IMAGe syndrome

Other Names: Intrauterine growth retardation-metaphyseal dysplasia-adrenal hypoplasia congenita-genital anomalies syndrome

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.

Epidemiology

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.

Cause

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.

Inheritance

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.

Signs and symptoms

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 sugar (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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Adrenal hypoplasia(Small adrenal glands)
• Cryptorchidism(Undescended testes)
• Depressed nasal bridge(Depressed bridge of nose)
• Frontal bossing
• Hydronephrosis
• Hypogonadism(Decreased activity of gonads)
• Hypospadias
• Intrauterine growth retardation(Prenatal growth deficiency)
• Low-set ears(Low set ears)
• Metaphyseal dysplasia
• Micromelia(Smaller or shorter than typical limbs)
• Muscular hypotonia(Low or weak muscle tone)

5%-29% of people have these symptoms

• Global developmental delay
• Macrocephaly(Increased size of skull)

Diagnosis

IMAGe syndrome is an acronym for the major findings in this disorder: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities (in males) .

No formal clinical diagnostic criteria for IMAGe syndrome have been defined.

Suggestive Findings IMAGe syndrome should be suspected in individuals with the following clinical, imaging, and suggestive laboratory findings.

Clinical findings

• Intrauterine growth restriction (IUGR)*
• Postnatal growth deficiency, with variable growth hormone deficiency
• Adrenal hypoplasia congenita (AHC)*, often presenting as spontaneous adrenal crisis in the first week to month of life, with hypotension, hyponatremia, and hyperkalemia, which can be life-threatening.
• Some individuals with AHC may present with adrenal insufficiency during childhood or early adulthood.
• Later-onset adrenal insufficiency can be precipitated by stress, such as illness or surgery.
• Genital abnormalities in males, including unilateral or bilateral cryptorchidism, hypospadias, micropenis, and chordee.

Imaging findings Metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones, and delayed bone age on radiographs Note: Skeletal abnormalities, which are age dependent, can be absent or subtle. Adrenal imaging that suggests small or normal-sized adrenal glands, in contrast to enlarged adrenal glands seen in individuals with congenital adrenal hyperplasia (CAH)

Suggestive laboratory findings Evidence of adrenal insufficiency during a crisis including hyponatremia, hyperkalemia, and elevated ACTH levels, frequently greater than 1000 pg/mL (normal 10-60) Lack of findings consistent with other causes of adrenal insufficiency. 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

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.

NIH genetic and rare disease info

• NIH info on IMAGe syndrome

IMAGe syndrome is a rare disease.

IMAGe syndrome Resources
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