Abstract: Transient hypogammaglobulinemia of infancy (THI) is a heterogenous disorder characterized by reduced serum IgG levels in early infancy. A putative diagnosis is initially made after exclusion of other causes of hypogammaglobulinemia while a definitive diagnosis of THI can only be made a posteriori in patients with normalization of IgG levels. The aim of this study is to characterize clinical and immunological features of children with an initial diagnosis of THI in correlation to natural outcome, and to assess predictive laboratory parameters of clinical evolution for this disorder. We prospectively analysed clinical and immunological characteristics of 77 THI children at initial diagnosis and of 57 patients at follow-up. Memory B cell subsets and in vitro immunoglobulin production were evaluated. Seventy patients (91 percent) showed clinical symptoms. Patients suffered from infections (91 percent), allergies (47 percent) and autoimmune disease (4 percent). During follow-up 41/57 children (72 percent) normalized IgG values, mostly within 24 months of age (p less than 0.001), allowing the diagnosis of THI. The 16 children who did not normalize their IgG levels showed a higher frequency of severe infections and autoimmune disease (p less than 0.01). Moreover, they expressed a reduced frequency of IgM and switched memory B cells (p less than 0.01) and an inability to produce IgG in vitro (p less than 0.02). We conclude that most patients with an initial diagnosis of THI spontaneously recover within 24 months of age and have a benign clinical course, while a subgroup of children with undefined hypogammaglobulinemia share a clinical and immunological profile with other primary immunodeficiencies. Early recognition of children with hypogammaglobulinemia during infancy who are likely to suffer from permanent immunodeficiencies later in life would allow prompt and appropriate laboratory and clinical interventions.
Abstract: BACKGROUND: PRF1 gene mutations are associated with familial haemophagocytic lymphohistiocytosis type 2 (FHL2). Genotype-phenotype analysis, previously hampered by limited numbers of patients, was for the first time performed by data pooling from five large centres worldwide. PATIENTS AND METHODS: Members of the Histiocyte Society were asked to report cases of FHL2 on specific forms. Data were pooled in a common database and analysed. RESULTS: The 124 patients had 63 different mutations (including 15 novel mutations): 11 nonsense, 10 frameshift, 38 missense and 4 in-frame deletions. Some mutations were found more commonly: 1122 G-->A (W374X), associated with Turkish origin, in 32 patients; 50delT (L17fsX22) associated with African/African American origin, in 21 patients; and 1090-91delCT (L364fsX), in 7 Japanese patients. Flow cytometry showed that perforin expression was absent in 40, reduced in 6 and normal in 4 patients. Patients presented at a median age of 3 months (quartiles: 2, 3 and 13 months), always with fever, splenomegaly and thrombocytopenia. NK activity was absent in 36 (51%), <or=2% in 18 (26%), 3-<or=5% in 10 (14%), >5% in 4 (6%), "reduced" in 2 (3%) (not reported, n = 54). Nonsense mutations were significantly associated with younger age at onset (p<0.001) and absent natural killer activity (p = 0.008). CONCLUSION: PRF1 mutations are spread over the functional domains. Specific mutations are strongly associated with Turkish, African American and Japanese ethnic groups. Later onset and residual cytotoxic function are observed in patients with at least one missense mutation.
Abstract: A retrospective clinical and immunological survey was conducted in 60 patients with Chronic Granulomatous Disease. A prospective controlled non-randomized study of the efficacy of long-term IFNgamma treatment was carried out. The mean age at the time of diagnosis was 4.4 years; mean duration of follow-up was 10.4 years. Lung and skin infections were the most frequent manifestations both prior to diagnosis and during follow-up. Aspergillus species was the first cause of infection and of death in our cohort. The mortality rate was 13%. Long term prophylaxis with IFNgamma did not significantly change the rate of total infection per patient-year compared to controls (p=0.07). Our data provide clear evidence that protocols of continuing intensive surveillance and monitoring of compliance with anti-infective regimens may significantly improve the quality of life and long-term survival in patients with CGD. No evidence justifying long-term prophylaxis with IFNgamma was obtained.
