To correctly answer this question it should be emphasized that among the symptomatology that is exposed we find: - 2-year-old child. - ENT infections. - Pulmonary infections. - Hospital admissions. - PTI. - Family history of infections with deaths due to infections in males (maternal family). - Atopic Dermatitis. All these data, in addition to the analytical data, are describing an immunodeficiency that by the family-maternal history, seems to be X-linked, as several males have died of a similar clinical condition (the father of the patient contributed the Y chromosome, the mother the X). Among the X-linked immunodeficiencies is Wiskott-Aldrich syndrome, an entity described with an initial triad of symptoms consisting of bleeding (typical BUT absent in the case: heavy bleeding after circumcision, bloody diarrhea), recurrent infections and eczema. In addition to thrombocytopenia, they are at increased risk for autoimmune phenomena and lymphoid neoplasms. The Hyper-IgE option lacks very characteristic clinical data such as bone alterations and skin lesions, which are not atopic dermatitis, since they follow a different pattern (papulopustular rash on the face and scalp). The option of transient hypogammaglobulinemia of infancy and the common severe and variable combined immunodeficiency fails, among other features, the determination of immunoglobulins G and M, which are at the lower limit, but within normality.

To correctly answer this question it should be emphasized that among the symptomatology that is exposed we find: - 2-year-old child. - ENT infections. - Pulmonary infections. - Hospital admissions. - PTI. - Family history of infections with deaths due to infections in males (maternal family). - Atopic Dermatitis. All these data, in addition to the analytical data, are describing an immunodeficiency that by the family-maternal history, seems to be X-linked, as several males have died of a similar clinical condition (the father of the patient contributed the Y chromosome, the mother the X). Among the X-linked immunodeficiencies is Wiskott-Aldrich syndrome, an entity described with an initial triad of symptoms consisting of bleeding (typical BUT absent in the case: heavy bleeding after circumcision, bloody diarrhea), recurrent infections and eczema. In addition to thrombocytopenia, they are at increased risk for autoimmune phenomena and lymphoid neoplasms. The Hyper-IgE option lacks very characteristic clinical data such as bone alterations and skin lesions, which are not atopic dermatitis, since they follow a different pattern (papulopustular rash on the face and scalp). [HIDDEN] [HIDDEN]

2-year-old boy. His personal history includes 3 episodes of acute otitis media, 1 meningococcal meningitis and 2 pneumonias (one middle lobe and one left upper lobe). She has been admitted on 3 occasions for thrombopenic purpura (on three occasions antiplatelet antibodies were negative and bone marrow showed normal megakaryocytes). Several males of the maternal family had died in childhood due to infectious processes. Physical examination showed lesions typical of atopic dermatitis. The immunological study showed a slight decrease in T-lymphocyte subpopulations; elevated IgA and IgE; decreased IgM and IgG at the lower limit of normal. What is the most likely diagnosis?

Transient hypogammaglobulinemia of childhood.

X-linked severe combined immunodeficiency.

[Wiskott-Aldrich syndrome].

The Wiskott-Aldrich syndrome is a primary immunodeficiency characterized by congenital microthrombocytopenia, eczema and recurrent infections. This paper reports the case of a 3-year-6-month male patient, whose maternal uncle died at the age of 3 months due to fulminant sepsis from a pulmonary infection. The patient was a product of the first pregnancy, he was born at 27 weeks' gestation and weighed 1,400 g. As a neonate he was hospitalized during the first 2 months of life because of a low gastrointestinal bleeding, thrombocytopenia and severe infections. In the next 4 months and before coming to our hospital the infant was hospitalized 54 times. On admission he presented disseminated dermatosis, enlarged neck lymph nodes and psychomotor retardation. Laboratory studies revealed hemoglobin 8.1 g/dL, platelets 31,000/uL, mean platelet volume 5.6 fL, IgM 39.3 mg/dL, IgA 67 mg/dL, IgG 1,380 mg/dL. On several occasions he received globular packages and platelet concentrates. The infusion of immunoglobulin G was started every 21 days. Bone marrow transplantation was delayed due to the complications that merited 13 hospitalizations and severe thrombocytopenia, low gastrointestinal bleeding, septic arthritis, infectious gastroenteritis, chronic suppurative otitis media and severe folliculitis. At the age of 4 years BMT of cord was performed, and 26 days after transplantation he presented septic shock and died. The prognosis of bone marrow transplantation in Wiskott-Aldrich syndrome and in other primary immunodeficiencies depends on the promptness of its performance at early stages in life. It is important that the first contact physicians be aware of the primary immunodeficiency signs and symptoms.

A case of IgG subclass deficiency with the initial presentation of transient hypogammaimmuno-globulinemia of infancy and a review of IgG subclass deficiencies.

