IMAGe and IMAGe-I Syndromes

Literature and regulatory information updated: 31 October 2026.

IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies) caused by gain-of-function variants on the maternal allele of CDKN1C, and IMAGe-I syndrome (IMAGe with variable immunodeficiency) caused by biallelic hypomorphic variants in POLE; includes the allelic disorders of each gene that overlap with the diagnosis (CDKN1C-related IUGR–short stature–diabetes syndrome and POLE-related FILS syndrome)

0. Initial Reference Table

1. Introduction

1.1 Definition and scope

The name IMAGe summarises four clinical components: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital anomalies, the last described only in males [1]. The same set of signs now has two distinct genetic causes, with different modes of transmission and risks: IMAGe syndrome proper, with autosomal dominant inheritance and imprinting, caused by gain-of-function variants on the maternal allele of CDKN1C, and IMAGe-I syndrome, with autosomal recessive inheritance, caused by biallelic POLE variants that reduce the amount of DNA polymerase ε and add an immunodeficiency of variable severity to the picture [2–4]. Orphanet keeps both forms in a single entry, ORPHA:85173, with both inheritance patterns recorded [8].

This article treats the two forms as a syndromic class of primary adrenal insufficiency with growth restriction of prenatal onset. Because they share the gene and appear in the same differential diagnosis, it also covers the CDKN1C variants that cause growth restriction with young-adult-onset diabetes, without adrenal insufficiency, and FILS syndrome (facial dysmorphism, immunodeficiency, livedo and short stature), a recessive allelic form of POLE [16, 17]. Disorders due to CDKN1C loss of function (Beckwith-Wiedemann syndrome), forms of Silver-Russell syndrome due to CDKN1C variants, X-linked adrenal hypoplasia due to NR0B1 and cancer predisposition due to variants in the POLE proofreading domain are mentioned only where the contrast helps diagnosis.

1.2 Initial clinical description

In 1999, Vilain and colleagues, at the University of California, Los Angeles, described three boys who presented shortly after birth with growth retardation and severe adrenal insufficiency, mild dysmorphic features, bilateral cryptorchidism, small penis and hypogonadotrophic hypogonadism; skeletal studies showed metaphyseal dysplasia in all three and epiphyseal dysplasia in two, and there was hypercalciuria and/or hypercalcaemia, with nephrocalcinosis in one patient and prenatal hepatic and splenic calcifications in another [18]. None had variants in DAX1 (NR0B1) or in steroidogenic factor 1, nor a DAX1 deletion, and creatine kinase and glycerol kinase were normal, which ruled out X-linked adrenal hypoplasia and the Xp21 contiguous gene deletion syndrome [18]. The authors proposed the name “IMAGe association”, used until the molecular basis was identified [1].

In the following years, isolated and familial cases with variable expression accumulated. Lienhardt and colleagues (2002) described four patients from two French families, including the first living woman with the diagnosis, identified at 5 years of age by family screening and with mild adrenal insufficiency since childhood, and proposed autosomal recessive inheritance [19]. Tan and colleagues (2006) reported two Australian sisters with the phenotype and cytomegalic adrenal histology and argued for the same recessive hypothesis [20]. In 2005, Bergadá and colleagues studied a five-generation Argentinian family with four affected children and ten members who had died in the neonatal period with growth restriction and/or hyperpigmentation, presumed to be affected; the disease always passed through the maternal line, even through unaffected women, which led them to propose an autosomal gene subject to imprinting and expressed on maternal transmission [21]. Amano and colleagues (2008) documented that metaphyseal dysplasia is absent at birth and becomes visible at the end of the first year [22].

1.3 Milestones of molecular discovery

In 2012, Arboleda and colleagues genotyped seven affected individuals and one unaffected sibling from the Argentinian family, found a 17.2 Mb region identical by descent on chromosome 11 (LOD score, logarithm of the odds, of 5.4) and, by targeted capture and sequencing, identified in CDKN1C five heterozygous missense variants clustered within six amino acids of the proliferating cell nuclear antigen (PCNA) binding domain, in two members of the family and in four unrelated patients [7]. Analysis of 24 family members showed that only carriers who had received the variant from their mother were affected [7]. Expression of the mutant proteins in Drosophila reduced eye and wing size, unlike the normal protein, which pointed to a gain-of-function mechanism [7]. In 2013, Hamajima and colleagues described a sixth variant in a Japanese sibship and showed that the mutant proteins are more stable than the normal one [23].

Some patients with the phenotype had no CDKN1C variants [24]. In 2018, Logan and colleagues, sequencing the genomes of 48 people with microcephalic primordial dwarfism, found POLE loss-of-function variants in compound heterozygosity with a rare intronic variant shared by all; on extending the analysis to patients with a clinical diagnosis of IMAGe without a CDKN1C variant, they assembled 15 individuals from 12 families, among them the patients previously published by Pedreira (2004) and by Tan (2006), and established POLE as the second gene of the syndrome, with variable immunodeficiency [3, 4]. The Australian sisters who had supported the recessive hypothesis before 2012 therefore had the recessive POLE form [3]. The allelic form FILS had been described in 2012 in a consanguineous French family, with a homozygous POLE splice variant [17, 25].

1.4 Nomenclature

GeneReviews adopted “IMAGe syndrome” after 2012 and replaced intrauterine growth retardation with intrauterine growth restriction [1]. In OMIM, the CDKN1C form has number 614732 and the POLE form number 618336 (IMAGEI); articles published before 2012 cite number 300290 [2, 21, 26]. The CDKN1C molecular literature uses transcript NM_000076.2 and the 316-amino-acid protein numbering (for example, p.Arg279Pro), whereas the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_001122630.2, with shifted numbering; section 2 presents the correspondence [1, 27].

2. Molecular Genetics and Pathophysiology

2.1 CDKN1C: gene, protein and imprinting

CDKN1C lies at 11p15.4, in the centromeric domain (domain 2) of the 11p15.5 region subject to genomic imprinting, that is, the epigenetic modification that makes expression of an allele depend on the parent who transmitted it [1, 5]. Domain 2 includes CDKN1C, KCNQ1 and the non-coding RNA KCNQ1OT1 and is regulated by imprinting centre 2 (IC2), normally methylated on the maternal chromosome and unmethylated on the paternal one; this results in expression of CDKN1C from the maternal allele [1, 28]. The Oxford Desk Reference includes CDKN1C (p57KIP2) in its list of maternally expressed genes and notes that its expression is preferential, not exclusive, from the maternal allele [28, 29].

The longest isoform, NP_000067.1, is the 316-residue p57KIP2 protein, an inhibitor of G1-phase cyclin-dependent kinases that acts as a negative regulator of proliferation and as a tumour suppressor [1]. It has three domains: an N-terminal cyclin-dependent kinase (CDK) binding domain, responsible for cell-cycle inhibition; a central PAPA domain, with highly polymorphic proline-alanine repeats; and a C-terminal PCNA-binding domain [1].

2.2 Gain-of-function mechanism in CDKN1C

All variants described in IMAGe syndrome up to the 2021 review are missense variants on the maternal allele and lie within an eight-amino-acid region of the PCNA-binding domain, between residues 271/274 and 279 (the GeneReviews text gives 274–279, the figure legend 271–279 and the table note nucleotide positions c.814 to c.836 in NM_000076.2) [1]. Arboleda and colleagues showed in HEK293T cells that the p.Phe276Val and p.Lys278Glu proteins no longer bind endogenous PCNA and that the p.Phe276Val protein loses a band of about 63 kDa consistent with monoubiquitination; the mutants retained the ability to arrest the cycle in G0/G1 through the CDK domain and did not alter nuclear transport or binding to α-importin [7]. Hamajima and colleagues confirmed loss of PCNA binding for p.Ile272Ser, p.Asp274Asn and p.Phe276Val and showed that, in the presence of cycloheximide, the mutants remain stable whereas the normal protein is degraded by the proteasome; the binding site of the C8 subunit of the 20S proteasome, defined in CDKN1A, overlaps the PCNA-binding site [23]. GeneReviews summarises the mechanism as gain of function: variants in the PCNA-binding site increase protein stability and prevent progression to S phase [1, 30]. Deletions or duplications of CDKN1C have therefore neither been described nor are expected as a cause of IMAGe [1].

Adrenal specificity is supported by expression data: CDKN1C is more highly expressed in the human adrenal gland at 7–8 weeks post-conception than in brain or muscle, with a maximum in a subset of cells of the developing subcapsular or definitive zone [7]. Patients with Beckwith-Wiedemann syndrome and Cdkn1c-null mice have adrenal hyperplasia, the reverse of the hypoplasia seen in IMAGe [7]. Kato and colleagues interpreted the relative macrocephaly as reflecting biallelic expression of CDKN1C in the fetal brain and attributed the genital anomalies mainly to placental dysfunction [24].

2.3 Inheritance, penetrance and silent transmission

Inheritance is autosomal dominant with imprinting: a variant inherited from the mother, or arising de novo on the maternal allele, causes the disease; the same variant inherited from the father remains silent [1]. In the Argentinian family of 24 people studied, all 7 affected individuals had received the c.826T>G variant from their mother; of the unaffected, 9 had received it from their father and 8 did not carry it [1, 7]. Adrenal insufficiency appeared fully penetrant in that family (7/7 carriers by maternal transmission), although GeneReviews allows for ascertainment bias of probands [1]. A woman who inherited the variant from her father is healthy and transmits the disease to half of her children, which explains disease in children of unaffected mothers [1, 21]. No genotype–phenotype correlations are known in IMAGe [1].