Abstract: Mutations of UNC13D have been described in patients affected by familial hemophagocytic lymphohistiocytosis (FHL3). The Munc13-4 protein contributes to the priming of the secretory granules. Mutation in this gene results in defective cellular cytotoxicity and the familial hemophagocytic lymphohistiocytosis clinical picture. Among reported mutations, few are predicted to impair splicing. Yet, functional impact of these mutations has not been addressed. We identified 18 out of 31 familial hemophagocytic lymphohistiocytosis families showing at least one mutation responsible for splicing error. We identified some known and three novel splicing mutations: one falls at the acceptor site of exon 11 and 2 are deep intronic mutations in IVS1 and in IVS30. We demonstrated that these deep intronic mutations affect regulatory sequences causing aberrant splicing. We report that UNC13D mutations leading to splicing errors represent the majority of mutations observed in familial hemophagocytic lymphohistiocytosis. This finding has implications for designing strategies for analysis of the families with suspected familial hemophagocytic lymphohistiocytosis.
Abstract: Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-gamma (IFNgamma) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the 'anti-inflammatory profile' determined by the intermediate producer genotype IFNgamma +874A/T (P = 0.029) and the high-producer genotypes IL-4 -590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.
Abstract: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare complication of cancer chemotherapy. We have recently observed two cases occurred simultaneously in children receiving different chemotherapy regimens, for hepatoblastoma and acute lymphoblastic leukaemia, respectively. Both children presented with altered mental status, severe visual disturbances, headache, seizures, backpain and hypertension. Magnetic resonance imaging showed cortical and subcortical lesions especially in the occipital and parietal regions, strongly consistent with RPLS. Both patients completely recovered from their neuropsychologic deficits in about ten days only with anticonvulsant and antihypertensive therapy, and chemotherapy regimen was promptly restarted according to the planned protocol, without any neuropsychological sequela. A mild left midriasis was the only neurologic defect that persisted in the patient with acute lymphoblastic leukemia.
Abstract: Familial haemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder characterised by constitutive defects in cellular cytotoxicity resulting in fever, hepatosplenomegaly and cytopenia, and the outcome is fatal unless treated by chemoimmunotherapy followed by haematopoietic stem-cell transplantation. Since 1999, mutations in the perforin gene giving rise to this disease have been identified; however, these account only for 40% of cases. Lack of a genetic marker hampers the diagnosis, suitability for transplantation, selection of familial donors, identification of carriers, genetic counselling and prenatal diagnosis. Mutations in the Munc13-4 gene have recently been described in patients with FHL. We sequenced the Munc13-4 gene in all patients with haemophagocytic lymphohistiocytosis not due to PRF1 mutations. In 15 of the 30 families studied, 12 novel and 4 known Munc13-4 mutations were found, spread throughout the gene. Among novel mutations, 2650C-->T introduced a stop codon; 441del A, 532del C, 3082del C and 3226ins G caused a frameshift, and seven were mis sense mutations. Median age of diagnosis was 4 months, but six patients developed the disease after 5 years of age and one as a young adult of 18 years. Involvement of central nervous system was present in 9 of 15 patients, activity of natural killer cells was markedly reduced or absent in 13 of 13 tested patients. Chemo-immunotherapy was effective in all patients. Munc13-4 mutations were found in 15 of 30 patients with FHL without PRF1 mutations. Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.
Abstract: The disease presentation of autosomal recessive polycystic kidney disease (OMIM #263200, ARPKD) is highly variable and includes polycystic kidneys, pulmonary hypoplasia, and congenital hepatic fibrosis. The authors report an unusual case of ARPKD presenting with hepatosplenomegaly and cytopenia mimicking acute leukemia.
Abstract: OBJECTIVES. To evaluate: (1) the incidence of pneumonia monthly distribution; (2) the rate of pneumonitis due to Mycoplasma Pneumoniae; (3) the suitability of choosing an empirical-based antibiotic-therapy; (4) the need of a critical revision of Mycoplasma serological data. PATIENTS AND METHODS. We studied 188 patients admitted to the Palermo University Pediatrics Department, from september 1998 to august 2001, with admission diagnosis of pneumonia. RESULTS. The highest incidence of pneumonia was in december and march as in both months 28 cases occurred in the whole period 1998-2001 (average of 9.3 cases per each month). The highest rate of pneumonias by Mycoplasma Pneumoniae was in may with a total number of 11/21 cases (52.3%, average of 3.67 cases per month) in the above mentioned three-year period. CONCLUSIONS. Incidence of Mycoplasma pneumonitis is more represented in subjects that are at school age. Our study confirms the enormous variability of the prevalence of the infection by Mycoplasma Pneumoniae and how difficult it is to make an accurate diagnosis lacking standardized, rapid, specific and comparative methods.
