A variant of uncertain significance of the HMGA2 gene in a child with Silver-Russell syndrome-like phenotype: a case report.

Silver-Russell syndrome 5 (SRS5) is characterized by asymmetric intrauterine growth restriction (IUGR), poor postnatal growth, macrocephaly at birth, and feeding difficulties. Other possible features include triangular shaped face, prominent forehead, hypertelorism, epicanthus, micrognathia, brachydactyly, clinodactyly of the 5th finger, and syndactyly of the 2nd and 3rd toes. Pathogenic variants of the HMGA2 (high mobility group AT-hook 2) gene, on chromosome 12q14, which regulates the transcription of growth factor IGF2, have recently been associated with this syndrome. Herein, we present a 2.5-year-old boy with growth delay, SRS-like phenotype, and a variant of uncertain significance in the HMGA2 gene, which has not, to the best of our knowledge, been described to date in the medical literature. So far, 28 pathogenic variants of the HMGA2 gene in patients with clinical SRS phenotype have recently been reported. Therefore, HMGA2 gene testing should always be done in SRS patients who are found to be negative for the typical 11p15 (epi)mutations and matUPD7, while the mutations should also be added to growth retardation disorder panels.

Primary Thyroid Diffuse Large B-cell Lymphoma in a Child with Hashimoto's Thyroiditis: A Case Report

Primary thyroid lymphoma (PTL) is a rare thyroid gland cancer, with diffuse large B-cell lymphomas (DLBCL) being extremely rare in children and adolescents. Thus, optimal therapy is debatable. We describe a rare case of thyroid DLBCL in an adolescent girl with a history of Hashimoto thyroiditis (HT), the difficulty in diagnosis and the outcome of treatment. A 12-year-old girl with a nine-year history of HT was admitted with a right-sided painless progressive swelling of the neck. Physical examination and imaging including ultrasound (US), computed tomography (CT) and positron emission tomography/CT revealed an enlarged thyroid gland with right side lymphadenopathy and no metastasis. Two fine needle aspirations were done showing suspected lymphoblastic lesions for non-Hodgkin lymphoma without precise diagnosis. US guided core needle biopsy was finally performed confirming the diagnosis of DLBCL. She was treated according to LMB 96-group B protocol with no surgical removal of thyroid. The patient responded very well to treatment and 14 months later there is no evidence of relapse or metastases. PTL is an extremely rare cause of thyroid malignancy in children. However, it should be considered in the differential diagnosis of a thyroid mass in adolescents presenting with a rapidly enlarging neck mass and a history of HT. It is a treatable condition with a good prognosis, even in aggressive histological subtypes, with no need for thyroidectomy.

Laser treatment for lipoatrophy in children with diabetes type 1.

Introduction: Lipoatrophy (LA) is one of the complications of insulin treatment. It has become rare thanks to insulin analogues but it can still be observed in patients with diabetes type 1(T1DM). No effective treatment exists. Herein, we report for the first time two children with T1DM and LA successfully treated with laser treatment. Clinical cases: A 6-year-old child with T1DM presented with LA 4 months post-diagnosis. He was on continuous subcutaneous insulin infusion (CSII). LA presented on body sites where insulin catheter was never inserted. He underwent different treatment options with no positive effect. Laser treatment was tried with impressive improvement. The second 9-year-old child presented with LA 5 years postdiagnosis. He changed the insulin type, the site of insulin injection, and tried topical use of sodium chromoglycate cream with partial improvement. Laser treatment was finally used with remarkable outcome. Conclusion: Insulin-induced LA is now a rare skin complication with no effective treatment up to now. Laser treatment seems to be an effective treatment option.

Lipoatrophy, a rare complication of diabetes: a single-center experience.

