What is IMAGe Syndrome? Causes, Diagnosis, Genetics and Treatment

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.

Introduction
What is IMAGe syndrome?
Genetics and causes
Clinical features
Diagnosis
Management
Prognosis
Genetic counseling
Current research
Conclusions
References
Further reading

IMAGe syndrome is a rare, maternally inherited CDKN1C-related disorder characterized by prenatal growth restriction, adrenal hypoplasia, skeletal anomalies, and genital abnormalities. Early diagnosis and lifelong adrenal management significantly improve outcomes and guide accurate genetic counseling.

Image Credit: Maxim Ibragimov / Shutterstock.com

Introduction

This article explains IMAGe syndrome, a rare genetic condition caused by mutations in the cyclin-dependent kinase inhibitor 1C (CDKN1C) gene, and presents rare IMAGe-like presentations due to biallelic variants in the DNA polymerase epsilon catalytic subunit A (POLE1), while summarizing key symptoms, diagnosis, adrenal management, prognosis, and genetic counseling.^3,4,8

What is IMAGe syndrome?

Intrauterine growth restriction (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) syndrome is a multisystem disorder. Infants affected with IMAGe syndrome are small for gestational age with dysmorphic features, with some boys presenting with micropenis and cryptorchidism.^1,2

IMAGe syndrome is exceptionally rare, with an unclear prevalence rate. Orphanet classifies IMAGe syndrome as affecting fewer than 1 in 1,000,000 children. As of 2021, GeneReviews identified 31 affected individuals from 19 families worldwide, thus suggesting significant under-ascertainment.⁸

Sporadic cases are most commonly reported; however, familial clusters may occur. Inheritance of IMAGe syndrome is typically autosomal dominant due to gain-of-function variants in CDKN1C on 11p15.^3,5

Importantly, only maternally inherited variants lead to disease, as CDKN1C is expressed from the maternal allele.^3,5 Each child of an affected woman has a 50% risk of being affected, whereas each child of a man with the variant has a 50% chance of inheriting the disease but is generally unaffected, although his daughters can transmit the variant in an affected form to their own children.^3,5

Both sexes are clinically affected in similar numbers. Ongoing case reports of novel CDKN1C variants indicate increasing recognition, as neonatal adrenal insufficiency and intrauterine growth restriction often prompt targeted testing and exome/genome sequencing.^2,8

Genetics and causes

IMAGe syndrome typically arises from pathogenic variants in CDKN1C on chromosome 11p15.5, an imprinted locus where expression is primarily from the maternal allele. Notably, the paternal allele is repressed by the noncoding ribonucleic acid KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1).³

CDKN1C variants cluster in the proliferating cell nuclear antigen (PCNA)-binding domain and act through a gain-of-function mechanism. More specifically, these mutations impair PCNA-dependent, Cullin-RING ubiquitin ligase 4 with Cdc10-dependent transcript 2 (CRL4^Cdt2) mediated polyubiquitination and degradation of CDKN1C, thereby stabilizing the inhibitor and intensifying G1 cell-cycle arrest.^3,5,8

Notably, the same gene exhibits dosage sensitivity across related disorders. Whereas loss-of-function mutations in CDKN1C cause Beckwith-Wiedemann syndrome, gain-of-function mutations in the PCNA motif produce IMAGe syndrome or, rarely, SRS, which is consistent with maternal expression.³

Clinical features

Growth is restricted before birth, with IUGR a defining feature associated with pathogenic variants in CDKN1C and, occasionally, deoxyribonucleic acid (DNA) polymerase epsilon catalytic subunit A (POLE1), which act through a PCNA-related mechanism that constrains somatic growth.^1,2,4,8 Skeletal involvement includes bone disorders/metaphyseal anomalies, particularly longitudinal metaphyseal striations and epiphyseal dysplasia that may evolve over time.^1,2

Primary adrenal hypoplasia leads to adrenal hormone deficiency. Without timely glucocorticoid and mineralocorticoid replacement, patients are vulnerable to adrenal crisis, which is a potentially life-threatening condition that causes salt-wasting and risk of sudden death if left untreated.^4,6