Primary immunodeficiency diseases are not common in children. The possibility of an immunological defect should be considered in any individual with repeated infections. A definite diagnosis for immodeficiency is sometimes difficult to achieve because of overlapping clinical manifestations. Immunoglobulin subclass deficiency is an immunological deficiency disease with which, one or more IgG subclasses are deficient. T cell immunity is normal. Patients may develop recurrent bacterial and respiratory infections or could remain asymptomatic. The authors report a case of immunoglobulin G subclass deficiency presenting initially as transient hypogammaglobulinemia of infancy. A 2 month-old boy presented to Siriraj Hospital with a history of chronic protracted diarrhea, disseminated scabies and sepsis. On presentation, he had generalized scaly and maculopapular rash with no palpable lymph nodes. CBC revealed WBC 22,100 cells/cm3 with PMN 42 per cent, lymphocytes 38 per cent, Eosinophils 4 per cent, Basophil 2 per cent and platelets 254,000/cm3. The immunoglobulin levels were as follows: IgG 181 mg/dl, IgA < 6.6 mg/dl, IgM 26.3 mg/dl. Lymphocyte enumerations revealed CD4 of 2,433 cells/cm3 (N 1,460-5,160); CD8 4,682 cells/cm3 (N 650-2,450); CD19 1,588 cell/cm3 (N 500-1,500); CD16 230 cell/cm3 (N 573 +/- 264). The initial diagnosis was X-linked agammaglobulinemia vs common variable immunodeficiency disease. His diarrhea and five courses of sepsis responded well to antibiotics administration and courses of intravenous immunoglobulin (IVIG) replacement. His through IgG became normal at 2 years of age (after 12 months of IVIG). IVIG was stopped and the diagnosis was changed to transient hypogammaglobulinemia of infancy (THI). Nevertheless, during his 4 month follow-up he developed recurrent sinopulmonary infections (i.e, otitis media and pneumonia). Repeated immunoglobulin profile showed IgG 1,200 mg/dl, IgA 135 mg/dl, IgM 26 mg/dl, IgG subclass were IgG, 1,030 mg/dl (N 280-830), IgG2 30 mg/dl (N 40-2,400), IgG3 22 mg/dl (N 6-130), IgG4 3 mg/dl (N 3-120). A diagnosis of IgG2 subclass deficiency presenting early as transient hypogammaglobulinemia of infancy was then made. Treatment with monthly IVIG was reinitiated and the patient is currently doing well. The authors present a case of IgG subclass deficiency presenting as transient hypogammaglbulinemia of infancy. Follow-up of the immune profile and clinical manifestation is necessary for a definite diagnosis.

De novo mutation causing X-linked hyper-IgM syndrome: a family study in Taiwan.

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency disorder caused by mutations of the gene encoding the CD40 ligand (CD40L). It is characterized by recurrent infections with markedly decreased serum IgG, IgA and IgE levels but normal or elevated IgM levels. We report the clinical manifestations and complete immune studies in the first family with molecularly proven XHIM in Taiwan. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgA, and IgE were noted in his plasma specimen: IgM, 128 mg/dl; IgG, 18 mg/dl; IgA, 4 mg/dl); IgE, 1 IU/ml. Whole blood flow cytometry when he was 21 months old showed that only a small percentage (0.48%) of his in vitro-activated CD4+ T cells expressed CD40L. When he was 3 years old, repeated flow cytometry showed essentially the same result (0.4%), compared with his father's CD40L expression of over 85%. The patient's mother had moderately decreased CD40L expression (74.4%). Hyper-IgM syndrome was confirmed by CD40L mutation analysis in the boy, which revealed a Lys 96 stop (nucleotide A307T) in exon 2 of CD40L, with a truncated protein resulting in the loss of the entire TNF domain. His mother was a carrier and apparently the individual in whom the mutation originated. Eleven other family members, including the patient's father, sister, and grandmother, and the mother's sisters and their children, all had normal results on CD40L mutation analysis. The patient has remained without significant bacterial infection on a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, although he has had recurrent oral ulcers and neutropenia. Bone marrow transplantation is planned.

Wiskott-Aldrich syndrome complicated by an atypical lymphoproliferative disorder: a case report.

Wiskott-Aldrich syndrome (WAS) is an X-linked syndrome consisting of eczema, recurrent pyogenic infection, and thrombocytopenia with decreased platelet volume. Immunologic studies reveal normal immunoglobulin G (IgG), decreased IgM, elevated IgA and IgE levels, and decreased T-cell function. Patients with WAS often have increased susceptibility to lymphoproliferative disorders (LPDs). We report a 3-year-old boy who had persistent thrombocytopenia with bleeding, recurrent infections, and chronic eczema with frequent skin infections since birth. A blood smear revealed small platelets (50% of normal size). Immunologic studies showed normal IgG (1880 mg/dL), decreased IgM (76 mg/dL) and increased IgA (228 mg/dL) and IgE (14,282 IU/mL) levels. The relative proportions of immune cells were CD2 52.2%, CD3 41.1%, CD4 23.4%, CD8 16.8%, CD19 8.0%, CD57 7.7% and active T cells 14.6%. T-cell dysfunction was detected on the multitest for cell-mediated immunity. The WAS diagnosis was confirmed by mutation analysis which demonstrated a 4-base pair deletion in WAS protein gene exon 1. His thrombocytopenia was uncontrolled despite intravenous immunoglobulin infusions, so splenectomy was performed. The platelet count then rose to about 60,000 to 80,000/microL. However, about 2 weeks after splenectomy, he developed generalized lymphadenopathy and lymphoma was misdiagnosed based on lymph node biopsy at another hospital where he was admitted for urgent care. However, our analysis of his lymph node pathology led to the diagnosis of atypical LPD (ALPD). The lymphadenopathy regressed spontaneously 1 month later without chemotherapy. Early and correct diagnosis of WAS complicated with ALPD is important to avoid unnecessary chemotherapy.

[Satisfactory evolution of a patient diagnosed in childhood with Bruton's disease].

