The combination of intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies is commonly known by the acronym IMAGe. This rare syndrome has signs and symptoms that affect many parts of the body.

Most affected individuals grow slowly before birth (intrauterine growth restriction) and are small in infancy. They have skeletal abnormalities that often become apparent in early childhood, although these abnormalities are usually mild and can be difficult to recognize on x-rays. The most common bone changes are metaphyseal dysplasia and epiphyseal dysplasia; these are malformations of the ends of long bones in the arms and legs. Some affected individuals also have an abnormal side-to-side curvature of the spine (scoliosis) or thinning of the bones (osteoporosis).

Adrenal hypoplasia congenita is the most severe feature of IMAGe syndrome. The adrenal glands are a pair of small glands on top of each kidney. They produce a variety of hormones that regulate many essential functions in the body. Underdevelopment (hypoplasia) of these glands prevents them from producing enough hormones, a condition known as adrenal insufficiency. The signs of adrenal insufficiency begin shortly after birth and include vomiting, difficulty with feeding, dehydration, extremely low blood glucose (hypoglycemia), and shock. If untreated, these complications can be life-threatening.

The genital abnormalities associated with IMAGe syndrome occur only in affected males. They include an unusually small penis (micropenis), undescended testes (cryptorchidism), and the opening of the urethra on the underside of the penis (hypospadias).

Several additional signs and symptoms have been reported in people with IMAGe syndrome. Some affected individuals have distinctive facial features, such as a prominent forehead, low-set ears, and a short nose with a flat nasal bridge. Less commonly, people with this condition have premature fusion of certain bones of the skull (craniosynostosis), a split in the soft flap of tissue that hangs from the back of the mouth (cleft or bifid uvula), a high-arched roof of the mouth (palate), and a small chin (micrognathia). Other possible features of IMAGe syndrome include high levels of calcium in the blood (hypercalcemia) or urine (hypercalcuria) and a shortage of growth hormone in childhood that results in short stature.

IMAGe syndrome is caused by mutations in the CDKN1C gene. This gene provides instructions for making a protein that helps control growth before birth. The mutations that cause IMAGe syndrome alter the structure and function of the CDKN1C protein, which inhibits normal growth starting in the early stages of development before birth. Researchers are working to determine how these genetic changes underlie the bone abnormalities, adrenal gland underdevelopment, and other signs and symptoms of this condition.

People inherit one copy of most genes from their mother and one copy from their father. For most genes, both copies are fully turned on (active) in cells. The CDKN1C gene, however, is most active when it is inherited from a person's mother. The copy of CDKN1C inherited from a person's father is active at much lower levels in most tissues. This sort of parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting. When genomic imprinting reduces the activity of the copy of a gene inherited from the father, that gene is said to be paternally imprinted.

Normal Function

The CDKN1C gene provides instructions for making a protein that helps regulate growth. This protein acts as a tumor suppressor, which means that it keeps cells from growing and dividing too fast or in an uncontrolled way. It also is involved in controlling growth before birth, preventing the developing fetus from becoming too large.

People inherit one copy of most genes from their mother and one copy from their father. Both copies are typically active, or "turned on," in cells. However, the activity of the CDKN1C gene depends on which parent it was inherited from. In most tissues, the copy of the gene inherited from a person's mother (the maternally inherited copy) has much higher activity than the copy inherited from the father (the paternally inherited copy). This sort of parent-specific difference in gene activation is caused by a phenomenon called genomic imprinting.

CDKN1C is part of a cluster of genes on the short (p) arm of chromosome 11 that undergo genomic imprinting. A nearby region of DNA known as imprinting center 2 (IC2) or KvDMR controls the parent-specific genomic imprinting of CDKN1C and several other genes thought to help regulate growth. The IC2 region undergoes a process called methylation, which is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. Methylation, which occurs during the formation of an egg or sperm cell, is a way of marking or "stamping" the parent of origin. The IC2 region is normally methylated only on the maternally inherited copy of chromosome 11.

Health Conditions Related to Genetic Changes

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome is a condition that causes overgrowth and has other signs and symptoms that affect many parts of the body. At least half of all cases of Beckwith-Wiedemann syndrome result from changes in methylation of the IC2 region. Specifically, the maternally inherited copy of the IC2 region has too few methyl groups attached (hypomethylation). This abnormality disrupts the regulation of several genes that are normally controlled by IC2, including CDKN1C. Because this gene normally restrains cell growth and division, a reduction in its activity leads to overgrowth and the other features of Beckwith-Wiedemann syndrome.

In a few cases, Beckwith-Wiedemann syndrome has been caused by deletions of a small amount of DNA from the maternally inherited copy of the IC2 region. Like abnormal methylation, these deletions disrupt the activity of several genes, including CDKN1C.

Beckwith-Wiedemann syndrome can also result from variants (also known as mutations) within the maternally inherited copy of the CDKN1C gene. More than two dozen such variants have been identified. Some of these genetic changes lead to an abnormally short, nonfunctional version of the CDKN1C protein, while others alter single protein building blocks (amino acids) or delete a small number of amino acids from the protein. All of these variants are described as "loss-of-function" because they alter the structure of the CDKN1C protein such that it can no longer control growth effectively. The resulting problems with growth regulation lead to overgrowth and the other features of Beckwith-Wiedemann syndrome.

Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies

Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, commonly known by the acronym IMAGe, is a rare syndrome that affects the growth of many parts of the body. The condition is characterized by slow growth before and after birth, skeletal abnormalities, hormonal changes, and genital abnormalities in males. Variants in the CDKN1C gene have been found to cause this condition. Because this gene is paternally imprinted, IMAGe syndrome results only when the variant is present on the maternally inherited copy of the gene.

The CDKN1C gene variants that cause IMAGe syndrome replace single amino acids in a region known as the proliferating cell nuclear antigen (PCNA)-binding domain near the end of the gene. These variants appear to increase the stability of the CDKN1C protein, preventing it from being broken down normally. These changes increase the amount of the protein that is available to restrain cell growth and division. Because these variants enhance the protein's usual function, they are described as "gain-of-function." The excess CDKN1C protein leads to IMAGe syndrome by impairing normal growth and development starting before birth.

Other Names for This Gene

• BWCR
• CDN1C_HUMAN
• cyclin-dependent kinase inhibitor 1C
• cyclin-dependent kinase inhibitor 1C (p57, Kip2)
• cyclin-dependent kinase inhibitor p57
• KIP2
• p57
• p57KIP2

Genomic Location

The inheritance of IMAGe syndrome is complex. The condition is described as having an autosomal dominant inheritance pattern because one copy of the altered CDKN1C gene in each cell is sufficient to cause the disorder. However, because this gene is paternally imprinted, IMAGe syndrome results only when the mutation is present on the maternally inherited copy of the gene. When a mutation affects the paternally inherited copy of the CDKN1C gene, it does not cause health problems. Therefore, IMAGe syndrome is passed only from mothers to their children.

IMAGe syndrome is very rare, with only about 20 cases reported in the medical literature. The condition has been diagnosed more often in males than in females, probably because females do not have associated genital abnormalities.