Melinda Erdos

IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease

Background: About 2% of childhood episodes of invasive pneumococcal disease (IPD) are recurrent, and most remain unexplained. Objective: To report two cases of otherwise healthy, unrelated children with recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor-κB(NF-κB)-dependent immunity. Results: One child carried two germline mutations in IRAK4, and had impaired cellular responses to interleukin (IL)1 receptor and toll-like receptor (TLR) stimulation. The other child carried a hemizygous mutation in NEMO, associated with a broader impairment of NF-κB activation, with an impaired cellular response to IL-1R, TLR and tumour necrosis factor receptor stimulation. The two patients shared a narrow clinical phenotype, associated with two related but different genotypes. Conclusions: Otherwise healthy children with recurrent IPD should be explored for underlying primary immunodeficiencies affecting the IRAK4-dependent and NEMO-dependent signalling pathways.

Novel sequence variation of AIRE and detection of interferon-ω antibodies in early infancy.

Objective  Autoimmune polyendocrine syndrome type I (APS I) is a rare primary immunodeficiency disorder characterized by chronic mucocutaneous candidiasis, multi‐organ autoimmunity and ectodermal dysplasia. Autoantibodies to parathyroid and adrenal glands and type I interferons (IFN) are hallmarks of APS I, which results from mutations in the autoimmune regulator (AIRE) gene. We wished to study clinical, immunological and genetic features of APS I in Hungarian patients, and to correlate anti‐IFN‐ω serum concentration with APS I and other multi‐organ autoimmune diseases.

Rebound hepatosplenomegaly in type 1 Gaucher disease

Abstract: A 19‐yr‐old male patient with type 1 Gaucher disease was put on regular biweekly infusions of alglucerase. After 1 yr of treatment, hepatic and splenic volumes decreased from 38 and 45 mL/kg to 31 and 34 mL/kg, respectively. In addition, hemoglobin concentration, platelet count and white cell count increased, acid phosphatase level decreased, and the patient gained weight and energy. Despite improvement, the patient refused enzyme replacement therapy (ERT) because of muscle rigidity, chest pain, trembling and anxiety, which he attributed to enzyme substitution. Two and 4.5 yr after cessation of therapy, hepatic and splenic volumes increased to 36 and 53 mL/kg and to 53 and 110 mL/kg, respectively. The patient developed non‐tractable hematuria because of compression and dislocation of the left kidney by the enlarged spleen, which necessitated splenectomy. This report suggests that cessation of ERT in Gaucher disease may result in severe and complicated rebound visceromegaly.

Recurrent CXCR4 sequence variation in a girl with WHIM syndrome

WHIM (warts‐hypogammaglobulinemia‐infections‐myelokathexis) syndrome is a recently described primary immunodeficiency disorder caused by mutation of the CXCR4 chemokine receptor gene. We report here of a 6.5‐yr‐old girl with bacterial infections, severe chronic neutropenia, and hypogammaglobulinemia. Sequencing the CXCR4 gene revealed a c.1013C>G sequence variant suggesting WHIM syndrome. Recurrent c.1013C>G sequence variant of the CXCR4 gene resulting in p.S338X truncation mutation of this chemokine receptor protein is first reported here.

Dectin-1 deficiency and mucocutaneous fungal infections.

n engl j med 362;4 nejm.org january 28, 2010 367 (HAPO) study.3,4 Fifteen institutional review boards approved our protocol, and none rejected the trial on ethical grounds. In addition, an independent data and safety monitoring committee regularly reviewed the trial. Some participants would not even have met the criteria for gestational diabetes (more evidence of clinical equipoise). We strongly disagree with an assertion that we unnecessarily exposed participants to harm. Randomized trials are necessary provided that there is sufficient uncertainty and that the results will resolve the dispute among physicians, which was the case for the treatment of mild gestational diabetes.5 We agree that our results may encourage previously reluctant physicians to treat gestational diabetes, but such treatment is now supported by evidence from a clinical trial rather than by expert opinion alone.

A multi-centre study of efficacy and safety of Intratect®, a novel intravenous immunoglobulin preparation.