Bruton's agammaglobulinemia is a primary immunodeficiency with a disease onset during the first months of age, when the maternal serum immunoglobulin levels decrease. It is characterized by recurrent infections and agammaglobulinemia. We report the case of a 6-year-old male patient with third-degree consanguinity, product of a third pregnancy and complete immunization scheme. He had a history of oral candidiasis at the age of 3 months, chicken pox at the age of 7 months, and two episodes of complicated bronchopneumonia at the age of 1 year and 6 years. He was admitted to the hospital because of fever and cough. Examination of the chest showed rales and right basilar hypoventilation, and a blood cell count revealed leukocytosis and neutrophilia. The diagnosis of pneumonia was made. He was treated with IV antibiotics. Serum immunoglobulins were reported to be low (IgM 55 mg/dL, IgA 0.9 mg/dL, and IgG 199 mg/dL). With these findings the clinical diagnosis of X-linked agammaglobulinemia (ALX) was concluded. A molecular test was performed fining a BTK gene confirming the diagnosis of Bruton's disease. Therapy with intravenous IgG was started every 21 days. During his evolution, he presented three episodes of rhinosinusitis, one of suppurative otitis media, and four events of pneumonia that required 37 days of hospitalization. After hospital discharge, the patient was free of infections and he returned to his daily activities. In cases of recurrent and severe respiratory infections in children, we must consider primary immunodeficiency disease in the differential diagnosis, mainly antibiotic deficiency. Early diagnosis and treatment improves the survival and quality of life in these patients.

Recurrent pneumonia as warning manifestation for suspecting primary immunodeficiencies in children.

Two hundred and eight children with recurrent pneumonia were studied over a 5-year period. Among these patients we found 10 cases with primary immunodeficiency disease: 6 cases of IgA deficiency, 1 case of X-linked agammaglobulinemia, 1 case of common variable immunodeficiency, 1 case of hyper IgM syndrome, and 1 case of Wiskott-Aldrich syndrome. This study describes the clinical features of these cases and assesses the usefulness of our immunodeficiency screening protocol. In this group 6 were males; the mean age at first episode of pneumonia was 3 years (range 3 months to 18 years), and the age of diagnosis ranged between 10 months and 19 years. The average number of episodes of pneumonia in each patient was 5 (range 2 to 12), and the number of hospitalizations ranged up to 13. The etiologic agents isolated from this recurrent pneumonia were S. pneumoniae, Moraxella, adenovirus, respiratory syncytial virus, and influenza B virus. Intravenous immunoglobulin was used in four cases. Two patients had chronic pulmonary damage with bronchiectasis and interstitial pneumonia. Only one patient died (Wiskott-Aldrich syndrome) during the follow-up from an intracranial hemorrhage. We found that the screening protocol applied to patients with recurrent pneumonia is a useful tool for ruling out the primary immunodeficiency disorders.

Serum IgD and IgE concentrations in immunodeficiency diseases.

Concentrations of IgD and IgE were measured in sera from 165 patients with well-defined immunodeficiency in an effort to find information possibly relevant to the roles of antibodies of these classes in host defense. Values for both immunoglobulins were generally quite low in patients who had marked deficiencies of all three major immunoglobulins, although occasional normal or high normal values for IgD were seen in hypogammaglobulinemic patients. Group mean IgD concentrations were also depressed in patients with Wiskott-Aldrich syndrome and in those with selective IgA deficiency; IgE concentrations were depressed in patients with X-linked immunodeficiency with hyper-IgM and in those with ataxia telangiectasia. IgD and IgE were both significantly elevated in patients with extreme hyperimmunoglobulinemia E and undue susceptibility to infection and in a patient with the Nezelof syndrome; none of these patients had histories suggestive of atopy. In addition, the mean IgE concentration was significantly elevated in patients with selective IgA deficiency, many of whom were atopic, and in those with the Wiskott-Aldrich syndrome. The highest IgD concentration (163 mg/100 ml) was found in serum from a boy with variable immunodeficiency who had a lifelong history of severe recurrent pharyngeal infections, primarily streptococcal in etiology. Recurrent staphylococcal infection was a feature common to many but not all patients with elevated serum IgE concentration. These data may prove useful in the future delineation of biologic roles for antibodies in these two immunoglobulin classes.

[Hypogammaglobulinemia G and A with hypergammaglobulinemia M. Apropos of 12 cases].

Hyper IgM with low IgG and IgA is a rare humoral immunodeficiency. We presently report 12 new observations which have been clinically and immunologically studied. On one occasion the syndrome was found to be associated with congenital rubella. Since 10/12 children were male, X-linked inheritance is suggested which has been confirmed in 2 cases. In most cases (9/12), the first infections occurred within the first year of life. The syndrome is causing upper and lower respiratory tract infections due to bacteria, as well as gut infections. Lymphoid organ hyperplasia has been noted in 11/12 patients. Polyclonal hyper IgM serum contrasts with low or absent IgG, IgA and IgE. In some instances, some IgM antibody response was detected. A dysfunction of cellular immunity was not detected. Autoimmunity was detected in 3 patients. Finally, transient neutropenia occurred in 50% of the patients. Intravenous immunoglobulin G substitution treatment resulted in a significant reduction in the occurrence of infections as well as in normalization of growth rate. Immunoglobulin infusion also frequently induced correction of hyper IgM and neutropenia.

