BackgroundGlycogen storage disease type 1b (GSD1b) is an ultra-rare autosomal recessive disorder, caused by mutations in SLC37A4 gene. Affected patients present with episodes of fasting hypoglycemia and lactic acidosis, hepatomegaly, growth retardation, hyperlipidemia and renal impairment. In addition, patients present neutropenia, neutrophil dysfunction and oral, and skin infections as well as a significant predisposition to develop inflammatory bowel disease (IBD). Low neutrophil counts and function is related to the toxic accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Recently, several reports have shown that off-label treatment with empagliflozin (EMPA), an inhibitor of the renal glucose transporter SGLT2, decreased blood 1,5-anhydroglucitol (1,5-AG), and neutrophil 1,5-AG6P, thus resulting in a new therapeutic option for neutropenia and neutrophil dysfunction in patients.MethodsOff-label treatment with EMPA was established in two GSD1b patients after signed informed consent. The patients were followed clinically. We monitored neutrophil counts and function, 1,5-AG levels in plasma and its renal clearance before and during EMPA treatment.ResultsA 17 year-old girl who had long standing oral ulcers and developed IBD, requiring systemic steroid and regular granulocyte colony-stimulating factor (GCSF) therapy and an 8 year-old boy who had steady non healing oral lesions were treated with empagliflozin during 18–24 months. Treatment led to increase of neutrophil counts and function with substantial clinical improvement. This included remission of IBD in the first patient which allowed to discontinue both GCSF and steroid therapy and resolution of oral lesions in both patients. The concentration of 1,5-AG in blood was greatly decreased within two weeks of treatment and remained stable thereafter.ConclusionsRepurposing of empagliflozin to treat neutropenia in two GSD1b patients was safe and resulted in the urinary excretion of 1,5-AG, the normalization of neutrophil function, and a remarkable improvement of neutropenia-related clinical traits. We showed for the first time that empagliflozin increases concomitantly the renal clearance of both 1,5-anhydroglucitol and glucose in GSD1b patients.
Gastroenteritis is common among children. Campylobacter jejuni is one of the main causative bacterial pathogens, together with Shigella, Salmonella and invasive Escherichia coli. campylobacteriosis is a zoonotic, usually self-limited disease that does not always require antibiotic treatment. In cases of protracted diarrhoea in healthy children or immunocompromised patients, antibiotic treatment is recommended, and the drug of choice is still macrolides, with very low resistance rates in Campylobacter species. However, it is crucial to isolate the causative organism, because some cases, such as Shigella encephalitis, call for initiation of empiric antibiotic treatment. In this study, we compared the incidence, epidemiology, clinical findings and laboratory results of gastroenteritis with dysentery caused by these organisms in children in our area. C. jejuni was found to be the leading pathogen in children hospitalized with bacterial gastroenteritis, followed by Shigella and Salmonella. Macrolides were the drug of choice for Campylobacter, and ceftriaxone and ciprofloxacin were the best empiric treatments for Shigella and Salmonella, respectively. Acute bacterial gastroenteritis is a common disease in infants and children. The clinical presentation includes fever, diarrhoea, bloody stool, vomiting, dehydration and abdominal pain. Campylobacter species, Shigella, Salmonella and invasive Escherichia coli are the main bacterial organisms causing acute infection in the gastrointestinal tract 1. Campylobacter organisms are thin curved Gram-negative non-spore-forming rods. The Campylobacter group includes 26 species: the most frequent types that cause disease in humans are Campylobacter jejuni, Campylobacter coli and Campylobacter fetus 2 , these are also the most common types in Israel 3. Campylobacteriosis is a zoonotic disease, with wild birds, poultry and domestic pets as the main reservoirs. Outbreaks are often linked to contaminated water, unpasteurized milk products, consumption of under-cooked chicken, environmental exposure and contact with farm animals 4. It is difficult to differentiate acute gastroenteritis caused by Campylobacter from gastroenteritis caused by Shigella or Salmonella based only on clinical signs or routine blood analysis; stool culture provides the definitive diagnosis of the causative organism. In cases of severe dehydration, toxic appearance, signs of sepsis and gastroenteritis caused by Shigella or Salmonella, initiation of empiric antibiotic treatment, such as third-generation cephalosporin, is required; in cases suspected of Shigella encephalitis, empiric treatment is also recommended. Third-generation cephalosporin has no effect against Campylobacter 4. Campylobacter is considered the causative organism in most cases of bacterial gastroenteritis in young children. It is usually a self-limited disease and does not always require antibiotic treatment. In cases of protracted diarrhoea in healthy children, or infection in immunocompromised patients, antibiotic treatment is recommended, and ...
Cleft lip and/or cleft palate are a common group of birth defects that further classify into syndromic and non-syndromic forms. The syndromic forms are usually accompanied by additional physical or cognitive abnormalities. Isolated cleft palate syndromes are less common; however, they are associated with a variety of congenital malformations and generally have an underlying genetic etiology. A single report in 2019 described a novel syndrome in three individuals, characterized by cleft palate, developmental delay and proliferative retinopathy due to a homozygous non-sense mutation in the LRRC32 gene encoding glycoprotein A repetitions predominant (GARP), a cell surface polypeptide crucial for the processing and maturation of transforming growth factor β (TGF-β). We describe a patient who presented with cleft palate, prenatal and postnatal severe growth retardation, global developmental delay, dysmorphic facial features and progressive vitreoretinopathy. Whole exome sequencing (WES) revealed a very rare homozygous missense variant in the LRRC32 gene, which resulted in substitution of a highly conserved isoleucine to threonine. Protein modeling suggested this variant may negatively affect GARP function on latent TGF-β activation. In summary, our report further expands the clinical features of cleft palate, proliferative retinopathy and developmental delay syndrome and emphasizes the association of LRRC32 pathogenic variants with this new syndrome.
Autoimmune myelofibrosis (AIMF) is an uncommon cause of myelofibrosis associated with favorable outcome. Primary AIMF, AIMF without a known systemic autoimmune disorder, has been described in adults, but never in children. Here, we present, for the first time, an apparent case of primary AIMF in a 15‐year‐old boy admitted with profound hypoproliferative anemia.
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