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IMAGe Syndrome

Synonym: Intrauterine Growth Restriction, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, and Genital Anomalies

, MD, PhD, , MD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: September 8, 2016.

Estimated reading time: 22 minutes


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:

  • 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.

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 pregnancies at increased risk (i.e., when the mother has the pathogenic variant).


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) [Vilain et al 1999].

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.

*Note: The clinical features of IUGR and AHC, with or without a family history of IMAGe syndrome, are highly suggestive of the diagnosis.

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

Establishing the Diagnosis

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 (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. For a suspected diagnosis of IMAGe syndrome, sequence analysis of CDKN1C should be performed first. Deletions and duplications in CDKN1C have not been reported to cause IMAGe syndrome.
  • A multigene panel that includes CDKN1C and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes CDKN1C) fails to confirm a diagnosis in an individual with features of IMAGe syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in IMAGe Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
CDKN1CSequence analysis 39/9 families 4
Gene-targeted deletion/duplication analysis 5No abnormalities anticipated 6
Unknown 7NA

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


At present all six reported pathogenic variants in CDKN1C in persons with IMAGe syndrome have been located within an eight-amino-acid region of the PCNA-binding domain (nucleotides c.814 to c. 836, based on NM_000076​.2) [Arboleda et al 2012, Hamajima et al 2013].


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


No deletions or duplications of CDKN1C have been reported or are anticipated in persons with IMAGe syndrome due to the gain-of-function disease mechanism.


Although all individuals with typical clinical features of IMAGe syndrome tested to date have had an identifiable CDKN1C pathogenic variant, it is possible that other loci may play a role in its etiology.

Clinical Characteristics

Clinical Description

Twenty-eight individuals reported from 16 families have features consistent with the clinical diagnosis of IMAGe syndrome [Vilain et al 1999, Lienhardt et al 2002, Pedreira et al 2004, Bergadá et al 2005, Hutz et al 2006, Tan et al 2006, Ko et al 2007, Amano et al 2008, Balasubramanian et al 2010, Arboleda et al 2012, Hamajima et al 2013, Bodian et al 2014, Kato et al 2014]. Of these 28 individuals, 17 from nine unrelated families have had the diagnosis confirmed molecularly [Arboleda et al 2012, Hamajima et al 2013]. Of the 11 who have not had confirmatory genetic testing, nearly all have clinical findings that significantly overlap those of the individuals with a molecularly confirmed diagnosis.

A diagnosis of IMAGe syndrome has been considered in other published cases; however, the clinical information was either significantly different from the 28 typical cases or insufficient to determine the diagnosis with certainty, and pathogenic CDKN1C variants were not reported [Blethen et al 1990, Hall & Stelling 1991, Le & Kutteh 1996, Coman et al 2007, McDonald et al 2010, Lindemeyer et al 2014]. Several of these cases are further discussed in Differential Diagnosis.

Because the genetic etiology of IMAGe syndrome has only recently been elucidated, it is likely that the spectrum and natural history of IMAGe syndrome will be refined as more affected individuals are identified.

Although intrauterine growth restriction (IUGR) may be detected prenatally, IMAGe syndrome is typically evident at birth with IUGR, mild dysmorphic features, adrenal insufficiency, and, in males, genitourinary abnormalities. Of 23 individuals with information about age and findings at presentation, one was identified prenatally, 13 at birth, four in the first month of life, three from age one month to one year, one at age five years, and one at age 15 years.

Growth. All neonates have had IUGR with birth weights from -2 to -4 SD and birth lengths from -1.8 to -4.5 SD. Of the nine for whom information was available at birth, five had a normal OFC and four had an OFC from -2 to -3 SD.

Individuals with IMAGe syndrome consistently demonstrate continued short stature (height -2.7 to -6.5 SD) and postnatal failure to thrive (weight -2 to -7 SD). Of the nine on whom longitudinal information was available, postnatal OFC was normal in seven and below -2 SD in two.

Skeletal. All affected individuals have had some skeletal abnormality, most commonly delayed bone age and short stature. Metaphyseal and epiphyseal dysplasia of the long bones are common. The metaphyses are frequently described as striated and the diaphyses as gracile.

A significant degree of age-dependent variation is observed: in some, the metaphyseal dysplasia may be late, mild, and/or easily missed. Most children have radiologic evidence of skeletal abnormality by age five years.