2.4 Spectrum of CDKN1C variants and normalisation

The table brings together the variants of clinical significance for this article. Conversion to the MANE Select transcript (NM_001122630.2) was performed in VariantValidator from GRCh38 genomic coordinates, and ClinVar status was checked on the same day [27, 31]. The historical numbering of Arboleda and OMIM (for example, “825T>G” for p.Phe276Val) is shifted by one nucleotide relative to the current NM_000076.2 numbering (c.826T>G), which VariantValidator confirms [5, 7, 27].

The 11-amino-acid difference between NP_000067.1 and NP_001116102.1 results solely from the reference transcript; a report using MANE numbering (NM_001122630.2:c.803G>C p.(Arg268Pro)) describes the same variant that the literature designates NM_000076.2:c.836G>C p.(Arg279Pro) [27]. The condition name in ClinVar is assigned by the submitter: the p.Asp274Asn variant, described in IMAGe, is recorded for Beckwith-Wiedemann syndrome [31].

2.5 Allelic disorders of CDKN1C

CDKN1C loss-of-function variants — truncating or missense outside the PCNA-binding domain — cause Beckwith-Wiedemann syndrome on maternal transmission, about 5% of sporadic and 40% of familial cases, with a distinctive tumour profile (risk of neuroblastoma) [28, 37, 38]; Smith gives about 10% of sporadic and 40% of familial cases and recommends targeted CDKN1C analysis in familial cases and in patients with cleft palate, posterior fossa anomalies, omphalocele or hypospadias [39]. Three families with 13 individuals with Silver-Russell syndrome and the variants NM_000076.2:c.836G>T p.(Arg279Leu) or c.835C>A p.(Arg279Ser) (MANE NM_001122630.2: p.(Arg268Leu) and p.(Arg268Ser)), without adrenal insufficiency, described by Brioude (2013), Sabir (2019) and Binder (2020), show the overlap between the two forms of growth restriction; according to GeneReviews, the p.Arg279Leu variant slightly stabilises the protein without a significant effect on cycle progression [1, 32, 34, 40, 41]. Kerns and colleagues described in a six-generation Ecuadorian family (15 affected and 26 unaffected individuals genotyped) the variant NM_000076.2:c.842G>T p.(Arg281Ile) (MANE NM_001122630.2:c.809G>T p.(Arg270Ile)), which cosegregates with growth restriction, short stature and young-adult-onset diabetes, with low testicular volume and normal adrenal function; unlike the IMAGe variants, it does not completely abolish PCNA binding [16]. Berland and colleagues studied a Norwegian boy with a mixture of Beckwith-Wiedemann and IMAGe features, developmental delay and microcephaly: the c.822_826delinsGAGCTG variant, inherited from his asymptomatic mother, who had in turn inherited it from her father, mosaic with mild Beckwith-Wiedemann features, generated at least three transcripts through tissue-specific splicing, one truncating and another with IMAGe-type substitutions [35]. Orphanet classifies IUGR–short stature–early adult-onset diabetes syndrome as a separate entity (ORPHA:436144) [42].

2.6 POLE and polymerase ε deficiency

POLE (12q24.33) encodes POLE1, the catalytic subunit of DNA polymerase ε, the main leading-strand polymerase and an essential gene; it has polymerase activity and a 3'→5' proofreading exonuclease [4, 6]. Heterozygous missense variants in the exonuclease domain predispose to adenomas and colorectal carcinoma (polymerase proofreading-associated polyposis, autosomal dominant), whereas biallelic variants that reduce the amount of protein cause the recessive disorders FILS and IMAGe-I [6, 43].

The 15 patients described by Logan shared the intronic variant NM_006231.4:c.1686+32C>G (rs762985435; allele frequency 0.000071) on a common haplotype of about 921 kb, in trans with a different loss-of-function variant in each family or, in one family, with the missense c.3019G>C p.(Ala1007Pro) in the polymerase domain [4]. The intronic variant alters splicing of exon 15, retains 47 bp of intron and creates p.Asn563Valfs*16 at the start of the catalytic domain, but allows some normal splicing; in fibroblasts from two patients, POLE1 was reduced to 5% ± 3% and 11% ± 4% of control, in the soluble and chromatin-bound fractions, with delayed S phase [4]. Nakano and colleagues found in two unrelated Japanese patients another deep intronic variant, c.1226+234G>A, which inserts 309 bp or 106 bp between exons 12 and 13 and which SpliceAI did not predict, in trans with c.711_713del or c.2593T>G p.(Trp865Gly); the mutant proteins, including p.(Ala1007Pro), accumulated in the cytoplasm owing to proteasomal degradation in the nucleus [11]. Mao and colleagues described in three Chinese families the variant c.6747+39_6748-47delinsG, which causes skipping of exon 48 (p.Val2220_Gln2249del), in trans with c.1351C>T p.(Gln451*), c.847dup p.(Leu283Profs*5) or c.2319+65G>A, the last without effect in the minigene assay [9]. The common pattern is the combination of a “leaky” allele, which retains residual activity, with a null allele; the absence of constraint against loss of function (pLI = 0) and the lack of healthy null homozygotes indicate that the disease requires residual activity [11].

The link between the two causes of the syndrome has a probable mechanistic basis: PCNA is loaded with polymerase ε at the start of replication, and in Xenopus degradation of CDKN-type inhibitors depends on PCNA and on polymerase loading; both accumulation of stable p57KIP2 and lack of polymerase ε delay S phase [4]. Logan and colleagues include IMAGe-I in a group of replisome disorders with growth restriction and adrenal failure and/or immunodeficiency, alongside MCM4, POLE2 and GINS1, and close to Meier-Gorlin syndrome [4]. Pole4−/− mice, also deficient in the holoenzyme, show prenatal growth restriction, a small brain, marked lymphopenia and more lymphomas, with replication stress due to fewer active replication origins [4]; according to Mao, loss of p53 restores lymphocytes in these mice [9].

2.7 Allelic disorders of POLE and cancer risk

FILS syndrome, described in a consanguineous French family with 11 affected individuals, results from the homozygous variant c.4444+3A>G, which causes 90% of transcripts to lose exon 34; T cells, B cells, chondrocytes and osteoblasts show deficient proliferation and G1→S transition [17, 25]. Roberts and colleagues described two siblings with c.1686+32C>G in trans with p.(Glu709*) (published designation; the single substitution that produces it is NM_006231.4:c.2125G>T, VCV000649184 in ClinVar) and concluded that the recessive partial loss-of-function forms make up a continuum of short stature and facial dysmorphism, with or without immunodeficiency [43]. IMAGe-I variants do not lie in the exonuclease domain, and heterozygous carriers cannot be presumed to have the colorectal predisposition of the dominant form; even so, the c.1686+32C>G variant appears in ClinVar associated by submitters with cancer predisposition syndromes, which calls for care in interpreting oncology panels [4, 31]. The lymphomas observed in patients with IMAGe-I (section 3) were, in the cases studied, of low mutational burden, which points to replication stress rather than to proofreading failure [11].

3. Clinical Spectrum and Manifestations by System

3.1 Sources and limits of the data

Clinical data on CDKN1C-related IMAGe syndrome come from case series and isolated reports, brought together by GeneReviews as 31 individuals from 19 families up to 2021, of whom 19 (from 11 families) had molecular confirmation; the remaining 12 had significant clinical overlap without a confirmatory test [1]. Of this group, 22 were male, a probable ascertainment bias, because genital anomalies occur only in boys [1]. In the light of the 2018 data, some patients with an older clinical diagnosis belong to the POLE form (this is the case for the patients of Pedreira and Tan) [3]. The IMAGe-I form has 15 patients in the original description and 19 in the 2026 review, to which 3 new ones are added [4, 9]. All figures that follow refer to published patients, mostly treated, and not to population cohorts.

3.2 CDKN1C-related IMAGe syndrome

Presentation and age. Of the 23 patients with information on age at presentation, 1 was identified prenatally, 13 at birth, 4 in the first month, 3 between 1 month and 1 year, 1 at 5 years and 1 at 15 years [1].

Growth. All newborns had IUGR, with birth weight between −2 and −4 SD and length between −1.8 and −4.5 SD; of the 9 with data at birth, 5 had a normal head circumference and 4 between −2 and −3 SD [1]. Short stature persists (height −2.7 to −6.5 SD) with poor weight gain (weight −2 to −7 SD); of the 9 with longitudinal data, postnatal head circumference was normal in 7 and below −2 SD in 2 [1]. Kato described relative macrocephaly in three Japanese patients [24]. Growth hormone (GH) deficiency is variable: one child had a poor GH response to glucagon (Pedreira's patient, later reclassified as IMAGe-I), and others with normal secretion grew with GH [1, 3].

