ligase IV and Cernunnos-XRCC4-like factor have been identified. Most exhibit immunodeficiency, with a spectrum of presentation and overlap between conditions^ref. In all variants there is differentiation defect and a failure to produce T cells
Affected cell lines :
• B lymphocytes
• B cells⁺ (B⁺ SCID) (70%)
• T^-B⁺NK^- SCID :

Aetiology : autosomal recessive mutations in ZAP70 : profound depletion of peripheral CD8⁺ T cells. The absolute counts of CD4⁺ T cells are normal in these patients, although these cells have a defect of the CD3–TCR signal transduction pathway^{ref1, ref2, ref3}. Moreover, a defective expression of the PTK p56^Lck was recently shown in a SCID child who had also a selective loss of CD4⁺ T cells^ref.
• mutations in the genes for the CD3 complex :
• CD3d^ref
• CD3e^ref
• CD3g (milder immunodeficiencies^ref)
• CD3z chain of the pre-TcR complex^ref (< 1%) causes a block at the pre-TcR stage of development. It was associated with three somatic CD3 mutations, all located at the mutated codon 70 of the CD3 gene in the population with normal levels of the TcR–CD3 complex, which were obtained from 10% of the patient's T cells. The latter mutation (termed Q70X) reduced numbers of T cells and expression of the TcR. Furthermore, the mutation led to the deletion of the signaling portion of the molecule, resulting in impairment of the intracellular signaling needed to mount a response to antigens such as tetanus toxoid. In a fascinating twist, multiple somatic mutations in about 10% of the child's T cells had occurred at the same site (Q70) as the germ-line mutations in the z-chain gene. These cells expressed normal levels of the TcR and contributed to the residual response of the patient's immune system. The deficiency of the z chain seems to cause a less severe form of immunodeficiency than is caused by mutations in the CD3d or CD3e gene but a more severe form than is caused by mutations in the CD3g gene, which result in only a slight reduction in T-cell numbers and mild immunodeficiency
• B cells^- (30%) : B-1 B cells survive thanks to autoreactivity (T-independence) while B-2 B cells die.
• genes are required for somatic V, D, and J rearrangements that encode the antigen-binding site of the pre-TcR and the mature TcR
• RAG1 and RAG2
• amorphic mutations => T^- B^- SCID
• hypomorphic mutations that impair but do not abolish the process of VDJ recombination, leading to the generation of residual autoreactive T (± B) cells with a highly restricted receptor repertoire => loss of central tolerance =>
• Omenn syndrome / familial reticuloendotheliosis with hypeosinophilia (20%)

Pathogenesis : oligoclonal expansion of T cells with a T_h2 phenotype, with eosinophilia and hyper-IgE syndrome. T_h2 T cells infiltrate the skin, the gastrointestinal tract, and other organs, possibly in relation to autoimmune reactivity caused by defective central tolerance^{ref1, ref2}. There is profound reduction in the levels of autoimmune regulator (AIRE) mRNA and protein in patients as compared with a normal control subject. Lack of AIRE was associated with normal or even increased levels of keratin and lymphotoxin-ß receptor mRNAs, while mRNAs of the self-antigens insulin, CYP1A2, and fatty acid–binding protein were undetectable in thymi from immunodeficiency patients. The few residual T cell clones that develop may escape negative selection and thereafter expand in the periphery, causing massive autoimmune reactions^ref. Residual RAG1/2 activity enables a certain number of precursor cells to rearrange their TCR and BCR genes successfully^{ref1, ref2, ref3}, this rearrangement being followed by the massive expansion of a few autoaggressive T cell clones^ref
Symptoms & signs : putative autoimmune manifestations of the skin and gastrointestinal tract
• atypical SCID/Omenn syndrome due to recessive RAG1 or RAG2 mutations^ref. In patients with this syndrome, T cells are detectable in the periphery, albeit in small numbers, and there are only milder manifestations of immunopathological reactions in the skin or gastrointestinal tract, but most T cells express memory/activation markers. In half of these patients, B cells are also detectable
• immunodeficiency with gd T cell expansion and autoimmunity : a different recessive RAG1 hypomophic mutation increase susceptibility to early onset of multivisceral and recurrent HHV-5 / CMV infection, which drives oligoclonal expansion of TCRgd T cells combined with TCRab T cell lymphopenia. Another striking feature in 3 of these 4 patients was autoimmunity to blood cells (anemia in 3 patients and neutropenia in 1). No such autoimmunity has previously been reported in patients with RAG1/2 mutations, with the exception of 1 patient with mild immunodeficiency who presented both autoimmune thrombocytopenia and neutropenia^ref. This may reflect a trend toward the development of antibody-mediated immunity, provided that the disease is not fatal in the first few months of life and that B cells with sufficiently diverse BCRs are present, which is not the case in most patients with RAG1/2 mutations. Nevertheless, it is also possible that the expanded  T cell clones do also promote autoimmunity, as previously suggested^ref. Chronic CMV infections are also known to be frequently associated with autoimmune hemolytic anemia, possibly due to the production of cross-reactive antibodies^ref. An antibody production deficiency was also found in these patients. It may be the consequence of defective T cell help and/or reduced B cell repertoire diversity in the setting of a defective V(D)J rearrangement of B cell receptor genes^ref. The RAG1/2 gene mutations causing the OS and atypical SCID/OS phenotypes have yet to be clearly defined. There is clearly an overlap, because the same mutations have been found in patients with each of these phenotypes (A444V mutation, for example)^ref. A milder phenotype has also been described in a 6-year-old girl presenting a combination of maternal T cells and autologous functional B cells that produced anti–HSV antibody upon infection. This phenotype was associated with 2 mutations of RAG1, one leading to the insertion of a premature stop codon in RAG1 (R897X) and the second being a missense mutation (R559S) in the core region of RAG1^ref. The missense mutant has been shown to display low but detectable levels of recombination activity in a cellular assay^ref. Further overlap between a typical T^–B^– SCID phenotype and OS, as observed in patients with the same mutations in several families^ref, has suggested that the phenotypic consequences of RAG1 or RAG2 mutations depend on (a) the existence of residual V(D)J recombination activity^{ref1, ref2, ref3} and (b) other yet-unknown genetic or environmentally determined factors. In this setting, it is tempting to conclude that the phenotype observed in the 4 patients described here results from such an environmental factor. The common feature of all 4 patients is early CMV infection. In all 4 patients, dissemination and recurrence of infection was observed each time antiviral therapy was decreased or stopped, probably reflecting a limited appropriate anti-CMV T cell immunity. The severity of the immunodeficiency was also demonstrated by the severe coinfections observed in 2 patients (Pseudomonas aeruginosa sepsis, Pneumocystis jerovici pneumonitis). Thus, prolonged CMV infection in patients with profound (but not complete) inherited T cell immunodeficiency may have led to the activation and expansion of gd⁺ T cell clones. This assumption is based on the known ability of + T cells to recognize products from microorganisms directly. The expansion of various  T cells has been reported to occur in recipients of kidney allografts developing CMV infection^ref. In this case, most of the Vd1⁺ and Vd3⁺ T cells detected were activated in vitro by CMV, demonstrating their specificity^{ref1, ref2}. An analysis of junctional diversity in these gd⁺ T cells showed that the size distribution of CDR3 cells was restricted, indicating the probable selective expansion of antigen-specific clones^ref. In the 4 patients carrying hypomorphic RAG1 mutations, the diversity of TCR and  CDR3 chain length was found to be fairly restricted. In vitro assay of CMV-infected stromal cell–induced  T cell proliferation, cytotoxic activity, and TNF-a release^ref did not provide evidence to suggest that gd T cells were CMV specific. Nevertheless, the striking similarity between these patients’ phenotype and the one of CMV-infected kidney transplant recipients with acquired immunodeficiency strongly suggests that expansion of the population of gd TCR T cells is directly related to the persistence of CMV infection^{ref1, ref2}. The predominant location of CMV infection in mucosae (lung and gastrointestinal tract, where mostly Vd2^– gd T cells are located^ref) could also favor local gd T cell population expansion. Of note, in mice, Vd1 cells were also found to exert a protective effect against CMV infection in the liver^ref. The lack of in vitro–detectable reactivity to CMV of patients’ TCR T cells can either reflect usage of inadequate assays or the fact that these  T cells do not directly react to CMV molecules. It has not been proven that expanded  T cells found in chronically infected patients after organ transplantation directly recognize CMV molecules, although the  TCR is required for activation^ref. Vd1 T cells have been shown to be activable by self lipids associated to CD1c^{ref1, ref2} or through stress-induced MICA/B MHC class I–related molecules^{ref1, ref2}. Presence of IL-12 produced by dendritic cells has also been shown to be necessary to induce in vitro Vd1 T cell activation^ref. It is thus possible that chronic CMV infection, in patients with partial RAG1 deficiency, triggered the expression of stress proteins and/or self lipids leading to the activation of these  T cells. CMV products might also trigger a superantigen effect, although the diversity of the TCRV and TCRV families (with restricted CDR3 length distribution) in the patients is consistent with the antigen-induced activation of a particular set of available clones. The CD45RO⁺CD27^–CD28^– phenotype of the gd T cells is itself evidence for in vivo activation. del T631 and del 368–369 lead to translation starting from an alternative initiation site, at a second methionine codon downstream from the deletion^ref. The missense mutations found in P2 (Q981P) and P3 (R841W) involve amino acids within the minimal core of RAG1, but the mutant proteins nonetheless display residual RAG1 activity. The R841W mutation has been found in OS patients^ref, and RAG1 mutations leading to residue changes at positions close to 981 (R973, K992, R975) have also been reported to encode proteins with residual activities in vitro^ref
• Athabascan, Athabaskan-type or radiosensitive SCID (RS-SCID)

Epidemiology : found among Athabascan-speaking Native Americans
Aetiology : loss of function mutations in ARTEMIS, which associates with DNA-PK_cs
to form a complex that has hairpin-opening activity in NHEJ.
Symptoms & signs : after the appearance of lymphopenia during infancy, the children develop severe infections, and sometimes lymphomas
• NK cells
• NK cells⁺
• IL-7Ra^ref : lacking only mature T cells
• mutations in the gene for CD45 (< 1%)^{ref1, ref2} : lacking only mature T cells
• reticular dysgenesia
• veno-occlusive disease with immunodeficiency, an autosomal recessive disorder of severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, absent tissue plasma cells and hepatic veno-occlusive disease. This is the first report of the involvement of a nuclear body protein in a human primary immunodeficiency and of high-penetrance genetic mutations in hepatic veno-occlusive disease^ref
• autosomal recessive (40%)
• Omenn syndrome / familial reticuloendotheliosis with hypeosinophilia
• Athabascan, Athabaskan-type or radiosensitive SCID (RS-SCID)
• ADA-SCID (20%)

Aetiology : loss of function mutations in adenosine deaminase (ADA)
Therapy :
• PEG-ADA
• gene therapy
• DNA-PK_CS / XRCC7
• T^-B⁺NK⁺ SCID
• NK cells^-
• SCID1 (5%)

Aetiology : autosomal recessive loss of function mutations in JAK3
• recessive X-linked SCID / SCIDX1 (50-60%)

