IgG4 deficiency with Rothmund-Thomson syndrome: A case report

We describe a patient with Rothmund-Thomson syndrome and IgG₄ deficiency. In vitro examination of his peripheral mononuclear cells revealed impaired IgG₄ synthesis. Susceptibility to sinus and pulmonary infections was cured by monthly immunoglobulin infusions.     

Successful intravenous immunoglobulin therapy for recurrent pneumococcal otitis media in young children

Serum immunoglobulin levels and naturally occurring antibody titres againstStreptococcus pneumoniae were measured in seven children aged 1–1.9 years with recurent pneumococcal acute otitis media (AOM). Three of them had low IgG₂ levels. Mean antibody levels of anti-pneumococcal IgG₁ and anti-pneumococcal IgG₂ were significantly lower in patients when compared to those of healthy controls and children who had less frequent episodes of AOM. Following treatment with intravenous immunoglobulin (IVIG) for 6 months, anti-pneumococcal IgG₁ and IgG₂ antibody levels increased and the number of episodes of AOM decreased in all patients. Following the discontinuation of IVIG therapy, no AOM episode occurred. Serum levels of anti-pneumococcal IgG₁ and IgG₂ were normal, which were measured in three subjects at 5,6, and 12 months after the cessation of IVIG therapy. These results suggested that delayed maturation of anti-pneumococcal antibody production caused recurrent AOM and this condition was corrected by IVIG therapy.     

Unusual course of a chlamydia pneumonia in an infant with IgG2/IgG4-deficiency

An unusual case ofChlamydia trachomatis (C. trachomatis) pneumonia, complicated by the development of a pneumothorax, is reported in an IgG₂/IgG₄ deficient infant delivered by caesarean section.C. trachomatis was isolated initially from a throat smear and subsequently from pleural effusions. Serological examinations using the complement fixation test were negative in sera of both mother and child. However, using immunofluorescence the presence of an acute or recent infection was confirmed by IgM-antibodies in the serum of the infant and IgA-antibodies in the serum of the mother. At the age of 7 months the girl suffered from impetigo contagiosa which was partially resistant to antibiotic treatment. IgG-subclass deficiency was diagnosed after the onset of this disease and the girl was then treated by immunoglobulin transfusion.Abbreviations C. trachomatis Chlamydia trachomatis - ELISA enzyme linked immuno assay - IFT immunofluorescence technique     

Immunoglobulin G subclasses in wheezing infants

Background: The wheezing infant is a common but difficult patient to approach diagnostically. The prevalence of immunoglobulin (Ig) G subclass deficiency in wheezing infants is still controversial. Methods: We studied the serum concentration of IgG subclasses in 38 wheezing infants (aged6–24 months) who had not received systemic steroids before investigation and in 30 healthy age matched controls6–31 months). Results: The prevalence of one or more IgG subclass deficiencies was 3 1.6% in wheezing infants and 26.7% in controls. There was no significant difference in prevalence of IgG subclass deficiency between patients and controls (P > 0.05). The mean concentration of IgG subclasses in patients were compared with controls. There was no significant difference in mean serum concentration of IgG₁, G₂ and G₃ subclasses. However, there a trend towards higher concentrations of IgG₄ in wheezing infants and this difference for IgG₅ was significant (P < 0.01). Immunoglobulin G subclass deficiency was found in 25 and 36.4% of wheezing infants who experienced from two to four and five or more wheezing episodes in 2 years, respectively (P > 0.05). Conclusion: Our findings suggest that wheezing in infancy is not associated with IgG subclass deficiency, and in wheezing infants low IgG subclasses levels do not increase the frequency of wheezing. However, is a relationship between recurrent wheezing and serum IgG₄ subclass concentration.     

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     

Immunoglobulin G subclass concentrations and infections in children and adolescents with severe asthma

