Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Hypoparathyroidism-Retardation-Dysmorphism Syndrome due to a Variant in the Tubulin-Specific Chaperone E Gene as a Cause of Combined Immune Deficiency.

BACKGROUND: Hypoparathyroidism-retardation-dysmorphism (HRD) syndrome is a disease composed of hypoparathyroidism, growth retardation, severe developmental delay, and typical dysmorphic features caused by the tubulin-specific chaperone E gene variant. Many patients succumb in infancy to HRD due to overwhelming infections mainly caused by Pneumococcus spp. Knowledge related to the immune system in these patients is scarce. PURPOSE: To define the immune phenotype of a cohort of HRD patients including their cellular, humoral, and neutrophil functions. METHODS: The study included HRD patients followed at Soroka University Medical Center. Clinical and immunological data were obtained, including immunoglobulin concentrations, specific antibody titers, lymphocyte subpopulations, lymphocyte proliferation, and neutrophil functions. RESULTS: Nine patients (5 females and 4 males) were enrolled, aged 6 months to 15 years. All received amoxicillin prophylaxis as part of a routine established previously. Three patients had bacteremia with Klebsiella, Shigella spp., and Candida. Three patients had confirmed coronavirus disease 19 (COVID-19), and two of them died from this infection. All patients had normal blood counts. Patients showed high total IgA and IgE levels, low anti-pneumococcal antibodies in spite of a routine vaccination schedule, and reduced frequency of naive B cells with increased frequency of CD21lowCD27- B cells. All patients had abnormal T-cell population distributions, including reduced terminally differentiated effector memory CD8, inverted CD4/CD8 ratios, and impaired phytohemagglutinin (PHA)-induced lymphocyte proliferation. Neutrophil superoxide production and chemotaxis were normal in all patients tested. CONCLUSION: HRD is a combined immunodeficiency disease with syndromic features, manifesting in severe invasive bacterial and viral infections.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Glomerular involvement in children with H syndrome.

BACKGROUND: H syndrome is a multisystem inflammatory disease caused by mutations in the SLC29A3 gene (OMIM #602782). The protein product, hENT3, is a nucleoside transporter essential for DNA salvage synthesis. Clinical manifestations are hyperpigmentation, hypertrichosis, hepatosplenomegaly, hearing loss, heart anomalies, hypogonadism, short stature, skeletal deformities, and diabetes mellitus. Laboratory findings are consistent with inflammatory processes. Structural kidney anomalies have been described in 6% of patients. CASE REPORTS: Three family members with genetically diagnosed H syndrome (c.1279G>A, p.Gly427Ser). Two of them presented with hypoalbuminemia and nephrotic range proteinuria. Kidney ultrasound was normal. Kidney biopsy performed in one patient presenting with generalized peripheral pitting edema revealed membranous nephropathy. Different treatments including ACE inhibitors, corticosteroids, and immunomodulatory agents failed to improve the clinical outcome. CONCLUSIONS: Generalized peripheral pitting edema and glomerulopathy broaden the clinical spectrum of H syndrome. Periodic bloodwork and urinalysis are recommended.

Pituitary stalk interruption syndrome broadens the clinical spectrum of the TTC26 ciliopathy.

Ciliopathies are a heterogeneous group of disorders, related to abnormal ciliary function. Severe biliary ciliopathy, caused by bi-allelic mutations in TTC26, has been recently described in the context of a syndrome of polydactyly and severe neonatal cholestasis, with brain, kidney and heart involvement. Pituitary involvement has not been previously reported for patients with this condition. Pituitary stalk interruption syndrome (PSIS) is a congenital anomaly of the pituitary gland, diagnosed by characteristic MRI findings. We now describe four patients with TTC26 ciliopathy due to a homozygous c.695A>G p.Asn232Ser mutation and delineate PSIS as a novel clinical feature of this disorder, highlighting an important role of TTC26 in pituitary development.

Diagnostic Yield of Critical Sample and Elective Fast-Test in Children After a Hypoglycemic Event: Experience From a Single Center in Israel.

