Phenytoin-induced IgG2 and IgG4 deficiencies in a patient with epilepsy

A five-year-old girl with epilepsy and recurrent respiratory infections was investigated for serum IgG subclass concentrations. She was diagnosed as having a combined deficiency of IgG2 and IgG4 with a decreased serum concentration of IgA and IgG3 and was given replacement therapy with i.v. immunoglobulins. Since then, she has been free from respiratory infections. After phenytoin therapy was stopped, IgG subclass deficiency improved. This case describes the further action of phenytoin on the immune system, adding IgG subclass deficiency to the list.     

IgG subclass deficiencies in children: Facts and fiction

The chance to analyse the four IgG subclasses arose with the publication of Terry and Fahey¹. Since then, a lot of new information on the role of subclasses and their deficiency states in humans has been obtained. This review tries to analyse critically our current knowledge of subclass deficiencies in children.     

Undetectable IgG4 in immunoprecipitation: association with repeated infections in children?

A total of 210 patients with repeated infections were screened for IgG4 deficiency. In 30 patients (14%) IgG4 was undetectable by radial immunodiffusion (<30 mg/l). Of these patients 17 (57%) were less than 2 years of age. Concomitant IgA deficiency (IgA<0.05 g/l) was demonstrated in 11 cases (37%). IgG2 serum levels below the normal range were found in 26 children. IgG4 could be demonstrated at a concentration of 0.5–29 mg/l in all 30 patients using a more sensitive enzymelinked immunosorbent assay technique. Although a highly selected group of patients was investigated, the percentage of individuals without detectable IgG4 by immunodiffusion was in the same range as reported in the literature for healthy control persons. It is thus concluded that IgG4 serum reference levels have to be defined using more sensitive methods and that the observed severe infections are more likely to be connected with low serum IgG2 and/or IgA levels than undetectable IgG4 as measured by immunodiffusion.This work was supported by a grant from the Deutsche Forschungsgemeinschaft BA 872/1-1     

Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency

Immunoglobulins (Ig) A and G subclass deficiencies are common immune system disorders which cause morbidity especially between 2 and 6 yr of age. Prognosis of these defects and therapeutic approach is unclear. The aim of the present retrospective study was to review the clinical and laboratory records of 87 children with IgA and/or IgG subclass deficiency to determine whether these patients experience changes in serum Ig concentrations during follow-up and to give more clinic and laboratory information to the families about the course of these diseases. Among 87 patients studied, the most frequent defect was partial IgA deficiency combined with IgG3 subclass deficiency (41%). The other groups were as follows; partial IgA deficiency (32%), selective IgA deficiency (8%), partial IgA combined with IgG2-G4 subclass deficiency (6%), and IgG subclass deficiency (13%). The commonest clinical presentations were recurrent upper respiratory tract infections (76%), pneumonia (14%), acute gastroenteritis (3%), urinary tractus infection (3%), sinusitis (2%), and acute otitis media (2%). Atopy was widely represented in the patients studied (24%). The number of patients who were given prophylactic treatment with benzathine penicilline, prophylactic oral antibiotic, or oral bacterial extract to prevent infections was 68 (78%). Frequency of recurrent infections decreased from 7.9 +/- 4.9 per year to 2.5 +/- 2.3 in 68 patients receiving any prophylactic regimen; however, decrease in frequency of infections did not show any significant difference between different prophylactic groups. None of the patients in the selective IgA deficiency group had reached normal serum levels of IgA. At the age of 58.3 +/- 21.4 months, 52% of patients in partial IgA deficiency group and 51% of patients in partial IgA + IgG subclass deficiency group, serum IgA increased to normal ranges. Serum IgG subclass levels increased to normal range for age in 67% of patients in partial IgA + IgG subclass deficiency group and in 30% of patients in isolated IgG subclass deficiency group. The mean age for reaching age-related normal IgG subclass levels for these patients was 69.0 +/- 14.5 months. In conclusion, findings of this study suggest that IgA and/or IgG subclass deficiency may be either progressive or reversible disorders and emphasize the value of monitoring Ig levels in affected individuals.     