Skeleton. All patients had some skeletal anomaly, mainly delayed bone age and short stature; metaphyseal and epiphyseal dysplasia of the long bones is frequent, with striated metaphyses and gracile diaphyses [1]. Variation with age is marked: metaphyseal changes are absent in the neonatal period, appear in early childhood and may be mild or go unnoticed; most children have radiological signs by 5 years [1, 12]. The bone dysplasia atlas describes, in the newborn, delayed epiphyseal ossification, ovoid vertebral bodies, narrow greater sciatic notches, widening of the triradiate cartilage, the pubic symphysis and the ischiopubic synchondrosis, slender tubular bones and generalised osteoporosis; later, mild metaphyseal cupping, irregularity and longitudinal striations, mainly in the distal femur [12]. Less frequent are progressive, severe scoliosis with onset before 5 years, short first metatarsals, hallux valgus and hip dysplasia; one patient had fractures of the humerus and tibia at birth [1]. Balasubramanian proposed that epiphyseal dysplasia, consistently described, should count as a criterion when metaphyseal dysplasia is not clear [2]. Absence of metaphyseal dysplasia does not exclude the diagnosis: three siblings with p.Ile272Ser did not have it at 1, 3 and 5 years [23].

Adrenal. Adrenal insufficiency appears universal in published patients, with the ascertainment bias already mentioned [1]. Adrenal crisis, with hyponatraemia, hyperkalaemia and hypotension that may be fatal, appears in the first month, typically in the first week; adrenocorticotrophic hormone (ACTH) often reaches values above 1000 pg/mL (normal 10–60 pg/mL) and causes intense hyperpigmentation [1]. Some patients have milder insufficiency, with poor weight gain and recurrent vomiting: a child with vomiting since birth associated with mild infections was diagnosed only at 5 years, after the diagnosis of her younger brother [1, 19]. One patient had hypoaldosteronism without glucocorticoid deficiency, and Kato described a familial glucocorticoid deficiency-like phenotype [1, 24]. Late forms may be precipitated by illness or surgery [1]. On imaging, the adrenal glands are small or of normal size, unlike congenital adrenal hyperplasia; in the three Japanese siblings they were not visible, but in an Iranian girl with an intronic CDKN1C variant ultrasound showed enlarged adrenals [1, 23, 36].

Genitalia and gonads. Genital anomalies are almost universal in males and have not been described in females: cryptorchidism (usually bilateral), micropenis, hypospadias and chordee [1]. The atlas and the original description mention hypogonadotrophic hypogonadism in boys [12, 18]; Kato, by contrast, found apparently normal pituitary–gonadal function, and Lienhardt described normal puberty in the boys and in the girl [19, 24]. Hydronephrosis has been described, but most have a normal renal ultrasound [1]. Two affected women have had children; no affected man with offspring is known [1].

Neurology and development. Of the 16 patients with information, 15 had normal cognitive development, the oldest being 26 years old [1]. Hypotonia was described in 6 and was absent in 4; part of the reported delay is motor and secondary to hypotonia [1]. One patient with facial and distal muscle atrophy had non-specific myopathic changes on biopsy, and the 7 available brain imaging studies were normal [1]. A boy with bilateral sensorineural deafness was described by Balasubramanian [2].

Face. Frontal bossing, a depressed or broad nasal bridge and small, low-set ears, noticeable at around 1 year; the profile resembles the triangular face of Silver-Russell syndrome and changes over time; micrognathia or retrognathia are frequent; less frequent are cleft palate or bifid uvula, craniosynostosis, short palpebral fissures, smooth philtrum and microglossia [1, 12].

Calcium and kidney. Eight of 16 patients with information had variable hypercalcaemia of uncertain cause, sometimes with soft-tissue calcifications; several had hypercalciuria with nephrocalcinosis, and there were prenatal hepatic and splenic calcifications [1, 18]. GeneReviews notes that hypercalcaemia may be secondary to the sodium chloride supplementation used in treatment [1].

Neoplasms. One patient had rhabdomyosarcoma; it is the only tumour described in the CDKN1C form [1, 36].

3.3 POLE-related IMAGe-I syndrome

Growth and face. In Logan's 15 patients, birth weight was −3.0 ± 0.8 SD and postnatal height −8.1 ± 2.4 SD (range −5.5 to −11.27 SD), with head circumference −5.4 ± 1.5 SD (range −2.7 to −8.03 SD), giving relative macrocephaly on a background of absolute microcephaly [3, 4]. The face is recognisable: micrognathia, crowded teeth, a long thin nose, a short broad neck and small, low-set, posteriorly rotated ears [4]. One adult patient measured 1.19 m and weighed 24.9 kg at 22 years [10].

Adrenal and pituitary. Twelve of 15 patients had adrenal insufficiency [4]; in the 2026 review, the frequency was 79% (15/19) [9]. Age at onset varies: crisis at 4 years in an American patient, insufficiency manifesting at 4.5 years in Pedreira's Australian boy, cortisol started at 22 years in a Japanese patient with pigmentation and raised ACTH, and ACTH of 998 pg/mL at birth in a Chinese boy [3, 9–11]. Two of Logan's patients had hypopituitarism, one Japanese patient had GH deficiency with atrophy of the adenohypophysis and one adult woman had secondary hypothyroidism and hypogonadism with a small pituitary [4, 10, 11].

Genitalia. All of Logan's male patients had bilateral cryptorchidism and/or hypospadias (89% of males in the 2026 review), but the two Chinese boys had normal genitalia [4, 9].

Immunity. The immunodeficiency is variable: 11 of Logan's 15 patients had lymphocyte subset deficiencies and/or IgM hypogammaglobulinaemia, 3 had natural killer (NK) cell deficiency, and 5 had recurrent respiratory infections [3, 4]. One patient had cytomegalovirus (CMV) pneumonitis followed by Epstein-Barr virus (EBV)-associated haemophagocytic lymphohistiocytosis, treated with allogeneic bone marrow transplantation; his sister, with the same genotype, died at 22 months of herpes simplex virus infection [4]. Two patients and the affected sister of a proband died of respiratory infections [3]. In the 2026 review, immunodeficiency was present in 68% (13/19) [9]. The Japanese patients had NK cytopenia (73/µL and 89/µL) with NK cytotoxicity of 6% and 5% (reference 18–40%), and the first had seven admissions for severe infections by 2 years of age [11]. In a Chinese boy, IgG was 3.15 g/L at 3 years (reference 4.82–12 g/L), with a CD4/CD8 ratio of 0.76 and NK cells at 1.8%, but at 19 years immunoglobulins and lymphocyte subsets were normal [9].

Neoplasms. Logan described a T-cell lymphoma at 11 years and Hodgkin lymphoma at 28 years; Nakano, two EBV-associated diffuse large B-cell lymphomas, at 2 and 17 years [4, 11]. The 2026 review counts neoplasms, mainly lymphomas, in 4 patients with IMAGe-I [9].

Other systems. Osteopenia and developmental dysplasia of the hip are frequent; café-au-lait macules occur in about one third [4]. Logan also recorded seizures, gastrostomy in 7 patients, eczema, absent or hypoplastic patella, scoliosis, atrial septal defect, hypercalcaemia in infancy and IgM paraproteinaemia [4]. The Chinese series added epilepsy, macrocytic anaemia with dyserythropoiesis, neonatal jaundice, reticulate hyperpigmentation, enamel hypoplasia and developmental delay, with intellectual disability in one patient; one of the Japanese patients had an intelligence quotient of 33 at 9 years [9, 11]. One woman developed type 2 diabetes at 22 years, with normal insulin and C-peptide and negative autoantibodies [10].

3.4 Comparison of the recessive POLE forms

FILS syndrome is characterised by a high forehead and malar hypoplasia, livedo from birth with later telangiectasias, variable short stature with relative macrocephaly, painful bone dysplasia in some and immunodeficiency with respiratory infections and meningitis, low IgM and IgG2, absent antibodies to polysaccharides and reduced memory B and naive T lymphocytes; no neoplasms were observed in the original family [17, 45]. By 2026, 17 patients from four families had been described; a 2026 letter added an Israeli boy of Arab origin, born to consanguineous parents, homozygous for c.4444+3A>G, with a small face with malar and mandibular hypoplasia, low birth weight (2700 g, 3rd centile), bicuspid aortic valve, dysplasia of both hips, bilateral calcaneovalgus foot, pectus carinatum, severe anaemia at 5 weeks, growth deficit of −4 standard deviations at 12 months and severe infections from 14 months [44].

3.5 Allelic CDKN1C forms without adrenal insufficiency

In the Ecuadorian family with NM_000076.2:c.842G>T p.(Arg281Ile) (MANE NM_001122630.2:c.809G>T p.(Arg270Ile)), affected individuals had IUGR, short stature, low testicular volume and young-adult-onset diabetes, with normal adrenal function and no metaphyseal dysplasia [16]. In the families with Silver-Russell syndrome due to variants at residue 279, there was no detectable adrenal insufficiency [1]. The Norwegian boy with the c.822_826delinsGAGCTG variant had Beckwith-Wiedemann and IMAGe features, developmental delay and microcephaly [35].