Hyper-IgM syndrome: report of one case.

The hyper-IgM syndrome (HIM) is a rare primary immunodeficiency disorder caused by defects in the CD40 ligand (CD40L)/CD40-signaling pathway. It is characterized by recurrent infections with markedly decreased IgG, IgA and IgE levels but normal or elevated serum IgM levels. A 5-month-old boy presented with rapidly progressive pneumonia which responded poorly to antibiotics. High levels of IgM and very low levels of IgG, IgE and IgA were noted in his plasma specimen (IgM, 128 mg/dl; IgG, 18 mg/dl; IgE, 1 IU/ml; IgA, 4 mg/dl). The relative proportions of immune cells were CD3 24.6%, CD4 10.3%, CD8 2.2%, CD19 30.2%, CD57 1.0% and active T cells 1.1%. After IVIG treatment, the pneumonia improved. Repeat assessment at the age of 15 months showed IgM decreased to the normal range (32 mg/dl). Whole blood flow cytometry assay for CD40L expression confirmed the diagnosis of hyper-lgM syndrome when he was 21 months old. Only a small percentage (0.48%) of the patient's in vitro activated CD4+ T cells expressed CD40L, compared with 33.54% from a healthy control. The patient's father, mother and sister all had a normal CD40L expression activation patterns (43.52%, 40.78%, 34.11%, respectively). On a regimen of monthly IVIG infusion and oral trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis, the patient has had no recurrent infections.

[Clinical features of X-linked agammaglobulinemia: analysis of 8 cases].

X-linked agammaglobulinemia (XLA), caused by mutations in Bruton's tyrosine kinase (BTK), is a common form of inherited antibody deficiency. There were very few case reports of this disease that were diagnosed only based on clinical findings in China. The purpose of this study was to evaluate the clinical features of 8 Chinese cases with XLA with BTK defect which were confirmed by flow cytometry and/or gene analysis. Based on clinical findings, 8 suspected XLA patients were confirmed by detecting the expression of BTK by flow cytometry and/or gene analysis of BTK. The history and thorough physical examination and routine immunological evaluation of 8 cases were collected and reviewed. The age of onset of all the 8 male patients were from 3 months to 3 years. The mean age at diagnosis was 6 years. Recurrent upper respiratory infection and pneumonia with fever were seen in all the patients. Nasopharynx infection was mainly contributed to upper respiratory infection. Very few or no otitis (1/8) and sinusitis (0/8) were involved. Polyarthritis without evidence of infection was common (3/8). Chronic diarrhea was documented during the first 2 years after the onset of the disease in 2 cases. Two of the patients suffered from meningitis one time each. Skin infection was not serious in two patients. Osteomyelitis occurred in one case, which occurred secondary to a trauma. One case had poliomyelitis-like disease that was considered to be related to polio vaccine. Only two cases had unconfirmed maternal family history of XLA. The prominent signs at diagnosis were dystrophia, growth and developmental retardation and markedly decreased or absent tonsils and lymph nodes. Concentration of all classes of serum immunoglobulins (Igs) and the number of B cells in the peripheral circulation were dramatically decreased. The ratio of CD4/CD8 in most of the patients (6/8) was markedly inverse. The age at diagnosis of this reported group was older. Clinical symptoms displayed recurrent upper respiratory infection (nasopharynx infection but rare or no otitis or sinusitis) and pneumonia; polyarthritis was common. There were no confirmed family history of XLA. Most of the patients showed inverse ratios of CD4/CD8, the reason and potential significance are unclear.

Wiskott–Aldrich syndrome

Signs and symptoms WAS occurs most often in males due to its X-linked recessive pattern of inheritance, affecting between 1 to 10 males per million. The first signs are usually petechiae and bruising, resulting from a low platelet count (i.e. thrombocytopenia). Spontaneous nose bleeds and bloody diarrhea are also common and eczema typically develops within the first month of life. Recurrent bacterial infections typically develop by three months of age. The majority of children with WAS develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. Immunoglobulin M (IgM) levels are reduced, IgA and IgE are elevated, and IgG levels can be normal, reduced, or elevated. In addition to thrombocytopenia, WAS patients have abnormally small platelets (i.e. microthrombocytes) and ~30% also have elevated eosinophil counts (i.e. eosinophilia).

Wiskott–Aldrich syndrome

Diagnosis The diagnosis can be made on the basis of clinical findings, the peripheral blood smear, and low immunoglobulin levels. Typically, IgM levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. Skin immunologic testing (allergy testing) may reveal hyposensitivity. Individuals with Wiskott–Aldrich syndrome however are at higher risk for severe food allergies. Not all patients have a positive family history of the disorder; new mutations do occur. Often, leukemia may be suspected on the basis of low platelets and infections, and bone marrow biopsy may be performed. Decreased levels of WASp are typically observed. The current gold standard for diagnosis is DNA sequence analysis, which can detect WAS and the related disorders XLT and XLN in 95% of patients and carriers.

List of primary immunodeficiencies

Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subclass deficiency, selective immunoglobulin A deficiency Specific antibody deficiency to specific antigens with normal B cell and normal Ig concentrations Transient hypogammaglobulinemia of infancy (THI)

Early bone marrow transplantation in an infant with Wiskott-Aldrich syndrome.