Genital anomalies, such as cryptorchidism, or broader genitourinary anomalies are often reported and are more frequent and severe in males, whereas females may have milder or absent genital findings.^1,2,8 Dysmorphic facial features, hypercalciuria and/or hypercalcemia, craniosynostosis, scoliosis, cleft palate, and rare sensorineural hearing loss have also been observed, with some patients, particularly those with POLE1-related disease, affected by immunodeficiency.^1,2,4,8

Diagnosis

Affected newborns are typically small for gestational age with IUGR and dysmorphic appearances like bifrontal bossing and abnormal ears and nose. Early, potentially life-threatening primary adrenal insufficiency is common, with adrenal crises usually occurring within the first days to weeks of life, although later onset in childhood has been reported.^1,2 Skeletal imaging often identifies delayed bone age, small epiphyses, and striated, irregular metaphyses, with craniosynostosis and osteopenia variably observed.^1,2,8

Because of the frequency and early age at onset of adrenal crises, newborn screening programs are not yet specific for IMAGe syndrome; however, heightened vigilance is warranted. Growth-restricted neonates with dysmorphic features should receive prompt adrenal testing and expedited CDKN1C sequencing, or broader adrenal/growth gene panel or exome/genome sequencing when a single-gene test is not available to enable life-saving steroid replacement and genetic counseling.^3,5,8

Image Credit: SWKStock / Shutterstock.com

Management

Management of IMAGe syndrome is multidisciplinary, involving pediatric endocrinology, orthopedics, nutrition, and developmental services. Primary adrenal insufficiency requires lifelong replacement with physiologic glucocorticoids and mineralocorticoids, in addition to oral sodium chloride during infancy; hydrocortisone is usually given in two to three divided daily doses with fludrocortisone for mineralocorticoid replacement, adjusted according to blood pressure, electrolytes, and plasma renin activity.^4,6

Doses should be optimized to support normal linear growth while maintaining fluid-electrolyte balance. Growth and nutrition are monitored at every visit, as assessment for growth hormone (GH) deficiency can guide GH therapy in selected cases.^6,7,1,2

Orthopedic follow-up manages skeletal complications such as scoliosis and hip dysplasia, with physical/occupational therapy prescribed as needed. Annual endocrine surveillance includes adrenal function, blood pressure, and monitoring for hypercalciuria/nephrocalcinosis, whereas urologic care addresses cryptorchidism or hypospadias in males.^6,7 Patient and caregiver education on sick-day rules, perioperative “stress-dose” steroids, emergency injectable hydrocortisone, and anesthetic planning is essential to prevent adrenal crises during illness, surgery, or dental procedures.^6,7

Prognosis

Primary adrenal insufficiency in IMAGe syndrome may arise during the neonatal period or later. Patients with IMAGe syndrome typically require ongoing glucocorticoid and mineralocorticoid replacement with stress dosing for illness, surgery, or anesthesia.^1,2,6

Treatment improves pigmentation and energy; however, linear growth may remain poor, and growth hormone deficiency or suboptimal GH secretion can coexist.^1,2 Developmental outcomes are mixed, with intellect often normal despite delayed motor milestones reflecting orthopedic complications.

Long-term outcome also depends on associated complications such as hypercalciuria, skeletal deformities, and, in POLE1-related cases, susceptibility to infections due to variable immunodeficiency.^4,8 Speech can improve after endocrine and ear care, including management of any associated hearing loss.² Multidisciplinary follow-up supports best outcomes and informed genetic counseling.¹

Genetic counseling

Since CDKN1C is maternally expressed, affected individuals typically inherit the variant from an affected mother. Paternal transmission usually does not cause disease; however, germline mosaicism and de novo variants occur.^3,5,8

Recurrence risk is up to 50% with maternal transmission and low, but not zero, after a de novo case. Males who carry a CDKN1C variant are usually clinically unaffected but can have affected grandchildren through their daughters because only the maternal allele is expressed in offspring.^3,5 Reproductive guidance includes carrier testing of relatives, preimplantation genetic testing (PGT-M), prenatal diagnosis through chorionic villus sampling or amniocentesis, and early neonatal planning.⁸

Current research

IMAGe syndrome is classified as a CDKN1C-related disorder, as mutations in the PCNA-binding domain of CDKN1C cause the phenotype and distinguish it from other syndromic adrenal hypoplasias.^3,5 Case reports and small series describe recurrent features like prenatal growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies; relative macrocephaly and hypercalciuria are variably reported in IMAGe syndrome and may help to distinguish it from overlapping entities.^1,2,8

MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital anomalies, enteropathy) arises from sterile alpha motif domain-containing 9 (SAMD9) variants, which typically cause frequent, severe infections and chronic diarrhea with enteropathy.⁹ Thus, careful phenotyping and CDKN1C sequencing are recommended in suspected families to avoid misclassification as MIRAGE, and SAMD9 analysis should be considered when recurrent infections, enteropathy, or bone marrow failure are prominent.^8,9

Conclusions

IMAGe syndrome is a rare CDKN1C-related disorder characterized by prenatal growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, with rare overlapping cases due to POLE1 variants.^1,2,4,8 Diagnosis of IMAGe syndrome is based on clinical recognition, radiology, and molecular confirmation of pathogenic variants in CDKN1C, and in selected cases, POLE1.^3-5,8

Patient outcomes improve with early, lifelong glucocorticoid and mineralocorticoid replacement, stress-dose education, and coordinated orthopedic and developmental care.^1,6 Genetic counseling should address a 50% recurrence risk with maternal transmission and offer options such as carrier testing, prenatal diagnosis, and preimplantation testing.^3,5,8

References

1. Pedreira, C. C., Savarirayan, R., & Zacharin, M. R. (2004). IMAGe syndrome: a complex disorder affecting growth, adrenal and gonadal function, and skeletal development. The Journal of Pediatrics 144(2); 274-277. DOI: 10.1016/j.jpeds.2003.09.052. https://www.sciencedirect.com/science/article/abs/pii/S002234760300742X
2. Balasubramanian, M., Sprigg, A., & Johnson, D. S. (2010). IMAGe syndrome: case report with a previously unreported feature and review of published literature. American Journal of Medical Genetics 152(12); 3138-3142. DOI: 10.1002/ajmg.a.33716. https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.33716
3. Eggermann, T., Binder, G., Brioude, F., et al. (2014). CDKN1C mutations: two sides of the same coin. Trends in Molecular Medicine 20(11); 614-622. DOI: 10.1016/j.molmed.2014.09.001. https://www.sciencedirect.com/science/article/abs/pii/S1471491414001385
4. Pignatti, E., & Flück, C. E. (2021). Adrenal cortex development and related disorders leading to adrenal insufficiency. Molecular and Cellular Endocrinology 527. DOI: 10.1016/j.mce.2021.111206. https://www.sciencedirect.com/science/article/pii/S0303720721000502
5. Arboleda, V. A., Lee, H., Parnaik, R., et al. (2012). Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nature Genetics 44(7); 788-792. DOI: 10.1038/ng.2275. https://www.nature.com/articles/ng.2275
6. Khan, U., & Lakhani, O. J. (2017). Management of primary adrenal insufficiency: Review of current clinical practice in a developed and a developing country. Indian Journal of Endocrinology and Metabolism 21(5); 781-783. DOI: 10.4103/ijem.IJEM_193_17. https://journals.lww.com/indjem/fulltext/2017/21050/management_of_primary_adrenal_insufficiency_.27.aspx
7. Lindemeyer, R. G., Rashewsky, S. E., Louie, P. J., & Schleelein, L. (2014). Anesthetic and dental management of a child with IMAGe syndrome. Anesthesia Progress 61(4); 165-168. DOI: 10.2344/0003-3006-61.4.165. https://anesthesiaprogress.kglmeridian.com/view/journals/anpr/61/4/article-p165.xml
8. Dalili, S., Hoseini Nouri, S.A., Sharifi, A., et al. (2025). An Intronic Variant in CDKN1C Gene Causing IMAGe Syndrome in an Iranian Girl. Molecular Genetics & Genomic Medicine 13(11). DOI: 10.1002/mgg3.70154. https://onlinelibrary.wiley.com/doi/10.1002/mgg3.70154
9. Kim, Y. M., Seo, G. H., Kim, G. H., et al. (2018). A case of an infant suspected as IMAGE syndrome who were finally diagnosed with MIRAGE syndrome by targeted Mendelian exome sequencing. BMC Medical Genetics 19(1). DOI: 10.1186/s12881-018-0546-4. https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-018-0546-4

Further Reading

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Last Updated: Dec 11, 2025