4. Clinical Recognition and Warning Signs

4.1 When to suspect

GeneReviews considers the association of IUGR with adrenal hypoplasia congenita, with or without a family history of IMAGe, highly suggestive of the diagnosis [1]. In the neonatal period, the combination of a small-for-gestational-age newborn, skin hyperpigmentation, hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia and, in boys, bilateral cryptorchidism, micropenis or hypospadias should prompt measurement of cortisol and ACTH before the first dose of hydrocortisone, without delaying it [1, 13]. The British NICE (National Institute for Health and Care Excellence) guideline recommends considering adrenal insufficiency in babies and children with differences of sex development, such as ambiguous genitalia or bilateral undescended testes [46]. The Endocrine Society recommends testing for primary adrenal insufficiency in acutely ill patients with volume depletion, hypotension, hyponatraemia, hyperkalaemia, fever, abdominal pain, hyperpigmentation or, especially in children, hypoglycaemia [13].

Outside the neonatal period, warning signs are poor weight gain with recurrent vomiting during trivial infections, progressive hyperpigmentation, short stature of prenatal onset with delayed bone age and adrenal crisis precipitated by illness or surgery [1]. Mild adrenal insufficiency may go undiagnosed for years, as in the girl identified at 5 years after her brother's diagnosis [19]. In a Turkish cohort of 73 children with primary adrenal insufficiency, the most frequent presenting symptoms of causes other than congenital adrenal hyperplasia were hyperpigmentation (81.8%), symptoms of hypoglycaemia (40.9%) and weakness or tiredness (31.8%) [47].

4.2 Clues to the POLE form

Suspicion of IMAGe-I increases when, in addition to the adrenal picture, there is extreme short stature (mean height −8.1 SD), microcephaly with relative macrocephaly, a face with a long thin nose, small posteriorly rotated ears, crowded teeth and a short broad neck, severe or recurrent infections, lymphopenia, IgM hypogammaglobulinaemia, NK-cell deficiency, café-au-lait macules, macrocytic anaemia, epilepsy or EBV-associated lymphoma [4, 9, 11]. Consanguinity is not required: the Japanese and Chinese families described were non-consanguineous, and in all series the disease resulted from compound heterozygosity [4, 9, 11].

4.3 Clues to the CDKN1C form

A history of transmission through the maternal line, with unaffected women having affected children, or of fetal losses with growth restriction and skeletal dysplasia in the mother's family, points to CDKN1C [21, 36]. The Argentinian family included ten children who died in the neonatal period with IUGR and/or hyperpigmentation, presumed to be affected, and the authors warned of the possibility of the disease in the children of unaffected women related to patients [21].

4.4 Emergency signs

The bone dysplasia atlas stresses that unawareness of the endocrine symptoms may result in unexpected death, because early diagnosis depends on clinical and endocrinological findings and not on radiology [12]. Vomiting, feeding refusal, lethargy, hypotension, hypoglycaemic seizure or altered consciousness in a child with the diagnosis, or in a newborn sibling not yet tested, require immediate parenteral hydrocortisone [13, 48]. In IMAGe-I, fever, opportunistic infection, cytopenias or progressive lymphadenopathy require immunological and haematological assessment, given the risk of severe infection and of lymphoma described [4, 11].

4.5 Newborn screening

The sources consulted do not describe specific newborn screening for IMAGe or IMAGe-I. In the reported cases, 17-hydroxyprogesterone was normal in the newborn with MIRAGE mimicking IMAGe and low in the girl with an intronic CDKN1C variant, so a normal congenital adrenal hyperplasia screening result does not rule out adrenal hypoplasia [36, 49]. In newborn siblings of a patient, GeneReviews recommends molecular testing when the familial variant is known and, otherwise, monitoring of electrolytes, ACTH and skeletal signs [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no formal clinical criteria for IMAGe syndrome [1]. The diagnosis is established in a proband with suggestive findings and/or a heterozygous pathogenic CDKN1C variant in the PCNA-binding domain of the maternal allele; identification of a variant of uncertain significance (VUS) in CDKN1C neither establishes nor excludes the diagnosis [1]. For IMAGe-I, OMIM defines the disease by compound heterozygosity for POLE variants with the IMAGe phenotype and variable immunodeficiency; there are no published criteria either, and the 2026 review notes the lack of a consensus diagnostic criterion [3, 9].

Suggestive findings fall into three groups [1]. The clinical ones are IUGR, postnatal growth failure with variable GH deficiency, adrenal hypoplasia congenita (often as a spontaneous crisis between the first week and the first month) and, in boys, unilateral or bilateral cryptorchidism, hypospadias, micropenis and chordee. The imaging ones are metaphyseal and/or epiphyseal dysplasia, mesomelia, osteopenia, gracile long bones and delayed bone age, which are age-dependent and may be absent, and small or normal-sized adrenal glands. The laboratory ones are hyponatraemia, hyperkalaemia and raised ACTH during crisis, with exclusion of other causes of adrenal insufficiency.

5.2 Biochemical confirmation of adrenal insufficiency

The Endocrine Society recommends, when the clinical condition allows, the intravenous corticotropin (synthetic ACTH) stimulation test at standard dose — 250 µg in adults and children aged 2 years or over, 125 µg under 2 years and 15 µg/kg in infants — with cortisol at 30 or 60 minutes; a peak below 500 nmol/L (18 µg/dL), assay-dependent, indicates adrenal insufficiency (weak recommendation, low evidence) [13]. If the test is not possible, a morning cortisol below 140 nmol/L (5 µg/dL) with raised ACTH serves as a preliminary test; an ACTH more than twice the upper reference limit with confirmed cortisol deficiency is consistent with primary insufficiency; renin and aldosterone should be measured simultaneously to assess mineralocorticoid deficiency [13]. In crisis, intravenous hydrocortisone should not wait for results (strong recommendation) [13]. NICE recommends, under 1 year of age, measuring cortisol at any time of day and seeking paediatric endocrinology advice for interpretation [46]. In the initial evaluation of a patient with IMAGe, GeneReviews includes serum and urine electrolytes with calcium, glucose, ACTH, blood gases, assessment of growth and, in boys, of hypogonadotrophic hypogonadism; in shock, hyponatraemia, hyperkalaemia, hypoglycaemia, acidosis, very high ACTH and increased urinary sodium excretion are usually found [1]. Small or normal adrenal glands help to separate hypoplasia from congenital adrenal hyperplasia, in which the glands are enlarged, and a 17-hydroxyprogesterone above 1000 ng/dL is diagnostic of 21-hydroxylase deficiency [1, 13]; the exception described is the Iranian girl with enlarged adrenals on ultrasound [36].

5.3 Genetic testing

When clinical, radiological and laboratory findings suggest IMAGe, GeneReviews proposes sequencing of CDKN1C, which detects small insertions and deletions and missense, nonsense and splicing variants, or a multigene panel including CDKN1C and the genes in the differential diagnosis; when the phenotype is indistinguishable from other disorders with growth failure and adrenal hypoplasia, exome (or genome) sequencing is the best option [1]. Sequencing identified the variant in 11 of 11 families with a molecular diagnosis; deletion/duplication analysis is of no use for IMAGe, because the mechanism is gain of function [1]. CDKN1C has a GC content of 80% or more, which reduced coverage in the capture sequencing of the original study and required Sanger confirmation; insufficient coverage of this region is a possible cause of a false negative [7].

When IMAGe-I is suspected, the strategy must allow for deep intronic variants. The c.1686+32C>G variant was identified by genome sequencing, after it was found that the probands' loss-of-function variants were present in unaffected parents; the c.1226+234G>A variant was found only after RT-PCR of all exon–exon junctions, because the exome did not show it and SpliceAI did not predict it; and one Chinese patient had two negative exomes until family reanalysis [4, 9, 11]. Therefore, in an IMAGe phenotype with normal CDKN1C, and especially if there is immunodeficiency or a single POLE loss-of-function variant, the second allele must be sought by genome sequencing, by targeted analysis of known intronic variants or by RNA study [4, 11]. The Chinese series did not include a search for copy number variants (CNV) by multiplex ligation-dependent probe amplification (MLPA), which the authors point out as a limitation [9].

5.4 Practical algorithm

5.5 Report and interpretation

A report should state the gene, the transcript with version, the variant in Human Genome Variation Society (HGVS) nomenclature, zygosity, the pathogenicity class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, in which “pathogenic” and “likely pathogenic” have the same clinical value [37], and, for CDKN1C, the parental origin when studied. For CDKN1C, the laboratory may use the MANE transcript (NM_001122630.2) or the historical one (NM_000076.2); correspondence with the literature requires stating both (for example, NM_001122630.2:c.803G>C p.(Arg268Pro), corresponding to NM_000076.2:c.836G>C p.(Arg279Pro)) [27]. Variants in the PCNA-binding domain may be associated with IMAGe, Silver-Russell syndrome or the phenotype with diabetes, so the residue affected and the phenotype must be read together [1, 16]. Segregation helps classification: in the Iranian family, the presence of the intronic variant in the healthy mother and maternal grandfather is consistent with the parent-of-origin effect, but without an RNA study the authors kept the VUS classification [36]. In IMAGe-I, ClinVar records the c.1686+32C>G variant as pathogenic or likely pathogenic, but also associated with cancer predisposition, and the FILS variant c.4444+3A>G with conflicting classifications [31].

