Emerging phenotypes linked to variants in SAMD9 and MIRAGE syndrome

Abstract

BackgroundHeterozygous de novo variants in SAMD9 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.ObjectiveWe aimed to investigate: 1) the range of reported SAMD9 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).MethodsPublished data were analyzed, particularly reviewing position/type of variant, pregnancy, growth data, and associated endocrine features. Genetic analysis of SAMD9 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).ResultsTo date, SAMD9 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 SAMD9 in the pregnancy loss/growth restriction cohorts studied.ConclusionMIRAGE 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.

A Small-for-Gestational-Age Infant with MIRAGE Syndrome Who Developed Heat Stroke and Rhabdomyolysis due to Severe Temperature Instability

“…Acquiring monosomy 7 may be an adaptation that allows cells carrying the mutation to avoid the growth-restricting effect of the mutant SAMD9 protein [4]. Patients with MIRAGE syndrome can show myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy; however, other features such as hypothyroidism and gastroesophageal reflux have been reported [4,[6][7][8][9][10]. Here, we report heat stroke and rhabdomyolysis caused by anhidrosis as a symptom of MI-RAGE syndrome.…”

“…The diverse clinical picture of MIRAGE syndrome is becoming clearer [7]. Approximately 20% of patients with MIRAGE syndrome do not have adrenal insufficiency [7].…”

“…The diverse clinical picture of MIRAGE syndrome is becoming clearer [7]. Approximately 20% of patients with MIRAGE syndrome do not have adrenal insufficiency [7]. Preterm births are common in patients with MI-RAGE due to severe FGR, and infants are often SGA [7,10].…”

Investigating ultrastructural morphology in MIRAGE syndrome (SAMD9)-derived fibroblasts using transmission electron microscopy.

“…We have recently undertaken a meta-analysis of all published SAMD9associated variants and shown that the range of clinical phenotypes is very variable. 3 Increasingly, children with MIRAGE syndrome are diagnosed who do not have adrenal insufficiency, and a large proportion of children and young people with SAMD9 variants present with myelodysplastic syndrome (MDS) alone. 3,4 SAMD9 has been extensively shown to be a growth repressor in in vitro cellular models, explaining the typical phenotypic growth restriction and tissue hypoplasia observed in children with this condition.…”

“…3 Increasingly, children with MIRAGE syndrome are diagnosed who do not have adrenal insufficiency, and a large proportion of children and young people with SAMD9 variants present with myelodysplastic syndrome (MDS) alone. 3,4 SAMD9 has been extensively shown to be a growth repressor in in vitro cellular models, explaining the typical phenotypic growth restriction and tissue hypoplasia observed in children with this condition. However, the molecular mechanism or mechanisms by which SAMD9 affects cell growth and proliferation are still unknown.…”