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Frontiers in Endocrinology 2023MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we...
Case report: a premature infant with severe intrauterine growth restriction, adrenal insufficiency, and inflammatory diarrhea: a genetically confirmed case of MIRAGE syndrome.
INTRODUCTION
MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we report the case of a girl with MIRAGE syndrome who presented with adrenal insufficiency and chronic diarrhea.
CASE PRESENTATION
The patient was born at 29 + 6 weeks of gestational age with a birth weight of 656 g (<3p). Her height and head circumference were also <3p. At birth, she presented with respiratory distress, meconium staining, and pneumomediastinum, which were managed with high-frequency ventilation and empirical antibiotics. Physical examination showed generalized hyperpigmentation and normal female genitalia. A few days after birth, polyuria and hypotension developed, and laboratory findings revealed hypoglycemia, hyponatremia, and hyperkalemia. Plasma adrenocorticotropic hormone levels were elevated with low serum cortisol levels and high plasma renin activity, which were suggestive of adrenal insufficiency. Hydrocortisone and fludrocortisone were introduced and maintained, and hyperpigmentation attenuated with time. Both kidneys looked dysplastic, and adrenal glands could not be traced on abdominal ultrasound. From the early days of life, thrombocytopenia and anemia were detected, but not to life-threatening level and slowly recovered up to the normal range. Despite aggressive nutritional support, weight gain and growth spurt were severely retarded during the hospital stay. Additionally, after introducing enteral feeding, she experienced severe diarrhea and subsequent perineal skin rashes and ulcerations. Fecal calprotectin level was highly elevated; however, a small bowel biopsy resulted in non-specific submucosal congestion. The patient was diagnosed with MIRAGE syndrome with SAMD9 gene mutation. She was discharged with tube feeding and elemental formula feeding continued, but chronic diarrhea persisted. By the time of the last follow-up at 15 months of corrected age, she was fortunately not subjected to severe invasive infection and myelodysplastic syndrome. However, she was dependent on tube feeding and demonstrated a severe developmental delay equivalent to approximately 5-6 months of age.
CONCLUSION
The early diagnosis of adrenal crisis and hormone replacement therapy can save the life of -patients with MIRAGE syndrome; however, chronic intractable diarrhea and growth and developmental delay continue to impede the patient's well-being.
Topics: Humans; Infant, Newborn; Infant; Female; Fetal Growth Retardation; Intracellular Signaling Peptides and Proteins; Adrenal Insufficiency; Infant, Premature; Diarrhea; Myelodysplastic Syndromes; Hyperpigmentation
PubMed: 37745698
DOI: 10.3389/fendo.2023.1242387 -
Viruses Jun 2022Belgium has actively participated in clinical research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since the beginning of the pandemic to help... (Review)
Review
Belgium has actively participated in clinical research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since the beginning of the pandemic to help identify effective and safe treatments for COVID-19. The objective of this review is to provide a picture of the clinical studies carried out in hospitalized patients with COVID-19 in Belgium. We collected data on all randomized, interventional trials in patients with COVID-19 that were registered on two recognized clinical trial registers, started enrollment before 31 December 2021, and included at least one patient in a Belgian center. Data were collected concerning the therapies investigated and the nature of the trials performed. Thirty-three hospitals (32% of all Belgian hospitals) participated in at least one of 28 trials (13 sponsored by the industry and 15 by academic centers) on therapeutics for COVID-19 in hospitalized patients: 7 (25%) evaluated antivirals, 17 (61%) immunomodulators, 2 (7%) anti-coagulants, and 1 (3%) nitric oxide to improve respiratory function. Nineteen (68%) were phase II trials. Only three (11%) of the trials were international platform trials. Despite numerous trials, less than 3% of all Belgian patients hospitalized with COVID-19 participated in a clinical trial on therapeutics. As in many other countries, more efforts could have been made to avoid running small, under-powered, mono- or bicenter trials, to create better collaboration between the different Belgian hospitals, and to participate in more international clinical trials, and more specifically in adaptive, platform trials.
Topics: Antiviral Agents; Belgium; Humans; Pandemics; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 35891407
DOI: 10.3390/v14071427 -
Frontiers in Endocrinology 2021Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to...
