Novel sonic hedgehog gene variant in a patient with hyponatremia, microsomia, and midline defects; phenotype description in association with a variant of unknown significance [c.755_757del p.(Phe252del)] and an approach to salt-wasting in SHH-related adrenal disorders.

OBJECTIVES: To contribute a novel sonic hedgehog (SHH) gene variant in association with a novel-meagerly described phenotype and discuss SHH signaling pathway pathology. CASE PRESENTATION: We present a 5-year-old boy with excessive hyponatremia and natriuresis, microform holoprosencephaly and microsomia, with morphologically intact hypothalamic-pituitary-adrenal (HPA) axis, and hypoaldosteronism, yet without hyperreninemia, hyperkalemia, dehydration episodes, or glucocorticoid insufficiency. Extensive workup excluded common causes of salt-wasting and revealed a novel variant of unknown significance on the sonic hedgehog (SHH) gene; NM_000193.4:c.755_757del (p.Phe252del), in heterozygosity. CONCLUSIONS: Salt-wasting in children is predominantly caused by central nervous system lesions, renal tubular dysfunction, or adrenal insufficiency. The SHH protein is a signaling molecule, essential in embryogenesis-including HPA axis differentiation. Inactivating SHH variants disrupt the signaling pathway, leading to dysplasia or dysfunction of target organs. What's new: • We analyze the patient's phenotype in the light of this novel variant • Patient's isolated aldosterone deficiency possibly implies a selective signaling defect affecting the development of adrenal zona glomerulosa • Unexplained hyporeninemia and hypokalemia in the context of hypoaldosteronism raise questions on SHH signaling pathophysiology.

Herpes Zoster Ophthalmicus in a Healthy Toddler Fully Immunized Against Varicella-Zoster Virus: A Case Report and Review of Treatment Strategies in Children.

Herpes zoster ophthalmicus (HZO) is a rare presentation of herpes zoster in children; however, it may become chronic and debilitating. The pathophysiology of HZO complications is not completely understood and may include virus virulence, vascular and neural inflammation and immune reactivity. Therefore, clinical experts suggest an antiviral agent combined with topical steroids, but treatment duration and the need for secondary prophylaxis, given the likelihood of recurrence, are not clearly defined. We present a complex case of HZO in a varicella zoster virus (VZV)-vaccinated toddler successfully treated with acyclovir and topical steroids. We also present a review of the relevant literature regarding the therapeutic management and long-term sequelae of HZO in children.

Nasal eosinophilia as a preliminary discriminative biomarker of non-allergic rhinitis in every day clinical pediatric practice.

BACKGROUND: Non-allergic rhinitis (NAR) in children, named local allergic rhinitis (LAR) and non-allergic rhinitis with eosinophilia syndrome (NARES), are recently termed entities in childhood characterized by symptoms suggestive of allergic rhinitis in the absence of systemic atopy. Nasal eosinophils (nEo) are the principal cells involved in the allergy inflammation and nasal allergen provocation test is the gold standard method for the diagnosis, albeit with several limitations. The aim of this study was to validate the presence of nEo in combination with the therapeutic response to nasal steroids, as a preliminary discriminator of NAR in real life data. METHODS: In a prospective cohort study, 128 children (63.3% male, aged 72 ± 42 m) with history of NAR were enrolled and followed up for 52 ± 32 m. Nasal cytology was performed and nasal steroids trial was recommended initially in all and repeatedly in relapsing cases. Response to therapy was clinically evaluated using 10-VAS. RESULTS: Significant nEo was found in 59.3% of the cases and was related to reported dyspnea episodes. 23.4% had no response to therapy, whereas 51.5% were constantly good responders. Response to therapy was related to nEo and a cutoff point of 20% was defined as the most reliable biological marker with 94% sensitivity and 77% specificity. CONCLUSIONS: In children with symptoms of NAR, the presence of nEo > 20% constantly responding to nasal steroid therapy, is a clear indicator of atopy. In an everyday clinical setting, it emerged as an easy, preliminary, cell biomarker suggestive of further investigation such as NAPT, to discriminate LAR from NARES.