Development of hypogammaglobulinaemia in a patient with common variable immunodeficiency

A 3-year-old boy who developed common variable immunodeficiency was investigated for the development of hypogammaglobulinaemia. During a period of 4 years, the combined deficiency of IgA, IgG2 and IgG4 proceeded to include IgG1 and finally IgG3 and IgM. This order of isotypes of IgG subclass deficiencies corresponded to the gene order for the heavy chain constant region for immunoglobulins on chromosome 14.     

Cardiac tamponade due to systemic lupus erythematosus in a 7-year-old boy with selective IgG subclass deficiency

Systemic lupus erythematosus (SLE) was observed in a 7-year-old boy with IgG₂ and IgG₄ subclass deficiencies who had been treated with immunoglobulin (100–200 mg/kg/4 weeks) since 2 years of age. The mother and the half-brother displayed the same deficiency. Serum IgG mainly consisted of IgG₁ (98.9%) during the acute phase of SLE due to transient IgG₃ deficiency. While he had no common manifestations of SLE such as arthritis or nephropathy, he developed cardiac tamponade due to massive pericardial effusion. Conclusion The clinical features of SLE in the present case such as the development of cardiac tamponade and the absence of renal involvement may result from the markedly imbalanced IgG subclass distribution among auto-antibodies. Received: 20 May 1997 and in revised form: 7 October 1997 / Accepted: 21 October 1997     

Transient low level of IgG3 induced by sepsis

Staphylococcus aureus sepsis developed in a 14 year old girl. Immunological evaluation revealed low level of IgG3, although total IgG level was normal. The level of IgG3 increased gradually along with the recovery from sepsis. Immunoglobulin replacement therapy might have been useful in this patient, even though the total immunoglobulin level was within normal limits.     

Recurrent pneumococcal meningitis in a patient with transient IgG subclass deficiency

We report the case of a 3 year old boy who exhibited recurrent serious infections with a transient imbalance of IgG subclass in the second year of life. He suffered from pneumococcal meningitis at 3 months, hepatitis at 9 months, and purulent arthritis at 11 months of age. The second episode of pneumococcal meningitis occurred at 14 months. Serum IgG level was normal for age. Low level of IgG2, undetectable level of IgG4 and negligible level of pneumococcus-specific IgG1-G2 antibodies were found. No other primary immunodeficiency was apparent. Serum IgG2-G4 levels but not pneumococcus-specific IgG1-G2 titers increased by the age of 30 months. At that time, he was inoculated with a polyvalent pneumococcal vaccine along with acellular diphtheria-pertussis-tetanus vaccine. He acquired the immunity against these agents, and had no episodic infections in the following 2 years. This observation stresses the existence of transient IgG subclass deficiency associated with delayed development of the anti-polysaccharide antibody response.     

Neurodevelopmental delay and focal seizures as presenting symptoms of human immunodeficiency virus I infection

Three children presenting with neurological symptoms were subsequently diagnosed as being infected with the human immunodeficiency virus I (HIV). All children showed normal development for about 12–18 months of age but later developed psychomotor and developmental regression. One child presented with generalised hypotonia, another with focal seizures, and the third with spastic quadriplegia. Two of the children showed areas of abnormal brain density on computed tomography and in one case there was calcification of the basal ganglia. In two of the children cerebrospinal fluid contained reduced amounts of total folate and elevated concentrations of neopterin. The possibility of a link between the deranged folate metabolism and the neurological symptoms in HIV infections is discussed.Abbreviations HIV human immunodeficiency virus - CSF cerebrospinal fluid - CNS central nervous system - CD cluster determinant - CT computed tomography     

IgG and IgG subclasses deficiency in children undergoing continuous ambulatory peritoneal dialysis and its provocative factors

BACKGROUND: Low levels of serum IgG or IgG subclasses may be responsible for the defective peritoneal defense and for peritonitis attacks in continuous ambulatory peritoneal dialysis (CAPD) children. Malnutrition, peritoneal loss or frequent peritonitis may lead to IgG or IgG subclasses deficiency. METHODS: Levels of IgG subclasses were determined in 12 children undergoing CAPD treatment. Radial immunodiffusion technique was used for determination. Patients were aged from 6 to 16 years (mean age 12.3 years) and had been on CAPD for 11-26 months (mean duration 19.4 months). We evaluated whether IgG and IgG subclasses deficiency are related to malnutrition, the peritonitis rate and the duration of CAPD using the SPSS program. RESULTS: Serum total IgG levels were found to be low in eight out of 12 patients. Eight patients showed low levels of IgG1, four patients IgG2, one patient IgG3 and three patients IgG4. Total IgG values were found to be positively correlated to malnutrition status, peritonitis rate and duration of CAPD. The IgG2 values were found to be related to the duration of CAPD. The IgG4 values were found to be correlated to the peritonitis rates. CONCLUSIONS: The IgG and IgG subclasses deficiency may develop in children while on CAPD treatment. Periodical determinations of either serum IgG or the subclasses may be useful in the follow-up of these patients.     