The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked immunohematological disorder characterized by eczema, profound thrombocytopenia, and progressive immunodeficiency. Severe hemorrhage, overwhelming sepsis, or lymphoreticular malignancy usually cause death in childhood. Recently, bone marrow transplantation (BMT) has been curative in some well-established cases, but there is no general agreement about the place of BMT in infants with WAS before the development of significant immunological abnormalities. We describe the successful use of early histocompatible BMT in a 10-month-old infant in whom WAS was diagnosed on the basis of eczema, thrombocytopenia, small platelets, and raised serum immunoglobulin A (Ig) and IgE, but before the development of immunodeficiency as evidenced clinically by recurrent infections, or immunologically by low serum IgM or consistently abnormal lymphocyte responses to mitogens. After an unstable period for several weeks posttransplantation when he developed marked hepatomegaly and severe interstitial pneumonitis, he made a good recovery. His eczema and thrombocytopenia resolved and he has shown no clinical or laboratory evidence of immunodeficiency. It is now over 2 years since his BMT. Because of the poor prognosis of WAS, where a histocompatible donor is available, BMT at the earliest opportunity, despite the inherent risks of such a procedure, may be the best option for an infant with WAS.

[Clinical features and genotype analysis of 132 patients with Wiskott-Aldrich syndrome].

To investigate the clinical and immunological laboratory features, gene mutations, treatment and prognosis in children with Wiskott-Aldrich syndrome (WAS). The clinical, laboratory characteristics, treatment and prognosis of 132 children with WAS, who visited Children's Hospital of Chongqing Medical University from April 2000 to June 2015, were analyzed retrospectively. All patients were male. The median age of disease onset was 15 days and the median age at diagnosis was 10 months. Of the 132 cases, 112 had classic WAS, 20 had X-linked thrombocytopenia (XLT). The median platelet count was 23×10(9)/L. All cases had the clinical characteristics of WAS including bleeding, eczema, and being susceptible to infection. The initial symptoms include hemorrhage (75.0%) and eczema (16.7%). Twenty-one cases had autoimmune diseases and one patient had leukemia. WAS protein (WASP) expression in 115 cases were measured by flow cytometry, 88 cases were negative, in 12 cases WASP decreased, in 5 cases it was normal, 10 cases had bimodal distribution. Eighty-one kinds of mutations were found in 122 families, including eight kinds of hot-spot mutations, which were 290 C> N / 291G> N (R86C / H / L), 665 C> T (R211X), 155 C> T (R41X), 168 C> T (T45 M), IVS1+ 1 g> t/ a, IVS6 + 5 g> a, IVS8 + 1 g> a and IVS8 + 1to + 6del gtga. Meantime, 29 kinds of novel mutations were found, which were 321T>C, 415C>A, 471C>T, 102-105delC, 521 del C, 1330 del A, IVS2-2 a>c, 168 C>A/1412 C> T, exon1-2 del/1412 C>T, and so on. The proportion of CD3(+) T cells (31.3%), helper T cells (37.3%) and cytotoxic T cells (38.6%) in the peripheral blood declined. The serum levels of IgG (51.1%), IgA (43.3%) and IgE (40.0%) increased, IgM (25.6%) decreased. Of the 132 cases, 72 remain survived, of whom 36 cases received hematopoietic stem cell transplantation (HSCT), 14 patients with classic WAS received intravenous immunoglobulin (IVIG) therapy. With regular IVIG therapy, the frequency of infections was reduced and the patients' symptoms were improved. The clinical characteristics of Wiskott-Aldrich syndrome were early age of onset, microthrombocytopenia, eczema and recurrent infections. The proportion of T lymphocyte declined, the serum levels of IgG, IgA, and IgE increased, and level of IgM decreased in a part of patients. The detection of WAS gene mutation and WAS protein detection was the key diagnostic methods. Regular IVIG can gain more time for children who will receive HSCT and improve their quality of life.

Antibody Deficiency Disorder -- Differential Diagnosis

The most important differential diagnosis includes the following: X-linked agammaglobulinemia characterizes by recurrent bacterial infections in boys, and genetic studies may reveal the presence of Bruton tyrosine kinase (BTK) mutations. Transient hypogammaglobulinemia of newborns presents in newborns above the age of 4 months and characterizes by recurrent pneumonia, meningitis, otitis media, and other problems that resemble Bruton disease. It is a physiological defect in the immune system caused by maternal IgG disappearance and corrected soon but requires treatment. In super-IgM syndrome, recurrent bacterial infections occur, but the cause of this illness is a mutation in the gene encoding for CD40 on T lymphocytes that causes a failure in T and B lymphocyte cooperation. Common variable immunodeficiency presents with recurrent bacterial infections, including sinopulmonary problems but later in life (second-fourth decade), and the diagnosis is made once all causes of immunodeficiency have been ruled out. [6] [7] [21] [33]

Hypogammaglobulinemia

of primary immunodeficiency (PID). These different forms can affect different parts of the immune system, including immunoglobulin production. Primary immunodeficiencies usually have a delay of several years between initial clinical presentation and diagnosis. Some primary immune deficiencies include ataxia-telangiectasia (A-T), autosomal recessive agammaglobulinemia (ARA), common variable immunodeficiency (CVID), hyper-IgM syndromes, IgG subclass deficiency, isolated non-IgG immunoglobulin deficiencies, severe combined immunodeficiency (SCID), specific antibody deficiency (SAD), Wiskott-Aldrich syndrome, or X-linked agammaglobulinemia. CVID is the most common form of primary immunodeficiency. SCID is considered a medical emergency and suspected cases require immediate specialist center referral for diagnosis and treatment. It is more often that hypogammaglobulinemia develops as a result of another condition, which are called secondary or acquired immune deficiencies. These