OBJECTIVE: To determine the diagnostic yield of the critical sample and fast-tests as dynamic function tests for the work-up of hypoglycemia in children. METHODS: A retrospective record review of children (0-18 years) with a diagnosis of hypoglycemia (glucose ≤ 50 mg/dL) was performed. A comparison of results of critical sample (obtained during an episode of hypoglycemia) and fast-test (performed to induce hypoglycemia in fasting state) was done. RESULTS: In 317 patients with hypoglycemia, data of 89 critical samples and 52 fast-tests were taken. Only 7 (7.8%) patients who underwent critical sample testing received an endocrine or metabolic diagnosis. No confirmatory diagnoses were made using the fast-tests. Idiopathic ketotic hypoglycemia was detected in 33/89 (37.1%) of critical samples and 21/52 (40.4%) of fast-tests. The completeness of workup including the hormonal and metabolic profile was <80% in both tests. CONCLUSION: The confirmatory yield of critical sample was better than fast-test. The processing of metabolic analytes was incomplete in a few, suggesting the need to rationalize the dynamic function testing.

GHRH-GH-IGF1 axis in pediatric Down syndrome: A systematic review and mini meta-analysis.

Objective: To analyze and determine the quality of functioning in different components of GHRH-GH-IGF1 axis in children with Down syndrome (DS). Design: Systematic review and mini meta-analysis of the literature. Methods: A search was performed in PubMed, Embase, Scopus, and PsycINFO through August 2022. Eligible studies included pediatric patients with DS who had undergone any laboratory evaluation of the GHRH-GH-IGF1 axis. Two reviewers independently screened articles for eligibility. Results of each type of test were weighed together in patients both with and without DS and were pooled using a random effects meta-analysis. Results: In total, 20 studies assessed the GHRH-GH-IGF1 axis function. A defect in three major components of GHRH-GH-IGF1 axis was found in a significant proportion of pediatric DS patients. Conclusions: A significant portion of short-stature pathogenesis in children with DS is associated with impaired GHRH-GH-IGF1 axis function.

GH treatment in pediatric Down syndrome: a systematic review and mini meta-analysis.

Objective: To analyze and determine the safety and efficacy of growth hormone (GH) treatment in Down syndrome (DS) pediatric patients and to weigh ethical aspects involved. Design: Systematic review and mini meta-analysis of the literature. Methods: A search was performed in PubMed, Embase, Scopus, and PsycINFO through August 2022. Eligible studies included those who answered at least one of the following two questions: 1) What is the effect of growth hormone treatment in children with Down syndrome? 2) What are the ethical arguments in favor and against growth hormone treatment for children with Down syndrome? Multiple reviewers independently screened each article for eligibility. Results: In total sixteen reports detailed medical effects of GH treatment in pediatric DS patients and eight studies dealt with ethical aspects of GH treatment. Treatment with GH resulted in significantly higher growth velocity in patients with DS. The ethical complexity is great but does not present insurmountable difficulties to the therapeutic option. Conclusions: As GH treatment is safe and effective for short-term height growth, GH therapy should be considered in long-term treatment of DS children.

Hypoparathyroidism-retardation-dysmorphism syndrome-Clinical insights from a large longitudinal cohort in a single medical center.

Background: Hypoparathyroidism, retardation, and dysmorphism (HRD) Syndrome is a rare disease composed of hypoparathyroidism, retardation of both growth and development, and distinctive dysmorphic features. Here, we describe the long-term morbidity and mortality in a large cohort of HRD patients and suggest recommendations for follow up and treatment. Methods: Medical records of 63 HRD syndrome patients who were followed at Soroka Medical Center during 1989-2019 were reviewed retrospectively. Information regarding demographics, medical complications, laboratory findings, and imaging studies was collected. Results: The mortality rate was 52%. The main causes of death were infectious diseases including pneumonia, septic shock, and meningitis. Multiple comorbidities were found including brain anomalies in 90% of examined patients (basal ganglia calcifications, tightening of corpus callosum, Chiari malformation, hydrocephalous, and brain atrophy), seizures in 62%, nephrocalcinosis and/or nephrolithiasis in 47%, multiple eye anomalies were recorded in 40%, bowel obstructions in 9.5%, and variable expression of both conductive and senso-neural hearing loss was documented in 9.5%. Conclusion: HRD is a severe multisystem disease. Active surveillance is indicated to prevent and treat complications associated with this rare syndrome.