Obesity as a risk factor for severe influenza infection in children and adolescents: a systematic review and meta-analysis.

Obesity has been recently identified as a predisposing factor for a worse prognosis in viral illnesses such as SARS-CoV-2; however, its role in children with influenza is not yet clarified. The current systematic review and meta-analysis aims to assess whether obesity is a risk factor for either hospitalization or a worse prognosis when hospitalized among children infected by influenza. We systematically searched the following databases using a structured algorithm: MEDLINE, Clinicaltrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL). Statistical meta-analysis was performed using the "meta" package in R software, and included studies were evaluated using the Newcastle-Ottawa scale. Among children with influenza, obesity increased the odds of hospitalization with a pooled OR of 1.89 (95% CI [1.23, 2.9], I2 = 0, p = 0.003). When hospitalized, children with obesity were also more likely to have a worse outcome than their healthy-weight counterparts, with a pooled OR of 1.24 (95% Cl [1.02; 1.51], I2 = 11, p = 0.03). In an effort to lower heterogeneity, a leave-one-out meta-analysis was conducted. Publication bias was assessed with the visual inspection of funnel plots and the trim-and-fill method. Certainty assessment was evaluated using the GRADE score. CONCLUSIONS: The findings of our meta-analysis suggest that obesity in children with influenza is associated with a worse prognosis, both hospitalization and ICU admission/death. WHAT IS KNOWN: • Obesity has been identified as a risk factor for non-communicable as well as communicable diseases. • A previous meta-analysis failed to demonstrate a statistically significant association between obesity and influenza infection severity. WHAT IS NEW: • Children with high BMI and influenza infection are more likely to get hospitalized. • Pediatric inpatients with increased BMI and influenza infection may have a worse prognosis.

Atypical food protein-induced enterocolitis syndrome in children: Is IgE sensitisation an issue longitudinally?

BACKGROUND: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presentation remains poorly understood. OBJECTIVE: Aim of this study was to present the 10-year experience of a referral centre highlighting the atypical FPIES cases and their long-term outcome. METHODS: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation. RESULTS: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At presentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow's milk and egg. Tolerance acquisition was earlier for cow's milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms. CONCLUSION: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sensitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predisposing to atopic respiratory symptoms; albeit further research is required.

Atypical food protein-induced enterocolitis syndrome in children: Is IgE sensitisation an issue longitudinally?

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presentation remains poorly understood. Objective: Aim of this study was to present the 10-year experience of a referral centre highlighting the atypical FPIES cases and their long-term outcome. Methods: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation. Results: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At presentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow’s milk and egg. Tolerance acquisition was earlier for cow’s milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms. Conclusion: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sensitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predisposing to atopic respiratory symptoms; albeit further research is required (AU)

A Rare Case of Measles-Associated Hemophagocytic Lymphohistiocytosis in an Infant.

Measles continues to be a threat in most European countries due to suboptimum vaccination coverage. Although measles leads to several complications, measles-related hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Herein, we present a case of a four-month-old male infant, the first child of unrelated, healthy parents, with no significant medical history or unexplained infant death in the family, otherwise healthy, who was diagnosed with measles-associated HLH and was successfully treated with IV dexamethasone and IV immunoglobulin (IVIG). Additionally, we review previously reported cases of HLH secondary to measles and highlight the diagnostic and therapeutic challenges associated with its early recognition and treatment. High suspicion, early recognition, and appropriate treatment are essential for a favorable outcome of measles-associated HLH.

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality.

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.

The Greek Registry of Shwachman Diamond-Syndrome: Molecular and clinical data.

This study presents the clinical phenotype and molecular analysis findings from 11 patients recorded in the Greek Shwachman-Diamond syndrome (SDS) Registry. The most severely affected patient in our registry was diagnosed at birth and is the first patient reported to require bone marrow transplantation so early in life. Severe psoriasis, a feature not previously reported in SDS, was observed in one patient. Mutations in the Shwachman-Bodian-Diamond syndrome gene (SBDS) were found in all patients. Cytogenetic analyses revealed clonal abnormalities, one novel, in two patients.

