IMAGe Syndrome

Excerpt

Clinical characteristics: 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:

1. IUGR;

2. Some type of skeletal abnormality (most commonly delayed bone age and short stature, and occasionally, metaphyseal and epiphyseal dysplasia of varying severity);

3. 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;

4. 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 CDKN1C pathogenic variant in the PCNA (proliferating cell nuclear antigen)-binding domain of the maternally expressed allele identified by molecular genetic testing.

Management: 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 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.

Surveillance: 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.

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 CDKN1C 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.

Pregnancy management: Risks to a mother with IMAGe syndrome during pregnancy include possible adrenal insufficiency; risks during delivery include cephalopelvic disproportion.

Genetic counseling: 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 a pregnancy at increased risk (i.e., when the mother has the pathogenic variant).