5.6 Prenatal and preimplantation diagnosis

Once the CDKN1C variant has been identified in an affected relative, prenatal testing (pregnancy of a carrier woman) and preimplantation genetic testing are possible [1]. The GeneReviews entry on Silver-Russell syndrome allows the same for maternally transmitted CDKN1C variants, by chorionic villus sampling or amniocentesis [40]. IUGR may be detected on prenatal ultrasound (at 28 weeks in a patient with IMAGe-I), and the Iranian girl had severe asymmetric IUGR, short limbs and mild polyhydramnios [9, 36]. Ultrasound findings are not specific and do not allow diagnosis without a molecular test.

6. Differential Diagnosis

6.1 Comparative table

6.2 Main differentials

Congenital adrenal hyperplasia is much more frequent than IMAGe and shares adrenal crisis in infancy; it is distinguished by the rarity of IUGR, by virilisation of girls (in IMAGe girls have normal genitalia and boys are undervirilised) and by hypertrophic adrenals [1]. In a Turkish cohort of 73 children with primary adrenal insufficiency, 69.9% had congenital adrenal hyperplasia and only one had IMAGe [47].

X-linked adrenal hypoplasia due to NR0B1 overlaps in the newborn boy (adrenal insufficiency, small glands, cryptorchidism), but does not have IUGR, metaphyseal dysplasia or the IMAGe facies [1]. The original description of IMAGe excluded it precisely by DAX1 sequencing and by normal creatine kinase and glycerol kinase, markers of the Xp21 contiguous deletion [18].

MIRAGE syndrome is the closest differential in the neonatal period. The bone dysplasia atlas notes that onset is similar to that of IMAGe and that recurrent infections, chronic diarrhoea and haematological changes appear with age [12]. A Korean boy born at 31 weeks weighing 882 g, with micropenis, bilateral cryptorchidism and adrenal crisis on day 3, suspected of IMAGe and without a CDKN1C variant, had a SAMD9 variant and died of recurrent infection at 4 months [49]. In the British series of primary adrenal insufficiency of unknown cause, the five children with SAMD9 variants were all born preterm and with fetal growth restriction [54]. Before 2012, some cases labelled IMAGe had monosomy 7 or myelodysplasia, conditions now consistent with MIRAGE, and GeneReviews considers them different from the 31 typical cases [1].

Between CDKN1C-related IMAGe and IMAGe-I, the distinguishing elements are the immunodeficiency, the microcephaly with much shorter stature and the distinctive face of the POLE form, and the maternal transmission of the CDKN1C form [1, 4]. Among the recessive POLE disorders, FILS is distinguished by constant livedo and the absence of described adrenal insufficiency, but the data of Roberts and of the 2026 review point to a continuum, and the same c.1686+32C>G variant appears in both descriptions [9, 43].

Silver-Russell syndrome shares IUGR, frontal bossing, relatively preserved head circumference and genital anomalies, and variants at residue 279 of CDKN1C can themselves cause Silver-Russell without adrenal insufficiency [1, 40]. Body asymmetry, clinodactyly, café-au-lait macules and absence of adrenal insufficiency point to Silver-Russell [1].

7. Treatments and Risk Management Strategies

7.1 Principles

There is no mechanism-directed treatment for either form: GeneReviews refers to ClinicalTrials.gov and the EU clinical trials register, and a search of ClinicalTrials.gov in October 2026 found no interventional trials for these disorders [1, 55]. Management of adrenal insufficiency in IMAGe follows that of other causes and should be supervised by endocrinology; it includes glucocorticoid and mineralocorticoid replacement, oral sodium chloride, increased doses in situations of stress and fine dose adjustment to allow linear growth without risk of crisis [1]. There are no specific guidelines for IMAGe or IMAGe-I; the doses that follow come from the Endocrine Society primary adrenal insufficiency guidelines (2016), the British Society for Paediatric Endocrinology and Diabetes (BSPED, 2023) consensus, NICE guideline NG243 (2024) and the Endo-ERN recommendations (2021), and their application to IMAGe is an extrapolation from an analogous condition treated with the same drugs [13, 46, 48, 56]. The labels (INFARMED SmPC, EMA EPAR and FDA label) are cited for comparison; where they diverge, the guideline is the reference.

7.2 Adrenal crisis

GeneReviews describes the management of acute adrenal insufficiency as monitoring of blood pressure, hydration, clinical status, glucose and electrolytes, with intravenous normal saline, glucose and cortisol; if electrolytes do not improve, fludrocortisone is added or cortisol increased [1]. The table brings together the guideline doses.

If hydrocortisone is unavailable, the Endocrine Society suggests prednisolone, and dexamethasone only as a last resort [13]. Before the first dose in a first presentation, electrolytes, glucose, ACTH, cortisol, renin, aldosterone, 17-hydroxyprogesterone and a urinary steroid profile should be drawn if possible [48]. Fludrocortisone does not need adjustment in illness or crisis, because hydrocortisone at stress doses has sufficient mineralocorticoid effect; it is resumed when the patient tolerates the oral route [48].

7.3 Chronic glucocorticoid replacement

In children, doses above 8 mg/m²/day may already exceed physiological production and compromise growth; in congenital adrenal hyperplasia, doses above 20 mg/m²/day in infants and 15–17 mg/m²/day in adolescents have been associated with loss of final height [13]. The dose increases with body surface area and is adjusted to weight gain, growth velocity and signs of insufficiency (tiredness, anorexia, hyperpigmentation) [13]. This balance is the same one GeneReviews asks for in IMAGe: optimal linear growth without crisis [1]. Endo-ERN notes that, until paediatric granules became available, low doses were obtained by crushing 10 mg (Europe) or 5 mg (USA) tablets or with compounded capsules, up to 25% of which did not meet European Pharmacopoeia criteria [56]. Enzyme-inducing drugs require the glucocorticoid to be increased [46]. In an adult woman with IMAGe-I and type 2 diabetes, the hydrocortisone dose was physiological (8.4 mg/m²/day), and the authors recommend caution with glucocorticoid doses in this population [10]. The prednisone used in a Chinese girl with IMAGe-I (10 mg/m²/day) departs from the recommendation to avoid synthetic glucocorticoids during growth [9, 13].

7.4 Mineralocorticoid and sodium chloride

The Endocrine Society recommends fludrocortisone in all patients with confirmed aldosterone deficiency, without salt restriction (strong recommendation): starting dose of 50–100 µg in adults and 100 µg/day in children; for infants, it recommends sodium chloride supplements in the neonatal period and up to 12 months [13]. The guideline text specifies 1–2 g/day of sodium chloride (17–34 mmol/day), divided across several feeds, especially in the first 6 months, owing to mineralocorticoid resistance of the immature kidney and the low sodium content of milk; the fludrocortisone dose in children is not adjusted to body surface area and often remains the same throughout life; in adults and adolescents, 0.05–0.2 mg/day is usually sufficient [13]. NICE gives a starting dose of 50–200 µg/day under 1 year, 50–300 µg/day between 1 and 16 years and 50 µg titrated up to 300 µg over 16 years (doses above 300 µg/day off-label in the UK in 2024), and sodium chloride under specialist guidance when hyponatraemia persists at the maximum dose [46]. Monitoring is clinical (salt craving, postural hypotension, oedema), with electrolytes and renin; hypertension requires reduction of fludrocortisone and, if it persists, addition of an antihypertensive while maintaining it [13, 46].

The Portuguese SmPC of Inocort® 0.1 mg (fludrocortisone acetate) gives 0.05–0.3 mg/day in adult Addison's disease and, in the paediatric population, half a tablet (0.05 mg) to one tablet (0.1 mg) per day, adjusted to age, weight and severity [62]. The US label gives 0.1 mg/day (0.1 mg three times a week to 0.2 mg/day) and reduction to 0.05 mg/day if transient hypertension develops [63]. The guideline's reference paediatric dose (100 µg/day) coincides with the upper limit of the Portuguese SmPC.

In IMAGe, sodium chloride has a particular feature: GeneReviews allows that the hypercalcaemia described in half of the patients may be partly secondary to salt supplementation, so serum and urinary calcium should be monitored during treatment [1].

7.5 Intercurrent illness, procedures and education

Sick day rules differ between societies. The Endocrine Society advises doubling the replacement dose with fever above 38 °C and tripling it above 39 °C until recovery (usually 2 to 3 days), with more electrolyte-containing fluids; if the patient cannot tolerate the oral route, IM or subcutaneous (SC) hydrocortisone (adult 100 mg; child 50 mg/m² or, as an estimate, 25 mg in infants, 50 mg at school age and 100 mg in adolescents) [13]. The BSPED consensus prefers, in children, a total dose of about 30 mg/m²/day in 4 equal doses throughout the illness (maximum 200 mg/24 h, the same as for adults, in older adolescents), to avoid long intervals with a short half-life hydrocortisone, and considers 1 or 2 sick day doses for vaccinations [48]. The Alkindi® SmPC and the Portuguese hydrocortisone SmPC advise doubling or tripling the dose (or multiplying it 2 to 4 times) and switching to the parenteral route in gastroenteritis with vomiting, high fever or extensive physical stress [58, 61]. Repeated vomiting, drowsiness, major trauma or shock require an immediate IM injection and urgent transfer [48].