Epidemiology : brought to the public's attention in a popular 1976 film called The Boy in the Plastic Bubble, starring John Travolta. He played David Vetter, a young man who spent his entire life in a sterilised environment. The real-life Vetter died in 1984.
Aetiology : loss of function mutations in CD132 / g_c (subunit of IL-2R, IL-4R, IL-7R, IL-9R and IL-15R and IL-21R) : normal or augmented B lymphocytes.
Therapy :
• gene therapy
• BMT from a histocompatible sibling. For the vast majority of children, however, an allogenic transplant is the best option, which carries a 5-year success rate of just 65%.
Web resources : X-linked SCID Mutation Database
• T^-B⁺NK^- SCID
• DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a SCID in 2 microcephalic siblings with cellular radiosensitivity. In 1 patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and ab T cells 10-fold, whereas gd T cells were normal. Spectratyping of all 3 cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of gd T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype^ref
Therapy :
• gene therapy
• BMT : a perfectly matched sibling donor is available in only 20% of cases, 1 in 4 transplantations fail and there can be both short- and long-term complications (including lymphoid malignancy) from this procedure.  The debate over the need for preparative conditioning in patients with SCID continues, with strongly held opinions on each side^ref. In some genetic subtypes with a T and natural killer (NK) lymphocyte–negative, B lymphocyte–positive immunophenotype, the bone marrow space is full of recipient HSCs and mature B lymphocytes, but the thymus is empty of T-lymphocyte precursors. An infusion of donor stem cells permits engraftment of donor T-lymphocyte progenitors in the thymic niche and leads to long-term thymopoiesis with a diverse T-lymphocyte repertoire (panel A). Donor B-lymphocyte engraftment occurs more rarely; usually, chemotherapy is required to empty the bone marrow niche to enable HSC engraftment, subsequent B-lymphocyte progenitor development, and establishment of B-lymphocyte function and freedom from treatment with immunoglobulin replacement. For other genetic subtypes with T and B lymphocyte–negative, NK lymphocyte–positive immunophenotype, the bone marrow space is full of recipient HSCs and B-lymphocyte precursors, and the thymus is full of T-lymphocyte precursors. An infusion of donor marrow permits engraftment of peripheral T lymphocytes, but no HSC or thymic T-lymphocyte progenitor engraftment with thymopoiesis or B-lymphocyte development, because the bone marrow and thymic niches are occupied (panel B)^ref. Peripheral T lymphocytes confer medium-term but finite immune protection, with a limited T-lymphocyte receptor repertoire. Chemotherapy is required to empty the bone marrow and thymic niches to facilitate HSC engraftment and subsequent B- and T-lymphocyte progenitor development^ref. However, chemotherapy is associated with short- and long-term morbidities and serious adverse effects, including infertility, impaired endocrine function, and poor growth^ref. Infants with SCID commonly present with life-threatening, persistent viral, or opportunistic infection. The outcome of transplanting such patients is impaired by the presence of end-organ damage^ref. Recently, many states within the United States have implemented newborn screening, using the neonatal blood spot to detect T-lymphocyte receptor excision circles. A number of infants have been diagnosed at only a few days of age using this technique, before severe or recurrent infection develops^ref. The optimum treatment of such infants remains hotly debated—with concerns about the toxicity of chemotherapy administered to such young infants vs the long-term outcome of incomplete immune reconstitution after infusion of donor HSCs in infants treated without conditioning. Ideally, engraftment of donor (or autologous gene-corrected) HSCs would be achieved without requirement of toxic chemotherapeutic agents. Derderian et al^ref administered a murine anti-c-Kit receptor antibody (ACK2), which interrupts a key signaling pathway in the homing, adhesion, maintenance, and survival of HSCs in the hematopoietic niche, to fetal mice, with the aim of depleting recipient HSCs and making space for donor HSC engraftmen
  
Spectrum of primary immunodeficiencies associated with RAG1 mutations :

	T-B- SCID	Omenn syndrome	atypical SCID/Omenn syndrome-mild ID	ID with gd T cell expansion and autoimmunity
T cells	0	normal or increased (oligoclonal)	moderately decreased	normal (gd oligoclonal)
B cells	0	0 or profoundly decreased	profoundly decreased to normal	moderately decreased to normal
RAG1 mutation consequences	null	hypomorphic	hypomorphic	hypomorphic
associated factors	-	?	?	HHV-5 / CMV infection

Prognosis : without treatment, these babies die of infection within 6 to 12 months
Web resources : The SCID Homepage
• T cell primitive immunodeficiencies
• DiGeorge syndrome (DGS) / velocardiofacial syndrome (VCFS)
• T-cell immunodeficiency, congenital alopecia (nude syndrome) and nail dystrophy : WHN. See analogous disease in Mus musculus.
• TcR complex deficits
• deficit of CD3e
• deficit of CD3g
• bare lymphocyte syndrome (BLS) / MHC deficiency
• type I BLS / class I MHC deficiency

Aetiology :
• TAP2
• TAPBP / tapasin
Symptoms & signs : the syndrome resembles Wegener's granulomatosis both clinically and histologically. Patients have chronic necrotising granulomatous lesions in the upper respiratory tract and skin, recurrent infections of the respiratory tract, and skin vasculitis. A predominant NK population within the granulomatous lesions suggests that the pathophysiology of the skin lesions may relate to the inability of HLA class-I molecules to turn off NK cell responses. Accurate genetic analysis of a defined syndrome can provide a better understanding of the cause and pathogenesis of a disease^ref.
Laboratory examinations : reduced CD8⁺ T lymphocytes in peripheral blood; autoreactive NK cells and gd T lymphocytes in the peripheral blood^ref
• type II BLS / class II MHC deficiency

Aetiology :
• CIITA (complementation group A)
• RFX-B / RFXANK (complementation group B)
• RFX5 (complementation groups C and E)
• RFXAP (complementation group D)
Laboratory examinations : reduced CD4⁺ T lymphocytes in peripheral blood
• type III BLS : impaired expression of both class I and class II antigens

Laboratory examinations : reduced CD4⁺ and CD8⁺ T lymphocytes in peripheral blood
• selective T-cell defect (STD) : ZAP70
• purine nucleoside phosphorylase (PNP)deficiency
• Nezelof syndrome / cellular immunodeficiency with immunoglobulins : any of a heterogeneous group of immunodeficiency disorders characterized by profoundly deficient cellular immunity and varying degrees of humoral immunodeficiency. Immunoglobulin levels may be normal or increased, but antibody response to immunization may be absent. Patients are highly susceptible to life-threatening infections with low-grade or opportunistic pathogens, such as Candida albicans, Pneumocystis carinii, and cytomegalovirus. Both autosomal recessive and X-linked inheritance have been described
• immunodeficiencies impairing only B-cells


• hypogammaglobulinemia (< 70 mg/dl)
• physiologic hypogammaglobulinemia : a normal period of hypogammaglobulinemia seen in all infants at about 5–6 months of age as the level of transplacentally acquired maternal immunoglobulins declines before endogenous immunoglobulin synthesis rises to normal levels
Aetiology :
• mutations in genes involved in B-cell differentiation. Such genetic defects block the differentiation of immature B cells in bone marrow, thereby causing both a deficiency of mature B cells in the peripheral circulation and agammaglobulinemia
• X-linked agammaglobulinemia (XLA) occurs only in males
• Bruton agammaglobulinemia^{ref1, ref2, ref3}

Aetiology : sex-linked mutations in Bruton's tyrosine kinase (Btk)
Symptoms & signs : 25% develop cancer, mostly NHL and acute leukemia
• AGMX2

Aetiology : ?
• mutations that interfere with the pre-B-cell–receptor stage
• CD179b / l5 surrogate light chain deficiency^ref
• CD79a / Iga deficiency^ref
• Ig heavy chain deletion
• m heavy chain deficiency / autosomal recessive, non-Bruton-type agammaglobulinemia^ref
• g₁ heavy chain deficiency
• mutations in coreceptors :
• CD19 mutation resulted in the deletion of the signaling portion of the protein (frameshift mutations, causing premature stop codons that result in the deletion of the total cytoplasmic domain or a major part of the cytoplasmic domain), with normal numbers of B cells, able to undergo antigen-dependent differentiation, albeit with reduced efficiency, and impaired terminal differentiation of B cells into memory B cells and plasma cells^ref. Both truncations result in the lack of the 3 C-terminal tyrosine residues, 2 of which have been shown to be critical for signal transduction through CD19^ref. These mutations are not likely to be polymorphisms; CD19 is the most broadly used B-cell marker for flow-cytometric immunophenotyping of lymphocytes and has not been found to be lacking in large-scale studies of healthy children^{ref1, ref2}.
• BLNK^ref
• defects in the maturation process : there are mature B cells in blood and a deficiency of some, but not all, immunoglobulin classes (dysgammaglobulinemia) or hypogammaglobulinemia
• hypergammaglobulinemias
• hyper-IgM syndrome (HIGM) (> 280 mg/dl)

Aetiology : at least 5 genes, directly or indirectly involved in B-cell signaling via CD40 and required for class switch recombination (CSR) and somatic hypermutation (SHM), have been identified to cause HIGM if mutated.
• X-linked :
• HIGM1 (the most common) : CD154 / 40L / gp39 (Xq26) defects^{ref1, ref2, ref3, ref4, ref5, ref6}

Symptoms & signs : most CD40L-deficient patients present in infancy with severe recurrent sinopulmonary infections, Pneumocystis carinii pneumonia (PCP), chronic diarrhea due to Cryptosporidium infection that may lead to sclerosing cholangitis and intermittent or persistent neutropenia^{ref1, ref2, ref3, ref4, ref5, ref6}
Web resources : CD40Lbase
• HIGM4 : IKK-g (NEMO) gene (Xq28) : NEMO serves as a scaffold protein, forming a complex with IKK and IKK, 2 phosphokinases. Following CD40 crosslinking, NF-kB inhibiting protein (I-B) is phosphorylated, resulting in its degradation and the release of NF-kB, allowing its transfer from the cytoplasma to the nucleus. Mutations of NEMO block NF-kB release and thus interfere with NF-kB signaling. Male patients with mutations of NEMO may present with hypohidrotic (anhidrotic) ectodermal dysplasia (EDA) and immunodeficiency (ID)^{ref1, ref2, ref3}; some, but not all, have hypogammaglobulinemia with elevated IgM^ref
• autosomal recessive :
• HIGM2 : AID (12q13)

Symptoms & signs : patients with AID deficiency often have lymphoid hyperplasia, lack opportunistic infections, and generally have a better prognosis^{ref1, ref2}
• HIGM3 : CD40 (20q12-q13.2)^ref
• HIGM5 : uracil-DNA glycosylase (UNG) (12q24.1)^ref  is known to generate abasic sites within the variable Ig regions, a process required for efficient CSR and SHM^ref. UNG-deficient mice characteristically have defective CSR, SHM, and decreased deoxyguanine (dG) and deoxycytidine (dC) transversion^ref. Recently, 3 unrelated patients with autosomal recessive HIGM due to a mutation of UNG have been reported^ref
• other not yet identified^ref
Symptoms & signs : recurrent infections.
Laboratory examinations : low serum levels of IgG, IgA, normal or increased IgM, and grossly intact T-cell function
Prevention : preimplantation genetic diagnosis (PGD)
• autosomal recessive hyper-IgE syndrome : differ from those with the classic hyper-IgE syndrome described here in that they have fewer pulmonary infections and pneumatoceles, more viral infections, and vasculitis^ref. In keeping with these clinical differences, an index patient with autosomal recessive hyper-IgE syndrome from an original report^ref had no STAT3 mutations
• hyper-IgE (HIE) syndrome (HIES) / hyperimmunoglobulin E recurrent infection syndrome / Buckley's syndrome : a primary immunodeficiency disorder characterized by recurrent staphylococcal abscesses of skin, lungs, joints, and other sites, pruritic dermatitis, very high serum IgE levels (> 0.025 mg/dl or > 150 E/l), normal levels of IgG, IgA, and IgM, blood and sputum eosinophilia, low anamnestic antibody responses to booster immunization, and poor antibody and cell-mediated responses to neoantigens. It is usually associated with red hair and fair skin. Most cases reported have been in girls. The syndrome described as Job's syndrome by Davis et al. in 1966^ref and as hyperimmunoglobulinemia E by Buckley et al. in 1972^ref was originally characterized by recurrent cold staphylococcal abscesses, pneumonia, eczema simulating atopic dermatitis, hyperextensibility, hyperkeratotic fingernails owing to candida infection, multiple atraumatic fractures due to osteoporosis, and extreme elevation of IgE levels. In 1966, a report on two unrelated young girls who had had recurrent staphylococcal abscesses since infancy was introduced with the biblical quote, "So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown" (Job 2:7)^ref. The authors called this disorder the Job syndrome because of the phenotypic similarity to the biblical figure Job. Subsequently, similar patients were recognized and noted to have markedly elevated IgE levels, leading to the name "hyper-IgE syndrome" (HIES). Since then, additional features of the hyper-IgE syndrome have been recognized, including scoliosis, pathologic fractures, pneumatoceles, delayed dental deciduation^{ref1, ref2}, coronary-artery aneurysms^ref, brain lesions, and Chiari's malformations^ref. Pneumonia in patients with the hyper-IgE syndrome is typically caused by infections with Staphylococcus aureus, Haemophilus influenzae, or Streptococcus pneumoniae and leads to pneumatoceles^ref, providing portals for fatal infections with bacteria and filamentous fungi^ref. Eosinophilia, eczema, and elevated IgE levels focused attention on the T helper cell T_h1/T_h2 profile^ref, but no primary defect was uncovered. Cytogenetic and linkage data suggested the presence of a locus on chromosome 4q, but no disease gene was found there^ref. Microarray-based approaches have yielded inconsistent results^{ref1, ref2}.