Clinical phenotype and genetic analysis of RPS19, RPL5, and RPL11 genes in Greek patients with Diamond Blackfan Anemia.

BACKGROUND: Diamond Blackfan Anemia (DBA) is a rare congenital, bone marrow failure syndrome characterized by normochromic macrocytic anemia, reticulocytopenia and absence or insufficiency of erythroid precursors in normocellular bone marrow, frequently associated with somatic malformations. Here, we present our findings from the study of 17 patients recorded in the Greek DBA registry. PROCEDURE: Clinical evaluation of patients and data collection was performed followed by the molecular analysis of RPS19, RPL5, and RPL11 genes. Mutation screening included PCR amplification, ECMA analysis, and direct sequencing. RESULTS: Congenital anomalies were observed in 71% of the patients. Six patients (35.2%) were found to carry mutations on either the RPS19 gene (three patients,) or the RPL5 gene (three patients). Mutations c.C390G (p.Y130X) and c.197_198insA (p.Y66X) detected in the RPL5 gene were novel. No mutations at the RPL11 gene were identified in Greek patients with DBA. CONCLUSIONS: The clinical course of the patients was similar to previous reports. The occurrence of thyroid carcinoma in an adult patient with DBA is the first to be reported in DBA.

Assessment of iron distribution between liver, spleen, pancreas, bone marrow, and myocardium by means of R2 relaxometry with MRI in patients with beta-thalassemia major.

PURPOSE: To investigate the correlation between the degree of hepatic, splenic, pancreatic, vertebral bone marrow (VBM), and myocardial siderosis, as expressed by relaxation rate (R2 = 1/T2) values, in patients with thalassemia. MATERIALS AND METHODS: R2 relaxation rate values of liver, spleen, VBM, pancreas, and myocardium were estimated in 68 consecutive transfusion-dependent patients with beta-thalassemia major and 10 healthy controls using a respiratory triggered 16-echo Carr-Purcell-Meiboom-Gill (CPMG) spin echo sequence. RESULTS: Hepatic R2 values were significantly increased in all 68 patients; VBM, pancreatic, and myocardial R2 values were increased in 67/68, 35/47, and 47/61 patients, whereas five patients showed decreased pancreatic R2 attributed to fatty degeneration. Of the 39 nonsplenectomized patients, splenic R2 values were decreased in 30 and normal in nine patients. Hepatic R2 values correlated with splenic (r = 0.63, P < 0.001), VBM (r = 0.52, P < 0.001), but not with myocardial and pancreatic R2 values. CONCLUSION: Despite positive correlations between the degree of hepatic, splenic, and VBM siderosis, as expressed by respective R2 values, there was variability of iron distribution patterns in thalassemic patients. Unpredictable patterns of iron distribution may be seen, such as normal signal of the spleen in the presence of siderotic liver, resembling primary hemochromatosis. Fatty degeneration of the pancreas was not uncommon.

Abrupt and durable remission of Henoch-Schönlein purpura nephritis with cyclosporine A.

Henoch-Schönlein purpura glomerulonephritis (HSP-GN) is a common form of systemic small vessel vasculitis in children. Although prognosis is usually favourable, the disease is occasionally associated with a risk of renal insufficiency. Various immunosuppressive agents have been used in patients with severe HSP-GN, but none have shown convincing favourable effects. We report a case of biopsy-proven HSP-related GN in a 4-year-old girl that responded remarkably well to cyclosporine A (CsA), following failure to respond to other immunosuppressive agents. At 8 months post-CsA treatment, repeat renal biopsy findings were consistent with histological improvement. We conclude that CsA treatment not only exerts beneficial effects on resistant HSP-related GN but may also arrest progression of the disease.

The pancreas in beta-thalassemia major: MR imaging features and correlation with iron stores and glucose disturbances.