We studied the efficacy, safety and pharmacokinetic profiles of Intratect®, a recently developed polyvalent intravenous immunoglobulin (IVIG) preparation. Fifty‐one patients (aged 6–48 years) with primary immunodeficiencies (PID) and established replacement therapy using a licensed IVIG were enrolled and treated for 12 months with Intratect®. Retrospective patient data served as prestudy controls. The primary efficacy variable was the annual rate of acute serious bacterial infection (ASBI) per patient. Secondary parameters were annual rate of acute relevant infection (ARI), days with antibiotic use, fever, absence from school/work and hospitalization. The average IVIG dose was 0·49 g/kg, with an average infusion rate of 2·4 ml/kg/h. The annual ASBI rate/patient was 0·02 and ARIs were detected 128 times during the 630 adverse events in 40 patients, specified mainly as bronchitis, sinusitis, respiratory tract infection, rhinitis and pharyngitis. The annual rate of respiratory ARIs/patient was 2·0 and the rates/patient for days with fever >38°C, school/work absence and hospitalization were 1·81, 3·99 and 0·36, respectively. A total of 630 adverse events (AEs) were observed in 50 of 51 (98·0%) of patients. In 46 of 51 patients the AEs were not related to infusion. Pharmacokinetic studies after the first infusion revealed a mean elimination half‐life of 50·8 ± 30·3 days. During this study, 19 of 649 (2·9%) IgG trough levels were below 6 g/l, better than that of reference IVIGs during the 6 months before study start (10 of 201). These data suggest that Intratect® is a well tolerated, safe and effective IgG concentrate for the treatment of patients with PID.

Nijmegen breakage syndrome complicated with primary cutaneous tuberculosis

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosomal instability syndrome characterized by severe immunodeficiency, growth retardation, microcephaly, a distinct facial appearance, and a high predisposition to lymphoid malignancy. We report a 7-year-old white girl with NBS associated with cutaneous tuberculosis. The patient presented with multiple red-brown, centrally scaring plaques on the leg and had neither pulmonary nor systemic manifestation of tuberculosis. Polymerase chain reaction testing using Mycobacterium genus- and Mycobacterium tuberculosis species-specific primers confirmed the clinical diagnosis of cutaneous tuberculosis. This is the first report describing the simultaneous presentation of NBS and cutaneous tuberculosis.

Enzyme replacement therapy for Gaucher disease introduced in late adulthood

Gaucher disease is the most prevalent lysosomal storage disorder caused by recessive mutation of the beta-glucocerebrosidase gene, which leads to massive lysosomal accumulation of glucocerebrosids especially in macrophages of bone marrow, liver and spleen. The most common presenting signs and symptoms are hepatosplenomegaly, bone pain, pathologic fractures, fatigue, bleeding tendency and recurrent infections. Regular enzyme replacement therapy which is available since 1992 in Hungary successfully reverses the symptoms of the disorder, including hematological abnormalities, bone infiltration and hepatosplenomegaly. Authors present here two cases diagnosed in late adulthood to emphasize the importance of early diagnosis and treatment.

[Gaucher disease: importance of early diagnosis and therapy].

Gaucher disease is the most common lysosomal storage disorder caused by deficiency of the lysosomal enzyme glucocerebrosidase. By the end of 2006, the total enrollment in the international Gaucher Disease Registry included 4584 patients, 34 of them were Hungarian. The disease has three main types: non neuropathic (Type 1), acute neuropathic (Type 2), and chronic neuropathic (Type 3). The non-neuropathic type has the highest prevalence and also the greatest variability. The first symptoms occur before 10 years of age in more than 50% of the patients. Early onset of the clinical symptoms and signs predispose patients to severe phenotype and irreversible complications. Safe and efficient enzyme substitution therapy has been available from 1991 and applied since 1992 in Hungary. Optimal dose and early therapy are effective in stopping disease progression, leading to the regression of visceral and haematological abnormalities, preventing irreversible bone deformities, and providing a better quality of life. The authors present here three patients with Gaucher disease diagnosed in early childhood. They highlight the importance of early diagnosis and treatment before the development of severe co-morbidities or irreversible complications. They also analyse the challenges for pediatricians in establishing correct diagnosis of Gaucher disease in time.

Molecular pathology and clinical manifestations of Fabry disease

Fabry disease is a rare, progressive lysosomal storage disorder caused by mutation in the GAL gene and an impaired function of the alpha-galactosidase A enzyme. The enzymatic defect results in the progressive accumulation of glycosphingolipids in endothelial cells, smooth muscle cells, leucocytes and fibroblasts leading to organ damage in the skin, eye, nervous system, kidney and heart. Major clinical manifestations include acroparesthesis, angiokeratoma, corneal opacities, vascular diseases of the heart, kidney, and the central nervous system. Enzyme replacement therapy has recently become available for the treatment of Fabry patients. In this review the authors describe clinical features of Fabry disease in 31 Hungarian patients. At the time of this analysis the database consisted of 31 cases (15 males, 16 females) of whom 5 have died (4 males, 1 female). The most common disease-specific manifestation was angiokeratoma in males, and eye symptoms in females. 25% of female subjects were symptom free. Genotyping was performed in all cases and disease-causing mutations were found in all families. Three new mutations were identified. Twelve patients (8 males and 4 females) are currently receiving enzyme replacement therapy.