Aetiology : autosomal dominant negative mutations in DNA-binding or SH2 regions of STAT3 : mutations of arginine at position 382 account for nearly half the identified mutations^ref

Pathogenesis : STAT3 is an essential mediator of the immunosuppressive action of interleukin-10, and the loss of responsiveness of this interleukin may underlie much of the proinflammatory nature of the hyper-IgE syndrome. STAT3 is implicated in the differentiation of interleukin-17–producing CD4⁺ T lymphocytes^ref, important for immunity to some bacterial infections. Loss of these functions in patients with the hyper-IgE syndrome could contribute to impairment of the immune response.
• primary immunodeficiency with mild IgE elevation due to homozygous recessive tyrosine kinase 2 deficiency^ref : but this patient differs from our patients with classic hyper-IgE syndrome in the pattern of inheritance, susceptibility to viral infection, the degree of IgE elevation, and the absence of nonimmune features.
• common variable immunodeficiency (CVID) / acquired hypogammaglobulinemia

Epidemiology : onset before age 40; prevalence of about 1 in 50 000
Aetiology : 20% have dominant heredity
• 90% of cases are unexplained
• in 10% of cases familiarity exists
• homozygous null mutations in ICOS ( 2q33) (< 5%) on activated T cells may result in an adult onset form of CVID with autosomal recessive inheritance (AR-CVID). T cells from these individuals were normal with regard to subset distribution, activation, cytokine production and proliferation. In contrast, naive, switched and memory B cells were reduced^ref => panhypogammaglobulinemia. Worldwide, there are a total of 9 patients diagnosed with ICOS deficiency most likely due to a common founder. ICOS-L deficiency could not be identified in families with AR-CVID^ref. Marked defects in CSR and germinal center formation were observed in ICOS and ICOSL (B7-H2) knockout mice^{ref1, ref2}. These findings in mice and the recent discovery of homozygous mutations of ICOS in adult patients with CVID phenotype^ref make this receptor/ligand pair candidate genes for patients with the HIGM phenotype. Recurrent bacterial infections, adult as well as childhood onset, splenomegaly, autoimmune phenomena (autoimmune neutropenia), intestinal lymphoid hyperplasia, and malignancy (carcinoma of the vulva). The severe reduction of class-switched memory B cells resulted from poor germinal center formation in the absence of ICOS. The additional decrease of naive B cells was associated with a partial inhibition of the early B-cell development at the pre-B-I stage. T-cell homeostasis seemed not to be affected, but low IL-10 production by ICOS-deficient T cells may contribute to the disturbed germinal center reaction^ref. Generation of GCs is severely disturbed, and the numbers of circulating CXCR5⁺CD45RO⁺ memory CD4 T cells are significantly reduced, indicating an essential role of ICOS in the differentiation of CXCR5⁺CD4 T cells. The GC-specific CD57⁺CXCR5⁺ subpopulation is virtually absent. In ICOS^-/- mice, the decrease of circulating CXCR5⁺CD4 T cells reflects the reduction of CXCR5⁺ follicular Th cells in lymph nodes and spleen. Therefore, in concurrence with the absence of CXCR5⁺ T cells in the blood of CD40L-deficient patients, these data support the hypothesis that circulating CD57⁺CXCR5⁺ T cells are GC derived and thus may serve as a surrogate marker for the presence of functional GCs in humans^ref.
• homozygous and heterozygous mutations in TNFRSF13B / TACI. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b^-/- mouse model^{ref1, ref2}.
• BAFF-R^ref
• a susceptibility locus exists in the class III MHC region
• an HIGM/CVID phenotype has also been observed in subsets of male patients with mutations of Btk or SAP/SH2D1A^{ref1, ref2}, the genes responsible for X-linked agammaglobulinemia (XLA) and X-linked lymphoproliferative disease (XLP), respectively
• approximately 20% of patients with hypogammaglobulinemia and major histocompatibility complex class II (MHCII) deficiency and a subset of patients with ataxia telangiectasia (AT) have elevated serum IgM levels. These disorders, however, can be recognized by experienced clinicians and confirmed by simple laboratory tests; for example, lack of MHCII molecules on the surface of B cells or elevated a-fetoprotein in the serum of patients with AT. However, in a considerable proportion of patients with the HIGM phenotype, the molecular defect remains unknown^ref
Pathogenesis : disturbed T, NK and B-cell function^ref => decreased serum IgG and IgA levels and generally decreased serum IgM, low CD19 and CD4^ref subsets, high serum IL-4 and IL-6^ref, reduced sCD23^ref. B cells from patients with CVI have impaired capacity to differentiate into Ig-secreting cells in response to IL-10 and anti-CD40 MoAbs, and that this unresponsiveness can be restored by exogenous IL-4 in a proportion of the patients^ref. Pax5 gene expression is not detected at baseline but can be induced by IL-2, IL-10 and anti-CD40 mAb^ref. There is a dramatic reduction in Ig V gene SHM with 40-75% of IgG transcripts totally devoid of mutations in the circulating memory B cell compartment^ref. Deficiency of somatic hypermutation of IgG transcripts is a better predictor of severe respiratory tract infections than lack of memory B cells^ref. Decrease in L-selectin⁺ T lymphocytes^ref. Defective surface expression of attractin on T cells^ref. Impaired bone marrow clonogenic capability, cytokine production, and thymic output^ref. T and B lymphocyte abnormalities are age-dependent and mutually related^ref : CD8⁺HLA-DR⁺ T lymphocytes are increased in patients with impaired memory B-cell differentiation^ref.
Symptoms & signs : protean manifestations, and as a result diagnosis is often delayed until the second or third decade, with resultant irreversible organ damage, in particular bronchiectasis
• furunculosis^ref, recurrent respiratory (Haemophilus spp., Streptococcus pneumoniae, HHV-3 / VZV) and gastrointestinal infections
• 20-30% of the patients develops additional autoimmune phenomena (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis, celiac disease)
• non-Hodgkin lymphomas and adenocarcinomas
• lack of antibody production in response to vaccination
Laboratory examinations :
• Piqueras classification^ref :
• group MB2 (19%) with normal memory B cells
• group MB1 (33%) with defective switched memory (IgD^-CD27⁺) but normal nonswitched memory B cells (IgD⁺CD27⁺)
• group MB0 (47%) with almost no memory B cells
• Warnatz classification^ref :
• CVID type I (77%) : class switched memory B cells (CD19⁺27⁺IgD^-IgM^-IgG⁺ or IgA⁺) in their peripheral blood < 0.4% : intrinsic signalling or expression defect for CD70/CD86 at the level of naive B cells^ref
• CVID type II (23%)  : class switched memory B cells (CD19⁺27⁺IgD^-IgM^-IgG⁺ or IgA⁺) in their peripheral blood > 0.4%
• the size of the peripheral CD19^hiCD2^lo/neg B cell pool as a marker for CVID patients with autoimmune cytopenia and splenomegaly^ref
Therapy :  3-4-weekly infusions of IVIg
Prognosis : the occurrence of granulomatous inflammation is associated with a worse prognosis compared with CVID patients without granuloma. CVID patients who are seropositive for anti-IgA antibodies have a predisposition for anaphylactoid reactions to IVIg. Among 88 CVID patients, 8 had IgG anti-IgA antibodies (9%). All 8 completely lacked IgA (<0.0009 g/l). All 8 IgG anti-IgA-positive patients lacked IgA⁺ B cells in peripheral blood. Moreover, CVID patients with retained class-switched CD27⁺IgM^-IgD^- memory B cells (Freiburg classification group II) and total IgA deficiency seem to have an increased risk for developing anti-IgA antibodies. In 7 of the eight patients, lymphoproliferation was observed (most prominently nodular lymphatic hyperplasia), 2 had granulomatous disease, and 2 showed autoimmune phenomena^ref
• dysgammaglobulinemia / specific antibody deficiency (SAD) : imbalance of isotypes
• IgA deficiency (IgAD)

Epidemiology : is the most common form of primary immunodeficiency and affects approximately 1 of every 600 Caucasian / European individuals and 1 of every 18,500 Japanese individuals.
Aetiology :
• intrinsic : polygenic inheritance
• IGAD1 in the class III MHC locus
• mutations in TNFRSF13B, encoding TACI^ref
• HLA-A1
• HLA-A28
• HLA-B8
• HLA-B14
• HLA-B44
• HLA-DR3
• HLA-DR1
• HLA-DR7
• combinations reflected extended, conserved, or ancestral haplotypes
• HLA-A1-B8-DR3 (the most common haplotype associated with IgAD in Caucasians)
• HLA-A28-B14-DR1
• HLA-B44-DR7
• telomeric part of MHC class III region
• telomeric part of the MHC class II region
In Spanish white IgAD patients, HLA-DR1 and HLA-DR7 are even more frequent than HLA-DR3, reflecting the distribution of HLA-DR alleles and extended haplotypes in southern Europe, where HLA-DRB1*0102 (carried on the B14-DR1 haplotype) and DR7 are more frequent than in northern Europe and the U.S.. Studies performed in Italy have also shown the DRB1*0102 allele and the B14-DR1 extended haplotype as the most frequently associated with IgAD patients in their population.
• extrinsic :
• intrauterine infections
• Toxoplasma gondii
• rubella virus
• HHV-5 / CMV
• drugs
• phenytoin / diphenylidantoin
• D-penicillamine
Pathogenesis : patients are predisposed to chronic respiratory and gastrointestinal infections, allergic bronchial asthma, autoimmune diseases (celiac disease, rheumatoid arthritis, systemic lupus erythematosus, autoimmune thyroid diseases), and non-Hodgkin lymphomas, but some are asymptomatic. The overall incidence of concomitant IgG subclass deficiency found in the IgA deficient group was 18.5%. MBL deficiency was found to be 3.7%
Symptoms & signs : the most common clinical manifestations of antibody deficiency syndromes are repeated and prolonged infections usually involving the respiratory system. Thus, rhinosinusitis, bronchitis, asthma, bronchiectasis, and pneumonia are all well recognized. Patients with Ig deficiencies may also have radiologic and/or functional evidence of interstitial lung disease (ILD), but their frequency and type are incompletely appreciated. Several histologic patterns have been reported in the lungs of patients with CVID, including lymphocytic interstitial pneumonitis (LIP)^ref, granulomatous interstitial pneumonitis^{ref1, ref2}, bronchiolitis obliterans organizing pneumonia (BOOP)^ref, and usual interstitial pneumonitis (UIP)^ref. For the most part, these descriptions come from small series or individual case reports^{ref1, ref2} that are difficult to interpret. Severe infections are more common in patients with combined deficiencies, either IgA and any of the IgG subclasses or IgA and MBL deficiency^ref. Selective IgA deficiency rarely leads to destructive lung disease, unless there is an associated IgG subclass deficiency, especially of IgG₂^ref : ILD leading to restrictive ventilatory abnormality occurs in 20-30% of patients with symptomatic Ig deficiency^ref
Laboratory examinations :
• [IgA]_serum < 5 mg / dL
• immunophenotype : increase in the relative number of CD8⁺ cells and a decrease in the absolute number of CD4⁺ cells compared to healthy people, but similar abnormalities in CVID patients were much more expressed. IgAD patients had significantly decreased expression of HLA-DR and increased expression of CD25 on CD4⁺ lymphocytes, also CD29 expression was decreased on CD8⁺ cells, while other activation/differentiation markers on T cells (including the expression of CD45RA and CD45RO antigens) were not changed. There were no statistically significant abnormalities in B lymphocyte developmental stages in IgAD patients compared to healthy controls^ref
Therapy : symptomatic ; patients need to be followed up regularly as some of them ultimately develop a CVID^ref. Maintenance prophylactic antibiotic or IVIg replacement (if even IgG₂ and IgG₄ subclasses are deficient) is beneficial, but there is a risk of anaphylactic reaction to the latter due to the inherent presence of anti-IgA in some of these patients^ref.
Prognosis : may progress to IgG deficiency^ref and CVID^ref
• selective deficiency of IgG subclasses (with or without IgA deficiency)
• selective IgG₁ deficiency
• selective IgG₂ deficiency (rarely presenting early as transient hypogammaglobulinemia of infancy^ref)

