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IMAGe Syndrome.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2014 Mar 13 [updated 2016 Sep 8].

Author information

Division of Genetic Medicine, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington
Division of Medical Genetics and Metabolism, Department of Pediatrics, Children’s Hospital of the King’s Daughters, Eastern Virginia Medical School, Norfolk, Virginia
Division of Human Genetics, Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, Philadelphia, Pennsylvania



IMAGe syndrome is an acronym for the major findings of intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary 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; cognitive outcome appears to be normal in the majority.


The diagnosis of IMAGe syndrome is established in a proband with suggestive findings and/or by the identification of a heterozygous CDKN1C pathogenic variant in the PCNA (proliferating cell nuclear antigen)-binding domain of the maternally expressed allele.


Treatment of manifestations: 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 supplements of sodium chloride. Steroid doses should be optimized to allow for linear growth without risking an adrenal crisis. Assessment for growth hormone deficiency 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, or physical therapy as needed, particularly in those with hypotonia. Prevention of secondary complications: Vigilance during illnesses and surgeries to prevent adrenal crisis. Surveillance: Routine evaluations by an endocrinologist to monitor adrenal function. Evaluation as needed by an orthopedist to monitor for skeletal complications and/or a neurologist to monitor for developmental delay and/or hypotonia. Evaluation of relatives at risk: To allow early diagnosis and management of adrenal insufficiency in at-risk newborns, molecular genetic testing should be pursued if the familial CDKN1C pathogenic variant in the family is known; if the familial pathogenic variant is not known, screening for serum electrolyte abnormalities, elevated serum ACTH level, and skeletal features of IMAGe syndrome can be performed. Pregnancy management: Risks to a mother with IMAGe syndrome during pregnancy include possible adrenal insufficiency; risks during delivery include cephalopelvic disproportion.


Typically a CDKN1C 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 CDKN1C variant has a 50% chance of inheriting the variant and being affected. Each child of a man with a heterozygous pathogenic CDKN1C 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 pregnancies at increased risk (i.e., when the mother has the pathogenic variant).

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