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Clinical Endocrinology Jan 2020Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are... (Review)
Review
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1). Reaching a specific diagnosis can have life-long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, "Addison's disease."
Topics: Addison Disease; Humans
PubMed: 31610036
DOI: 10.1111/cen.14109 -
Frontiers in Endocrinology 2022Heterozygous variants in cause MIRAGE syndrome, a complex multisystem disorder involving Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital...
BACKGROUND
Heterozygous variants in cause MIRAGE syndrome, a complex multisystem disorder involving Myelodysplasia, Infection, Restriction of growth, Adrenal hypoplasia, Genital phenotypes, and Enteropathy. The range of additional clinical associations is expanding and includes disrupted placental development, poor post-natal growth and endocrine features. Increasingly, milder phenotypic features such as hypospadias in small for gestational age (SGA) boys and normal adrenal function are reported. Some children present with isolated myelodysplastic syndrome (MDS/monosomy 7) without MIRAGE features.
OBJECTIVE
We aimed to investigate: 1) the range of reported variants, clinical features, and possible genotype-phenotype correlations; 2) whether SAMD9 disruption affects placental function and leads to pregnancy loss/recurrent miscarriage (RM); 3) and if pathogenic variants are associated with isolated fetal growth restriction (FGR).
METHODS
Published data were analyzed, particularly reviewing position/type of variant, pregnancy, growth data, and associated endocrine features. Genetic analysis of was performed in products of conception (POC, n=26), RM couples, (couples n=48; individuals n=96), children with FGR (n=44), SGA (n=20), and clinical Silver-Russell Syndrome (SRS, n=8), (total n=194).
RESULTS
To date, variants are reported in 116 individuals [MDS/monosomy 7, 64 (55.2%); MIRAGE, 52 (44.8%)]. Children with MIRAGE features are increasingly reported without an adrenal phenotype (11/52, 21.2%). Infants without adrenal dysfunction were heavier at birth (median 1515 g versus 1020 g; P < 0.05) and born later (median 34.5 weeks versus 31.0; P < 0.05) compared to those with adrenal insufficiency. In MIRAGE patients, hypospadias is a common feature. Additional endocrinopathies include hypothyroidism, hypo- and hyper-glycemia, short stature and panhypopituitarism. Despite this increasing range of phenotypes, genetic analysis did not reveal any likely pathogenic variants/enrichment of specific variants in in the pregnancy loss/growth restriction cohorts studied.
CONCLUSION
MIRAGE syndrome is more phenotypically diverse than originally reported and includes growth restriction and multisystem features, but without adrenal insufficiency. Endocrinopathies might be overlooked or develop gradually, and may be underreported. As clinical features including FGR, severe infections, anemia and lung problems can be non-specific and are often seen in neonatal medicine, SAMD9-associated conditions may be underdiagnosed. Reaching a specific diagnosis of MIRAGE syndrome is critical for personalized management.
Topics: Adrenal Insufficiency; Chromosome Deletion; Chromosomes, Human, Pair 7; Female; Fetal Growth Retardation; Humans; Hypospadias; Intracellular Signaling Peptides and Proteins; Male; Myelodysplastic Syndromes; Phenotype; Placenta; Pregnancy; Syndrome
PubMed: 36060959
DOI: 10.3389/fendo.2022.953707 -
Children (Basel, Switzerland) Mar 2024MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor... (Review)
Review
MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the "de novo" mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.
PubMed: 38539345
DOI: 10.3390/children11030310 -
Leukemia May 2018Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome,... (Review)
Review
Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L. Furthermore, the complete or partial loss of chromosome 7q may cause myelodysplastic syndrome in these patients. SAMD9 mutations appear to associate with a more severe disease phenotype, including intrauterine growth restriction, developmental delay and hypoplasia of adrenal glands, testes, ovaries or thymus, and most reported patients died in infancy or early childhood due to infections, anemia and/or hemorrhages. SAMD9L mutations have been reported in a few families with balance problems and nystagmus due to cerebellar atrophy, and may lead to similar hematological disease as seen in SAMD9 mutation carriers, from early childhood to adult years. We review the clinical features of these syndromes, discuss the underlying biology, and interpret the genetic findings in some of the affected family members. We provide expert-based recommendations regarding diagnosis, follow-up, and treatment of mutation carriers.