Less common skeletal features include progressive and severe scoliosis with onset before age five years, ovoid-shaped vertebral bodies, short first metatarsals, hallux valgus, and hip dysplasia.

In one individual, fractures of the humerus and tibia were present at birth [Lienhardt et al 2002].

Adrenal insufficiency appears to be universal. Although this may be due to an ascertainment bias for probands, in one family it appeared fully penetrant, with adrenal insufficiency present in 7/7 individuals who possessed a maternally inherited CDKN1C pathogenic variant [Arboleda et al 2012].

Adrenal crisis, presenting with hyponatremia, hyperkalemia, and life-threatening hypotension, can occur within the first month of life, typically within the first week; extremely elevated ACTH levels, frequently above 1000 pg/mL (normal 10-60), can cause severe hyperpigmentation in these infants [Vilain et al 1999].

A few individuals do not have adrenal crisis, but rather milder adrenal insufficiency, presenting with failure to thrive and recurrent vomiting. One child, who experienced recurrent vomiting associated with mild infections from birth, was diagnosed with adrenal insufficiency at age five years following diagnosis of IMAGe syndrome in her younger brother [Lienhardt et al 2002]. Another affected individual was diagnosed with hypoaldosteronism without glucocorticoid deficiency [Bodian et al 2014].

Genitourinary abnormalities. Genital abnormalities, which are nearly universal in males with IMAGe syndrome, have not been reported in females. Reported abnormalities include cryptorchidism (usually bilateral), micropenis, and hypospadias.

Of the 28 individuals reported with IMAGe syndrome 20 are male, which may represent ascertainment bias due to the presence of genital abnormalities in males only. Two females with IMAGe syndrome have had children [Authors, unpublished observations]. No males with IMAGe syndrome are known to have reproduced.

Hydronephrosis has been reported; however, the majority of affected individuals are reported to have normal renal ultrasound examinations.

Neurologic. Developmental outcome is believed to be normal, as 15 of the 16 individuals in whom cognitive outcome was mentioned were reported as normal; the oldest reported was 26 years old.

Hypotonia was reported in six individuals and noted to be absent in four others; some of those reported with developmental delay likely had motor delays secondary to hypotonia.

In one affected individual who had wasting of facial and distal muscles, muscle biopsy showed nonspecific myopathic changes [Lienhardt et al 2002].

Of seven affected individuals with classic IMAGe syndrome for whom head imaging was reported (3 via cranial ultrasound examination, 1 via head CT, and 3 via brain MRI), all were normal.

Other. Characteristic facial features that have been reported in the vast majority of individuals include frontal bossing, depressed or wide nasal bridge, and small/low-set ears; features are typically appreciated by toddler age. The facial profile can be similar to the “triangular” facies seen in Silver-Russell syndrome. The facial profile may change with time. Micrognathia or retrognathia are also frequently reported. Less commonly reported are cleft palate or cleft uvula, craniosynostosis, short palpebral fissures, smooth philtrum, and microglossia.

Variable hypercalcemia of unclear etiology, occasionally with evidence of soft tissue calcifications, was reported in eight of 16 affected individuals on whom information was available. Several individuals have had nephrocalcinosis-associated hypercalcuria. While this hypercalcemia may be a part of IMAGe syndrome itself, it may be secondary to sodium chloride supplementation, which is part of the treatment of the mineralocorticoid deficiency associated with adrenal insufficiency [Bergadá et al 2005].

Genotype-Phenotype Correlations

Currently, no genotype-phenotype correlations are known.


Although few large pedigrees with IMAGe syndrome have been reported to date, it is clear that the mode of inheritance is autosomal dominant in which only maternal transmission of the imprinted pathogenic variant results in IMAGe syndrome [Arboleda et al 2012].

In one large family of 24 individuals, all seven individuals with IMAGe syndrome inherited the CDKN1C pathogenic variant from their mother. Consistent with the imprinted expression of CDKN1C, unaffected individuals either inherited the pathogenic variant from their father (n=9) or did not have the pathogenic variant (n=8) [Bergadá et al 2005, Arboleda et al 2012].


Prior to the identification of its molecular basis [Arboleda et al 2012], IMAGe syndrome was referred to as IMAGe association [Vilain et al 1999].