The BSPED consensus advises neonatal dosing (4 mg/kg) for infants who are very small for gestational age or have poor weight gain, which applies to many infants with IMAGe; the child should be first on the operating list, with no more than 6 hours of fasting without sodium- and glucose-containing fluids [48]. Sedation and anaesthesia in a patient with micrognathia require planning; there is a report of anaesthesia and dental treatment in a child diagnosed with IMAGe, but GeneReviews considers that diagnosis uncertain [1, 64].

All patients should have an emergency card and medical identification, an injectable hydrocortisone kit for self-administration or administration by relatives, and education on dose adjustment (ungraded Endocrine Society recommendations) [13]. GeneReviews strongly recommends a medical alert bracelet [1]. Endo-ERN has harmonised a bilingual European emergency card (national language and English) and recommends a medication reserve for at least 3 months [56]. The NICE paediatric emergency kit includes glucose gel under 16 years and a needle and 1 mL syringe suitable for infants [46].

7.6 Growth and growth hormone

Information on adult height is scarce; GeneReviews recommends assessing GH deficiency, because one child had a poor GH response to glucagon (a patient later reclassified as IMAGe-I) and others, with normal secretion, responded to treatment [1, 3]. In the three Japanese siblings with p.Ile272Ser, without GH deficiency, GH started at 11, 8 and 6 years was accompanied by heights of −5.4, −3.4 and −2.3 SD (from −5.5, −4.5 and −3.7 SD) [23]. In the Iranian girl with GH deficiency, treatment did not significantly improve height, and the authors urged caution because of the association of CDKN1C with tumours in Beckwith-Wiedemann syndrome, although in IMAGe only one rhabdomyosarcoma has been described [36]. A Japanese patient with IMAGe-I and documented GH deficiency received GH [11].

Somatropin has no specific indication for IMAGe. In the Portuguese SmPC of Genotropin® (somatropin), the paediatric indications that may apply are GH deficiency (0.025–0.035 mg/kg/day or 0.7–1.0 mg/m²/day, subcutaneously) and children born small for gestational age, with birth weight and/or length below −2 SD, height below −2.5 SD, parent-adjusted height below −1 SD and no catch-up growth by 4 years of age or later (0.035 mg/kg/day or 1.0 mg/m²/day) [65]. Outside these criteria, use is off-label. The same SmPC recommends measuring fasting insulin and blood glucose before starting and annually in children born small for gestational age, warns of the risk of second neoplasms in cancer survivors and of slipped capital femoral epiphysis in endocrine disorders, and lists leukaemia in children among adverse reactions of unknown frequency [65]. In IMAGe-I, the described lymphoma risk and the diabetes of one adult patient make these warnings relevant; the sources consulted do not describe the safety of GH in this form [4, 10].

7.7 Gonads, urinary tract, skeleton and development

Cryptorchidism and hypospadias are treated surgically by paediatric urology [1]. Boys with hypogonadotrophic hypogonadism need increasing doses of testosterone to induce puberty, and long-term adrenal and androgen replacement should be managed by experienced endocrinology [1]. In an adult woman with IMAGe-I, secondary hypogonadism was treated with transdermal estradiol and secondary hypothyroidism with levothyroxine [10]. Scoliosis and hip dysplasia may require orthopaedics, and hypotonia and developmental delays benefit from occupational therapy, speech therapy and physiotherapy [1].

7.8 Immunodeficiency and neoplasms in IMAGe-I

There is no published protocol for the immunodeficiency of IMAGe-I; the sources describe individual management. One patient with CMV pneumonitis and EBV-associated haemophagocytic lymphohistiocytosis received allogeneic bone marrow transplantation [4]. A Japanese patient with EBV-positive diffuse large B-cell lymphoma, resistant to rituximab-containing chemotherapy, received umbilical cord blood transplantation and was relapse-free more than 7 years later; another patient achieved complete remission with rituximab-containing chemotherapy, maintained for more than 13 years [11]. In FILS syndrome, an allelic disorder of POLE, a letter of August 2026 describes the first published use of replacement immunoglobulin: a boy homozygous for NM_006231.4:c.4444+3A>G had septic shock at 24 months, with oral mucositis, oropharyngeal candidiasis, hepatitis, pancytopenia and pneumonia, with herpes simplex virus type 1 and Candida albicans isolated from oral secretions and Pseudomonas aeruginosa from blood; he recovered with broad-spectrum antibiotics, aciclovir, fluconazole, granulocyte colony-stimulating factor (G-CSF) and intravenous normal human immunoglobulin (IVIG) [44]. Prophylaxis with aciclovir, fluconazole and amoxicillin was then started, but between 24 and 28 months there were five admissions for pneumonia with intravenous antibiotics; chest computed tomography (CT) at 27 months showed bronchiectasis and monthly IVIG was started, after which, over 30 months of follow-up, there were no new admissions and febrile episodes were treated at home [44]. The letter does not state the dose, the product or the IgG levels achieved [44]. The authors considered haematopoietic cell transplantation, but stress that the POLE-associated defect of DNA replication and proofreading requires conditioning regimens chosen to limit hypersensitivity to radiation and chemotherapy and the risk of secondary neoplasm; none of the previous FILS patients with c.4444+3A>G had received IVIG or transplantation [44]. This is a single patient, without comparison, and the authors' conclusion that IVIG is safe and effective in POLE deficiency with severe immune dysfunction rests on that case [44]. Immunological assessment and decisions on prophylaxis, replacement immunoglobulin and vaccines lie with clinical immunology, with ERN RITA as the reference network [15].

7.9 Agents to avoid and precautions

The Endocrine Society advises against dexamethasone in primary adrenal insufficiency and, in children, against long-acting synthetic glucocorticoids (prednisolone, dexamethasone) [13]. Enzyme inducers increase glucocorticoid requirements [46]. NICE advises against hydrocortisone by subcutaneous pump or by the IM or IV route for daily replacement [46]. Sodium chloride should be accompanied by calcium monitoring, given the hypercalcaemia and nephrocalcinosis described in IMAGe [1]. In IMAGe-I, the sources do not define vaccine restrictions; the decision depends on immunological assessment.

7.10 Pregnancy, perioperative care and transition

Pregnant women with IMAGe are at increased risk of adrenal insufficiency and should be followed by endocrinology; delivery carries a risk of cephalopelvic disproportion [1]. The Endocrine Society suggests at least one review per trimester, an increase in hydrocortisone especially in the 3rd trimester, hydrocortisone rather than cortisone acetate, prednisolone or prednisone, never dexamethasone (which is not inactivated by the placenta; strong recommendation), and a stress dose during the active phase of labour, equal to that for major surgery (strong recommendation) [13]. Perioperative doses are in section 7.5. At transition to adult care, the woman with IMAGe-I described by Horvit had, at 22 years, type 2 diabetes, secondary hypothyroidism and hypogonadism and primary amenorrhoea, which shows the need for a comprehensive endocrine reassessment at that stage [10]; NICE includes its own recommendations on transition [46].

7.11 Regulation

No medicine has an approved indication for IMAGe or IMAGe-I syndrome as such.

7.12 Clinical trials and recent developments

There are no trials to compare, and the management described (GH, haematopoietic cell transplantation, immunoglobulin) rests on individual reports, without a control group or systematic follow-up. The absence of registered trials does not prove that there are no ongoing studies outside those registries.

In the 6 to 12 months before 31 October 2026, the following were published: a series of three Chinese patients with IMAGe-I and a review of 19 cases of IMAGe-I and 17 of FILS (published article, case series) [9]; the first intronic CDKN1C variant associated with IMAGe, classified as a VUS (case report) [36]; a case of type 2 diabetes in IMAGe-I (case report) [10]; and a letter with a case of FILS treated with monthly IVIG, with no admissions in 30 months (case report) [44]. There were no regulatory applications, opinions or authorisations specific to these disorders.

7.13 Divergences between guidelines

The guidelines agree on hydrocortisone as the glucocorticoid of choice in children, on the physiological dose of about 8 mg/m²/day (8–10 mg/m²/day in NICE and the Alkindi® labels), on fludrocortisone without salt restriction and on sodium chloride in infants [13, 46, 58]. They differ in sick day rules (doubling or tripling according to fever, in the Endocrine Society, versus about 30 mg/m²/day in 4 doses, in BSPED) and in how the emergency dose is calculated (by body surface area versus by age or weight) [13, 48]. The paediatric dosing in the Portuguese SmPC of Hidrocortisona Roussel (12–20 mg/m²/day) is higher than that of all the guidelines [60]. The strength of the Endocrine Society recommendations for children is weak (low evidence) for the hydrocortisone dose and strong (low evidence) for fludrocortisone and sodium chloride in infants [13].

8. Reproductive Options and Family Counselling

8.1 CDKN1C form: inheritance with imprinting

The CDKN1C variant that causes IMAGe is transmitted in an autosomal dominant manner, but only maternal transmission produces disease [1]. The table summarises the risks.

