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MVK mutations and associated clinical features in Italian patients affected with autoinflammatory disorders and recurrent fever

Autosomal recessive autoinflammatory disorder caused by mutations of the mevalonate kinase gene (MVK), leading to mild, incomplete MK enzyme deficiency (MKD), has been known so far as Hyper-IgD and periodic fever syndrome (HIDS) and regarded as mostly occurring in Northern Europe. Here we report the results of the molecular characterization of the first Italian series of patients affected with autoinflammatory disorders and periodic fever. A total of 13 different mutations, scattered throughout the MVK coding region, were identified in either homozygous or compound heterozygous state in 15 patients. The mutation leading to the V377I amino-acid change, already described also in other series, resulted the most common with a frequency of 50% of all MKD alleles. Among the other mutations, eight had never been described before, including an interstitial deletion of 19 nucleotides in exon 2. In addition to these nucleotide changes, private and polymorphic MVK variants have been detected in the patients under analysis and checked also in a set of control individuals. Clinical features are reported for each of the 15 MKD patients, and life-threatening infections and systemic amyloidosis presented as unexpected MKD-related complications. Our study demonstrates that MKD is a common cause of recurrent fever also in the Italian population, where it is associated with both a wide spectrum of previously unreported MVK mutations and peculiar phenotypic features.

Clinical Features and Follow-Up in Patients with 22q11.2 Deletion Syndrome.

OBJECTIVE To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. STUDY DESIGN A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. RESULTS The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations (P = .015) and speech disorders (P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. CONCLUSIONS Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.

Evaluation of the Antibacterial Activity of a Special Silk Textile in the Treatment of Atopic Dermatitis

Background: Increased skin Staphylococcus aureus colonization is frequently found in atopic patients. The reduction of local overinfection decreases skin inflammation and improves the flares. Objective: To evaluate the effectiveness of the antimicrobial activity of a silk fabric (MICROAIR DermaSilk®) coated with alkoxysilane quaternary ammonium with durable antimicrobial properties (AEGIS AEM 5572/5) in children affected by atopic dermatitis (AD). Methods: Sixteen children, 12 affected by AD with symmetric eczematous lesions on the antecubital areas and 4 without any cutaneous disease, used, for 7 days, tubular arm covers made of this special silk fabric but only one of each pair was coated with AEGIS AEM 5572/5. Microbiological examinations were done with standard cultural swabs and by means of quantification of bacterial agents using agar plates at baseline, after 1 h and after 7 days. Results: After 7 days a significant improvement in the mean value of the ‘local SCORAD’ index was observed in both the covered areas compared to the values obtained at baseline. The reduction in the mean number of colony forming units per square centimetre was similar in both areas. Conclusions: Although this special silk fabric seems to be able to improve skin lesions in AD, we were unable to demonstrate that such silk fabrics coated with AEGIS AEM 5572/5 have an antibacterial activity in vivo, as shown in vitro.

Immunological Parameters in Darier’s Disease

Patients with Dariers disease have frequently been observed to develop severe bacterial and viral infections. Previous studies have indicated some derangement in the immune system, even though no consistent or specific abnormality has yet been demonstrated. We performed the results of immunologic studies in 10 patients with Dariers disease. In each patient humoral immunity and cell-mediated immunity (in vivo and in vitro) were evaluated and leukocyte chemotactic function was assayed. Humoral immunity was normal; as regards clusters of differentiation (CD), a slight increase in CD4 lymphocyte subpopulations was observed in 7 patients and of CD4/CD8 ratio in 1 case. The lymphocyte responses to phytohemagglutinin and concanavalin A were normal, whereas the response to pokeweed mitogen was decreased slightly, but not significantly. Normal random and chemotactic mobility was found in all the patients except one. The data obtained do not show important immunological alterations. Our patients did not have a high propensity to develop severe infections and this may explain the absence of significant immunological derangement. Our data confirm that no immunological derangement is associated with Dariers disease.

Gianotti-Crosti syndrome and allergic background

The aim of the study was to verify whether there is a relationship between Gianotti-Crosti syndrome and an allergic background in children. Twenty-nine children affected by Gianotti-Crosti syndrome were first screened for a large panel of microbiological examinations, including serological and cultural tests for viruses and bacteria. A causative agent was identified in only 10 cases (34.4%). In five cases a diagnosis of Epstein-Barr virus infection was made on the basis of significant titres of anti-Epstein-Barr virus antibodies (IgM) associated with constitutional symptoms (fever, pharyngitis-tonsillitis). Our data concur with several clinical studies demonstrating that Epstein-Barr virus is now the most common viral agent associated with Gianotti-Crosti syndrome. For allergic evaluation, a group of 59 age- and sex-matched children investigated for recurrent infections were used as controls. The presence of atopic dermatitis (24.1%) in those with Gianotti-Crosti syndrome was significantly higher (p < 0.005) than in the control group (6.8%). In addition, a more common family history for atopy was 51.7% vs. 31% (p < 0.027) and the percentage of patients with total IgE greater than +2 SD for age higher than in controls (27.6% vs. 13.7%), as was the percentage of specific IgE present (31% vs. 17.2%). These results indicate that atopy is significantly associated with Gianotti-Crosti syndrome.

Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.

Evolution of hypogammaglobulinemia in premature and full-term infants.

There are few data in the literature reporting the evolution of hypogammaglobulinemia in premature and full-term infants during the first years of life. The aim of this study was to assess the clinical and immunological evolution of premature and full-term infants with hypogammaglobulinemia. We included 24 children (11 premature and 13 full-term infants), aged 0–36 months, with hypogammaglobulinemia. Fifteen (62.5%) children had an isolated reduction in IgG, 7 (29.2%) had a decrease in both IgG and IgA and 2 (8.3%) a reduction in IgG and IgM. Normalization of IgG serum levels occurred in the premature infants at a mean age of 7.2 months. Full-term infants were divided into 3 groups based on age at normalization of IgG serum level: A) hypogammaglobulinemia with normalization within 12 months of life; B) with normalization within 36 months of life; C) normalization after 36 months. All the premature infants with hypogammaglobulinemia recovered, even though in the lower limits for age in the first years, while transient hypogammaglobulinemia observed in full-term infants has a different age of recovery.

Progressive severe B cell deficiency in pediatric Rubinstein-Taybi syndrome

The Rubinstein-Taybi syndrome (RSTS; OMIM #180849, #613684) is a rare disease affecting equally males and females with a prevalence at birth of 1:100.000 to 1:125.000 [1]. Since the original description in 1963 [2], more than 1000 cases have been reported in the literature, offering a quite variable clinical presentation, including craniofacial dysmorphisms and skeletal abnormalities (such as broad thumbs and large toes), intellectual disability, post-natal growth deficiency and others; thus, diagnosis may become difficult. The genetic cause of RSTS may be related to mutations in the cAMP response elementbinding protein (CREB)-binding protein (CREBBP) or, with minor frequency, in the E1A-associated protein p300 (EP300) [3,4]. Besides the classical presentation, affected patients may frequently present recurrent respiratory infections. However, immunological evaluation has been reported in a limited number of RSTS patients showing variable levels of humoral defects [5–7]. We report on a female patient affected with RSTS that developed progressive severe B cell deficiency and agammaglobulinemia. The patient was born to unrelated healthy Italian parents. At the age of 4, clinical suspicion of RSTS was made based on typical features such as craniofacial dysmorphisms, broad thumbs, large toes and mild intellectual disability. Genetic analysis of the CREBBP gene evidenced the de novo p.Glu1278Ala mutation that has not been previously reported. At the age of 5 years, the patient came to our attention for neutropenia (WBC: 3.660/mm; Neutrophils: 9% (329 cells/mm)) and low platelet count: Platelets = 5.000/mm. Immunological evaluation at this timepoint showed normal immunoglobulin serum levels and normal to elevated peripheral B cells (Fig. 1A and B); bone marrow aspirate and DEB testing were normal. High dose immunoglobulin treatment achieved prompt increase in the platelet count, confirming the diagnosis of idiopathic thrombocytopenic purpura (ITP). The neutrophil count normalized as well. During follow-up, the patient presented recurrent episodes of ITP with prompt response to high dose immunoglobulin treatment. At the age of 13 years, immunological evaluation showed reduced levels of all immunoglobulin serum levels: IgG 289 mg/dl (normal values for age: 640–1909 mg/dl); IgA 10mg/dl (normal values for age: 61–301), IgM 13 mg/dl (normal values for age: 59–297 mg/dl) (Fig. 1A) with reduction of peripheral B cells (4%) (Fig. 1B). A similar

Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes

We assessed the prevalence of TNFRSF13B mutations and the clinical correlates in an Italian cohort of 189 CVID, 67 IgAD patients, and 330 healthy controls to substantiate the role of TACI genetic testing in diagnostic workup. We found that 11% of CVID and 13% of IgAD carried at least one mutated TNFRSF13B allele. Seven per cent of CVID had monoallelic-mutations and 4% had biallelic-mutations. The frequency of C104R monoallelic-mutations was not higher than that found in healthy controls. Biallelic-mutations were exclusively found in CVID. CVID patients carrying monoallelic-mutations had an increased prevalence of lymphadenopathy, granulomata, and autoimmune cytopenias. CVID carrying biallelic-mutations had a low prevalence of autoimmunity in comparison with TACI wild-type CVID. Moreover, biallelic-mutated CVID had higher frequency of switched memory B-cells and higher IgM and IgA antibodies to polysaccharide antigens than TACI wild-type and monoallelic-mutated CVID. TACI-mutated IgAD patients had only monoallelic-mutations and did not display clinical difference from IgAD wild-type patients. In conclusion, TNFRSF13B genetic screening of antibody deficiencies may allow the identification of mutational patterns. However, as with counseling for risk assessment, geneticists should be aware that the interpretation of genetic testing for TACI mutations is difficult and the potential impact on clinical management is still limited.

Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications

Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.