Historically the term “intrauterine growth retardation” was used. More recently, the term “intrauterine growth restriction” has come into favor.


The prevalence of IMAGe syndrome is currently unknown. A total of 28 affected individuals from 16 families have been reported to date.

Differential Diagnosis

Adrenal Insufficiency

Congenital adrenal hyperplasia (CAH) resulting from 21-hydroxylase deficiency, 11-beta hydroxylase deficiency (OMIM 202010), 3-beta hydroxysteroid dehydrogenase deficiency (OMIM 201810), or 17-alpha hydroxylase deficiency (OMIM 202110) can present with ambiguous genitalia at birth and adrenal crisis in infancy or childhood. CAH is far more common than IMAGe syndrome. In addition to distinct biochemical profiles, CAH and IMAGe syndrome differ in the following ways:

  • Infants with CAH rarely have IUGR.
  • The genital abnormalities of CAH are typically virilization of females, whereas the genital abnormalities of IMAGe syndrome are undervirilization of males, including cryptorchidism and hypospadias.
  • The adrenal glands are hypertrophic in CAH and hypoplastic in IMAGe syndrome.

X-linked adrenal hypoplasia congenita (X-linked AHC) is caused by mutation of the X-linked gene NROB1 (DAX1). Males with X-linked AHC can present with adrenal crisis, Addison disease, and/or hypogonadotropic hypogonadism. Onset of adrenal insufficiency in affected males is in infancy (average age 3 weeks) in approximately 60% and in childhood in approximately 40%. A few affected males present in adulthood with infertility.

Affected males may have cryptorchidism and typically have delayed puberty (onset age >14 years) caused by hypogonadotropic hypogonadism. Males are infertile despite treatment with exogenous gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH). Heterozygous females may occasionally have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism.

Although males with X-linked AHC typically do not have growth restriction, metaphyseal dysplasia, or the facial features of IMAGe syndrome, in the newborn period their phenotypic features can overlap with males who have IMAGe syndrome, as both conditions include adrenal insufficiency, adrenal hypoplasia, and cryptorchidism.

The disorders are typically distinguished clinically by the presence of growth restriction in IMAGe syndrome and molecularly by the following findings in males with X-linked AHC:

Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (see Cytochrome P450 Oxidoreductase Deficiency) is characterized by growth deficiency, skeletal anomalies, genital abnormalities, and adrenal crises. However, affected individuals typically present with craniosynostosis and often have radiohumeral synostosis, midface retrusion, choanal stenosis or atresia, and multiple joint contractures. Pathogenic variants in POR, the gene encoding NADPH-cytochrome P450 oxidase, have been implicated; inheritance is autosomal recessive.

Mosaic monosomy 7. Several males with features of IMAGe syndrome (IUGR [~-2 SD], adrenal hypoplasia or insufficiency, micropenis with severe hypospadias), and mosaic monosomy 7 have been reported [Le & Kutteh 1996, McDonald et al 2010]. As in familial monosomy 7 syndrome, these individuals may also manifest persistent thrombocytopenia, myelodysplasia, anemia, or neutropenia.

Disorders of Growth

Frequently children with IMAGe syndrome have short stature with a normal head size and normal cognitive development. Other disorders of growth with these features should be considered:

  • Silver-Russell syndrome (SRS) is characterized by intrauterine growth restriction and postnatal growth deficiency. Affected individuals typically display proportionate short stature, normal head circumference, fifth digit clinodactyly, genital abnormalities, hemihypotrophy or limb-length asymmetry, and café au lait spots. Growth velocity is normal in children with SRS.
    Hypomethylation of the paternal imprinting region of 11p15 and maternal uniparental disomy of chromosome 7 have been shown to be causative in a subset of affected individuals. (Abnormalities of 11p15 region resulting in SRS are summarized in Figure 1.) Hence, SRS is genetically heterogeneous, and the diagnosis is therefore primarily based on identification of consistent facial and clinical features that include prenatal and postnatal growth retardation with normal head circumference.
  • 3-M syndrome is characterized by severe pre- and postnatal growth retardation (final height 5-6 SD below the mean), distinctive facial features (including a triangular face, fleshy earlobes, bulbous nose) and normal intelligence. Additional features include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with 3-M syndrome have hypogonadism and, occasionally, hypospadias. 3-M syndrome is caused by biallelic pathogenic variants in one of three genes (CUL7, OBSL1, or CCDC8); inheritance is autosomal recessive.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with IMAGe syndrome, the following evaluations are recommended:

  • Endocrinologic evaluation* to manage adrenal insufficiency, typically including:
    • Serum and urine concentration of electrolytes
    • Serum concentration of glucose and ACTH
    • Assessment of arterial blood gases
    • Consultation with an endocrinologist
    *Of note, individuals who are in shock often have hyponatremia, hyperkalemia, hypoglycemia, acidosis, markedly elevated serum ACTH, and increased urinary excretion of sodium.
  • Urogenital evaluation and consultation with a urologist to consider management of undescended testicles and/or genital surgery
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Adrenal insufficiency. 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.

Episodes of acute adrenal insufficiency require close monitoring of blood pressure, hydration, clinical status, and serum concentration of glucose and electrolytes. Treatment with IV saline, glucose, and cortisol are utilized. If the serum electrolytes do not improve, a mineralocorticoid (fludrocortisone) is added or the dose of cortisol is increased.

Once the acute episode has been managed, replacement doses of glucocorticoids and mineralocorticoids and oral supplements of sodium chloride are given. Dosages must be increased with stress, such as intercurrent illness, surgery, or trauma. Steroid doses need to be managed to enable optimal linear growth without risking an adrenal crisis.

The wearing of a Medic Alert® bracelet is strongly recommended.

Growth hormone (GH) therapy. Although information regarding anticipated adult height in IMAGe syndrome is limited, assessment for GH deficiency should be considered, as one child showed poor GH response to glucagon stimulation [Pedreira et al 2004] and other children with normal GH secretion have demonstrated a response in growth with growth hormone therapy [Lienhardt et al 2002, Kato et al 2014].

Genitourinary abnormalities. Routine surgical management of cryptorchidism and hypospadias by a urologist is indicated.

Males with hypogonadotropic hypogonadism are likely to need increasing doses of testosterone to induce puberty. Long-term adrenal steroid replacement and testosterone replacement should be managed by an experienced endocrinologist.

Orthopedic intervention as necessary for skeletal complications, including scoliosis and hip dysplasia, is appropriate.

Occupational, speech, or physical therapy as needed is appropriate, particularly with the hypotonia that often accompanies the syndrome.

Neurologic evaluation is indicated if developmental delay and/or hypotonia are present.

Prevention of Secondary Complications

Vigilance is required during illnesses and surgeries to prevent adrenal crisis.


Surveillance includes:

  • Frequent evaluations by an endocrinologist for management of adrenal insufficiency and growth hormone therapy;
  • Evaluation by an orthopedist as needed to monitor skeletal complications such as scoliosis, tibial/femoral bowing, or pain associated with the skeletal dysplasia;
  • Neurologic follow up as needed for evaluation of developmental delay and/or hypotonia.

Evaluation of Relatives at Risk

If prenatal testing for IMAGe syndrome has not been performed, it is appropriate to evaluate newborn sibs of a proband to enable prompt diagnosis and management of adrenal insufficiency.

  • Molecular genetic testing is indicated if the CDKN1C pathogenic variant in the family is known;
  • If the CDKN1C pathogenic variant in the family is not known, family members can be screened for serum electrolyte abnormalities, elevated serum ACTH level, and skeletal features of IMAGe syndrome, including short stature and delayed bone age.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Risks to a mother with IMAGe syndrome during pregnancy include potential adrenal insufficiency; risks during delivery include cephalopelvic disproportion.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The CDKN1C pathogenic variant is inherited in an autosomal dominant maternally imprinted manner. In any given affected individual, a pathogenic variant that causes IMAGe syndrome can either be inherited from the mother or arise de novo on the maternally derived CDKN1C allele [Arboleda et al 2012]. See Figure 2.

Figure 2. . Pedigree of a family demonstrating autosomal dominant maternally imprinted inheritance of IMAGe syndrome.

Figure 2.

Pedigree of a family demonstrating autosomal dominant maternally imprinted inheritance of IMAGe syndrome. Individuals labeled T/G are heterozygous for the normal “T” allele and the “G” pathogenic variant (CDKN1C variant (more...)