Topics: Ataxia; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygote; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Pancytopenia; Proteins; Tumor Suppressor Proteins
PubMed: 29535429
DOI: 10.1038/s41375-018-0074-4 -
Pulmonology 2022Severe asthma management during the coronavirus disease 2019 (COVID-19) pandemic is a challenge and will continue to be, at least in the next few months, as herd... (Review)
Review
INTRODUCTION AND OBJECTIVES
Severe asthma management during the coronavirus disease 2019 (COVID-19) pandemic is a challenge and will continue to be, at least in the next few months, as herd immunity is still a mirage. A lot has to be learned about how COVID-19 affects underlying diseases, and severe asthma is no exception.
METHODS
Narrative review of papers available until February 2021 in PubMed and Google Scholar, relating severe asthma and COVID-19. Four main research topics were reviewed: SARS-CoV-2 infection: immunology and respiratory pathology; interrelationship of severe asthma endotypes and COVID-19 disease mechanisms; severe asthma epidemiology and COVID-19; and biologics for severe asthma in the context of COVID-19.
RESULTS
COVID-19 disease mechanisms start with upper respiratory cell infection, and afterwards several immunological facets are activated, contributing to disease severity, namely cell-mediated immunity and antibody production. Although infrequent in the COVID-19 course some patients develop a cytokine storm that causes organ damage and may lead to acute respiratory distress syndrome or multiorgan failure. Regarding severe asthma endotypes, type2-high might have a protective role both in infection risk and disease course. There is conflicting data regarding the epidemiological relationship between COVID-19 among severe asthma patients, with some studies reporting increased risk of infection and disease course, whereas others the other way round. Biologics for severe asthma do not seem to increase the risk of infection and severe COVID-19, although further evidence is needed.
CONCLUSIONS
Globally, in the era of COVID-19, major respiratory societies recommend continuing the biologic treatment, preferably in a self-home administration program.
Topics: Asthma; Biological Products; COVID-19; Humans; Immunologic Factors; Pandemics; Risk Factors; SARS-CoV-2; Severity of Illness Index
PubMed: 34053902
DOI: 10.1016/j.pulmoe.2021.04.001 -
World Journal of Critical Care Medicine Sep 2023Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection. It is a complex syndrome and is characterized by... (Review)
Review
Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection. It is a complex syndrome and is characterized by physiologic, pathologic and biochemical abnormalities in response to an infection. Diagnosis of sepsis is based on history, physical examination and other investigations (including biomarkers) which may help to increase the certainty of diagnosis. Biomarkers have been evaluated in the past for many diseases and have been evaluated for sepsis as well. Biomarkers may find a possible role in diagnosis, prognostication, therapeutic monitoring and anti-microbial stewardship in sepsis. Since the pathophysiology of sepsis is quite complex and is incompletely understood, a single biomarker that may be robust enough to provide all information has not been found as of yet. However, many biomarkers have been studied and some of them have applications at the bedside and guide clinical decision-making. We evaluated the PubMed database to search for sepsis biomarkers for diagnosis, prognosis and possible role in antibiotic escalation and de-escalation. Clinical trials, meta-analyses, systematic reviews and randomized controlled trials were included. Commonly studied biomarkers such as procalcitonin, Soluble urokinase-type plasminogen activator (Supar), presepsin, soluble triggering receptor expressed on myeloid cells 1, interleukin 6, C-reactive protein, ., have been described for their possible applications as biomarkers in septic patients. The sepsis biomarkers are still an area of active research with newer evidence adding to the knowledge base continuously. For patients presenting with sepsis, early diagnosis and prompt resuscitation and early administration of anti-microbials (preferably within 1 h) and source control are desired goals. Biomarkers may help us in the diagnosis, prognosis and therapeutic monitoring of septic patients. The marker redefining our view on sepsis is yet a mirage that clinicians and researchers continue to chase.