X-linked agammaglobulinemia

Signs and symptoms Affects males 50% of the time if mother is a carrier for the gene. Children are generally asymptomatic until 6–9 months of age when maternal IgG decreases. Present with recurrent infections with Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, hepatitis virus, and enterovirus CNS infections. Examination shows lymphoid hypoplasia (tonsils and adenoids, no splenomegaly or lymphadenopathy). There is significant decrease in all immunoglobulins. Genetics Most antibodies are gamma globulins. Antibodies are made mainly by plasma cells, which are daughter cells of the B cell line. The Btk enzyme plays an essential role in the maturation of B cells in the bone marrow, and when mutated, immature pro-B lymphocytes are unable to develop into pre-B lymphocytes, which normally develop into mature (naive) B cells that leave the bone marrow into the blood stream.

[Hyper-IgM syndrome in a boy with recurrent pneumonia and hepatosplenomegaly].

We present a boy diagnosed at age 14 years with hyper-immunoglobulin (Ig) M syndrome, a congenital immunodeficiency characterized by reduced plasma concentrations of IgA, IgE and IgG, with normal or elevated concentrations of IgM. This syndrome is caused by a defect of CD40 ligand (CD40L) on T-helper lymphocytes, impeding the "second signal" during activation of B lymphocytes and interactions of T cells with dendritic cells and macrophages, resulting in the absence of secondary immune response (class switching, affinity maturation, immune memory), as well as responses to T-dependent antigens, with an impairment of cellular immunity. The history of the presented patient was dominated by frequent lower respiratory infections and failure to thrive. Physical examination demonstrated severe hepatosplenomegaly. The suspicion of hyper-IgM syndrome was raised by low plasma IgA (0.36 g/l) with high plasma IgM (35.5 g/l), while the concentration of IgG was within the normal range (12.1 g/l). The diagnosis was confirmed by flow cytometry, which demonstrated the absence of expression of CD40L on lymphocytes following stimulation by phorbolmyristylacetate and calcium ionophore. Since the time of diagnosis, intravenous immunoglobulin therapy has led to catch-up growth, recession of hepatosplenomegaly and reduction in the frequency of respiratory infections. Our report emphasizes the importance for the primary healthcare paediatrician to be well informed about the clinical presentation and pathogenesis of hyper-IgM syndrome, in order to provide early detection and increase the likelihood of success in treating this rare immunodeficiency. To the best of our knowledge, this is the first case of hyper-IgM syndrome reported in the Republic of Serbia.

List of skin conditions

Bare lymphocyte syndrome Chronic granulomatous disease (Bridges–Good syndrome, chronic granulomatous disorder, Quie syndrome) Common variable immunodeficiency (acquired hypogammaglobulinemia) Complement deficiency DiGeorge syndrome (DiGeorge anomaly, thymic hypoplasia) Graft-versus-host disease Griscelli syndrome Hyper-IgE syndrome (Buckley syndrome, Job syndrome) Immunodeficiency with hyper-IgM Immunodeficiency–centromeric instability–facial anomalies syndrome (ICF syndrome) Isolated IgA deficiency Isolated primary IgM deficiency Janus kinase 3 deficiency Leukocyte adhesion molecule deficiency LIG4 syndrome Myeloperoxidase deficiency Neutrophil immunodeficiency syndrome Nezelof syndrome (thymic dysplasia with normal immunoglobulins) Omenn syndrome Purine nucleoside phosphorylase deficiency Severe combined immunodeficiency (alymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, thymic alymphoplasia) Shwachman–Bodian–Diamond syndrome

List of primary immunodeficiencies

Predominantly antibody deficiencies In primary antibody deficiencies, one or more isotypes of immunoglobulin are decreased or don't function properly. These proteins, generated by plasma cells, normally bind to pathogens, targeting them for destruction. Absent B cells with a resultant severe reduction of all types of antibody: X-linked agammaglobulinemia (btk deficiency, or Bruton's agammaglobulinemia), μ-Heavy chain deficiency, l 5 deficiency, Igα deficiency, BLNK deficiency, thymoma with immunodeficiency B cells low but present or normal, but with reduction in 2 or more isotypes (usually IgG & IgA, sometimes IgM): common variable immunodeficiency (CVID), CD19 deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes

Common variable immunodeficiency

Diagnosis According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if: the person presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA; the person is four years of age or older; the person lacks antibody immune response to protein antigens or immunization. Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Humoral immune deficiency

Absent B cells with a resultant severe reduction of all types of antibody: X-linked agammaglobulinemia (btk deficiency, or Bruton's agammaglobulinemia), μ-Heavy chain deficiency, l 5 deficiency, Igα deficiency, BLNK deficiency, thymoma with immunodeficiency B cells low but present, but with reduction in 2 or more isotypes (usually IgG & IgA, sometimes IgM): common variable immunodeficiency (CVID), ICOS deficiency, CD19 deficiency, TACI (TNFRSF13B) deficiency, BAFF receptor deficiency. Normal numbers of B cells with decreased IgG and IgA and increased IgM: Hyper-IgM syndromes Normal numbers of B cells with isotype or light chain deficiencies: heavy chain deletions, kappa chain deficiency, isolated IgG subclass deficiency, IgA with IgG subsclass deficiency, selective immunoglobulin A deficiency Transient hypogammaglobulinemia of infancy (THI)