Cartilage-hair hypoplasia associated with IgG2 deficiency

We report on a 1 year old boy with cartilage-hair hypoplasia (CHH). He suffered from recurrent upper respiratory infections and short-limbed dwarfism. As with most patients with CHH, he had impaired cellular immunity as determined by lymphocyte reactivity. In addition, he had a selective IgG2 deficiency. This combination of immunodeficiencies has not previously been reported for patients with CHH. His recurrent upper respiratory infections were likely to be associated with cellular immunodeficiency and IgG2 deficiency.     

IgG subclass deficiency

The different biological properties of human IgG subclasses make each subclass unique in its functional role in either resistance to infection, autoimmune diseases or allergy. Not only are there marked differences in the relative concentrations of IgG subclasses in serum (IgG₁ > IgG₂ > IgG₃/IgG₄) but the distribution of the antibody responses in the 4 subclasses of IgG can vary markedly depending on the nature of the antigen, the type of infection, the degree of antigen exposure, the immunization regimens, the age of individual, the immune disorder and the allotype of the individual. Measurement of the IgG subclass distribution of antibodies can be informative in identifying an immunological deficiency, evaluating the production of host protective antibodies, and assessing pathophysiology. Determination of IgG subclass concentrations is essential in the diagnosis of immunodeficiencies. However, there is still uncertainty about the accuracy of measurements in relation to standards, monoclonal antibodies and assay types. For the paediatric population, a sensitive assay, such as an enzyme linked immunoabsorbent assay, is essential. A standardised definition of IgG subclass deficiency is yet to be accepted; however, values substantially below the 5th percentile for a normal healthy population of appropriate age measured by a defined assay system may be indicative of significant abnormality. There is emerging evidence that some subclass deficiencies are associated with increased susceptibility to infection. Such IgG subclass deficiencies may be amenable to treatment with intravenous gammaglobulin preparations, but further carefully designed and controlled studies are needed to ascertain treatment efficacy.     

Immunoglobulin subclasses and HLA alleles in immunoglobulin A deficiency

Objective : The term “IgA Deficiency (IgAD)” should be reserved for the individuals who do not have detectable disorders known to be associated with low IgA levels. IgG subclass deficiency or a lack of the IgG2 subclass that is specific against polysaccharide antigens, can be seen in many cases.Methods : Forty-five patients (27 males and 18 females; mean age 8.6 years, range 6.3 to 12.8 years) with IgA deficiency who had been admitted to the Department of Pediatric Immunology in Uludag University School of Medicine, Turkey, were included in this study. Serum immunoglobulin (Ig) class and IgG subclass levels, and HLA haplotypes were prospectively determined in patients and healthy controls.Results : Of the 45 patients with IgAD, 1 was found to have a low level of IgG in the serum. Serum Ig levels were also examined in the families of 22 patients. Five patients had low-normal levels of IgM, whilst one had low levels of IgA and IgG. The levels of IgG sublasses were assessed in 23 patients. One patient had a low level of IgG1 ; 2 had low levels of both IgG2 and IgG3, and 11 had low levels of IgG3. IgG subclass concentrations were found to be normal in control groups. HLA alleles were tested in 25 patients. An increased prevelence of HLA-A1, -B8, -B14, -DR1, -DR3, and -DR7 were previously observed in patients with Ig A deficiency. In this study, HLA-A1 allel was found in 3 patients (12 %), HLA-B14 in 3 patients (12%), HLA-DR1 in 10 patients (40 %), HLA-DR7 in 4 patients (16 %) and HLA-DR3 in 1 patient (4 %). HLA-B8 allel was not found in any patient. Twenty-five children with normal IgA levels have chosen as a control group. They had HLA-DR1 (36%), HLA-DR7 (16 %), HLA-B8 (8%), HLA-DR3 (16%). HLA-A1 was not found in any member of our control group.Conclusion : No statistically significant difference in HLA susceptibility alleles was found between patients and healthy controls. Our data suggest that there may be heterogenous HLA distribution patterns in IgA deficiency, or that HLA allel-associated tendency to IgA deficiency may be polygenic.     