In many families, the variant was inherited from an unaffected mother, who received it from her father [1, 23]. At least two women with IMAGe and a known variant have had children, one of them affected [1]. In the Iranian family, the variant was present in the healthy mother and maternal grandfather, and the mother had had two fetal losses (a fetal death at 38 weeks and a termination after an ultrasound showing severe skeletal dysplasia), with recurrent miscarriages also in a maternal aunt [36]. In the Argentinian family, ten children in the maternal line died in the neonatal period with a suggestive picture [21]. Testing of the mother is always recommended for reliable counselling; if the variant is not in maternal blood, it may be a de novo variant or maternal mosaicism, and blood does not detect all somatic mosaicism or germline-only mosaicism [1]. The p.Asp274Asn variant arose de novo in a Japanese patient [24]. A case of paternal mosaicism with transmission through the asymptomatic daughter has been described in the mixed Beckwith-Wiedemann/IMAGe phenotype [35].

8.2 POLE form: autosomal recessive inheritance

IMAGe-I and FILS are autosomal recessive [3, 17]. The parents of a patient are, as a rule, unaffected heterozygotes and, by Mendelian segregation, each sibling has a 25% probability of being affected, 50% of being a carrier and 25% of inheriting neither variant. In the published families, including the non-consanguineous Japanese and Chinese ones, the disease resulted from the combination of a hypomorphic intronic variant (frequently c.1686+32C>G, on a shared haplotype) with a loss-of-function variant [4, 9, 11]. Both alleles should be studied in the parents to confirm phase. Logan and colleagues stress that the cancer predisposition of the dominant exonuclease-domain variants cannot be presumed in heterozygotes [4]; even so, the c.1686+32C>G variant appears in hereditary cancer panels and is also recorded in ClinVar for cancer predisposition, which may lead to misinterpretation in a healthy carrier [31, 43]. The dominant cancer predisposition of POLE belongs to the spectrum of polymerase proofreading-associated polyposis.

8.3 Cascade testing and at-risk newborns

In the CDKN1C form, molecular testing of newborn siblings is indicated when the familial variant is known, so as to treat adrenal insufficiency before a crisis; if it is not known, electrolytes, ACTH and skeletal signs (short stature and delayed bone age) are screened [1]. The extended maternal family should be informed, because unaffected carrier women transmit the disease [21]. In the POLE form, testing of siblings is relevant because of the risk of immunodeficiency and of late-onset adrenal insufficiency [4, 10].

8.4 Prenatal and preimplantation diagnosis

With the familial CDKN1C variant identified, prenatal testing in a pregnancy of a carrier woman and preimplantation genetic testing are possible [1, 40]. For POLE, with both variants known, the reasoning is the same as for any recessive disorder with identified variants; the sources consulted do not describe cases of prenatal diagnosis of IMAGe-I. The ideal time for discussion is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. When there is no molecular diagnosis, GeneReviews recommends banking the proband's DNA [1]. Views on prenatal testing vary among professionals and families, and the decision is personal [1].

8.5 Fertility and counselling of minors

Two women with IMAGe have had children, and no offspring of affected men are known [1]. Testing of at-risk asymptomatic minors has direct medical benefit in these disorders, because it allows adrenal crisis to be prevented; the Endocrine Society recommends genetic counselling for all patients with adrenal insufficiency of monogenic cause [1, 13].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

The prevalence of IMAGe syndrome is unknown; GeneReviews counted 31 individuals from 19 families up to 2021, 19 of them from 11 families with molecular confirmation [1]. Orphanet assigns entry ORPHA:85173 to the prevalence class below 1/1,000,000 and records 28 cases or families, based on the 2014 edition of GeneReviews [8]. For IMAGe-I, the 2018 description had 15 patients from 12 families, a 2025 review counted 17 patients (including its own) and the 2026 review counted 19, to which it added 3 [4, 9, 10]. These counts are of published cases and not population rates. FILS has 17 published patients according to the same review, and Orphanet records 11 cases and a class below 1/1,000,000 [9, 45].

Cohort studies of primary adrenal insufficiency give an idea of the relative weight of IMAGe. In the British series of 155 children and young people with primary adrenal insufficiency of unknown cause, studied between 1993 and 2018 in three research centres, with prior exclusion of congenital hyperplasia and autoimmune and metabolic causes, 103 (66.5%) received a genetic diagnosis and 2 (1.3%) had CDKN1C variants (NM_000076.2:c.820G>A p.(Asp274Asn) and c.832A>G p.(Lys278Glu), historical numbering); 5 (3.2%) had SAMD9 variants and none had MCM4 variants [54]. The series is referral-based and does not allow incidence to be estimated [54]. In a Turkish centre, 1 of 73 children with primary adrenal insufficiency over 21 years had IMAGe [47]. In Europe, the prevalence of primary and secondary adrenal insufficiency is estimated at 20–50/100,000 [56].

9.2 Geographical distribution and recurrent variants

The cases of CDKN1C-related or clinically diagnosed IMAGe cited in the sources come from centres in Argentina, France, Japan, Korea, the United Kingdom, Turkey, Poland and Iran [19, 21, 23, 24, 36, 47, 54, 66, 67]; the Australian patients of Pedreira and Tan, previously classified as IMAGe, had the POLE form [3]. The p.Asp274Asn variant recurred in the United Kingdom and Japan [24, 54]. The p.(Arg281Ile) variant with diabetes was described in a family from Ecuador, and the mixed Beckwith-Wiedemann/IMAGe phenotype in Norway [16, 35].

IMAGe-I has a different distribution. Logan's 12 families were from the United Kingdom, Ireland (four families), Australia, the USA and Canada, and all shared the c.1686+32C>G variant on a common haplotype of about 921 kb, which indicates a shared ancestral allele [4]. The two Japanese patients shared another intronic variant (c.1226+234G>A, frequency 0.0001 in the Japanese ToMMo database), and the three Chinese patients a third (NM_006231.4:c.6747+39_6748-47delinsG) [9, 11]. FILS has been described in a French family and in a Palestinian girl with the same homozygous variant [17].

The sources consulted contain no data from Portugal or Brazil on IMAGe or IMAGe-I.

9.3 Special populations

The sex distribution of published cases (22 of 31 male) reflects ascertainment through genital anomalies, which are absent in girls; in girls, diagnosis may be later [1, 19]. For infants who are very small for gestational age or have poor weight gain, a frequent situation in these disorders, the BSPED consensus advises neonatal weight-based hydrocortisone dosing for surgery [48].

9.4 Networks and patient organisations

Endo-ERN, the European reference network for rare endocrine conditions, has an adrenal area and brings together the European recommendations on crisis prevention [14, 56]. ERN RITA covers primary immunodeficiencies, relevant to IMAGe-I [15]. The European steroid emergency card is available at adrenals.eu [56]. GeneReviews lists MedlinePlus and parent support organisations [1]. The Potentials Foundation, which supports families with primordial dwarfism, collaborated in Logan's study [4]. The Primordial Dwarfism Registry (NCT04569149) collects data on these patients [55].

10. Illustrative Clinical Case

10.1 Three siblings with CDKN1C-related IMAGe

In 2013, Hamajima and colleagues described in PLoS One three Japanese siblings born to non-consanguineous parents of normal stature (father 182 cm, mother 158 cm), with no other affected relatives [23]. All three were born with severe IUGR: the first, a boy, at 37 weeks and 1 day, weighing 1374 g (−3.6 SD) and measuring 38 cm (−4.5 SD); his sister, at 39 weeks and 1 day, weighing 1772 g (−3.8 SD) and measuring 41 cm (−4.4 SD); the youngest brother, at 37 weeks and 4 days, weighing 1808 g (−2.8 SD) and measuring 41 cm (−3.2 SD) [23]. They had frontal bossing and a flat nasal bridge, and both boys had hypospadias and bilateral cryptorchidism [23].

Adrenal insufficiency manifested at 4 months, 1 month and 8 days, respectively, with recurrent acute episodes; the adrenal glands were not visible on imaging [23]. Hydrocortisone was started at 5 years in the eldest, at 2 years in the sister and at 8 days in the youngest [23]. There was no GH deficiency, but severe growth failure led to GH treatment, started at 11, 8 and 6 years with heights of −5.5, −4.5 and −3.7 SD; at 15, 12 and 10 years, heights were 128.4 cm (−5.4 SD), 130.2 cm (−3.4 SD) and 121.6 cm (−2.3 SD) [23]. None had metaphyseal dysplasia on radiographs taken from 5, 3 and 1 year of age; all three had slender proximal phalanges, the eldest had Perthes disease at 13 years and the youngest a cervical anomaly [23]. Psychomotor development was normal (the girl had a vocal tic); the eldest had pubic hair at 11 years and the girl menarche at 12 [23].

Exome sequencing of the three siblings and their parents found in all the siblings and in the unaffected mother the heterozygous variant NM_000076.2:c.815T>G p.(Ile272Ser), which corresponds on the MANE transcript to NM_001122630.2:c.782T>G p.(Ile261Ser); the father was homozygous for the normal allele [23, 27]. The mutant protein lost PCNA binding and was resistant to proteasomal degradation [23]. The figures of the article, consulted from the PubMed Central page, show the structure of CDKN1C with the position of the variants (https://pmc.ncbi.nlm.nih.gov/articles/PMC3787065/figure/pone-0075137-g001/), the pedigree with the unaffected carrier mother (https://pmc.ncbi.nlm.nih.gov/articles/PMC3787065/figure/pone-0075137-g002/) and the protein stability assay (https://pmc.ncbi.nlm.nih.gov/articles/PMC3787065/figure/pone-0075137-g005/) [23].