Biochemistry, Immunoglobulin M -- Clinical Significance -- Selective IgM Deficiency

Selective IgM deficiency (SIGMD) is a rare disorder with fewer than 300 cases reported. SIGMD is associated with an isolated deficiency in IgM in the presence of normal levels of other immunoglobulins such as IgG and IgA and normal levels of T cells and other leukocytes. [12] Individuals with SIGMD may be asymptomatic, or they may suffer from recurring infections from encapsulated bacteria (e.g., S. pneumoniae and H. influenzae ) in addition to viral infections. Additionally, SIGMD can be associated with malignancy, autoimmunity, or allergy. SIGMD may occur as a secondary effect of another disease, such as malignancy or bacteremia. Yet, primary causes of SIGMD have also been described, as some are associated with deletions on chromosome 22, for example. [12] The diagnosis of SIGMD is one of exclusion. Other diseases that result in low levels of multiple isotypes must be excluded, such as common variable immunodeficiency or X-linked agammaglobulinemia, which will likely result in reduced levels of several antibody isotypes. Conversely, Wiskott-Aldrich syndrome is often associated with low IgM yet elevated levels of IgG and IgA. Cold Agglutinin Disease

List of skin conditions

Severe combined immunodeficiency (alymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, thymic alymphoplasia) Shwachman–Bodian–Diamond syndrome Thymoma with immunodeficiency (Good syndrome) Transient hypogammaglobulinemia of infancy Warts–hypogammaglobulinemia–infections–myelokathexis syndrome (WHIM syndrome) Wiskott–Aldrich syndrome X-linked agammaglobulinemia (Bruton syndrome, sex-linked agammaglobulinemia) X-linked hyper-IgM syndrome X-linked hypogammaglobulinemia X-linked lymphoproliferative disease (Duncan's disease) X-linked neutropenia

Severe combined immunodeficiency with B-lymphocytes (T-B+SCID): report of two cases.

Severe combined immunodeficiency (SCID) is a rare pediatric medical emergency in Taiwan. The early diagnosis of infants with SCID is very important because it can save the life of these critical infants. The essential clues important for early diagnosis of SCID patients include positive family history of early infant death, paucity of tonsil and lymphoid tissue, cutaneous fungal infection and lymphopenia. Severe combined immunodeficiency is a heterogeneous group of inherited disorders characterized by the failure of both cellular and humoral immunity. It can be categorized into SCID with B-lymphocytes predominant (T-B+SCID) and SCID with paucity of B-lymphocytes (T-B-SCID), according to the number of B-lymphocytes in the patient's peripheral circulation. We report two male infants with T-B+SCID who had been suffering from severe pulmonary distress with persistent O2 desaturation when they were transferred to our pediatric intensive care unit. Tracing back these infant's family histories, it was discovered that both of them had an elder brother who had died to overwhelming infection within the first year of life, and Pneumocystis carinii pneumonitis (PCP) was confirmed in the elder brother of case 2. After hospitalization, the immune condition of these two infants were evaluated which showed a decrease in T-cell and NK cell number, an increase in B-cell number, and decreased serum levels of all the Igs except IgM, which was elevated in case 1. These were the diagnostic immunological findings for T-B+SCID, which included X-linked SCID and Jak-3-deficient SCID. During hospitalization, severe mucocutaneous candidiasis and PCP were noted and confirmed in case 1 and PCP was highly suspected in case 2. Bone marrow transplantation, the only curable treatment for T-B+SCID at present, could not be performed in these two patients because of their grave clinical condition. Both of them expired due to their progressively downhill pulmonary conditions.

[Recurrent fever, hepatosplenomegaly and eosinophilia in a boy].

A 2-year-old boy was admitted into the hospital because of cough and fever. Lymph node tuberculosis was noted when he was 2 months old and he was subsequently hospitalized several times because of cough and fever. After hospitalization the laboratory examination showed an increased eosinophia level in blood. The immune function tests shows decreased levels of IgG, IgA, and IgM. The patient had no response to anti-tuberculosis, anti-bacterial, and anti-fungal treatment, resulting in recurrent fever and progressive enlargement of the liver and spleen. Jam-like stools were noted 35 days after admission. B ultrasonography showed suspected intussusception. Laparotomy, reduction of intussusception and ileocecum angioplasty, biopsies of intestinal wall nodules and lymphoglandulae mesentericae, and hepatic biopsy were then performed under general anesthesia. The patient eventually died because of postoperative severe liver damage, disseminated intravascular coagulation and electrolyte disorder. Both the blood culture and hepatic biopsy tests showed Penicillium marneffei infecton. Immunodeficiency gene test was performed on the patient, his bother and their parents. T→G base substitution mutation (IVS1-3 T→G) in the CD40L gene was found in the patient. X-linked hyper-IgM syndrome was thus diagnosed in the patient. His mother was a carrier of the mutated CD40L gene, but his father was normal in the gene test. Hemizygous mutation in the CD40L gene was found in both the patient and his bother.

Bone and joint disease associated with primary immune deficiencies.