Aetiology : an A-->G transition in the fourth nucleotide in the 5' portion of intron 1 inactivates the normal splice site, and instead, a cryptic splice site in the C_H1 exon is used in RNA post-transcriptional processing, leading to a 16 bp deletion of the g₂ C_H1 exon^ref
• selective IgG₃ deficiency
• antibody deficiency with normal immunoglobulins
• kappa-chain deficiency : first reported in 1976 in a patient with cystic fibrosis with concurrent malabsorption, diabetes mellitus and IgA deficiency. The serum levels of IgM and IgG were 0.85 and 7.22 mg/ml, respectively. k type IgM and IgG was not present in serum and external secretions; g, m and l chains were probably polyclonal in character. Antibodies against k chains were not detected in either the patient or the mother. Plasma cells containing k-type immunoglobulins were absent in jejunum samples and bone marrow; k-chain-bearing B lymphocytes could not be detected in blood and bone marrow. The serum of one of the patient's sisters contained trace amounts of k-type immunoglobulins. The patient displays a complete absence of k-type immunoglobulins, probably owing to a genetic defect^ref. In another case reported in 1985, Both of his C k genes had a single point mutation, resulting in the loss of the invariant tryptophan from one allele and of an invariant cysteine from the other allele. These results indicate that neither of the patient's C kappa alleles encoded a k chain that could form a stable intradomain disulfide bond, although peculiarities in the expression of k chains in the patient's family suggest that other factors may be involved^ref
• light-chain deficiency :
• transient hypogammaglobulinemia of infancy (THI / THGI) : physiologic hypogammaglobulinemia is characterized by a prolongation and accentuation of the physiologic hypogammaglobulinemia normally occurring during the first 3 to 6 months of life (when maternal IgG has decreased and the infant's own synthesis is not yet fully developed). Occasionally, onset of spontaneous adequate immunoglobulin synthesis may be abnormally delayed until 18 and 36 months of age. Infants with THI may remain asymptomatic or develop recurrent sinopulmonary infections, but severe or life-threatening infections are rare. THI was first described by Gitlin and Janeway in 1956^ref. Although Tiller and Buckley reported that THI is rather uncommon^ref, a nationwide survey in Japan indicated that the disorder was evident in 18.5% of all patients with primary immunodeficiency disorders^ref. The causes of THI remain unknown. A previos study described deficiency of helper T cells^ref, but this has not been confirmed by others^{ref1, ref2, ref3}. Although the WHO Scientific Group on Primary Immunodeficiency includes diminished (sometimes extremely diminished^ref) IgG and IgA levels in its definition of THI^ref, the frequency with which different isotypes have been diminished varies from one report to another. Diminished values of IgG are generally considered to be an invariant feature of THI^ref. In contrast, the incidence of diminished IgA and IgM concetrations has ranged from 0% to 100% and 14% to 63% in different reports^{ref1, ref2}. In spite of this relative hypogammaglobulinemia, the number of B- and T-cells and the response of T-cells to mitogens are normal^{ref1, ref2, ref3, ref4}. Isohemagglutinin titers and specific antibody response after immunization are generally in the normal range^{ref1, ref2, ref3}, but live attenuated vaccines are not recommended^ref. McGeady found that acquisition of normal immunoglobulin levels was delayed beyond infancy in some cases, and usually resolved at 2-5 years of age^ref. Moreover, McGeady's study as well as study by Tiller and Buckley^ref found that a subgroup of THI patients did not recover from hypogammaglobulinemia and later developed selective IgA deficiency of other dysgammaglobulinemia. Based on this findings, McGeady argued that the name and definition of THI needs to be reconsidered and the alternative designation "hypogammaglobulinemia of early childhood" was suggested^ref. These findings indicate the importance of long-term follow-up. Indeed, by definition, the diagnosis of transient hypogammaglobulinemia, cannot be established with certainty until after the child's immunoglobulin levels have reached age-appropriate levels. Until that time, every effort should be made to differentiate THI from other more severe forms of primary humoral immunodeficiency such as X-linked agammaglobulinemia (XLA)^ref and CVID. Serum immunoglobulin concentrations, particularly of IgM and IgA, are usually considerably lower in XLA and CVID patients than in patients with THI. In addition, one of the distinguishing characteristics of THI is a normal capacity to synthetize antibodies in response to immunization, a feature that allows easy distinction of THI from XLA and CVID. The clinical manifestations of THI vary from patients who are free from any symptoms to others with recurrent infections (symptomatic hypogammaglobulinemia in infancy and childhood (SHIC))^{ref1, ref2}. However, severe life-threatening infections, such as sepsis and meningitis, have rarely been reported^{ref1, ref2, ref3, ref4}. This category includes term infants with the following characteristics : 1) one or more immunoglobulin classes > 2SD below mean, 2) protective antibody titer to tetanus and diphtheria, 3) intact cellular immunity, 4) no features of other syndromes. The children are 69.4% male and have recurrent otitis media (77.6%), wheezing (61.2%), and atopy (26.5%). Diminished IgA (95.9%) is most common, but 65.3% have multiple isotypes diminished. During follow-up, 51% normalize immunoglobulins, of whom 80% are male; only 48% normalize in infancy. Female immunoglobulin normalization was significantly delayed (p < .001). No deaths or serious infections occurred. This phenotype is predominantly seen in male infants with otitis media and wheezing^ref. Sometimes associated with transient erythroblastopenia of childhood (TEC)
In patients with idiopathic humoral immunodeficiencies, assessment of B cell switching more accurately predicts clinical prognosis than either classification of patients into SAD and CVID or serum immunoglobulin concentrations^ref.
Summary of alterations in serum immunoglobulins :

	IgD (n.v. 0.3-14 mg/dl)	IgM (40-280 mg/dl)	IgG (700-1600 mg/dl)	IgA (70-400 mg/dl)	IgE (< 0.025 mg/dl or < 150 E/l)
hyper-IgM	?	+/=	-	-	=
hyper-IgE	?	=	=	=	+
Omenn's syndrome					+
CVID	?	-	-	-	-
IgAD	?	?	?	-	?
IgG deficiency	=	=	-	=	=
liver cirrhosis	?	?	?	+	?
THI	?	-/=	-	-/=	?
HIDS	+			IgA1 +	+
WAS				+	+

• other well-defined immunodeficiencies syndromes
• IFNGR1 deficiency

Aetiology :
• nonsense^ref and splice^{ref1, ref2, ref3} mutations and frameshift insertions^ref and deletions^{ref1, ref2, ref3} all result in a premature stop codon upstream from the segment encoding the transmembrane domain, precluding cell surface expression of the receptors. The mutations affect different nucleotides in the IFNGR1 coding region, and neither founder nor recurrent mutations have been identified. However, all the reported mutations share two features. First, they are located in the segment encoding the extracellular domain of the receptor. Second, they result in a premature stop codon upstream from the region encoding the transmembrane domain, thereby precluding expression of the receptors at the cell surface. No IFNR1 molecules are detected at the cell surface by flow cytometry with specific mAb’. The cells of patients have been shown not to respond to IFN-g^ref in experiments with freshly prepared PBMCs^{ref1, ref2, ref3}, HHV-4 / EBV-transformed B-cell lines^ref, and SV40-transformed fibroblast cell lines^ref. Molecular complementation of the cellular defect by transfection with the wild-type IFNGR1 gene has demonstrated a causal relationship between the IFNGR1 mutations and the cellular phenotype^ref.
• mutations disrupting the IFN-g-binding site without affecting surface expression. 2 in-frame deletions and two missense IFNGR1 mutations were identified in the segment encoding the extracellular ligand-binding domain of the receptor^ref

Symptoms & signs : a rare, life-threatening, autosomal recessive human immune deficiency, unless allogeneic HSCT is undertaken (MIM107470) (McKusick, V.A. 1998. Mendelian inheritance in man: a catalog of human genes and genetic disorders. 12th edition. The Johns Hopkins University Press. Baltimore, Maryland, USA. 1930 pp..; Casanova, J.L., Newport, M., Fischer, A., and Levin, M. 1999. Inherited interferon gamma receptor deficiency. In Primary immunodeficiency diseases. H.D. Ochs, C.I.E. Smith, and J.M. Puck, editors. Oxford University Press. New York, New York, USA. 209–221). Affected children invariably develop disseminated bacille Calmette-Guérin (BCG) infection shortly after inoculation with live BCG vaccine^{ref1, ref2, ref3, ref4}. Rare survivors and nonvaccinated children develop severe infections caused by environmental non-tuberculous mycobacteria (NTM) in early childhood (which requires differential diagnosis with Langerhans' cell histiocytosis^ref)^{ref1, ref2, ref3, ref4, ref5}. Other clinical infectious diseases have been reported, but they are much less frequent and severe^{ref1, ref2}. The pathogens identified include intracellular bacteria, such as Salmonella spp.^ref and Listeria spp.^ref, and viruses, such as varicella-zoster virus^{ref1, ref2} and HHV-5 / CMV^{ref1, ref2}. Mycobacterial granulomas are often multibacillary and in all cases are poorly delimited (no surrounding lymphocytes) and differentiated (no epithelioid or giant multinucleated phagocytic cells). Affected children generally die in childhood because antibiotics do not give sustained remission of mycobacterial disease and IFN-g therapy is ineffective in the absence of specific receptors. Bone marrow transplantation is the only curative treatment available^ref
• IFNGR2 deficiency
• impaired cellular IFN-a/b and -l antiviral responses

Aetiology : autosomal recessive mutations in UNC93B1
Symptoms & signs : HSV-1 encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies^ref
• IL-12Rb₁ deficiency

Pathogenesis : disseminated infections from BCG and minor Salmonella spp.
• STAT1 deficiency

Aetiology : heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-a/b signaling pathway have been described^ref. 2 unrelated infants were reported homozygous with respect to mutated STAT1 alleles. Neither IFN-a/b nor IFN-g activated STAT1-containing transcription factors. Like individuals with IFN-gR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-a/b in cell lines from the 2 individuals. Inherited impairment of the STAT1-dependent response to human IFN-a/b thus results in susceptibility to viral disease^ref
• IRAK4 deficiency

Symptoms : recurrent infections caused by pyogenic bacteria
• spindle cell thymoma-associated immunodeficiency
• Wiskott-Aldrich syndrome (WAS) : Alfred Wiskott (1898–1978), a German authority on childhood pneumonias, first described the clinical syndrome in 1937 (Wiskott A. Familiarer, angeborenen Morbus Werhoffi? Monatschr. Kinderheilk. 68:212-216 (1937)), noting that it affected three brothers but not their sisters. In 1954, Robert Aldrich (1917–1998) and colleagues published an independent description of a large Dutch kindred in which segregation analysis showed X-linked recessive inheritance (Aldrich RA, Steinberg AG & Campbell DC. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea. Pediatrics 13:133-138 (1954)). By the mid-1960s, many additional cases had been recognized, and the clinical syndrome became known by the names of both pediatricians