The etiologic, microbiologic, clinical and outcome characteristics of immunocompetent young children <2 years of age hospitalized with acute neutropenia.

BACKGROUND: To describe the etiologic, microbiologic, clinical and outcome characteristics of acute neutropenia (absolute neutrophil count, ANC, <1.5 × 109/L) in hospitalized immunocompetent children. METHODS: Serious bacterial infections (SBI) were defined as culture-positive blood, urine, cerebrospinal fluid, articular fluid or stool infections, alveolar pneumonia, Brucellosis and Rickettsiosis. RESULTS: 431/671 (64.2%) healthy infants and children hospitalized with acute neutropenia were <2 years of age; 176 (40.8%), 167 (38.8%) and 88 (20.4%) patients were aged 0-3, 4-12 and 13-24 months, respectively. There were 19 (4.4%), 53 (12.3%), 140 (32.5%) and 209 (50.8%) patients with ANC count <200, 200-500, 501-1000 and 1001-1500 × 109 cells/L, respectively. Severe neutropenia (<500 × 109/L) was recorded in 72 (16.7%) patients. Fever >38 °C was present in 208/431 (48.3%) patients. Blood cultures were positive in 10 (2.3%), with Brucella melitensis, Staphylococcus aureus and Enterobacter spp. identified in 4, 3 and 2 patients, respectively; 5/10 patients with positive blood cultures were <3 months of age. Overall, 55/431 (12.7%) and 65/431 (15.1%) patients were diagnosed with SBIs and bacterial infections, respectively. Nasal washings-PCR for respiratory viruses was positive in 139/293 (47.4%) patients tested. An infectious etiology (bacterial and/or viral) was diagnosed in 190/431 (44.1%) patients. Three patients were diagnosed with acute lymphocytic leukemia. Resolution of neutropenia was achieved in 111/208 (53.4%) evaluable patients (63%, 50.6% and 48% of patients aged 0-3, 4-12 and >12 months, respectively and 56.8%, 53.5% and 52% of patients with severe, moderate and mild neutropenia, respectively). CONCLUSION: Acute neutropenia is common in immunocompetent children <2 years of age and is frequently associated with viral infections. We showed a substantial involvement of bacterial infections and particularly SBIs in the etiology of acute neutropenia. After a 1-month follow-up, resolution of neutropenia occurred in half of the patients, without association with age subgroups and with neutropenia severity.

Multiple Endocrine Deficiencies are Common in Hypoparathyroidism-Retardation-Dysmorphism Syndrome.

CONTEXT: The rare hypoparathyroidism-retardation-dysmorphism (HRD) syndrome (OMIM #241410) is caused by the mutated tubulin chaperone E (TBCE) gene. This gene encodes a critical protein in the microtubule assembly pathway. OBJECTIVE: To evaluate the endocrine profile of patients with HRD. METHODS: The study used a retrospective analysis of a large cohort of patients in a single university medical center. Sixty-three patients were diagnosed with HRD during 1990 to 2019; 58 of them had an endocrine evaluation. MAIN OUTCOME MEASURES: We investigated somatic growth parameters, the prevalence of hypoglycemia, growth hormone deficiency, hypothyroidism, hypogonadism, and cortisol deficiency. RESULTS: All patients were born small for gestational age, and severe growth retardation was found in all patients with mean height standard deviation score (SDS) of -8.8 (range: -5.1 to -15.1) and weight SDS -18 (range: -5.1 to -61.2). Serum insulin-like growth factor-1 concentrations were very low among the 21 studied patients: -2.32 SDS (range: -0.6 to -2.7). Four out of 14 (28%) investigated patients had growth hormone deficiency, and 55% of patients were hospitalized due to symptomatic hypoglycemia. Adrenal glucocorticoid insufficiency was diagnosed in 22% of those tested. Hypothyroidism was found in 36% of patients. Both hypogonadotrophic and hypergonadotrophic hypogonadism were observed. The main magnetic resonance imaging findings were small anterior pituitary gland, small hippocampus, brain atrophy, thin corpus callosum, Chiari type I malformation, and septo-optic dysplasia. CONCLUSION: Multiple endocrine abnormalities are common in patients with HRD syndrome. Periodic screening of thyroid and adrenal functions is recommended.

