ESPE Abstracts (2022) 95 P1-333

1Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; 2Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands; 3Department of Development Biology & Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom

Background: Heterozygous de novo variants in SAMD9 cause the complex multisystem growth disorder, MIRAGE syndrome. Core features are myelodysplasia, infection, restricted growth, adrenal hypoplasia, genital/gonadal phenotypes, and enteropathy. However, the range of additional associations is expanding and includes disrupted placental development, poor post-natal growth, and other endocrine features. Milder phenotypes are also described, such as hypospadias in boys born small for gestational age (SGA), and normal adrenal function. Some children present with isolated myelodysplastic syndrome (MDS/monosomy 7) without MIRAGE features.

Aims: We investigated: 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) if pathogenic variants cause isolated fetal growth restriction (FGR).

Methods: A systematic literature review was undertaken of SAMD9-associated conditions, focussing on position/type of variant, pregnancy and growth data, and associated endocrine features. Genetic analysis of SAMD9 was performed using next generation sequencing (NGS) in products of conception (POC, n=26) and RM couples (n=48; individuals n=96), and in children with FGR (n=44), SGA (n=24), Silver-Russell Syndrome (SRS, n=8), (total n=198).

Results: SAMD9 variants are currently reported in 117 individuals (MDS/monosomy 7, 65 (55%); MIRAGE, 52 (44%)). Increasingly, children with MIRAGE features are reported without an adrenal phenotype (12/52, 23%). Compared to MDS, MIRAGE-associated variants cluster in specific domains of SAMD9. Disruption of arginine residues is more common with adrenal dysfunction. MIRAGE patients without adrenal dysfunction were heavier at birth (median 1515 g vs 1020 g; P< 0.05) and born later (median 34.5 weeks vs 31.0; P< 0.05) compared to children with adrenal insufficiency. Hypospadias is a common feature, but 46,XX girls remain underreported. Additional endocrinopathies include hypothyroidism, hypo- and hyper-glycaemia, short stature and panhypopituitarism. Single cell RNA sequencing showed higher SAMD9 expression in late trimester human placenta, but no pathogenic variants in SAMD9 were identified in POC or RM couples. NGS analysis showed no likely pathogenic variants or enrichment of rare variants in SAMD9 in FGR, SGA and SRS cohorts.

Conclusions: MIRAGE syndrome is more phenotypically diverse than originally reported and includes children with neonatal growth restriction and multisystem features but without adrenal insufficiency. Other endocrinopathies are emerging and long-term follow-up needed. MIRAGE is likely underdiagnosed in the neonatal setting, especially in 46,XX girls. Reaching a diagnosis has important implications for personalised multidisciplinary management. Nevertheless, SAMD9 variants are not common in fetal growth disorders without additional features.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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