Epidemiology : estimated incidence of < 1 in 100,000 births
Aetiology : X-linked mutations in WASp, located at Xp11.22–p11.23 and cloned in 1994^{ref1, ref2, ref3} (Ancliff PJBM, Gale RE. Activating mutations in the Wiskott-Aldrich syndrome protein may define a sub-group of severe congenital neutropenia (SCN) with specific and unusual laboratory features. Blood 2001;98:439-439). > 160 different WAS mutations (> 50% unique) spanning all 12 exons of the gene have been found in more than 270 unrelated families. The unique 73–74delAC null mutation — a dinucleotide deletion in WAS exon 1 — carried by relatives of the boys Wiskott described was found in 2006^ref : even more gratifying is the authors' report of the successful cure, by transplantation of bone marrow from a matched, unrelated donor, of the affected boy in the current generation of the family — the original brothers' first cousin twice removed. In the span of two generations, a fatal condition has become treatable.
Pathogenesis : inability to produce antibodies to polysaccharide antigens and increased susceptibility to infection by capsulated bacteria (Haemophilus influenzae, meningococcus, pneumococcus). Female carriers of X-linked disorders are generally asymptomatic, but affected carriers with symptomatic WAS have been discovered. Some of these women had unbalanced X-chromosome activation. Moreover, researchers have discovered missense WAS mutations with variant phenotypes, either of mild disease or unexpected isolated neutropenia, illuminating how WASP folds onto itself in vitro and interacts with other proteins. In particular, in its resting state, WASP has a looping autoinhibitory structure, with its C-terminal portion (verprolin–central–acidic domain) involved in intramolecular binding to the central GTPase binding domain. The binding of activated GTPase to the GTPase binding domain is thought to release the folded structure, allowing the VCA domain to interact with the cellular Arp2/3 complex. Other WASP domains mediate the interaction with several important protein partners. For example, the WASP homology domain binds to the WASP interacting protein, a crucial regulator of WASP function; the basic region interacts with phosphatidylinositol 4,5-bisphosphate, which also activates WASP; and it has been suggested that the proline-rich region interacts with a variety of additional proteins, including tyrosine kinases (FYN, HCK, and BTK), adaptors (NCK, GRB2, and intersectin-2), and cytoskeletal components (proline–serine–threonine phosphatase-interacting protein and profilin). The function of WASP as a major regulator of actin polymerization and cytoskeleton reorganization explains many, though not all, clinical features of the disease as consequences of impaired intracellular actin-dependent events. For example, WASP plays a role in the remodeling of the cytoskeleton that is required to establish the immunologic synapse between T cells and antigen-presenting cells. Defects in WASP prevent formation of the synapse, resulting in defective T-cell activation. The inability to establish functional contact between T cells and antigen-presenting cells accounts for the T-cell immunodeficiency that is characteristic of patients with the WAS. Actin polymerization and cytoskeleton reorganization are also critical for cell motility, which they affect by means of podosomes that adhere to the extracellular matrix. In this way, the abrogation of WASP function impairs the adhesion, locomotion, and homing of B cells, monocytes, macrophages, and dendritic cells. These defects are also believed to contribute to the immunodeficiency phenotype of the syndrome. The functional roles of WASP in the development of thrombocytopenia and eczema, however, remain unclear. An additional fascinating aspect of the WAS is the high incidence of somatic revertant mosaicism among affected patients. A wide range of changes at the primary mutation site, including true genetic reversions to the wild-type sequence, silent nucleotide substitutions, and compensatory or second-site mutations of WAS that restore the reading frame or otherwise correct the genetic defect, have been found in many patients with the syndrome. A reversion event is thought to occur in a single hematopoietic progenitor, the progeny of which may accumulate over time. This phenomenon is consistent with a selective advantage in the survival and proliferative capacity of cells that express functional WASP. Although there is no proof that spontaneous clinical improvement in some patients is the result of revertant lymphocytes, these natural somatic correction events suggest that there may someday be effective gene therapy for the WAS, despite the low efficiency of current gene-transfer techniques^ref.
Symptoms & signs :  it has a broad range of phenotypes^{ref1, ref2, ref3} (Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. In: Ochs HD, Smith CIE, Puck JM, eds. Primary immunodeficiency diseases: a molecular and genetic approach. New York: Oxford University Press, 1999:292-305) : mutations in the WAS gene result in truncated or absent WASP in these cells, but there is no strict correlation between the mutant genotype and the expression of WASP or the phenotype of the syndrome^{ref1, ref2, ref3, ref4, ref5}. Hypereosinophilia, thrombocytopenia with small platelets (low platelet volume) => petechiae and bruising, bloody diarrhea may develop in the first days of life. Unusually prolonged bleeding after circumcision often leads to the discovery of the thrombocytopenia. Eczema — which may be severe — ensues, and throughout childhood there may be frequent episodes of otitis media, pneumonia, and diarrhea. Even sepsis or meningitis may occur. Increased risk for autoimmune diseases and B-cell non-Hodgkin's lymphomas

Laboratory examinations : IgM is low and IgA and IgE are elevated; cutaneous anergy is common.
Treatment :
• allogeneic HSCT : the first reports on the results of bone marrow transplantation in the WAS and SCID were published back-to-back in the Lancet by the teams of Mortimer M. Bortin and Robert A. Good, respectively, in 1968^ref
• gene therapy.
Web resources : WASPbase: database of published WAS gene mutations
• ataxia teleangiectasia
• X-linked lymphoproliferative (XLP) disease (XLPD) or syndrome / Duncan disease / Purtilo syndrome^ref

Aetiology :
• mutations in SAP / SH2D1A (60%), an adaptor that associates with SLAM family receptors and enables tyrosine phosphorylation signaling by these receptors through SAP-mediated recruitment of Src-related kinase Fyn.
• mutations in X-linked inhibitor-of-apoptosis (XIAP) / BIRC4 that lead to defective expression were identified in patients with XLP from 3 families : apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the TCR–CD3 complex, the death receptor CD95 and the TRAIL-R. XIAP-deficient patients, like SAP-deficient patients, have low numbers of NKT lymphocytes, indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV^ref
Pathogenesis : a functional SAP/Fyn pathway may be required for the efficient recruitment of PKC-q and BCL10, as well as proper patterns of activation of NF-kB1/p50 and T_h2 polarization of activated T lymphocytes^{ref1, ref2}
Symptoms & signs : > 50% of patients suffer from an extreme susceptibility to HHV-4 / EBV. 33% of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. In SH2D1A^-/- mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because GCs were absent in SH2D1A^-/- mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, it was examined whether SH2D1A^-/- B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed SH2D1A^-/- mice with CD4⁺ T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2D1A are essential for B cell activities resulting in antigen specific IgG production. Defects in naïve SH2D1A^-/- B cells became evident upon cotransfer with nonprimed wt CD4⁺ cells into Rag2^-/- recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of XLPD patients without involvement of EBV. Patients exposed to EBV have a severe and often fatal massive proliferation of abnormal T lymphocytes and decreased humoral responses. Those individuals who survive the EBV infection have a significant risk of developing lymphomas^ref. It is unclear which aspects of XLP disease are specific to herpesvirus infection and which reflect general immunological functions performed by SAP. SAP^- mice were examined during a chronic LCMV infection, specifically to address the question: which SAP-deficiency immunological problems are general, and which are EBV-specific? Illness, weight loss, and prolonged viral replication were much more severe in SAP^- mice. Aggressive immunopathology was observed. This inability to control chronic LCMV was associated with both CD8⁺ T cell and B cell response defects. Importantly, SAP^- CD8⁺ T cells are the primary cause of the immunopathology and clinical illness, as depletion of CD8 T cells blocked disease^ref.
• immunodeficiencies secondary or associated with other diseases
• chromosomal instability and repair defects
• Bloom syndrome
• Fanconi anemia
• immunodeficiency-centromeric instabilities-facial anomalies (ICF) syndrome
• Nijmegen breakage syndrome (NBS)
• Seckel syndrome
• xeroderma pigmentosum (XP)
• chromosomal defects
• Down syndrome
• Turner syndrome
• rings or deletions in chromosome 18 (18p- and 18q-)
• skeletal anomalies
• dwarfism with short limbs (short-limbed skeletal dysplasia)
• cartilage and hair hypoplasia (chondroplasia of metaphyses)
• immune deficiency with generalized growth retard
• Schimke-type immunoosseous dysplasia
• Dubowitz syndrome
• kyphomelic dysplasia with SCID
• Mulibrey dwarfism
• growth retardation, facial anomalies and immune deficiency
• progeria (Hutchinson-Gilford syndrome)
• immune deficiency with dermatological defects
• ectodermal dysplasia-ectrodactyly
• immune deficiency with lack of toes (pseudoainhum), and congenital deafness and ichthyosis
• partial albinism and immunodeficiency syndrome
• congenital dyskeratosis
• Netherton syndrome
• anhidrotic ectodermal dysplasia with immune deficiency (AED-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in NF-kB activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients' cells showed an impaired, but not abolished, NF-kB activation in response to a large set of stimuli, including TLR agonists. More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients' cells showed a specific impairment of the IRAK signalling pathway. NFkB- and MAPK pathways are impaired in response to all TIR agonists tested. These data, therefore, suggest that TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans^ref
• Papillon-Lefèvre syndrome
• congenital ichthyosis
• inherited metabolic defects
• acrodermatitis enteropathica : Zn malabsorption or deficitary intake
• transcobalamine 2 deficit
• type II hereditary oroticaciduria
• immunodeficiency with untreatable diarrhoea, abnormal facies and trichorrhexis
• methylmalonic acidemia
• multiple biotin-dependent carboxylase deficit (MCD) : holocarboxylase synthetase
• mannosidosis
• type 1b glycogenosis
• Chediak-Higashi syndrome (CHS) : reduced NK response
• Griscelli syndrome / hypopigmentation-immunodeficiency disease : an albinoidism of autosomal recessive inheritance, marked by hypomelanosis, frequent pyogenic infection, hepatosplenomegaly, neutro- and thrombopenia, and possible immunodeficiency
• hypercatabolism of immune globulins
• familial hypercatabolic hypoproteinemia
• intestinal lymphangiectasia
• others
• Ivemark syndrome
• congenital or hereditary hypo- or asplenia
• impairing complement cascade
• classical activation pathway (=> decrease of CH₅₀)
• C1q deficiency

Aetiology : point mutations
Symptoms & signs : immune complex syndrome, infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID)
• C1r deficiency

Aetiology : ?
Symptoms & signs :  immune complex syndrome, infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
• C1s deficiency

Aetiology : point mutations
Symptoms & signs :  immune complex syndrome, infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
• C4A / B deficiency

Aetiology :
• partial deficiency
• 1. complete gene deletion
• 2. gene conversion (isotype change)
• 3. nonexpression due to 2-bp insertion >> stop codon
Symptoms & signs : SSPE (C4A Q0), autoimmune diseases (SLE, PBC, AIH, SSc), infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID), SDS-PAGE
• C2 deficiency (C2D)

Aetiology :
• type I C2D : G954T transversion, 28-bp deletion at exon/intron junction 6 (linked to HLA-A25, HLA-B18, HLA-C2Q0, HLA-C4A4,B2, HLA-DR2) => MaeII RFLP and E298D mutation => splicing error => no synthesis
• type II C2D : G392A transition => C111Y mutation => impaired secretion
Symptoms & signs : immune complex syndrome (membranoproliferative glomerulonephritis^ref), rarely with infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp.), linear scleroderma 'en coup de sabre'^ref
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID), electrophoresis
• C1INH deficiency => Quincke's hereditary angioneurotic edema (HANE)

Aetiology : various point mutations and small deletions, exon deletions due to Alu repeat recombinations
• type 1 (HAE I) : loss of gene expression (80%)
• type 2 (HAE II) : loss of function (20%)
• type 3 (HAE III) : albumin-bound C1-INH protein without functional activity, which can be differentiated from the C1-INH protein of HAE II by electrophoresis
• type 4 ( HAE IV)
Symptoms & signs : angioedema, rare immune complex diseases, rarely with infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
Laboratory examinations : function, reduced levels of C1,C4,C2
Therapy :
• attenuated androgens
• fibrinolytic drugs
• C1-INH
• B₂ receptor antagonists
• kallikrein inhibitors
Web resources : HAEdb: an interactive, locus-specific mutation database for the C1INH gene
• alternative activation pathway (=> decreased AP₅₀)
• factor B deficiency