It was the aim of this study to investigate possible dysfunctions of the humoral immune system in asthmatic children with frequent respiratory infections. Forty‐one severe asthmatics (7–15 years of age), classified according to the Second Brazilian Consensus in Asthma (1998), were divided into two groups: group I (n = 12) had recurrent respiratory infections; and group II (n = 29) were without recurrent respiratory infections. Immunoglobulin (Ig)G, IgA and IgM levels (nephelometry), and IgE (radioimmunoassay) and IgG subclasses (enzyme‐linked immunosorbent assay), were evaluated using standard methods. Asthmatics with recurrent infections presented with worse clinical evolution, an increased number of hospital admissions, and a higher need of medication than the children without recurrent infections. There were no significant differences between the mean values of IgG, IgA or IgM levels, or IgE or IgG subclasses, in patients of both groups. A complete IgA deficiency was detected in two patients of group I (one was associated with IgG subclass deficiency). Deficiency of one or more IgG subclasses was verified in eight of 12 (66%) children from group I and in 16/29 (55%) from group II. The following deficiencies were found in both groups: IgG₃ (10/41), IgG₄ (three of 41), IgG₂ (two of 41), IgG₁ (one of 41), IgG₃‐IgG₄ (four of 41), IgG₁‐IgG₃ (two of 41), and IgG₁‐IgG₃‐IgG₄ (one of 41). There were a higher proportion of children with low IgG₄ levels in group I than in group II (p = 0.01). To conclude, IgA and IgG subclass deficiencies were detected in both severely asthmatic groups, with a predominance of IgG₃ subclass deficiency. However, low IgG subclass levels appear not to be a suitable predictor of the development of infections in asthmatic children.     

Immediate hypersensitivity to ovalbumin in children with hen's egg white allergy

Serum concentration of IgE, IgG₁ and IgG₄ antibodies to ovalbumin and basophil sensitivity to ovalbumin were compared with the results of a titrated oral provocation test with ovalbumin in 27 children sensitive to hen's egg white, of whom 17 responded with an immediate hypersensitivity reaction. Neither the serum level of IgE, IgG₁ and IgG₄ antibodies to ovalbumin nor a positive histamine release test predicted the clinical relevance of ovalbumin sensitivity. The children with a positive challenge test had a significantly higher IgE/IgE₄ ratio and tended to be younger and to have higher serum IgE levels and a higher IgG₁/IgG₄ ratio than those with a negative challenge test. We conclude that an oral provocation test is necessary to confirm the diagnosis of food allergy.     

Idiotype in myeloma terminating in erythroleukemia

A patient with multiple myeloma, IgG_K type, developed erythroleukemia with cytogenetic abnormalities three years after diagnosis. The latter disease progressed terminally to acute granulocytic leukemia. Anti-idiotype antibody reagents were prepared by injecting rabbits with the purified monoclonal IgG_K obtained from the patient's serum and subsequent absorption of the antisera with normal IgG coupled to Sepharose 4B. These reagents reacted specifically with autologous myeloma cells but failed to react with all tested allogeneic cells: these included myeloma cells, reactive lymphocytes and plasma cells, and established lymphoid cell lines. Common idiotypic determinants were found in lymphoid and plasmacytic cells of the patient's marrow, spleen, lymph node, and gastrointestinal tract at autopsy that were not present in the leukemic population. The findings indicate that myeloma and granulocytic leukemia cells have separate clonal origins.     

Relapse of neuroblastoma 38 months after high-dose chemotherapy and peripheral blood stem-cell autografts

A 5-year-old girl with stage IV neuroblastoma with diesseminated marrow involvement was treated with high-dose chemotherapy and autografts with peripheral blood stem/progenitor cells (PBSC), without local or total-body irradiation. After PBSC autograft, hematologic recovery was complete. Without further anticancer therapy, she remained tumor-free for 38 months until a local recurrence was identified. This case illustrates that late relapse can occur in advanced-stage neuroblastoma after long-term remission following high-dose chemotherapy without irradiation. Correspondence to: H. Takehara     

Protective immunogenicity of Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine in children who failed to respond to prior invasive H. influenzae type b disease

A polyribosylribitol phosphate (po1ysaccharide)-tetanus protein conjugate vaccine (PRP-T) against Haemophilus influenzae type b (Hib) was evaluated for protective immunogenicity in 25 previously PRP-unim-munized children who had failed to develop protective PRP antibody levels (< 1 μg/ml) after prior invasive Hib disease at median age 10 months. Children under 21 months of age at time of PRP-T immunization received one, two or three doses. Serum was obtained for total PRP antibody, complement mediated bactericidal activity and specific IgG₁ and IgG₂ PRP antibodies before (n = 25), 1 to 2 months (n = 24) and > 5 months (n = 13) after completed vaccination. One to 2 months after immunization, all but one patient developed > 1 μg/ml of antibody (geometric mean level 50.7 μg/ ml). The non-responder developed protective antibody levels when tested at 6 months after vaccination. Twenty out of 22 sera had detectable complement mediated bactericidal activity (median dilution titer 1:24), 1-2 months after vaccination. Three patients failed to demonstrate PRP antibodies in the IgG₁ or IgG₂ subclasses, although two of them had protective (> lμg/ml) total antibody levels. The second post immunization sera showed persistence of the total PRP antibody levels (geometric mean level 38.2 μg/ml) as well as of the bactericidal activity (median dilution titer 1:32). Conclusion: PRP-T conjugate vaccine is able to elicit a protective immune response in children who have low or unmeasurable PRP antibody levels after a systemic Hib infection.     