The effects of the COVID-19 pandemic on patients with lysosomal storage disorders in Israel.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the causative agent of the current COVID-19 pandemic. Lysosomal storage disorders (LSD) comprise of 70 inherited inborn errors of metabolism. Affected individuals suffer from multi-systemic involvement with variable severity and rate of disease progression between different diseases. Some of the LSDs have established treatments, whether parenteral or oral therapies. The full impact of the COVID-19 pandemic together with the lockdown on the wellbeing and medical management of patients with rare diseases, such as LSDs, is widely unknown. Herein, we describe the effects of the COVID-19 pandemic and its associated mandatory home lockdown on patients with LSDs in Israel. RESULTS: We present a prospective multi-center questionnaire study including 48 LSD patients from four medical centers in Israel. The study objective was to assess the impact of the COVID-19 pandemic restrictions on individuals with LSDs in Israel, as reported by their caregivers. Secondary objectives were to assess the morbidity from SARS CoV-2 in LSD patients and the impact of changes in mood and behavior on compliance to treatment and to assess the relationship between changes in mood to changes in cognition and behavior. Thirty one of 38 patients (82%) who received any kind of regular treatment did not miss treatments. Among patients receiving enzyme replacement therapy (ERT) in the in-hospital setting, 5 patients (20%) experienced treatment disruptions. Four patients had tested positive for SARS-Cov-2 virus infection by PCR. Seven out of the 48 patients (14%) described mood changes with cognitive and motor deterioration during the home quarantine. CONCLUSIONS: We observed high rates of treatment adherence and low morbidity through the COVID-19 pandemic in patients with LSDs in Israel. LSDs patients can be a model for patients with complex chronic diseases requiring routine treatments and surveillance during a pandemic or other disruption of daily routine.

The Infectious and Noninfectious Etiology, Clinical Picture and Outcome of Neutropenia in Immunocompetent Hospitalized Children.

BACKGROUND: Acquired neutropenia in immunocompetent children is common, and its differential diagnosis ranges from benign causes to life-threatening diseases. We described the etiology, clinical picture and outcome of new-onset neutropenia in immunocompetent children assessed in the emergency department and hospitalized at our medical center. METHODS: Previously healthy children admitted with neutropenia (absolute neutrophil count <1.5 × 10(9)/L) were included. Serious bacterial infections were defined as culture-positive blood, urine, cerebrospinal fluid, articular fluid or stool infections, pneumonia, Brucellosis and Rickettsiosis. RESULTS: A total of 601 patients (5 days-202 months old) were enrolled; 3 (0.5%), 48 (8%), 165 (27.5%) and 385 (64%) had absolute neutrophil counts <0.2, 0.2-0.5, 0.5-1.0 and 1.0-1.5 × 10(9)/L, respectively. Associated leukopenia and thrombocytopenia were diagnosed in 186 (39%) and 71 (11.8%) patients. Three hundred sixteen of 601 (52.6%) and 519 of 601 (86.4%) were <2 or 36 months of age, respectively. Fever at admission was present in 27.6% patients. Serious bacterial infections were diagnosed in 106 (17.6%) patients. Brucellosis and rickettsiosis were diagnosed in 8 of 52 (15.4%) and 9 of 39 (23.1%) tests obtained. Respiratory syncytial virus was diagnosed in 17 of 33 (51.5%) nasal washes. An infectious etiology was determined in 171 (28.5%) patients. Acute leukemia was diagnosed in 6 patients. A significant correlation was found between resolution of neutropenia and patient age, infectious etiology and severity of neutropenia. CONCLUSIONS: (1) Severe neutropenia was rare; (2) More than half of patients were <2 months of age; (3) An infectious etiology was diagnosed in a high number of patients, and serious bacterial infections were frequent and (4) Brucella spp. and rickettsial infections were frequent etiologies associated with neutropenia in our setting.