Primary immune deficiencies (PIDs) are characterized by functional and/or quantitative abnormalities of one or more immune system components. Several bone and joint abnormalities can occur in patients with PID, with arthritis being the most common. Joint manifestations, of which arthritis is the most common, occur chiefly in humoral PIDs (agammaglobulinemia, common variable immunodeficiency, hyper-IgM syndromes, and IgA deficiency) and occasionally in other PIDs (chronic granulomatous disease and Wiskott-Aldrich syndrome). Monoarthritis or oligoarthritis is the usual pattern, although polyarthritis may occur, occasionally with nodules suggesting rheumatoid arthritis. Arthritis in patients with PID is usually infectious in nature, the most common causative organism being Mycoplasma, followed by Staphylococcus, Streptococcus, and Haemophilus. These bacteria can induce not only synovial infections, but also aseptic arthritogenic inflammatory responses. Arthritis having no demonstrable relation to chronic infection has been reported also and ascribed to dysimmunity-driven mechanisms that exhibit a number of specific features. Bone lesions are far less common and usually due to infections complicating humoral PID. Distinctive bone manifestations occur in a number of rare PIDs (e.g., hyper-IgE syndrome and Di George syndrome) and in syndromes characterized by spondyloepiphyseal dysplasia. Familiarity with PID syndromes both enhances the diagnostic capabilities of physicians and provides insight into the pathophysiology of bone and joint abnormalities associated with immune dysfunction. In children and occasionally in adults, a combination of bone and/or joint manifestations and hypogammaglobulinemia may indicate PID. When there is no evidence of lymphoproliferative disease, infection, or iatrogenic complications, investigations for PID should be obtained. PID-related arthritis is a unique model for studying the pathogenesis of presumably postinfectious arthritis and of inflammatory joint diseases including rheumatoid arthritis.

Immune disorder

Primary immune deficiencies Severe combined immunodeficiency (SCID) DiGeorge syndrome Hyperimmunoglobulin E syndrome (also known as Job's Syndrome) Common variable immunodeficiency (CVID): B-cell levels are normal in circulation but with decreased production of IgG throughout the years, so it is the only primary immune disorder that presents onset in the late teens years. Chronic granulomatous disease (CGD): a deficiency in NADPH oxidase enzyme, which causes failure to generate oxygen radicals. Classical recurrent infection from catalase positive bacteria and fungi. Wiskott–Aldrich syndrome (WAS) Autoimmune lymphoproliferative syndrome (ALPS) Hyper IgM syndrome: X-linked disorder that causes a deficiency in the production of CD40 ligand on activated T-cells. This increases the production and release of IgM into circulation. The B-cell and T-cell numbers are within normal limits. Increased susceptibility to extracellular bacteria and opportunistic infections.

Hyper-IgM syndrome type 2

Hyper IgM Syndrome Type 2 is a rare disease. Unlike other hyper-IgM syndromes, Type 2 patients identified thus far did not present with a history of opportunistic infections. One would expect opportunistic infections in any immunodeficiency syndrome. The responsible genetic lesion is in the AICDA gene found at 12p13. Hyper IgM syndromes Hyper IgM syndromes is a group of primary immune deficiency disorders characterized by defective CD40 signaling; via B cells affecting class switch recombination (CSR) and somatic hypermutation. Immunoglobulin (Ig) class switch recombination deficiencies are characterized by elevated serum IgM levels and a considerable deficiency in Immunoglobulins G (IgG), A (IgA) and E (IgE). As a consequence, people with HIGM have an increased susceptibility to infections.

First_Aid_Step2

Combined (continued) Wiskott-Aldrich syndrome An X-linked disorder with less severe Band T-cell dysfunction. Patients have eczema, ↑ IgE/IgA, ↓ IgM, and thrombocytopenia. The classic presentation involves bleeding, eczema, and recurrent otitis media. ↑↑ risk of atopic disorders, lymphoma/leukemia, and infection from S. pneumoniae, S. aureus, and H. inﬂ uenzae type b. Phagocytic Chronic granulomatous disease (CGD) Leukocyte adhesion def ciency Chédiak-Higashi syndrome An X-linked (2/3) or autosomal-recessive (1/3) disease with def cient superoxide production by PMNs and macrophages. Anemia, lymphadenopathy, and hypergamma-globulinemia may be present. A defect in the chemotaxis of leukocytes. An autosomal-recessive disorder that leads to Chronic skin, pulmonary, GI, and urinary tract infections; osteomyelitis and hepatitis. Infecting organisms are catalase . ↑ risk of infection with Aspergillus. May have granulomas of the skin and GI/GU tracts. Recurrent skin, mucosal, and pulmonary

DOCK8 deficiency

Diagnosis A diagnosis can only be definitively made after genetic testing to look for a mutation in the DOCK8 gene. However, it can be suspected with a high IgE level and eosinophilia. Other suggestive laboratory findings include decreased numbers of B cells, T cells, and NK cells; and hypergammaglobulinemia. It can be distinguished from autosomal dominant hyper-IgE (STAT3 deficiency) because people with DOCK8 deficiency have low levels of IgM and an impaired secondary immune response. IgG and IgA levels are usually normal to high. It can be distinguished from the similar X-linked Wiskott–Aldrich syndrome by the presence of thrombocytopenia and the consequent bloody diarrhea, as well as its pattern of inheritance. WHIM syndrome, caused by a mutation in CXCR4, is associated with similar chronic cutaneous viral infections.