Recurrent meningitis secondary to isolated C3 deficiency

A 5-year-old child presented with the second episode of meningitis when we started investigating her to find a cause for recurrent episode of meningitis. During this she suffered from a third attack after which she was diagnosed as having isolated C₃ deficiency. She was put on penicillin prophylaxis and vaccinated against encapsulated bacteria, after which she is now doing well.     

Juvenile Classic Kaposi'S Sarcoma: A Report Of Two Cases,One With Family History

Two cases of juvenile classic Kaposi's sarcoma (KS), one with family history, are described, and the natural history of KS is briefly reviewed. Case 1a war a child whose disease ran an aggressive course and did not respond to therapy. Case 1b was the mother of the child: She had a relapsed localized form that was treated by surgery and chemotherapy, and she has been disease free since 1990. The second juvenile case was a 4–year-old boy with a localized form that relapsed but was successfully treated by surgery, chemotherapy, and radiation therapy. He has been free of disease since 1986. Family history in juvenile KS has not previously been reported unrelated to acquired immunodeficiency syndrome in a Western country.     

IgG2/IgG4 subclass deficiency in a patient with chronic mucocutaneous candidiasis and bronchiectases

A 22-year-old man with chronic mucocutaneous candidiasis (CMC) and hypothyroidism developed severe bronchiectases following recurrent bronchopneumonia. Immunological investigations revealed IgG₂/IgG₄ subclass deficiency and absence of antibodies against pneumococcal and Haemophilus polysaccharides. Under regular immunoglobulin substitution every 3 weeks pulmonary symptoms improved markedly.     

Non-infective colitis in infancy: evidence in favour of minor immunodeficiency in its pathogenesis

Accepted 4 November 1996
Forty two infants below the age of 2 years presenting with chronic non-infective diarrhoea and shown to have histologically proved colitis were investigated over a five year period. Allergic colitis was the most common cause of colitis, accounting for 62% of the cases. Other colitides diagnosed included: non-specific colitis, autoimmune enterocolitis, and ulcerative colitis accounting for 10% each; severe combined immunodeficiency 7%, and Crohn''s disease 3%. A positive family history and a personal history of atopy were obtained in 48% and 29% of the cases respectively. Serum immunoglobulin A, IgG₂, and IgG₄ were very low in over 50% of the entire cohort of infants with colitis; 66% of those with severe combined immunodeficiency, autoimmune enterocolitis, and ulcerative colitis (n = 11) had low CD3 and CD4 T lymphocytes with an accompanying increase in CD8 in two thirds of those with severe combined immunodeficiency. T lymphocytes were normal in those with allergic colitis. Thus infants with proved non-infective colitis as a group show a high prevalence of IgA, IgG₂, and IgG₄ deficiency. It is likely that this minor deficiency of mucosa associated immunoglobulin production has a role in the pathogenesis of the colitic process.

     

High levels of IgG4 antibodies to foods during infancy are associated with tolerance to corresponding foods later in life

Children with eczema and sensitization to foods are recommended skin care and, if food allergy is proven by challenge, an elimination diet. For most children the diet period is transient, but the process behind tolerance development and the influence of decreased allergen exposure is not fully known. The aim of the study was to investigate the effect of elimination diet on serum and salivary antibodies and to identify immunological parameters related to the ability to tolerate foods. Eighty‐nine children, below 2 yr of age, with eczema and suspected food allergy were included. Recommended treatment was skin care to all children, and 60 children had a period of elimination diet. At 4½ yr of age, the children were divided into two groups, based on if they had been able to introduce the eliminated foods, or not. Serum and salivary antibodies were analyzed with enzyme‐linked immunosorbent assay and UniCAP^® before and after a 6‐wk treatment period and at 4½ yr of age. Children sensitized to egg and/or milk that could eat and drink the offending foods at 4½ yr of age, had higher levels of Immunoglobulin G₄ antibodies to ovalbumin and β‐lactoglobulin and also higher IgG₄/Immunoglobulin E ratios on inclusion in the study, than those who had to eliminate egg and/or milk from their diet, beyond 4½ yr of age. The highest IgG₄/IgE ratios were found in children with circulating IgE antibodies to egg and/or milk but negative skin prick test on inclusion. The 6‐wk treatment period did not significantly affect the levels of serum and salivary antibodies. In conclusion, eczematous, food sensitized infants with high levels of IgG₄ and high ratios of IgG₄/IgE antibodies to food allergens are more likely to consume these foods at 4½ yr than infants with low levels and ratios.     