Analysis of IgG subclasses in chronic active Epstein–Barr virus infection

BACKGROUND: Although elevated serum levels of immunoglobulins are frequently observed in patients with chronic active Epstein-Barr virus (EBV) infection, there have been no reports concerning levels of IgG subclasses. METHODS: Serum levels of IgG subclasses were measured by the enzyme-linked immunosorbent assay (ELISA) in 30 children with severe chronic active EBV infection. RESULTS: Serum levels of IgG1 were elevated in most patients, except for one who showed an abnormally low level of IgG1 and progressive hypogammaglobulinemia. Serum levels of IgG2, IgG3 and IgG4 in the patients were comparable to those in control children, while abnormally low levels of IgG2, IgG3 and IgG4 were observed in six, three and four cases, respectively. CONCLUSION: Although not always susceptible to bacterial infections, low levels of IgG2 were frequently observed in patients with chronic active EBV infection and elevated IgG1 is responsible for the increase of serum IgG in these patients.     

Ewing's sarcoma in a child with human immunodeficiency virus (type 1) infection

A male child with vertically transmitted human immunodeficiency virus type 1 (HIV) infection developed a Ewing's sarcoma of the left fibula at 6.1 years of age. We report the antitumour chemotherapy given and the response of the tumour. Six months after tumour diagnosis the child died of probable HIV encephalopathy. This is the first reported case of Ewing's sarcoma in an HIV-infected child. © 1993 Wiley-Liss, Inc.     

Does the classification system fit disease progression in perinatal human immunodeficiency virus infection?

The objective was to test the applicability of the new classification for paediatric human immonodeficiency virus infection. The person-time of each state, transition probabilities and survival (± standard errors) at 5 years, and median sojourn-time were calculated on 39 perinatally infected children followed up from the first month of life for a median of 64.5 (1.2-120.1) months. The person-times of the N2, N3, B1, C1, and C2 states were low. The transition probabilities and sojourn-times were similar for A (48.1 ± 10.8%; 63.5 months), B (50.5 ± 15.5%; 44.9 months) and C (74.6 ± 15.1%; 43.1 months) clinical categories, which differed ( p < 0.025) from the N category (87.9 ± 5.5%; 12.05 months). The survival probabilities after 5 years of entering the A, B and C categories were 84.8 ± 10.7%, 60.5 ± 19.8% and 14.8 ± 13.5%, respectively ( p < 0.001). Immunological category 3 had lower transition probabilities and longer sojourn-times (58.8 ± 16.6%; 53.3 months) than categories 1 (71.3 ± 8.1%; 33.2 months) and 2 (75.6 ± 10.5%; 19.8 months) ( p < 0.01). The transition probabilities to C3 for states N3, A3 or B3 were 52.5 ± 13.5%. In conclusion, the classification tits the clinical history better than the immunological history.     

Human immunodeficiency virus type 2 infection in children

Human immunodeficiency virus type 2 infection is rare in children. This virus can be acquired through transfusion and also by the maternofetal route, especially when the mother becomes infected during pregnancy. Diagnosis based on specific serologic tests is simple after the age of 18 months. In the perinatal period, however, viral isolation by culture or polymerase chain reaction DNA amplification or both appears to be less sensitive than in the case of human immunodeficiency virus type 1. Disease progression is far slower than with human immunodeficiency virus type 1, but severe immunodeficiency can occur. (J Pediatr 1997;130:994-7)     

Isolated IgG3 deficiency in children: to treat or not to treat? Case presentation and review of the literature

Immunoglobulin G3 (IgG3) subclass deficiency has received rather little attention thus far. In this report, the clinical and immunologic characteristics of six children with isolated IgG3 deficiency are discussed. The currently available literature on IgG3 deficiency is reviewed with specific emphasis on the peculiarities of the IgG3 subclass, the clinical relevance of IgG3 deficiency as well as the therapeutic options.