BACKGROUND: Lipoatrophy (LA), a rare skin complication in patients with type 1 diabetes (T1D), has decreased dramatically over the past decades due to the use of human purified insulin preparations. METHODS: We collected data from the records of T1D patients with LA. Types of insulin and insulin regimen, presence of eosinophilia, anti-insulin (IAA), anti-GAD, anti-IA2 autoantibodies, other autoimmune disorders, site of atrophy and its relationship to catheter, HbA1c at LA onset and after resolution, and different treatment modalities (i.e., change of insulin type or site, sodium cromoglycate (SCG) cream, cortisone cream or percutaneous injections, and laser treatment) were recorded. RESULTS: Thirteen out of 1200 T1D subjects (1%) presented with LA. The majority were on insulin pump using rapid-acting analogs. Twelve out of 13 patients had changed the type of insulin, and most of them had switched injection sites. Ten out of 13 patients used SCG cream and 7/10 showed complete/partial improvement. One patient used dexamethasone injection with improvement. Five patients showed self-improvement. In 3/7 patients who were receiving SCG, treatment was combined with change of insulin type (glulisine); however, in 1/3, the result should be attributed to concomitant laser treatment. In 4/7 patients, there was a clear, beneficial effect of SCG. In 1/4 with partial resolution of LA, laser treatment was used after SCG, which further improved the result. CONCLUSIONS: LA is a rare skin complication seen even today with the use of insulin analogs. SCG alone or combined with change of insulin type seems to be the most effective treatment. Laser treatment is a promising new therapy.

A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes.

BACKGROUND: Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT: A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION: Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

Congenital Hypopituitarism: Various Genes, Various Phenotypes.

The ontogenesis and development of the pituitary gland is a highly complex process that depends on a cascade of transcription factors and signaling molecules. Spontaneous mutations and transgenic murine models have demonstrated a role for many of these factors, including HESX1, PROP1, PIT1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, SHH, GLI2, and FGF8 in the etiology of congenital hypopituitarism. Genetic mutations in any of these factors can lead to congenital hypopituitarism, which is characterized by the deficiency in one or more pituitary hormones. The phenotype can be highly variable, consisting of isolated hypopituitarism or more complex disorders. The same phenotype can be attributed to different gene mutations; while a given gene mutation can induce different phenotypes. This review highlights the genetic variations that lead to congenital hypopituitarism and their associated defects. The overall incidence of mutations in known transcription factors in patients with hypopituitarism is low; therefore many gene mutations or even gene- epigenetic interactions have to be unraveled in the future to explain the vast majority of still unclear cases of congenital hypopituitarism.

Hypotonic hyporesponsive episode and the 13-valent pneumococcal vaccine.

Hypotensive-hyporesponsive episodes are rare events after immunizations performed for diphtheria, tetanus, Haemophilus influenzae type b and hepatitis B virus vaccines, but most of the reported episodes have been associated with pertussis-containing vaccines. We report the case of a 3-month-old girl, previously healthy otherwise, presenting with the unusual event of a hypotonic-hyporesponsive episode after vaccination with the 13-valent pneumococcal vaccine. Diagnosis was established after a thorough evaluation of the patient and by exclusion of other clinical conditions.

The 10th anniversary of the Junior Members and Affiliates of the European Academy of Allergy and Clinical Immunology.

This year is the 10th anniversary of the European Academy of Allergy and Clinical Immunology (EAACI) Junior Members and Affiliates (JMAs). The aim of this review is to highlight the work and activities of EAACI JMAs. To this end, we have summarized all the initiatives taken by JMAs during the last 10 yr. EAACI JMAs are currently a group of over 2380 clinicians and scientists under the age of 35 yr, who support the continuous education of the Academy's younger members. For the past decade, JMAs enjoy a steadily increasing number of benefits such as free online access to the Academy's journals, the possibility to apply for Fellowships and the Mentorship Program, travel grants to attend scientific meetings, and many more. In addition, JMAs have been involved in task forces, cooperation schemes with other scientific bodies, organization of JMA focused sessions during EAACI meetings, and participation in the activities of EAACI communication platforms. EAACI JMA activities represent an ideal example of recruiting, training, and educating young scientists in order for them to thrive as future experts in their field. This model may serve as a prototype for other scientific communities, several of which have already adapted similar policies.

Cellular and animals models for rhinovirus infection in asthma.