Integration of ruxolitinib into dose‐intensified therapy targeted against a novel JAK2 F694L mutation in B‐precursor acute lymphoblastic leukemia

A 17‐year‐old girl with B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) with persistent minimal residual disease (MRD) who underwent standard chemotherapy was found to have a BCR‐ABL1‐like gene expression pattern. Genome sequencing revealed a JAK2 mutation not previously described in BCP‐ALL and a potential therapeutic target. Due to concern for an on‐therapy relapse, the JAK2 inhibitor ruxolitinib was incorporated into a modified chemotherapy backbone to achieve complete remission prior to stem cell transplant. Treatment was well tolerated and she had undetectable MRD prior to a matched allogeneic stem cell transplant and remained in remission at day +100.     

Development of immunoglobulin G subclass antibodies to ovalbumin,birch and cat during the first eight years of life in atopic and non-atopic children

Immune responses to allergens in young children include both Th1- and Th2-like immunity, which may regulate the secretion of immunoglobulin (Ig) G subclass antibodies differently. The time, route and level of exposure to an allergen may be decisive with regard to whether sensitization or tolerance will ensue. To study this, we investigated the development of IgG subclass antibodies to food and inhalant allergens during childhood. The study group comprised a cohort of 96 children participating in a prospective study. IgG subclass antibodies to ovalbumin, Bet v 1 and cat dander were analyzed at birth, 6 and 18 months and 8 years by ELISA. IgG₁ and IgG₃ subclass antibodies to ovalbumin peaked at 18 months and then declined up to 8 years of age, whereas antibodies to the inhalant perennial allergen cat, but not the inhalant seasonal allergen birch, increased with age. Exposure to cat and birch tended to be associated with high antibody levels to those allergens, whereas antibody levels to ovalbumin were not related to exposure to egg. The presence of positive skin prick tests and circulating IgE antibodies correlated with high levels of IgG subclass antibody responses to the allergens. Atopic symptoms were associated with high levels of IgG subclass, particularly IgG₄, antibodies to the allergens. The difference in antibody levels between atopic and non-atopic children was most marked at 6 months for ovalbumin. For the seasonal inhalant allergen birch, the difference was apparent from 18 months, whereas a difference in antibody levels to the perennial inhalant allergen cat was already present at 6 months. In conclusion, IgG subclass antibodies to food allergens peak in early infancy and are then down-regulated, whereas antibodies to the inhalant perennial allergen cat, but not the inhalant seasonal allergen birch, increase with age. Atopy is associated with high levels of IgG subclass, particularly IgG₄, antibodies to allergens, supporting a deviation of the immune system towards Th2-like responses in atopic children.     

Nutritional Vitamin B12 Deficiency in a Breastfed Infant Following Maternal Gastric Bypass

Breasfed infants of women who have had gastric or intestinal bypass procedures may develop nutritional deficiencies. We describe a 10-month-old exclusively breastfed white male infant who presented with vomiting, failure to thrive, and megaloblastic anemia. He was found to have vitamin B₁₂ deficiency. His mother had undergone a gastric bypass procedure for morbid obesity 2 years Prior to her pregnancy with this child. She had subclinical vitamin B₁₂ deficiency, with an abnormal Schilling test that corrected with the addition of intrinsic factor. Therefore, we believe that the mother's gastric bypass had caused a decrease in available intrinsic factor, resulting in subclinical vitamin B₁₂ deficiency and decreased breast milk B₁₂. Although she was asymptomatic, her breastfed infant developed symptomatic B₁₂ deficiency. This is the first reported case of a maternal gastric bypass resulting in vitamin B₁₂ deficiency in an infant. These mothers should receive vitamin supplements, including vitamin B₁₂ during and after pregnancy, and my require parenterally administered vitamin B₁₂.     

Neutropaenic enteropathy

Neutropaenic enterocolitis is an acute necrotising inflammation involving segments of small and large bowel occurring in patients with agranulocytosis, most commonly with acute leukaemia, after commencement of immunosuppressive chemotherapy. Twelve children aged 4 months to 15 years, 9 of whom were receiving treatment for acute lymphocytic leukaemia; were treated during the 9 year period 1983–1991. The symptoms included bile-stained vomiting, abdominal distension, and watery diarrhoea with right iliac fossa pain and tenderness. Eight children are alive following conservative management, and 1 survived following surgical resection of necrotic ileum. This study supports the conservative management of neutropaenic enterocolitis. Correspondence to: D. C. S. Gough