Schrier Vergano Samantha A, Deardorff Matthew A
Division of Medical Genetics and Metabolism Department of Pediatrics Children’s Hospital of the King’s Daughters Eastern Virginia Medical School Norfolk, Virginia
Departments of Pathology and Pediatrics Children's Hospital Los Angeles University of Southern California Keck School of Medicine Los Angeles, California
IMAGe syndrome is an acronym for the major findings of ntrauterine growth restriction (IUGR), etaphyseal dysplasia, drenal hypoplasia congenita, and nitourinary abnormalities (in males). Findings reported in individuals with a clinical and/or molecular diagnosis include: IUGR; Some type of skeletal abnormality (most commonly delayed bone age and short stature, and occasionally, metaphyseal and epiphyseal dysplasia of varying severity); Adrenal insufficiency often presenting in the first month of life as an adrenal crisis or (rarely) later in childhood with failure to thrive and recurrent vomiting; Genital abnormalities in males (cryptorchidism, micropenis, and hypospadias) but not in females. Hypotonia and developmental delay are reported in some individuals; cognitive outcome appears to be normal in the majority of individuals.
DIAGNOSIS/TESTING: The diagnosis of IMAGe syndrome is established in a proband with suggestive findings and/or a heterozygous pathogenic variant in the PCNA (proliferating cell nuclear antigen)-binding domain of the maternally expressed allele identified by molecular genetic testing.
Management of adrenal insufficiency in IMAGe syndrome is similar to management of adrenal insufficiency from other causes and should be under the supervision of an endocrinologist. Chronic treatment includes replacement doses of glucocorticoids and mineralocorticoids and oral sodium chloride supplements. Steroid doses should be optimized to allow for linear growth without risking an adrenal crisis. Consider assessment for growth hormone deficiency to determine if growth hormone should be considered. Routine management of cryptorchidism and hypospadias by a urologist, and routine hormone replacement by an endocrinologist for hypogonadotropic hypogonadism. Management by an orthopedist as needed for skeletal complications such as scoliosis and hip dysplasia. Occupational, speech, and/or physical therapy as needed, particularly in those with hypotonia. Growth assessment at each visit; annual evaluations by an endocrinologist to monitor adrenal function and for development of hypercalciuria and nephrocalcinosis; evaluation as needed by an orthopedist to monitor for skeletal complications as needed; assessment of hypotonia, developmental progress, and educational needs at each visit. To allow early diagnosis and management of adrenal insufficiency in at-risk newborns, molecular genetic testing should be pursued if the pathogenic variant in the family is known; if the familial pathogenic variant is not known, screen for serum electrolyte abnormalities, elevated serum ACTH level, and skeletal features of IMAGe syndrome. Risks to a mother with IMAGe syndrome during pregnancy include possible adrenal insufficiency; risks during delivery include cephalopelvic disproportion.
Typically, a pathogenic variant causing IMAGe syndrome is inherited in an autosomal dominant manner; however, only maternal transmission of the pathogenic variant results in IMAGe syndrome. Each child of a woman with a heterozygous pathogenic variant has a 50% chance of inheriting the variant and being affected. Each child of a man with a heterozygous pathogenic variant has a 50% chance of inheriting the variant but is expected to be unaffected. If the pathogenic variant has been identified in an affected family member, prenatal testing is possible for a pregnancy at increased risk (i.e., when the mother has the pathogenic variant).
IMAGe综合征是宫内生长受限（IUGR）、骨骺发育异常、先天性肾上腺发育不全以及（男性）泌尿生殖系统异常的首字母缩写。有临床和/或分子诊断的个体报告的发现包括：宫内生长受限；某种类型的骨骼异常（最常见的是骨龄延迟和身材矮小，偶尔也有不同严重程度的干骺端和骨骺发育异常）；肾上腺功能不全，通常在出生后第一个月表现为肾上腺危象，或（罕见）在儿童期后期表现为生长发育不良和反复呕吐；男性生殖器异常（隐睾、小阴茎和尿道下裂），女性则无。一些个体报告有肌张力减退和发育迟缓；大多数个体的认知结果似乎正常。
诊断/检测：IMAGe综合征的诊断基于先证者有提示性发现和/或通过分子基因检测在母系表达等位基因的PCNA（增殖细胞核抗原）结合域中鉴定出杂合致病变异。
IMAGe综合征中肾上腺功能不全的管理与其他原因导致的肾上腺功能不全的管理相似，应由内分泌学家监督。慢性治疗包括糖皮质激素和盐皮质激素的替代剂量以及口服氯化钠补充剂。应优化类固醇剂量，以促进线性生长而不引发肾上腺危象。考虑评估生长激素缺乏情况，以确定是否应考虑使用生长激素。由泌尿科医生对隐睾和尿道下裂进行常规管理，由内分泌学家对低促性腺激素性性腺功能减退进行常规激素替代治疗。根据需要由骨科医生处理脊柱侧弯和髋关节发育不良等骨骼并发症。根据需要进行职业、言语和/或物理治疗，特别是针对有肌张力减退的患者。每次就诊时进行生长评估；内分泌学家每年进行评估，以监测肾上腺功能以及高钙尿症和肾钙质沉着症的发生情况；根据需要由骨科医生进行评估，以监测骨骼并发症；每次就诊时评估肌张力减退、发育进展和教育需求。为了对有风险的新生儿进行肾上腺功能不全的早期诊断和管理，如果已知家族中的致病变异，应进行分子基因检测；如果家族性致病变异未知，则筛查血清电解质异常、血清促肾上腺皮质激素水平升高以及IMAGe综合征的骨骼特征。患有IMAGe综合征的母亲在怀孕期间的风险包括可能出现肾上腺功能不全；分娩期间的风险包括头盆不称。
通常，导致IMAGe综合征的致病变异以常染色体显性方式遗传；然而，只有致病变异的母系传递会导致IMAGe综合征。携带杂合致病变异的女性的每个孩子都有50%的机会继承该变异并受到影响。携带杂合致病变异的男性的每个孩子都有50%的机会继承该变异，但预计不会受到影响。如果在受影响的家庭成员中已鉴定出致病变异，则对于风险增加的妊娠（即母亲携带致病变异时）可进行产前检测。