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s mother:

  • When the mother of the proband has the CDKN1C pathogenic variant, the risk to the sibs is 50%.
  • If the CDKN1C pathogenic variant found in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.

Offspring of a proband

  • Each child of a woman with IMAGe syndrome has a 50% chance of inheriting the CDKN1C pathogenic variant and being affected.
  • Each child of a man with IMAGe syndrome has a 50% chance of inheriting the CDKN1C pathogenic variant but is expected to be unaffected.

Other family members. The risk to other family members depends on the status of the proband's mother: if the proband’s mother has the CDKN1C pathogenic variant, her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a child with IMAGe syndrome.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk (i.e., when the mother has the pathogenic variant) and preimplantation genetic diagnosis are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

IMAGe Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CDKN1C11p15​.4Cyclin-dependent kinase inhibitor 1CCDKN1C databaseCDKN1CCDKN1C

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for IMAGe Syndrome (View All in OMIM)


Molecular Pathogenesis

CDKN1C is located within an imprinted locus at 11p15 (Figure 1). Imprinting is the epigenetic modification of one of the two alleles of a gene which leads to differential expression depending on the parental origin of the allele. In the case of CDKN1C, the maternal allele is preferentially expressed.

See OMIM (130650, 180860) for other phenotypes resulting from dysregulation of the genes shown in Figure 1.

Gene structure. CDKN1C comprises three exons, two of which are coding. The longest transcript variant (NM_000076.2) has 1943 nucleotides, 948 of which are coding. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. All reported CDKN1C pathogenic variants in individuals with IMAGe syndrome are missense variants on the maternally inherited allele that fall within an eight amino-acid region of the PCNA (proliferating cell nuclear antigen)-binding domain (residues 274-279) [Arboleda et al 2012]. To date, 17 individuals from nine unrelated families with molecularly confirmed IMAGe syndrome have been reported: Arboleda et al [2012] reported 11 patients from five families, Hamajima et al [2013] three individuals from one family, Kato et al [2014] two individuals from two families, and Bodian et al [2014] one individual.

Table 2.

CDKN1C Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The longest isoform of CDKN1C, NP_000067.1, is cyclin-dependent kinase inhibitor 1C, also known as p57KIP2, a 316-residue protein that binds to and inhibits G1 phase cyclin-dependent kinases. It functions as a tumor suppressor and negative regulator of cellular proliferation. CDKN1C possesses an amino-terminal cyclin-dependent kinase-binding domain, a central PAPA domain consisting of highly polymorphic proline-alanine repeats, and a carboxy-terminal PCNA domain.

Abnormal gene product. Coimmunoprecipitation studies in HEK293T cells suggest that pathogenic variants associated with IMAGe syndrome disrupt binding to PCNA, which likely is required for ubiquitin-mediated degradation of p57KIP2/CDKN1C [Arboleda et al 2012]. Transient transfection experiments in HEK293T cells showed that IMAGe syndrome-associated CDKN1C pathogenic variants were more stable than wild-type CDKN1C protein, likely because the mutated CDKN1C protein is more resistant to proteasome-mediated degradation [Hamajima et al 2013].

Pathogenic variants in the PCNA-binding site of CDKN1C significantly increase CDKN1C protein stability and prevent cell-cycle progression into the S phase [Borges et al 2015]. Interestingly, p.Arg281Ile, which was associated with IUGR, short stature, and/or early-adulthood-onset diabetes but not adrenal insufficiency, did not abrogate PCNA binding [Kerns et al 2014].

This gain-of-function pathogenic mechanism causing IMAGe syndrome and related conditions is in contrast to loss-of-function pathogenic variants in CDKN1C that cause Beckwith-Wiedemann syndrome (BWS).


Literature Cited

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  • Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, Délot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergadá I, Dell'Angelica EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44:788–92. [PMC free article: PMC3386373] [PubMed: 22634751]
  • Balasubramanian M, Sprigg A, Johnson DS. IMAGe syndrome: Case report with a previously unreported feature and review of published literature. Am J Med Genet A. 2010;152A:3138–42. [PubMed: 21108398]
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Chapter Notes

Revision History

  • 8 September 2016 (ma) Comprehensive update posted live
  • 13 March 2014 (me) Review posted live
  • 11 September 2013 (md) Original submission
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