Aetiology : n.d., only heterozygotes detected
Symptoms & signs : clinically inapparent
Laboratory examinations : AP50, RID, electrophoresis
• factor D deficiency

Aetiology :  T638 > G (Val213 > Gly) and a T640 > C (Cys214 > Arg) ^ref
Symptoms & signs : infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis)
• properdin deficiency, X-linked

Aetiology : various point mutations causing stop codons, frame shifts and amino acid substitutions
Symptoms & signs : nonrecurrent, fulminant infections from Neisseria meningitidis, sepsis
Laboratory examinations : AP50
• factor I deficiency

Aetiology : Alu repeat-induced mutation
Symptoms & signs : meningitis, infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
Laboratory examinations : CH50, RID, reduced C3 levels
• factor H deficiency

Aetiology : 4-bp deletion >> stop codon, point mutations >> Cys substitutions (impaired secretion), stop codon
Symptoms & signs : HUS, Neisseria spp. infections, glomerulonephritis
Laboratory examinations : AP50, RID, reduced C3 levels
• C8BP, CD55 / decay accelerating factor (DAF), and CD59 / MIRL / protectin / HRF-20 / MACIF GPI anchor defect in paroxysmal nocturnal hemoglobinuria (PNH)

Laboratory examinations : FACS analysis, Ham test
• CD11bCD18 / a_Mb₂ integrin / Mac1 / CR3 deficiency (and LFA-1, gp150,95)

Aetiology : deficiency of common b chain LCAM-B
Symptoms & signs : recurrent bacterial skin infections
Laboratory examinations : FACS analysis
• C3 deficiency

Aetiology :
• various independent point mutations
• an amino acid substitution in the b-chain (ASP549 to ASN) impairs C3 secretion^ref
• 800bp deletion due to Alu repeat-induced mutation
Symptoms : immune complex syndrome (glomerulonephritis), infections from pyogenic capsulated Bacteria (i.e. not subjected to non-immune phagocytosis; e.g. Streptococcus pneumoniae, Haemophilus influenzae)
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID), electrophoresis
• common lytic pathway (=> decrease of CH₅₀ and AP₅₀)
• C5 deficiency

Aetiology : nonsense point mutation (exon 1 (C84AG to TAG), exon 36 (C4521GA to TGA)^ref) >> stop codon
Symptoms & signs : relapsing infections from Neisseria spp.^{ref1, ref2}, immune complex syndrome
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID)
• C6 deficiency

Aetiology : partial deficiency: splice site mutation >> loss of exons 16 & 17 (3' truncation)
Symptoms & signs : relapsing infections from Neisseria spp., immune complex syndrome
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID)
• C7 deficiency

Aetiology : various independent point mutations and 1-bp deletions >> stop codons, substitutions, splice site mutations; deletion of exons 7 and 8
Symptoms & signs : relapsing infections from Neisseria spp., immune complex syndrome
Laboratory examinations : complement haemolytic activity (CH₅₀), radial immunodiffusion (RID)
• C8 deficiency

Aetiology :
• type I / C8A gene :
• type II / C8B gene : point mutation in exon 9 >> stop codon (common); also other rare mutations
Symptoms & signs : relapsing infections from Neisseria spp., immune complex syndrome
Laboratory examinations : complement haemolytic activity (CH₅₀), SDS-PAGE
• C9 deficiency

Aetiology : point mutations >> stop codon, Cys substitution
Symptoms & signs : rare infections from Neisseria spp.
Laboratory examinations : radial immunodiffusion (RID)
• combined deficiencies :
• combined complete C5 and partial C4A / B deficiency^ref
• combined homozygous factor Hand heterozygous C2 deficiency^ref
Laboratory examinations : CH₅₀ or the APH₅₀ assay.

• Australian primary immune deficiency Yahoo group
• Primary Immunodeficiency Association (PIA)

• type 1 (APS1 / PGA-1)) / autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Epidemiology : 15-45 cases every 10⁶ people; in childhood.
Aetiology : autosomal recessive inheritance due to loss-of-function mutations in autoimmune regulator (AIRE). AIRE is involved in the ectopic expression of organ-specific antigens by medullary thymic epithelial cells (mTEC) during negative selection of T lymphocytes : the absence of AIRE results in the decreased expression of 100-300 genes and the 30 genes that are down-regulated to the greatest extent encode mainly tissue-specific proteins, several of which are known to be target of autoimmunity in patients with APS1, such as insulin,cytochrome P450 family members, and U2AF1.
Symptoms & signs :
• endocrine disorders
• in early childhood
• mucocutaneous candidiasis from Candida spp. (chiefly Candida albicans) before age 5 (75%)
• associated endocrinopathies
• autoimmune Addison's disease before age 15 (60%)
• hypoparathyroidism before age 10 (89%)
• premature ovarian failure (POF) (45%)
• Hashimoto's thyroiditis (12%)
• type-1 diabetes mellitus (1%)
• nonendocrine disorders
• celiac disease (25%)
• alopecia areata or totalis (20%)
• pernicious anemia due to type A gastritis (16%)
• autoimmune hepatitis (AIH) (9% : anti-CYP1A2)
• vitiligo (autoantigens : SOX9 and SOX10) (4%)
• type 2 (APS2 / PGA-2) / Schmidt's syndrome

Epidemiology: 1 case every 25,000 people ; in adulthood
Aetiology : polygenic autosomal dominant inheritance associated with HLA-DR3, HLA-B8 and HLA-DQ (HLA-DQA1*0301);  viral infection triggering the disease process
Symptoms & signs :
• endocrine disorders
• autoimmune Addison's disease (100%)
• autoimmune thyroid disease (AITD) (70%)
• type-1 diabetes mellitus (50%)
• premature ovarian failure (POF) (1-50%)
• nonendocrine disorders
• vitiligo (autoantigens : SOX9 and SOX10) (4%)
• others (1%)
• myasthenia gravis
• alopecia areata or totalis
• pernicious anemia due to type A gastritis
• thrombotic thrombocytopenic purpura
• rheumatoid arthritis
• type 3 (PGA3 / APS3)

Aetiology : HLA-DQA1*0301
Symptoms & signs :
• autoimmune thyroid disease (AITD) (the most frequent disease)
• one other organ-specific autoimmune disorder other than autoimmune Addison's disease
• type 4 (PGA4 / APS4)

Symptoms & signs :
• autoimmune Addison's disease
• other autoimmune diseases excluding autoimmune thyroid disease (AITD) and type-1 diabetes mellitus

• Canale-Smith syndrome (CSS)

Epidemiology : approximately 70 known cases described worldwide
Aetiology : germline mutations in the CD95 / Fas / Apo-1 gene^ref
Pathogenesis : defective apoptosis in activated lymphocytes; may develop into lymphoproliferative disease after early exposure to HHV-4 / EBV
Symptoms & signs : congenital massive lymphadenitis, hepatomegaly, splenomegaly and systemic autoimmunity to erythrocytes and platelets (in the latter case, autoantibodies have the same specificity than in idiopathic thrombocytopenic purpura)
Laboratory examinations : increased number of double negative T cells (DNTs) CD3⁺CD57⁺CD4^-CD8^-, usually ab-TcR, rarely gd-TcR^ref
Therapy : autoimmune cytopenias are difficult to treat; in a case report thrombocytopenia resistant to conventional therapy but which responded to a combination of rituximab and vincristine^ref. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized rapamycin would be effective in treating ALPS. This hypothesis was tested using rapamycin in murine models of ALPS. Treatment response was followed with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by ELISA for anti-dsDNA antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at sacrifice (r=0.9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin treated mice to control. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. Rapamycin was compared to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior^ref
• type II autoimmune lymphoproliferative syndrome

Aetiology : mutations in caspase 10.

hereditary periodic fever syndromes / hereditary autoinflammatory disorders are a group of systemic disorders characterized by recurrent attacks of systemic inflammation (autoinflammation) without infectious or autoimmune cause, resulting from a defect of the innate immune response^ref (Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions (15th ed). Philadelphia: Lippincott Williams and Wilkins; 2005:1411–1461), initially described as affecting primarily the serosal and synovial surfaces and the skin, but now recognized to include a somewhat broader distribution of affected tissues. The hereditary periodic fevers differ from autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis in that they lack high-titer autoantibodies or antigen-specific T-cells; they are termed autoinflammatory diseases to highlight this distinction

• hyper-IgD syndrome (HIDS) / Dutch type periodic fever

Epidemiology : first described in the Netherlands and still diagnosed most often in Northern Europeans^ref
Aetiology : specific autosomal recessive mutations in the gene encoding mevalonate kinase (MVK) on chromosome 12q24, resulting in depressed enzymatic activity. Different mutations in the same enzyme cause mevalonic aciduria, characterized by psychomotor retardation, cerebellar ataxia, recurrent fever attacks, and death in early childhood. Adults with phenotypic overlap between these 2 syndromes have been identified, which argues for a continuous spectrum of disease^ref
Symptoms & signs : recurrent fever, increased serum IgD (normal value < 100 U/ml) and generalized inflammation (lymphadenopathy, arthralgias/arthritis, abdominal complaints, skin rash, and headache). The attacks persist during the entire life although frequency and severity tend to diminish with age. Attacks often begin during the first year of life, lasting 3–7 days, and are sometimes triggered by childhood immunizations. Concomitant findings may include headache, abdominal pain, prominent cervical lymphadenopathy, polyarthralgia or polyarticular arthritis, diffuse maculopapular rash, and aphthous ulcerations^ref.
Laboratory examinations : as in FMF and TRAPS, HIDS attacks are accompanied by leukocytosis and elevated acute-phase reactants. Serum polyclonal IgD levels are also elevated in most HIDS patients, regardless of whether they are experiencing an attack, but do not correlate with disease severity, either over time for any given patient or when comparing patients. Increased serum IgD levels have also been observed in the minority of patients with FMF^ref and TRAPS^{ref1, ref2}, but the magnitude is usually much less in these latter 2 conditions. In contrast with FMF or TRAPS, systemic amyloidosis is extremely rare in HIDS, although it has been reported^ref.
Pathogenesis : in 1999 2 groups, using complementing positional and functional approaches, identified HIDS-associated mutations in MVK, an 11-exon gene on chromosome 12q that encodes the mevalonate kinase (MK) enzyme^{ref1, ref2}. MK catalyzes the conversion of mevalonic acid to 5-phospho-mevalonic acid in the synthesis of a number of important molecules, including cholesterol, vitamin D, bile acids, steroid hormones, and nonsterol isoprenoids. HIDS-associated mutations leave some residual enzymatic activity, while more profound mutations in MVK that totally ablate enzymatic activity cause mevalonic aciduria, a rare condition manifesting not only periodic fevers but also a number of other severe developmental abnormalities. Currently over 35 HIDS-associated mutations have been described^ref, and they are distributed throughout the 396 aa MK protein. The mutations associated with mevalonic aciduria cluster around the active sites of the enzyme^{ref1, ref2}. Recognition of the molecular genetic basis of HIDS permits the use of genetic testing and/or screening for urinary mevalonate (during attacks) to help establish the diagnosis. This is especially helpful in the minority of patients with borderline or normal serum IgD levels. In vitro studies suggest that HIDS-mutant MK functions best at 30°C, with progressive decreases in function at 37°C and 39°C^ref. This observation may account for the association of HIDS attacks with immunizations and infections, and may also explain the increased urinary mevalonate levels observed during HIDS attacks. It is unlikely that IgD plays a primary role in the pathogenesis of HIDS, given the poor correlation of IgD levels with disease severity, and the identification of occasional patients with the HIDS phenotype and MVK mutations but persistently normal IgD levels^{ref1, ref2, ref3}. Diminished cholesterol biosynthesis also appears an unlikely mechanism of disease, since HIDS patients generally have low-normal serum cholesterol levels, and more severe disorders of cholesterol synthesis do not exhibit a HIDS-like phenotype. Instead, current thinking on the pathogenesis of HIDS focuses either on the accumulation of mevalonic acid or the shortage of isoprenoids. Favoring the latter hypothesis are in vitro data demonstrating accentuated IL-1ß secretion by leukocytes from HIDS patients that can be reversed by the addition of farnesol or geranyl-geraniol^ref. Possibly, the small guanoside triphosphate-binding proteins, which undergo farnesylation or geranylation, may be the link between the mevalonate pathway and the innate immune system^ref
Therapy : there are currently no established therapies for HIDS, although TNF inhibition and HMG-CoA reductase inhibitors^ref are investigational (Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions (15th ed). Philadelphia: Lippincott Williams and Wilkins; 2005:1411–1461)
• cryopyrinopathies are a spectrum of clinical disorders caused by mutations in CIAS1^{ref1, ref2, ref3, ref4}, a 9-exon gene on chromosome 1q44 encoding a protein that has variously been denoted NALP3 / CIAS1 / PYPAF1 / CATERPILLER 1.1 / cryopyrin. The full-length cryopyrin/NALP3 protein is 920 aa in length, and consists of 3 major domains: an N-terminal PYRIN domain (aa 13–83) similar to the N-terminal domain of pyrin, a central NACHT domain (aa 217–513) that appears to be important both in intra- and inter-molecular interactions, and a C-terminal tandem array of 7 leucine rich repeats (LRR, aa 697–920). Nearly all of the > 40 known mutations in cryopyrin^ref are missense substitutions in the NACHT domain, encoded by exon 3 of CIAS1. Cryopyrin/NALP3 has been shown to play an important role in the regulation of IL-1ß activation through its participation in a macromolecular complex denoted the NALP3 inflammasome^ref. In addition to cryopyrin/NALP3, this complex includes ASC, caspase-1 (which cleaves pro-IL-1ß to produce biologically active IL-1ß), and Cardinal, a caspase-recruitment domain-containing protein. The NALP3 inflammasome is a potent activator of IL-1ß, and macrophages from patients with MWS spontaneously secrete active IL-1ß. Through its LRR, cryopyrin/NALP3 binds muramyl dipeptide^ref, a component of the bacterial cell wall, an event that increases inflammasome activity. Moreover, this process appears to be accentuated in the macrophages of patients with MWS.


