Genetics and Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.
Front Endocrinol (Lausanne). 2022 Aug 18;13:953707. doi: 10.3389/fendo.2022.953707. eCollection 2022.
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.
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).
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).
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.
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.
导致 MIRAGE 综合征的杂合变体是一种复杂的多系统疾病，涉及骨髓增生异常、感染、生长受限、肾上腺发育不全、生殖器表型和肠病。越来越多的额外临床关联正在被发现，包括胎盘发育不良、出生后生长不良和内分泌特征。在小胎龄（SGA）男孩中，越来越多的报告出现轻度表型特征，如尿道下裂和正常的肾上腺功能。一些儿童表现为孤立性骨髓增生异常综合征（MDS/单体 7）而没有 MIRAGE 特征。
我们旨在研究：1）报道的变体的范围、临床特征和可能的基因型-表型相关性；2）SAMD9 中断是否会影响胎盘功能并导致妊娠丢失/复发性流产（RM）；3）以及致病性变体是否与孤立性胎儿生长受限（FGR）相关。
分析了已发表的数据，特别是审查了变体的位置/类型、妊娠、生长数据和相关的内分泌特征。对 26 例妊娠产物（POC）、48 对 RM 夫妇（个体 96 例）、44 例 FGR 儿童、20 例 SGA 儿童和 8 例临床 Silver-Russell 综合征（SRS）儿童进行了 的基因分析（总共有 194 例）。
迄今为止，已在 116 名个体中报道了 变体[MDS/单体 7，64 名（55.2%）；MIRAGE，52 名（44.8%）]。越来越多的具有 MIRAGE 特征的儿童没有肾上腺表型（11/52，21.2%）。无肾上腺功能障碍的婴儿出生时体重更重（中位数 1515 克与 1020 克；P < 0.05）且出生时间较晚（中位数 34.5 周与 31.0 周；P < 0.05）。在 MIRAGE 患者中，尿道下裂是常见特征。其他内分泌疾病包括甲状腺功能减退症、低血糖和高血糖、身材矮小和全垂体功能减退症。尽管表型范围不断扩大，但遗传分析并未发现研究中妊娠丢失/生长受限队列中任何可能的致病性变体/特定变体的富集。
MIRAGE 综合征的表型比最初报道的更加多样化，包括生长受限和多系统特征，但没有肾上腺功能不全。内分泌疾病可能被忽视或逐渐发展，并且可能被漏报。由于包括 FGR、严重感染、贫血和肺部问题在内的临床特征可能不具有特异性，并且在新生儿医学中经常出现，因此 SAMD9 相关疾病可能被漏诊。明确 MIRAGE 综合征的具体诊断对于个性化管理至关重要。
