SAMD9杂合从头变异导致MIRAGE综合征,涉及骨髓增生异常的复杂多系统疾病,感染,增长的限制,肾上腺发育不全,生殖器表型,和肠病。其他临床关联的范围正在扩大,包括胎盘发育中断,出生后生长和内分泌特征差。越来越多,据报道,较轻的表型特征,例如小于胎龄(SGA)男孩的尿道下裂和正常的肾上腺功能。一些儿童出现孤立的骨髓增生异常综合征(MDS/7型),没有MIRAGE特征。
我们的目的是调查:1)报告的SAMD9变体的范围,临床特征,和可能的基因型-表型相关性;2)SAMD9破坏是否影响胎盘功能并导致妊娠丢失/复发性流产(RM);3)以及致病性变异是否与孤立的胎儿生长受限(FGR)有关。
对公布的数据进行了分析,特别是审查变体的位置/类型,怀孕,增长数据,和相关的内分泌特征。SAMD9的遗传分析是在受孕产物中进行的(POC,n=26),RM夫妇,(夫妇n=48;个人n=96),FGR儿童(n=44),SGA(n=20),和临床银-罗素综合征(SRS,n=8),(总n=194)。
到目前为止,在116个个体中报告了SAMD9变体[MDS/一元7,64(55.2%);MIRAGE,52(44.8%)]。越来越多地报道具有MIRAGE特征的儿童没有肾上腺表型(11/52,21.2%)。与肾上腺功能不全的婴儿相比,无肾上腺功能不全的婴儿出生时较重(中位数1515g对1020g;P<0.05),出生后(中位数34.5周对31.0周;P<0.05)。在MIRAGE患者中,尿道下裂是一个共同的特征。其他内分泌疾病包括甲状腺功能减退,低血糖和高血糖,身材矮小和全垂体功能减退。尽管表型的范围越来越大,在研究的妊娠丢失/生长受限队列中,遗传分析未发现SAMD9中任何可能的致病变异/特定变异的富集.
MIRAGE综合征的表型比最初报道的更多样化,包括生长受限和多系统特征。但没有肾上腺功能不全.内分泌病可能被忽视或逐渐发展,并可能被低估。作为包括FGR在内的临床特征,严重感染,贫血和肺部问题可以是非特异性的,常见于新生儿医学,SAMD9相关疾病可能未被诊断。达到MIRAGE综合征的特定诊断对于个性化管理至关重要。
Heterozygous 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.
We 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).
Published 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).
To 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.
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.