Activation of IL-1ß through the cryopyrin/NALP3 inflammasome. On the lower left, the major domain structure of cryopyrin is depicted. Interaction of cryopyrin with muramyl dipeptide (MDP) is thought to activate cryopyrin and allow it to interact with the other components of the inflammasome. In the upper left, activated cryopyrin binds ASC through cognate PYRIN-PYRIN domain interactions. ASC, in turn, binds caspase-1 through homotypic interactions of their caspase recruitment (CARD) domains (upper right). This complex then binds Cardinal, which has recruited a second caspase-1 molecule. The full assembly of this macromolecular complex, the inflammasome, induces proximity of the catalytic domains of the 2 caspase-1 molecules, leading to autocatalysis. The released catalytic domains are then available to activate pro-IL-1ß to its biologically active form, which mediates fever and inflammation. Abbreviations: PYD, PYRIN domain; NACHT, the nucleotide-binding domain of cryopyrin; LRR, leucine-rich repeat; FIIND, a domain of Cardinal that interacts with cryopyrin; CARD, caspase-recruitment domain.
Although a number of overlap syndromes have been described, 3 relatively distinct clinical disorders are recognized : an urticaria-like rash is common to all of the cryopyrinopathies and is characterized histologically by infiltrates of lymphocytes and neutrophils rather than mast cells, indicating that it is not true urticaria.
• familial cold urticaria (FCU) / familial cold autoinflammatory syndrome (FCAS) is characterized by episodes of fever, urticaria-like rash, and polyarthralgia, usually precipitated by generalized exposure to the cold and lasting about 12 hours

Therapy : pretreatment with the IL-1ß receptor antagonist anakinra effectively prevented clinical symptoms or acute-phase elevations in patients with FCAS exposed to cold temperatures^ref.
• Muckle-Wells syndrome (MWS) / urticaria-deafness-amyloidosi (UDA) syndrome

Pathogenesis : constitutive activation of NALP3 inflammasome => monocytes isolated from a patient produce IL-1b even in absence of stimulation, whereas monocytes from healthy individuals only produce it after activation with LPS^ref
Symptoms & signs : attacks are not usually precipitated by cold exposure but include the same urticaria-like rash as well as fever, malaise, limb pain, and, at times, abdominal pain, conjunctivitis, and arthralgia. Sensorineural hearing loss and/or systemic AA amyloidosis may also develop involving the kidneys and causing nephritis
Therapy : anakinra also induced a complete remission of clinical symptoms and biochemical changes in MWS^{ref1, ref2}.
• chronic infantile neurologic, cutaneous and articular (CINCA) syndrome / neonatal-onset multisystem inflammatory disease (NOMID)

Aetiology : mutations in CIAS1, mostly newly occurring ones, are present in about 60% of children who receive a clinical diagnosis of the disease. Patients with and those without CIAS1 mutations have similar disease phenotypes^ref
Symptoms & signs : the most severe of the cryopyrinopathies, develops within the first 6 weeks of life and often exhibit nearly continuous disease activity that fluctuates in severity. It shows characteristic bony overgrowth predominantly involving the knees in most affected children. In addition to the fevers, arthralgia, hearing loss, and amyloidosis seen in MWS, patients with NOMID/CINCA often develop a deforming arthropathy and central nervous system involvement that can include chronic aseptic meningitis, intracranial hypertension, cerebral atrophy, ventriculomegaly, and chronic papilledema, with associated optic-nerve atrophy and loss of vision, mental retardation, seizures, and sensorineural hearing loss. Other manifestations include short stature, hepatosplenomegaly. Factors determining the phenotype of the disease include the type of mutation and the patient's genetic background^ref
Laboratory examinations : leukocytosis, and an elevation in serum levels of amyloid A and CRP and in the ESR. Eosinophilia or coagulopathy can also be seen in some patients with NOMID/CINCA
Therapy : aimed at suppressing inflammation and have included high-dose corticosteroids, disease-modifying antirheumatic drugs, and biologic agents targeting TNF. Although these medications are moderately effective, inflammation persists in most children. In a series of 18 patients with NOMID/CINCA, anakinra doses of 1–2 mg/kg/d resulted in a resolution of uveitis, rash, and fever and a significant decline in cerebrospinal fluid pressure^{ref1, ref2, ref3} (Granel B, Serratrice J, Disdier P, Weiller PJ. Dramatic improvement with anakinra in a case of chronic infantile neurological cutaneous and articular (CINCA) syndrome. Rheumatology (Oxford) 2005;44:689-690). All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg/l), C-reactive protein (from a median of 5.29 mg to 0.34 mg/dl), and the ESR decreased at month 3 (all P<0.001), and remained low at month 6. MRI showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra at 3 months uniformly resulted in relapse within about 5 days; retreatment led to rapid improvement. There were no drug-related serious adverse events^ref.
Prognosis : a 20% mortality rate has been reported before adulthood^ref
Therapy : the newly recognized role of cryopyrin/NALP3 in IL-1ß activation has provided the conceptual basis for a series of studies establishing an important role for IL-1ß inhibition in the cryopryinopathies. These results will not only dramatically improve the quality of life and prognosis of patients with a potentially devastating disease, but will provide powerful support for a model that places cryopyrin/NALP3 at a critical juncture in the regulation of IL-1ß activation.
• familial Mediterranean fever (FMF) / benign paroxysmal peritonitis / periodic peritonitis / familial recurrent polyserositis / periodic or recurrent polyserositis

Epidemiology : Mediterranean area, primarily among persons of Sephardic Jewish, Armenian, Turkish, Arab, and Italian ancestry, but, with the availability of genetic testing, cases have been documented worldwide; onset is usually between the ages of 5 and 15 years.
Aetiology : recessive mutation in marenostrin / pyrin (MEFV)gene. The gene for FMF, MEFV, is located on human chromosome 16p13.3 and was independently identified by two positional cloning consortia in 1997^{ref1, ref2}. MEFV is comprised of 10 exons, spanning approximately 15 kb of genomic DNA. All 4 of the initial FMF-associated mutations in MEFV were in exon 10, and even now, with > 55 mutations having been identified^ref, exon 10 remains the major site of mutations, with a smaller cluster in exon 2. The most frequent are M694V, M694I, M680I, V726A and E148Q. The M694V mutation is the most frequent mutation in the various ethnic groups considered, although its frequency varies from group to group. The V726A mutation is observed mainly among Ashkenazi and Iraqi Jews, Druzes and Armenians, and the M680I among Armenians and Turks. M694I and A744S seem specific to Arab populations, and R761H is frequently found in Lebanese FMF patients. The M694V mutation is often correlated with severe phenotypes, mainly in the homozygous state. It has been specifically correlated with arthritis, pleuritis and especially amyloidosis. Patients with other mutations in the 694 and 680 codons can also have severe phenotypes. The V726A mutation, although identified in FMF patients with a relatively mild phenotype, has also been detected in patients with renal amyloidosis. E148Q is often associated with a mild phenotype, and whether it is even a polymorphism has been questioned^ref. Nearly all of the known FMF-associated mutations encode conservative missense changes. This suggests that the disease phenotype may require some level of residual protein function and that the episodic nature of FMF may be due to as yet uncharacterized environmental perturbations of the variant protein. Carrier frequencies for FMF mutations of 1:3 to 1:5 have been observed in several Mediterranean and Middle Eastern populations^{ref1, ref2, ref3, ref4}, raising the possibility of heterozygote selection. Intragenic convergence of single nucleotide polymorphism haplotypes strongly suggests independent ancient ancestral origins for ethnically diverse modern-day carriers of at least four different common mutations^{ref1, ref2}. Although genetic testing may help confirm the diagnosis of FMF, particularly in countries in which the disease is uncommon, there are substantial numbers of patients with the clinical picture of FMF who have only one identifiable mutation, and even some patients with no identifiable mutations in MEFV, and thus clinical judgment remains important in establishing the diagnosis (Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions (15th ed). Philadelphia: Lippincott Williams and Wilkins; 2005:1411–1461). Consistent with the biology of FMF, MEFV is expressed predominantly in granulocytes, monocytes, dendritic cells, and in fibroblasts derived from skin, peritoneum, and synovium^{ref1, ref2, ref3}. It encodes a full-length 781 aa protein denoted pyrin or marenostrin. In transfection experiments full-length pyrin is exclusively cytoplasmic, while endogenous pyrin is cytoplasmic in monocytes but is predominantly nuclear in granulocytes, DCs, and synovial fibroblasts^{ref1, ref2}. Although sui generis at the time pyrin was discovered, the domain encoded by exon 1 is now recognized as the prototype for a 92 aa motif, the PYRIN domain, that is found in 20 human proteins involved in the regulation of inflammation and apoptosis^{ref1, ref2, ref3, ref4}. This motif has a 6 a-helix structure similar to that of death domains, death effector domains, and caspase-recruitment domains, a configuration known to mediate homotypic interactions. Through cognate PYRIN-PYRIN interactions with the bipartite adaptor protein ASC (apoptosis-associated speck-like protein with a caspase recruitment domain, which is comprised of an N-terminal PYRIN domain and a C-terminal caspase recruitment domain), pyrin acts as an upstream regulator of IL-1ß activation^{ref1, ref2}. Pyrin appears to have both inhibitory and potentiating effects on IL-1ß production depending on experimental conditions, and thus the role of wildtype human pyrin in the IL-1 pathway remains controversial. There is also evidence that pyrin plays a role in regulating NF-kB activation and apoptosis, at least in part through its interactions with ASC^{ref1, ref2, ref3, ref4, ref5}. Perhaps reflecting the relevance of these PYRIN domain–mediated interactions to the development of autoinflammatory disease, mutations in exon 1 are extremely rare in FMF. In contrast, mutations in the C-terminal B30.2/rfp/SPRY domain of pyrin, encoded by exon 10, predominate in FMF. This motif is found in proteins with a variety of different functions, and is thought to mediate protein-protein interactions. Some authors have suggested the possibility that the B30.2/rfp/SPRY domain of pyrin might be an intracellular domain that binds pathogens, similar to the leucine-rich repeat domain of cryopyrin/NALP3 (vide infra)^{ref1, ref2}. This hypothesis is based on (1) the large number of FMF-associated mutations in this domain; (2) the evidence for heterozygote selection for exon 10 mutations in Mediterranean populations; (3) data suggesting selection for specific B30.2/rfp/SPRY sequences in primate evolution^ref; and (4) evidence that the B30.2/rfp/SPRY domain of another protein, TRIM5a, blocks infection with certain retroviruses, and has undergone positive selection in primate evolution similar to pyrin^{ref1, ref2}. Nevertheless, at the time of this writing there is no direct experimental evidence that the C-terminal domain of pyrin binds pathogen-derived molecules
Symptoms & signs : typically presenting in childhood or adolescence with 1- to 3-day episodes of fever often accompanied by severe abdominal pain (mimicking peritonitis), pleuritis, monoarticular arthritis. Erysipela-like erythema affecting mainly feet and legs and effort-induced myalgia are less frequently encountered symptoms. Between attacks, patients feel well, although biochemical evidence for inflammation may persist. Among some FMF patients, systemic (renal) AA amyloidosis develops due to the deposition of a misfolded fragment of serum amyloid A (SAA), one of the acute-phase proteins.
Laboratory examinatons :
• mutation analysis of the gene may be helpful in diagnosing FMF
• however, if this is not possible, a trial of colchicine is a helpful diagnostic tool
• during attacks there is usually neutrophilia and a brisk acute-phase response, and histologically there is a massive (sterile) influx of polymorphonuclear leukocytes into the affected anatomic compartment(s)
• high sedimentation rate and white blood cell count, but during and immediately after crises, diminished albumin concentrations and elevated fibrinogen, C-reactive protein, b₂ and a₂ M globulins, haptoglobin and lipoprotein concentrations are noted
• elevated serum levels of IgA, IgM, IgG, and IgD in 23%, 13%, 17% and 13%, respectively
• peritoneal fluid contains abnormally low levels of the inhibitor of complement fragment C5a and IL-8
Therapy of acute attacks is supportive. Prophylactic life-long treatment with colchicine 0.6 mg po tid or bid is effective in decreasing the frequency and severity of crises and preventing amyloidosis, and thus with early diagnosis the prognosis of FMF is good.
• autosomal dominant periodic fever syndrome / tumour necrosis factor receptor associated periodic syndrome (TRAPS)