INTRODUCTION
Primary adrenal insufficiency (PAI) presenting in the neonatal period can be life threatening and requires early recognition, diagnosis, and management. PAI due to adrenal hypoplasia (syndromic/non-syndromic) is a rare disorder. MIRAGE is a recently described syndrome with PAI and multisystem involvement.
CASE PRESENTATION
A preterm female neonate presenting with PAI and persistent severe thrombocytopenia was diagnosed to have MIRAGE syndrome due to a pathogenic variant c.3406G>C (p. Glu1136Gln) in the gene. In the first year of life, she had recurrent respiratory and gastrointestinal infection causing failure to thrive. At 17 months, she suffered recurrent intussusception requiring treatment with parenteral nutrition and high-dose steroids. Subsequently, she established oral feeds with hydrolysed formula and demonstrated good weight gain.
CONCLUSION
In neonates presenting with PAI and associated multisystem involvement, a thoughtful approach and genetic testing is valuable in discerning an etiological diagnosis. This case of MIRAGE adds to the spectrum of reported cases and is the first to report on recurrent intussusception and its management with high-dose steroids.
Topics: Adrenal Gland Diseases; Adrenal Hyperplasia, Congenital; Female; Humans; Infant, Newborn; Infant, Premature; Intracellular Signaling Peptides and Proteins; Intussusception; Mutation; Parenteral Nutrition; Recurrence; Steroids; Syndrome; Thrombocytopenia
PubMed: 34659124
DOI: 10.3389/fendo.2021.742495 -
Transplantation Direct Sep 2022Liver transplantation is an extremely complex procedure performed in an extremely complex patient. With a successful technique and acceptable long-term survival, a new... (Review)
Review
Liver transplantation is an extremely complex procedure performed in an extremely complex patient. With a successful technique and acceptable long-term survival, a new challenge arose: overcoming donor shortage. Thus, living donor liver transplant and other techniques were developed. Aiming for donor safety, many liver transplant units attempted to push the viable limits in terms of size, retrieving smaller and smaller grafts for adult recipients. With these smaller grafts came numerous problems, concepts, and definitions. The spotlight is now aimed at the mirage of hemodynamic changes derived from the recipients prior alterations. This article focuses on the numerous hemodynamic syndromes, their definitions, causes, and management and interconnection with each other. The aim is to aid the physician in their recognition and treatment to improve liver transplantation success.
PubMed: 36313127
DOI: 10.1097/TXD.0000000000001369 -
Human Genome Variation Jul 2021We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in...
We describe a case of posthumously diagnosed MIRAGE syndrome (Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital problems, and Enteropathy) in a girl with a new pathogenic SAMD9 variant (p.F437S), who was initially considered to have familial dysautonomia (FD)-like disease due to increased levels of catecholamine metabolites. Functional analyses of F437S-SAMD9 were performed, showing characteristics of disease-causing variants. This new SAMD9 variant (p.F437S) also causes MIRAGE syndrome.
PubMed: 34253717
DOI: 10.1038/s41439-021-00158-6 -
Biology of Blood and Marrow... Nov 2019Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy)...
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Topics: Allografts; Child, Preschool; Disease-Free Survival; Female; Genetic Diseases, Inborn; Germ-Line Mutation; Hematopoietic Stem Cell Transplantation; Humans; Infant; Intracellular Signaling Peptides and Proteins; Male; Myelodysplastic Syndromes; Retrospective Studies; Survival Rate; Syndrome; Tumor Suppressor Proteins
PubMed: 31306780
DOI: 10.1016/j.bbmt.2019.07.007 -
Biochemical Pharmacology Jul 2020Drug repurposing is a promising way in drug discovery to identify new therapeutic uses -different from the original medical indication- for existing drugs. It has many... (Review)
Review
Drug repurposing is a promising way in drug discovery to identify new therapeutic uses -different from the original medical indication- for existing drugs. It has many advantages over traditional approaches to de novo drug discovery, since it can significantly reduce healthcare costs and development timeline. In this review, we discuss the possible repurposing of drugs approved for cardiovascular diseases, such as β-blockers, angiotensin converting enzyme inhibitors (ACE-Is), angiotensin II receptor blockers (ARBs), statins, aspirin, cardiac glycosides and low-molecular-weight heparins (LMWHs). Indeed, numerous experimental and epidemiological studies have reported promising anti-cancer activities for these drugs. It is worth mentioning, however, that the results of these studies are often controversial and very few data were obtained by controlled prospective clinical trials. Therefore, no final conclusion has yet been reached in this area and no final recommendations can be made. Moreover, β-blockers, ARBs and statins showed promising results in randomised controlled trials (RCTs) where pathological conditions other than cancer were considered. The results obtained have led or may lead to new indications for these drugs. For each drug or class of drugs, the potential molecular mechanisms of action justifying repurposing, results obtained in vitro and in animal models and data from epidemiological and randomized studies are described.