The study aims at describing the MR features of pancreas in beta-thalassemia major, investigating the relations between MR findings and glucose disturbances and between hepatic and pancreatic siderosis. Signal intensity ratios of the pancreas and liver to right paraspinous muscle (P/M, L/M) were retrospectively assessed on abdominal MR imaging studies of 31 transfusion-dependent patients with beta-thalassemia major undergoing quantification of hepatic siderosis and 10 healthy controls, using T1- (120/4/90), intermediate in and out of phase - (120/2.7, 4/20), and T2*-(120/15/20) weighted GRE sequences. Using the signal drop of the liver and pancreas on opposed phase images, we recorded serum ferritin and results of oral glucose tolerance test (OGTT). Decreased L/M and P/M on at least the T2* sequence were noticed in 31/31 and 30/31 patients, respectively, but no correlation between P/M and L/M was found. Patients with pathologic OGTT displayed a higher degree of hepatic siderosis (p < 0.04) and signal drop of pancreas on opposed phase imaging (p < 0.025), implying fatty replacement of pancreas. P/M was neither correlated with glucose disturbances nor serum ferritin. Iron deposition in the pancreas cannot be predicted by the degree of hepatic siderosis in beta-thalassemia major. Fatty replacement of the pancreas is common and may be associated with glucose disturbances.

Abdominal lymphadenopathy in beta-thalassemia: MRI features and correlation with liver iron overload and posttransfusion chronic hepatitis C.

OBJECTIVE: The objective of our study was to describe the MRI features of abdominal lymphadenopathy in patients with beta-thalassemia major and investigate the relation of abdominal lymphadenopathy with the severity of iron overload and posttransfusion chronic hepatitis C. MATERIALS AND METHODS: Abdominal MRI studies of 60 consecutive patients with beta-thalassemia major, performed for quantification of liver iron overload at a single institution, were retrospectively studied for the presence of lymph nodes and their distribution, size, and number. The signal intensity ratios of liver, spleen, and the largest lymph node to the right paraspinous muscle (L/M, S/M, and LN/M, respectively) were calculated on T1-weighted gradient-echo images. MRI findings for the lymph nodes were compared with the histologically assigned activity level of chronic hepatitis C that was available in 17 patients who had undergone liver biopsy within 1 month of the MRI examination. RESULTS: Hypointense abdominal lymph nodes larger than 7 mm were seen in 19 (32%) of 60 thalassemic patients in perihepatic and paraortic distributions. Lymphadenopathy was related to both the severity of hepatic siderosis, as expressed by the L/M values, and the presence of chronic hepatitis C, given that 18 (95%) of the 19 thalassemic patients with lymphadenopathy had chronic hepatitis C. Moreover, thalassemic patients with a moderate or severe level of hepatic inflammation presented with abdominal lymphadenopathy more frequently than those with mild hepatic inflammation. CONCLUSION: The development of hypointense abdominal lymphadenopathy in patients with beta-thalassemia major who have received multiple transfusions depends both on the severity of liver iron overload and on the presence and the activity level of coexistent chronic hepatitis C.

Recurrent torticollis secondary to Langerhans cell histiocytosis: a case report.

Torticollis is a common clinical sign encountered by pediatricians and orthopaedic surgeons in a wide spectrum of childhood conditions ranging from benign to life-threatening. We report the case of a child with recurrent torticollis caused by Langerhans Cell Histiocytosis (LCH). The patient was a 1-year-old boy with recurrent torticollis, followed by a painless swelling over the right temporal bone. The diagnosis was confirmed by an open biopsy of the calvarial lesion. As LCH is a very rare cause of torticollis it was not considered in the initial differential by the primary care physicians and the diagnosis was delayed about 4 months. The patient received chemotherapy with steroids and etoposide for 52 weeks. He showed complete regression of the sign and imaging tests at the end of treatment were normal. No relapse of symptoms occurred during a follow-up period of 2 years. The rarity of this disease as well as the site and form of presentation are emphasised to alert physicians for an early diagnostic evaluation, which is important to prevent neurological lesions and other late complications.

Sustained response to interferon alpha-2a in thalassemic patients with chronic hepatitis C. A prospective 8-year follow-up study.

Eighty-nine thalassemic patients with chronic hepatitis C were treated with interferon alpha-2a for 12 months and followed up for 8 years. Interferon induced sustained virologic and biochemical response in 45% of participants and histologic improvement in 50% of patients who had paired liver biopsies. Splenectomy was the only independent predictor of an unfavorable outcome.