Epidemiology : most patients are of northern European descent, especially common among Scottish and Irish families. Several years before the discovery of these TNF receptor mutations, a dominantly inherited periodic fever syndrome that later proved to be TRAPS was described in a family of Irish and Scottish ancestry whose illness had been termed familial Hibernian fever. Subsequent studies have demonstrated a very broad population distribution of patients with periodic fever and TNF receptor mutations, and hence the more ethnically neutral TRAPS terminology is usually preferred. To be consistent with the original description of TRAPS, mutations in the TNFRSF1A gene in the appropriate clinical setting are required to make the diagnosis, although there remain a number of patients with TRAPS-like illnesses who do not have identifiable mutations (Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions (15th ed). Philadelphia: Lippincott Williams and Wilkins; 2005:1411–1461).
Aetiology : autosomal dominant mutations of the extracellular domains of TNFRSF1A / TNFR1 / p55 / CD120a, impairing its clearance. TRAPS is the first condition for which naturally occurring mutations in a TNF receptor were found; the mutations affect the soluble TNFRSF1A gene in the 12p13 region^ref.
Pathogenesis : in some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus. Thus, TRAPS is a model for a novel pathogenic concept characterized by failure to shed a cytokine receptor.  The p55 TNF receptor protein is 455 aa in length, including a 29 aa leader, a 182 aa extracellular domain, a 21 aa transmembrane domain, and a 223 aa intracellular region that includes a death domain. The extracellular domain is, in turn, divided into four cysteine-rich subdomains, each of which contains three disulfide-bonded pairs of cysteines that constrain the 3D folding of the protein. To date all of the over 45 known TRAPS mutations^ref reside in the extracellular domain of the protein, and most are in the first two cysteine-rich subdomains, with about half being missense substitutions at cysteine residues that disrupt normal disulfide bonding. To date no patients have been identified with mutations in the transmembrane or intracellular domains, with null mutations, or with mutations in the p75 TNF receptor, which is encoded on chromosome 1p. The pathophysiology of TRAPS is complex. Initial studies of a family with the C52F TNFRSF1A mutation indicated a defect in activation-induced ectodomain shedding of p55 (but not p75) receptors^ref. Since receptor shedding is thought to play a homeostatic role both by limiting available cell surface TNF receptors and by creating a pool of potentially antagonistic soluble receptors, it was attractive to hypothesize that the "shedding defect" observed in TRAPS patients might explain their autoinflammatory phenotype. Subsequent studies indicate that, while plausible, this hypothesis cannot fully explain the TRAPS phenotype, since the shedding defect is seen in patients with some, but not all, p55 mutations^{ref1, ref2, ref3, ref4}. Moreover, recent studies indicate a number of other functional abnormalities in mutant p55 receptors, including altered intracellular trafficking^ref, impaired TNF binding^ref, and a defect in TNF-induced leukocyte apoptosis^ref. Patients with TRAPS generally do not respond to treatment with colchicine, which is highly effective in FMF, and, although they are responsive to high-dose corticosteroids, side effects are often limiting. The recognition of the role of the TNF-pathway has led to the introduction of etanercept, the soluble p75 TNFR:Fc fusion protein, in the treatment of TRAPS. Etanercept is effective in reducing, although usually not totally eliminating, clinical and laboratory evidence of inflammation in TRAPS^{ref1, ref2, ref3}, a result that is consistent with a role for both TNF-dependent and -independent pathways in the pathogenesis of TRAPS.
Symptoms & signs : the attacks manifest as fever and pain in the joints, abdomen, muscles, skin, or eyes, with variations across patients. An acute-phase response occurs during the attacks. Patients with TRAPS are at risk for AA amyloidosis, the most common targets being the kidneys and liver. As is the case for FMF, TRAPS presents in childhood or adolescence, but in TRAPS the duration of attacks tends to be more variable, ranging from short episodes of one to two days to flares lasting weeks at a time and, in some cases, patients experience nearly continuous, fluctuating symptoms. In addition to fever, common clinical features of TRAPS include abdominal pain (due to sterile peritonitis), pleurisy, periorbital edema, a migratory erythematous skin rash with underlying myalgia, arthralgia or frank arthritis, and scrotal pain. Marked leukocytosis and elevation of acute-phase reactants is usually seen during attacks, and often persists into the intercritical period. Systemic amyloidosis may occur in up to 10% of patients, with an increased risk observed in patients with mutations involving cysteine residues^ref. Although the attacks of TRAPS can often be debilitating, amyloidosis appears to be the major factor limiting longevity (Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions (15th ed). Philadelphia: Lippincott Williams and Wilkins; 2005:1411–1461).
Laboratory examinations : soluble TNFRSF1A is usually low between the attacks and may be normal during the attacks, when TNF levels are high. TNFRSF1A is found in abnormally high numbers on leukocyte cell membranes
Therapy : colchicine neither relieves nor prevents the attacks, whereas oral glucocorticoid therapy is effective when used in dosages greater than 20 mg/day. The pathogenic hypothesis involving defective TNFRSF1A shedding suggests that medications targeting TNF may be effective in TRAPS.
Differential diagnosis : periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome (PFAPA syndrome) / Marshall syndrome

clinical features	FMF	TRAPS	HIDS	FCAS	MWS	NOMID/CINCA
usual ethnicity	Turkish, Armenian, Arab, Jewish, Italian	any ethnicity	Dutch, other Northern European	mostly European	mostly European	any ethnicity
duration of attacks	12-72 hours	days to weeks	3-7 days	12-24 hours	2-3 days	continuous, with flares
abdominal	sterile peritonitis, constipation	peritonitis, diarrhea, or constipation	severe pain, vomiting, diarrhea, rarely peritonitis	nausea	abdominal pain	not common
pleural	common	common	rare	not seen	rare	rare
arthropathy	monoarthritis, rarely protracted arthritis in knee or hip	arthritis in large joints, arthralgia	arthralgia, symmetric polyarthritis
polyarthralgia	polyarthralgia, oligoarthritis, clubbig	epiphyseal overgrowth, contractures, intermittent or chronic arthritis, clubbing
cutaneous	erysipeloid erythema on lower leg, ankle, foot	migratory rash, underlying myalgia	diffuse maculopapular rash, urticaria	cold-induced urticarial rash	urticaria-like rash	urticaria-like rash
ocular	rare	conjunctivitis, periorbital edema	uncommon	conjunctivitis	conjunctivitis, episcleritis	uveitis, conjunctivitis, progressive vision loss
neurologic	rarely aseptic meningitis	controversial	headache	headache	sensorineural deafness	sensorineural deafness, chronic aseptic meningitis, mental retardation, headache
lymphatic	splenomegaly, occasional lymphadenopathy	splenomegaly, occasional lymphadenopathy	cervical adenopathy in children	not seen	rare	hepatosplenomegaly, adenopathy
vasculitis	Henoch-Schonlein purpura (HSP), polyarteritis nodosa	HSP, lymphocytic vasculitis	cutaneous vasculitis common, rarely HSP	not seen	not seen	occasional
systemic amyloidosis	risk depends on MEFV and SAA genotypes; more common in Middle East	occurs in 10%; risk increased with cysteine mutations	rare	rare	occurs in 25%	may develop in some patients, usually in adulthood

Web resources : Infevers database was established in 2002 to provide investigators with access to a central source of information about all sequence variants associated with periodic fevers. Currently, the database contains 291 sequence variants in related genes (MEFV, TNFRSF1A, MVK, CARD15, PSTPIP1, and CIAS1), consisting of published data and personal communications, which has revealed or refined the preferential mutational sites for each gene^ref

• idiopathic febrile syndromes
• syndrome of periodic fever with aphthous stomatitis, pharyngitits, and cervical adenopathy (PFAPA) —- Not usually familial —
• systemic-onset juvenile idiopathic arthritis (SOJIA) 604302 Complex IL-6, MIF polymorphisms
• adult-onset Still’s disease — Not usually familial —
• granulomatous disorders
• Crohn’s disease 266600 Complex NOD2/CARD15, ABCB1 (Ala893), MEFV (?)
• Blau or Jabs syndrome / familial granulomatous synovitis / familial juvenile systemic granulomatosis / arthrocutaneouveal granulomatosis (ACUG) / chronic granulomatous synovitis with uveitis and cranial neuropathy and Crohn's disease

Aetiology : autosomal dominant mutations in NOD2 / CARD15 amino acid corresponding to the R260W mutation in NALP3 / CIAS1
• early onset sarcoidosis 609464 Sporadic, autosomal dominant NOD2/CARD15
• pyogenic disorders
• pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) syndrome / familial recurrent arthritis (FRA)

Aetiology : autosomal dominant mutations in proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene
Symptoms & signs : pyogenic arthritis, pyoderma gangrenosum, and severe cystic acne
• chronic recurrent multifocal osteomyelits (CRMO) 259680 Sporadic, autosomal recessive LPIN2, when associated with congenital dyserythropoietic anemia (Majeed syndrome)
• synovitis, acne, pustulosis, hyerostosis, and osteitis syndrome (SAPHO) : not usually familial
• hemophagocytic disorders
• primary hemophagocytic lymphohistiocytosis 603553, 607624 Autosomal recessive PRF1, RAB27A
• macrophage activation syndrome (MAS) — Not usually familial Pediatric rheumatic diseases
• complement disorders
• hereditary angioedema
• vasculitic syndromes
• Behçet’s disease
• metabolic disorders :
• gout
• pseudogout
• storage diseases :
• Gaucher’s disease
• Hermansky-Pudlak syndrome
• fibrosing disorders :
• idiopathic pulmonary fibrosis

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