The case illustrates four points: transmission through a healthy mother, variation in age at onset of adrenal insufficiency between siblings with the same variant, the possible absence of metaphyseal dysplasia and the variable response to GH. GH was used without documented deficiency, which corresponds to use outside the GH deficiency indication; the European somatropin label allows the indication of a child born small for gestational age when the criteria are met [23, 65].

10.2 Contrast: an adult woman with IMAGe-I

A 22-year-old American woman with IMAGe-I, carrying c.6518_6519del (paternal) and c.1686+32C>G (maternal), had primary adrenal insufficiency since a crisis at 4 years, immunodeficiency, delayed puberty with primary amenorrhoea and severe skeletal dysplasia, measuring 1.19 m and weighing 24.9 kg [10]. She was taking hydrocortisone 2.5 mg three times daily (8.4 mg/m²/day) and fludrocortisone 0.05 mg/day when, at transition to adult endocrinology, a blood glucose of 339 mg/dL and glycated haemoglobin of 8.9% were found, with normal insulin and C-peptide and negative autoantibodies [10]. Secondary hypothyroidism and hypogonadism were also diagnosed, with a small pituitary on magnetic resonance imaging [10]. Treated initially with prandial insulin and then with sitagliptin and metformin, she had a glycated haemoglobin of 6.2% at 10 months and 7.2% at 3 years [10]. The genotype matches that of one of the patients in Logan's series [4]. The facial photographs and growth charts of Logan's series are at https://pmc.ncbi.nlm.nih.gov/articles/PMC6288413/figure/fig2/ [4].

10.3 Contrast: combined immunodeficiency in FILS syndrome

A boy of Arab origin, born in Israel to consanguineous parents, with two healthy siblings and two cousins who had died in early childhood of fulminant febrile illness about 25 years earlier, was born at 41 weeks by emergency caesarean section, weighing 2700 g (3rd centile) with normal length and head circumference [44]. He had a small “bird-like” face, malar and mandibular hypoplasia, prominent nasal bridge and columella, downslanting palpebral fissures, a small mouth and low-set, posteriorly rotated ears, a bicuspid aortic valve, dysplasia of both hips, bilateral calcaneovalgus foot and pectus carinatum [44]. At 5 weeks he was admitted to intensive care for vomiting, diarrhoea and poor weight gain, with normocytic anaemia of 6.5 g/dL without signs of haemolysis, 6.9% atypical lymphocytes and thrombocytosis of 903 × 10⁹/L, and was transfused [44]. At 12 months weight and height were 4 standard deviations below the median, with head circumference at the 3rd centile; at 14 months he had severe varicella after vaccination, with a chronic granulomatous-looking rash on the limbs for 16 months, whose biopsy showed a lymphohistiocytic infiltrate of CD3+ T lymphocytes, without granulomas and with CD163+ and CD68+ histiocytes negative for langerin and S100 [44]. At 24 months he developed septic shock with mucositis, oropharyngeal candidiasis, hepatitis, pancytopenia and right lower lobe pneumonia, due to herpes simplex virus type 1, Candida albicans and Pseudomonas aeruginosa [44]. Absolute B, T and NK lymphocyte counts were normal; memory B lymphocytes (CD19+CD27+) were 0.5% (reference 6–15%) and CD8+CD45RO+ memory T cells 7% (reference 12.8–18%); IgA was raised (700 mg/dL; reference 27–300), with normal total IgG, IgM and IgE and IgG3 of 300 mg/dL (reference 17.3–67.7); antibody titres against tetanus, measles and mumps were low 9 months after IVIG; proliferation to mitogens was normal but absent to Bordetella pertussis and Candida antigens; T-cell receptor excision circles (TREC) on newborn screening were at the lower limit (16 and 18 copies/µL; normal above 12), and the repeat test at 24 months and the T-cell receptor repertoire were normal [44]. Chromosomal microarray was normal and trio exome (GRCh37) showed NM_006231.4:c.4444+3A>G in the homozygous state (NC_000012.11:g.133219990T>C; NC_000012.12:g.132643404T>C), inherited from both parents, with a frequency of 0.003% in gnomAD; the authors classified it as likely pathogenic (PM2, PP3, PP5), whereas ClinVar records conflicting classifications (VCV000041417, evaluation of August 2025) [27, 31, 44]. After antimicrobial prophylaxis, five admissions for pneumonia and bronchiectasis on CT at 27 months led to monthly IVIG, followed by 30 months without admissions [44]. Elsewhere the letter describes the neonatal anaemia as non-immune haemolytic, which diverges from the absence of signs of haemolysis mentioned in the report, and it does not describe livedo; figure 1 of the article shows the face at 36 months and the skin lesions at 27 and 36 months [44]. IVIG and prophylaxis are here an individual management decision in syndromic combined immunodeficiency, and not a recommendation for all patients with POLE variants.

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

In CDKN1C-related IMAGe syndrome, prognosis depends mainly on recognition of adrenal insufficiency: the bone dysplasia atlas stresses that unawareness of the endocrine symptoms may cause unexpected death, and in the Argentinian family ten children in the maternal line died in the neonatal period with a suggestive picture before the genetic basis was discovered [12, 21]. With treatment, cognitive development was normal in 15 of 16 patients with information, and the oldest described was 26 years old [1]. Short stature persists (−2.7 to −6.5 SD), and data on adult height are scarce; Lienhardt described short adult stature and normal puberty [1, 19]. In the general population with primary adrenal insufficiency, crises occur at 5–10 per 100 patient-years, with mortality of about 0.5 per 100 patient-years; in a prospective study of adults, the rate was 8.3 crises per 100 patient-years, which corresponds to about one in every 12 patients per year [13, 56]. In paediatric congenital adrenal hyperplasia, the rate was 5.8 crises per 100 patient-years, with respiratory infections as the main trigger in early childhood, and the median time between first symptoms and crisis was 1 day [13]. These figures have not been measured in IMAGe.

In IMAGe-I, prognosis also depends on the immunodeficiency and the risk of neoplasm. In the original series, the sister of a proband, with the same genotype, died at 22 months of herpes simplex virus infection, and OMIM states that two patients and the affected sister of a proband died of respiratory infections; one of Tan's Australian sisters died suddenly at 3 months after a respiratory infection [3, 4]. The 2026 review counts two deaths from infection in IMAGe-I and one in FILS [9]. Lymphomas have been described at 2, 11, 17 and 28 years [4, 11]. Adults aged 31, 39 and 50 years are described in Logan's series [4]. The immunodeficiency may attenuate: a Chinese patient with low IgG at 3 years had normal immunoglobulins and lymphocyte subsets at 19 years [9]. Type 2 diabetes at 22 years and the young-adult-onset diabetes of the CDKN1C p.(Arg281Ile) variant suggest that glucose metabolism should be monitored [10, 16].

11.2 Surveillance table

For IMAGe, GeneReviews sets measurement of growth at every visit, annual endocrinological assessment (adrenal insufficiency, hypercalciuria and nephrocalcinosis), orthopaedics as needed and neurological and developmental assessment at every visit [1]. The sources consulted do not describe an immunological or oncological surveillance protocol for IMAGe-I, and the intervals in those rows depend on the judgement of immunology.

12. Summary and Final Considerations

IMAGe and IMAGe-I syndromes share the association of growth restriction of prenatal onset, primary adrenal insufficiency due to glandular hypoplasia, skeletal changes that appear or become more marked after the first year and genital anomalies in boys, but they result from different mechanisms and modes of transmission [1, 4]. In the CDKN1C form, missense variants in an eight-amino-acid segment of the PCNA-binding domain stabilise the p57KIP2 protein and block entry into S phase; the disease manifests only when the variant comes from the mother, so that healthy women who inherited it from their father have half of their children affected [1, 7, 23]. In the POLE form, the combination of a hypomorphic intronic variant with a null variant reduces polymerase ε to a fraction of normal and adds variable immunodeficiency, microcephaly, much shorter stature, severe infections and lymphomas [4, 9, 11].

Diagnosis rests on the association of IUGR with adrenal insufficiency without glandular hyperplasia, and genetic testing must allow for the particularities of each gene: CDKN1C has a high GC content and only sequence variants cause IMAGe, and deep intronic POLE variants may escape the exome and require genome sequencing or RNA study [1, 7, 11]. The variant name should state the transcript, because the CDKN1C literature uses NM_000076.2 and the MANE transcript has different numbering [27].

Treatment is that of primary adrenal insufficiency: hydrocortisone at physiological dose (about 8–10 mg/m²/day in children), fludrocortisone, sodium chloride in infants with calcium monitoring, sick day rules, emergency injectable hydrocortisone, an alert card and family education [1, 13, 46, 48]. GH, urological surgery, pubertal induction and orthopaedics complete management; in IMAGe-I, immunology and surveillance for lymphoma and EBV infection are part of follow-up, and haematopoietic cell transplantation has been used in severe cases [1, 4, 11]; in FILS, monthly IVIG was followed by 30 months without admissions in a patient with bronchiectasis and recurrent pneumonia [44]. Neither form has a targeted treatment, clinical trial or dedicated guideline, and the data come from a few dozen published patients; family counselling, with attention to maternal transmission in the CDKN1C form and recessive inheritance in the POLE form, allows siblings to be diagnosed before the first crisis [1, 9].

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