Human rhinoviruses (RVs) are responsible for the majority of upper respiratory tract infections. Despite the high prevalence, the pathogenesis is incompletely understood. Experimental models would permit study of the immunological response to infections. Animal models have many limitations because of the anatomic and physiological differences between mammalian species. The only nonhuman animals susceptible to RV are chimpanzees and gibbons. Mouse models are not used because of host cell tropism of RV. This problem may have been partially overcome by transfecting mouse cells with viral RNA, by replacing mouse ICAM-1 with the human counterpart and by using a variant virus. It remains to be seen if these advances will translate into establishment of useful mouse models. In the absence of animal models, epithelial cell lines such as BEAS-2B, A549, 16HBE and HEp-2 have been used. Fibroblasts and smooth muscle cells have also been used. Although transformed cell lines have many properties in common with normal epithelial cells, they lose certain differentiated functions. Therefore, primary and recently well-differentiated cultures are used to study the immune response. In addition to a local inflammatory response, a systemic immune response to RV does develop; therefore peripheral blood mononuclear cells and dendritic cells have been infected with RV, shedding additional light on cell-mediated immunity. Cellular models are invaluable investigational tools for understanding mechanisms of RV-induced asthma and evaluating new targets for therapy.

Vascular endothelial growth factor-mediated induction of angiogenesis by human rhinoviruses.

BACKGROUND: Human rhinoviruses, major precipitants of asthma exacerbations, infect the lower airway epithelium inducing inflammation. The possibility that viral infection may mediate angiogenesis, thus contributing to airway remodeling, has not been evaluated. OBJECTIVE: To investigate whether epithelial infection with rhinovirus mediates angiogenesis in vitro, evaluate possible modulation by an atopic environment, and confirm angiogenic factor induction after in vivo rhinovirus infection. METHODS: Bronchial epithelial cells were infected with rhinovirus and levels of vascular endothelial growth factor (VEGF), and angiopoietins were measured. The angiogenic effect of epithelial products was assessed in in vitro models of angiogenesis. PBMCs, obtained from patients with atopic asthma and normal controls, were exposed to rhinovirus; the ability of supernatants from these cultures differentially to affect rhinovirus-mediated epithelial VEGF production was evaluated. VEGF levels were measured in respiratory secretions from patients with asthma, before and during rhinovirus-induced exacerbations. RESULTS: Epithelial infection with rhinovirus specifically stimulated mRNA expression and release of VEGF, but not angiopoietins, in a time-dependent and dose-dependent manner. Supernatants from these cultures were able to induce angiogenesis in vitro, significantly inhibited by a neutralizing anti-VEGF antibody. When bronchial cells were exposed to supernatants of rhinovirus-infected mononuclear cells from normal subjects or atopic patients with asthma, VEGF induction was significantly higher under the influence of the atopic environment. VEGF was elevated during rhinovirus-associated asthma exacerbations. CONCLUSION: Rhinovirus infection, a frequent event, induces VEGF production in bronchial epithelial cells and human airways, an effect enhanced in an atopic environment. Rhinovirus-associated, VEGF-mediated angiogenesis may contribute to airway remodeling in asthma.

Rhinovirus viremia in children with respiratory infections.

RATIONALE: Viremia has been implicated in many viral infections; however, viremia due to rhinovirus (RV; rhinoviremia) has been considered not to occur in normal individuals. OBJECTIVE: To evaluate whether RV enters the bloodstream and identify the possible risk factors. METHODS: Nasopharyngeal washes (NPWs) of 221 children with respiratory infections were examined for the presence of RV by reverse transcription-polymerase chain reaction. Blood from 88 children, whose NPW was RV-positive, and 31 of RV-negative control subjects was subsequently examined for the presence of RV in the blood by semi-nested reverse transcription-polymerase chain reaction. Rhinoviremia was then correlated with clinical characteristics of the disease. RESULTS: RV was detected in the blood of 10 out of 88 NPW RV-positive cases (11.4%): 7 of 28 children with asthma exacerbations (25.0%), 2 of 26 with common cold (7.7%), 1 of 25 with bronchiolitis (4.0%), and 0 of 9 with pneumonia (0%). All NPW RV-negative cases were negative in the blood. The proportion of rhinoviremia in children with asthma exacerbation was significantly higher compared with children suffering from the other diseases (25 vs. 5%, p = 0.01). Significant risk factors were: sampling