Summary
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 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).
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) [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 that associated with 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 radiographsNote: 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 >1000 pg/mL [normal: 10-60 pg/mL])
- 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 a heterozygous CDKN1C pathogenic variant in the PCNA (proliferating cell nuclear antigen)-binding domain of the maternally expressed allele identified by molecular genetic testing (see Table 1). Identification of a heterozygous CDKN1C variant of uncertain significance does not establish or rule out the diagnosis of this disorder.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
When the clinical, radiographic, and laboratory findings suggest the diagnosis of IMAGe syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel (see Option 1).
Option 1
Single-gene testing. Sequence analysis of CDKN1C is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. To date, 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 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.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by growth deficiency and adrenal hypoplasia, comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
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Table 1.
Molecular Genetic Testing Used in IMAGe Syndrome
Clinical Characteristics
Clinical Description
Thirty-one individuals reported from 19 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, Bolomiti et al 2021, Çamtosun et al 2021]. Of these 31 individuals, 19 from eleven unrelated families have had the diagnosis confirmed molecularly [Arboleda et al 2012, Hamajima et al 2013, Bolomiti et al 2021]. Of the twelve individuals 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 31 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.
It is likely that the spectrum and natural history of IMAGe syndrome will be refined as more affected individuals are identified.
Onset. 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 occipitofrontal circumference (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 individuals.
Skeletal. All affected individuals have had some skeletal abnormality with the most common manifestations being 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 pg/mL), 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 the 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]. Hypercalciuria, soft tissue calcification, and renal calculi were noted in one individual [Authors, unpublished observation].
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 31 individuals reported with IMAGe syndrome 22 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 age 26 years.
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 31 individuals with IMAGe syndrome, head imaging was reported for seven (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 age one year. 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 common features include cleft palate or cleft uvula, craniosynostosis, short palpebral fissures, smooth philtrum, and microglossia.
- One individual has been reported with rhabdomyosarcoma [Bolomiti et al 2021].
- 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 hypercalciuria. While hypercalcemia may be a feature of IMAGe syndrome, it may also 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.
Penetrance
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].
Nomenclature
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.
Prevalence
The prevalence of IMAGe syndrome is currently unknown. A total of 31 affected individuals from 19 families have been reported to date.
Genetically Related (Allelic) Disorders
CDKN1C is located in the chromosome 11p15 imprinting clusters (see Figure 1) where abnormal methylation and complex rearrangements can result in other, genetically related disorders (see also Molecular Genetics).
Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder, is associated with loss-of-function pathogenic variants including nonsense and truncating variants as well as missense variants outside the proliferating cell nuclear antigen (PCNA)-binding domain of CDKN1C. Dysregulation of the imprinting domain(s) and chromosome rearrangements of this region are also a cause of BWS and Silver-Russell syndrome (SRS).For details see Molecular Genetics and Soejima & Higashimoto [2013].
Three families comprising 13 individuals with SRS caused by CDKN1C pathogenic variants without detectable adrenal insufficiency have been reported. In these families, either a CDKN1C p.Arg279Leu or p.Arg279Ser variant segregates with the SRS phenotype. Although the variant occurs in the same residue as the IMAGe-causing p.Arg279Pro variant and mildly stabilizes the protein, the p.Arg279Leu variant has no significant effect on cell cycle progression [Brioude et al 2013, Sabir et al 2019, Binder et al 2020]. These families reflect the overlap of SRS and IMAGe syndrome phenotypes.
A mixed phenotype involving features of both BWS and IMAGe syndrome as well as developmental delay and microcephaly was reported in one individual with a novel multiple base-pair pathogenic variant that results in tissue-specific frameshifting [Berland et al 2022].
Kerns et al [2014] reported a family in which intrauterine growth restriction, short stature, and/or early-adulthood-onset diabetes was found in 20 members, none of whom demonstrated adrenal insufficiency. They identified a CDKN1C variant (c.842G>T;p.Arg281Ile) that cosegregated with the phenotype.
Differential Diagnosis
Adrenal Insufficiency
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Table 2.
Disorders with Adrenal Insufficiency in the Differential Diagnosis of IMAGe Syndrome
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with IMAGe syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
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Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with IMAGe Syndrome
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. Steroid dosages must be increased with stress, such as that associated with intercurrent illness, surgery, or trauma. Steroid doses need to be managed to enable optimal linear growth without risking an adrenal crisis.
Vigilance for proactive medical management and early recognition of adrenal insufficiency is required during illnesses and surgeries to prevent 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 in those with hypotonia and developmental delays is appropriate.
Surveillance
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Table 5.
Recommended Surveillance for Individuals with IMAGe Syndrome
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
Pregnant women with IMAGe syndrome are at increased risk for adrenal insufficiency and should be followed by an endocrinologist. Risks during delivery include cephalopelvic disproportion.
Therapies Under Investigation
Search ClinicalTrials.gov 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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.
Risk to Family Members
Parents of a proband
- In many families with molecularly confirmed IMAGe syndrome, the mother is heterozygous for the CDKN1C pathogenic variant identified in the proband.
- In many families, the pathogenic CDKN1C variant was inherited from an unaffected mother [Arboleda et al 2012, Hamajima et al 2013].
- In at least two other families, two women with IMAGe syndrome and a known CDKN1C pathogenic variant have had children (one of these children also had IMAGe syndrome) [Authors, unpublished observation].
- CDKN1C molecular genetic testing is recommended for the mother of the proband to confirm her genetic status and to allow reliable recurrence risk counseling.
- If the pathogenic variant identified in the proband is not identified in the mother and parental identity testing has confirmed biological maternity, the following possibilities should be considered:
- The proband has a de novo pathogenic variant.
- The proband inherited a pathogenic variant from a mother with germline (or somatic and germline) mosaicism. Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
- The father of an affected child with IMAGe syndrome caused by a pathogenic CDKN1C variant will not have the disorder nor will he be heterozygous for the CDKN1C pathogenic variant; therefore, he does not require further evaluation/testing.
Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s mother:
- If the mother of the proband has the CDKN1C pathogenic variant, the risk to the sibs of inheriting the CDKN1C pathogenic variant and being affected with IMAGe syndrome 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 theoretic 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).
Prenatal Testing and Preimplantation Genetic Testing
Once the CDKN1C 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 testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
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.
- MedlinePlus
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 Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table A.
IMAGe Syndrome: Genes and Databases
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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 and 180860 for other phenotypes resulting from dysregulation of the genes shown in Figure 1.
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.
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].
Mechanism of disease causation. Gain of function. 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 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).
CDKN1C-specific laboratory technical considerations. 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].
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Table 6.
Notable CDKN1C Pathogenic Variants
Chapter Notes
Author History
James Bennett, MD, PhD; Seattle Children’s Hospital (2014-2021)
Matthew A Deardorff, MD, PhD (2014-present)
Samantha A Schrier Vergano, MD (2014-present)
Revision History
- 5 August 2021 (sw) Comprehensive update posted live
- 8 September 2016 (ma) Comprehensive update posted live
- 13 March 2014 (me) Review posted live
- 11 September 2013 (md) Original submission
References
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Initial Posting: March 13, 2014; Last Update: August 5, 2021.
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Schrier Vergano SA, Deardorff MA. IMAGe Syndrome. 2014 Mar 13 [Updated 2021 Aug 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.