PubMed: 37745257
DOI: 10.5492/wjccm.v12.i4.188 -
Experimental Hematology Apr 2024SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are... (Review)
Review
SAMD9 and SAMD9L are two interferon-regulated genes located adjacent to each other on chromosome 7q21.2. Germline gain-of-function (GL GOF) mutations in SAMD9/SAMD9L are the genetic cause of MIRAGE syndrome, ataxia-pancytopenia (ATXPC) syndrome, myeloid leukemia syndrome with monosomy 7 (MLSM7), refractory cytopenia of childhood (RCC), transient monosomy 7 in children, SAMD9L-associated autoinflammatory disease (SAAD), and a proportion of inherited aplastic anemia and bone marrow failure syndromes. The myeloid neoplasms associated with GL GOF SAMD9/SAMD9L mutations have been included in the World Health Organization (WHO) 2022 classification. The discovery of SAMD9/SAMD9L-related diseases has revealed some interesting pathobiological mechanisms, such as a high rate of primary somatic compensation, with one of the mechanisms being (transient) monosomy 7 a mechanism also described as "adaption by aneuploidy." The somatic compensation in the blood can complicate the diagnosis of SAMD9/SAMD9L-related disease when relying on hematopoietic tissues for diagnosis. Recently, GL loss-of function (LOF) mutations have been identified in older individuals with myeloid malignancies in accordance with a mouse model of SAMD9L loss that develops a myelodysplastic syndrome (MDS)-like disease late in life. The discovery of SAMD9/SAMD9L-associated syndromes has resulted in a deeper understanding of the genetics and biology of diseases/syndromes that were previously oblivious and thought to be unrelated to each other. Besides giving an overview of the literature, this review wants to also provide some practical guidance for the classification of SAMD9/SAMD9L variants that is complicated by the nonrecurrent nature of these mutations but also by the fact that both GL GOF, as well as loss-of-function mutations, have been identified.
PubMed: 38649131
DOI: 10.1016/j.exphem.2024.104217 -
Reumatologia Clinica 2018Independent investigators have described the onset of a chronic painful dysautonomic syndrome soon after human papillomavirus (HPV) vaccination. The veracity of this... (Review)
Review
Independent investigators have described the onset of a chronic painful dysautonomic syndrome soon after human papillomavirus (HPV) vaccination. The veracity of this syndrome is hotly debated. Many of the reported post-HPV vaccination cases fullfill fibromyalgia diagnostic criteria. This article discusses the arguments favoring the existence of a syndrome associated to HPV vaccination. We propose that fibromyalgia dysautonomic-neuropathic model could help in the diagnostic and therapeutic process in those patients in whom the onset of a painful chronic illness began after HPV immunization. On the other hand, if its veracity is corroborated, HPV vaccination syndrome may become a new tragic fibromyalgia model.
Topics: Diagnosis, Differential; Fibromyalgia; Humans; Models, Biological; Papillomavirus Vaccines; Syndrome
PubMed: 29548896
DOI: 10.1016/j.reuma.2018.01.014 -
BMC Nephrology Aug 2020MIRAGE syndrome is a recently discovered rare genetic disease characterized by myelodysplasia (M), infection (I), growth restriction (R), adrenal hypoplasia (A), genital...
BACKGROUND
MIRAGE syndrome is a recently discovered rare genetic disease characterized by myelodysplasia (M), infection (I), growth restriction (R), adrenal hypoplasia (A), genital phenotypes (G), and enteropathy (E), caused by a gain-of-function mutation in the SAMD9 gene. We encountered a girl with molecularly-confirmed MIRAGE syndrome who developed steroid-resistant nephrotic syndrome.
CASE PRESENTATION
She was born at 33 weeks gestational age with a birth weight of 1064 g. She showed growth failure, mild developmental delays, intractable enteropathy and recurrent pneumonia. She was diagnosed as MIRAGE syndrome by whole exome sequencing and a novel SAMD9 variant (c.4615 T > A, p.Leu1539Ile) was identified at age four. Biopsied skin fibroblast cells showed changes in the endosome system that are characteristic of MIRAGE syndrome, supporting the genetic diagnosis. Proteinuria was noted at age one, following nephrotic syndrome at age five. A renal biopsy showed focal segmental glomerulosclerosis (FSGS) with immune deposits. Steroid treatment was ineffective. Because we speculated that her nephrosis was a result of genetic FSGS, we decided not to introduce immunosuppressive agents and instead started enalapril to reduce proteinuria. Although her proteinuria persisted, her renal function was normal at age eight.
CONCLUSIONS
This is the first detailed report of a MIRAGE syndrome patient with nephrotic syndrome. Because patients with MIRAGE syndrome have structural abnormalities in the endosomal system, we speculate that dysfunction of endocytosis in podocytes might be a possible mechanism for proteinuria.
Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Esophageal Motility Disorders; Female; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Growth Disorders; Humans; Hypoadrenocorticism, Familial; Immunologic Deficiency Syndromes; Infant; Infections; Intestinal Diseases; Intracellular Signaling Peptides and Proteins; Mutation; Myelodysplastic Syndromes; Nephrotic Syndrome; Syndrome; Treatment Failure; Urogenital Abnormalities; Exome Sequencing
PubMed: 32787808
DOI: 10.1186/s12882-020-02011-4