Topics: Acute Kidney Injury; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspirin; Bacterial Infections; Cardiac Glycosides; Cardiovascular Diseases; Drug Repositioning; Heparin, Low-Molecular-Weight; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Marfan Syndrome; Migraine Disorders; Mycoses; Neoplasms; Periodontitis
PubMed: 32145263
DOI: 10.1016/j.bcp.2020.113895 -
Journal of Clinical Research in... Mar 2024MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation,...
MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.
PubMed: 38529548
DOI: 10.4274/jcrpe.galenos.2024.2023-12-4 -
The American Journal of Case Reports Aug 2022BACKGROUND Major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome is a rare...
BACKGROUND Major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome is a rare genetic condition caused by a gain-of-function mutation in the SAMD9 gene. It acts as a growth repressor expressed in the endothelial cells. Pathogenic variants in the SAMD9 gene lead to profound growth-restricting activity intrinsic to the protein, which further reduces cellular proliferation and instigates this growth-limiting condition. Gastrointestinal features include chronic diarrhea, severe diaper rash, and colonic dilatation. Until now, there has been no description of exocrine pancreatic insufficiency as a possible cause of enteropathy in MIRAGE syndrome. CASE REPORT We report a case of MIRAGE syndrome affecting multiple systems in an infant who had severe enteropathy which responded well to porcine-derived pancreatic enzyme supplements despite normal pancreatic fecal elastase level. The infant is being followed up by multidisciplinary teams in our outpatient department. CONCLUSIONS Porcine-derived pancreatic enzyme is beneficial in enteropathy due to MIRAGE syndrome and is worth considering.
Topics: Adrenal Insufficiency; Animals; Endothelial Cells; Feces; Humans; Intracellular Signaling Peptides and Proteins; Pancreatic Elastase; Pancrelipase; Swine
PubMed: 35994417
DOI: 10.12659/AJCR.937057 -
The Journal of Clinical Investigation Feb 2021Autosomal dominant sterile α motif domain containing 9 (Samd9) and Samd9L (Samd9/9L) syndromes are a large subgroup of currently established inherited bone marrow...
Autosomal dominant sterile α motif domain containing 9 (Samd9) and Samd9L (Samd9/9L) syndromes are a large subgroup of currently established inherited bone marrow failure syndromes that includes myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE), ataxia pancytopenia, and familial monosomy 7 syndromes. Samd9/9L genes are located in tandem on chromosome 7 and have been known to be the genes responsible for myeloid malignancies associated with monosomy 7. Additionally, as IFN-inducible genes, Samd9/9L are crucial for protection against viruses. Samd9/9L syndromes are caused by gain-of-function mutations and develop into infantile myelodysplastic syndromes associated with monosomy 7 (MDS/-7) at extraordinarily high frequencies. We generated mice expressing Samd9LD764N, which mimic MIRAGE syndrome, presenting with growth retardation, a short life, bone marrow failure, and multiorgan degeneration. In hematopoietic cells, Samd9LD764N downregulates the endocytosis of transferrin and c-Kit, resulting in a rare cause of anemia and a low bone marrow reconstitutive potential that ultimately causes MDS/-7. In contrast, in nonhematopoietic cells we tested, Samd9LD764N upregulated the endocytosis of EGFR by Ship2 phosphatase translocation to the cytomembrane and activated lysosomes, resulting in the reduced expression of surface receptors and signaling. Thus, Samd9/9L is a downstream regulator of IFN that controls receptor metabolism, with constitutive activation leading to multiorgan dysfunction.
Topics: Animals; Chromosome Deletion; Chromosomes, Human, Pair 7; Disease Models, Animal; ErbB Receptors; Gain of Function Mutation; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Myeloproliferative Disorders; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Syndrome; Tumor Suppressor Proteins
PubMed: 33373325
DOI: 10.1172/JCI140147