Primary Adrenal Insufficiency: New Genetic Causes and Their long-Term Consequences

Federica Buonocore; John C. Achermann


Clin Endocrinol. 2020;91(1):11-20. 

In This Article

Complex Multisystem Growth Disorders: CDKN1C, SAMD9 and POLE1

Adrenal insufficiency has also been reported as part of three recently described multisystem growth restriction disorders: IMAGe syndrome, MIRAGE syndrome and POLE1. Although relatively rare, these conditions are associated with interesting pathogenic mechanisms and may be underdiagnosed.

CDKN1C: IMAGe Syndrome

IMAGe syndrome is characterized by intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genitourinary anomalies (often mild hypospadias) and was first described in 1999.[39] The adrenal dysfunction can be variable, including both glucocorticoid and mineralocorticoid insufficiency, and diabetes mellitus has been reported in some members of a large kindred.[40]

IMAGe syndrome is usually caused by heterozygous missense variants in the key negative cell cycle regulator, cyclin-dependent kinase inhibitor 1C (CDKN1C).[41] These changes are localized to the PCNA-binding domain and cause a gain-of-function and growth repression (Figure 2A).[41–44] The mechanism is unclear but may involve decreased degradation of CDKN1C, allowing prolonged cell cycle repression and delayed S-phase progression. CDKN1C is an imprinted gene, which is only expressed from the maternal allele, so inheritance can mimic an X-linked condition (although both boys and girls are affected). Interestingly, loss-of-function of this growth repressor, CDKN1C, is found in approximately 10% of patients with Beckwith-Wiedemann syndrome (BWS), an "overgrowth" syndrome.[41,45] Children with BWS are at risk of adrenal tumours highlighting how developmental hypoplasia and cancer can sometimes be at opposite ends of a molecular spectrum.

Figure 2.

Complex multisystem growth disorders associated with gain-of-function mutations in CDKN1C and SAMD9. (A) CDKN1C is an inhibitor of cell cycle progression. Loss of CDKN1C is associated with the overgrowth condition, Beckwith-Wiedemann syndrome, whereas gain-of-function mutations of CDKN1C cause adrenal hypoplasia as part of IMAGe syndrome. (B) SAMD9 also inhibits cell proliferation during normal foetal development. Gain-of-function mutations in SAMD9 (magenta) cause multisystem growth restriction as part of (M) IRAGE syndrome. Cells that develop somatic reversion events such as the monosomy 7 (blue) or loss-of-function mutations in SAMD9 (green) have a proliferative advantage and can partially "rescue" the phenotype. However, monosoomy 7 may be associated with secondary events, such as myelodysplasia in the haematopoietic system. IUGR, intrauterine growth restriction. Panel (B) modified from Buonocore F, Kühnen P, Suntharalingham JP, et al Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. J Clin Invest. 2017;127(5):1700–1713. © 2017 The Authors (

SAMD9: MIRAGE Syndrome

Another multisystem growth restriction disorder occurs due to gain-of-function variants in the growth repressor, Sterile Alpha Motif Domain Containing 9 (SAMD9) (Figure 2B).[46,47] Most children with this condition are born preterm with growth restriction and develop variable, salt-losing adrenal insufficiency in early life, although a small proportion of children do not exhibit adrenal features. Penoscrotal hypospadias or more female-typical genitalia can be seen in 46,XY children and other features occur, such as infections, enteropathy, respiratory distress, anaemia and thrombocytopaenia, and hydrocephalus. The condition has been termed MIRAGE syndrome (myelodysplasia [see below], infections, restricted growth, adrenal hypoplasia, gonadal anomalies and enteropathy).[46] Mortality can be high.

Most gain-of-function SAMD9 variants occur de novo, although some germline inheritance and variable penetrance has been described.[46,48] SAMD9 may be involved in recycling growth factor receptors (eg EGFR) through endosome trafficking, so that gain-of-function reduces availability of these receptors and leads to growth restriction.

SAMD9 is located on the long arm of chromosome 7 (7q21). One fascinating feature of this condition is that children with SAMD9 mutations who survive early infancy often develop monosomy 7, partial 7q deletions or somatic nonsense (stop gain) changes in SAMD9 in haematopoietic cell lines, which "remove" the mutant SAMD9 allele and confer a clonal growth advantage on those cells (Figure 2B).[46,47,49–51] This phenomenon can rescue the blood phenotype in the short term. However, loss of 7q21 (including SAMD9 and SAMD9L) can result in myelodysplastic syndrome in the bone marrow (the "M" in MIRAGE) and further somatic "hits" can sometimes lead to the development of leukaemia.[52] In contrast, some children have different forms of revertant mosaicism, such as gene conversion or uniparental disomy, which replace the mutant SAMD9 allele with a wild-type allele.[51,53] In these situations, the bone marrow features reverse and no haematopoietic issues develop.

It is hypothesized that such dynamic changes may modify the phenotype in different organs, explaining why some children have a mild or even no adrenal features.[47] Indeed, somatic modulation and revertant mosaicism could play a wider role in the phenotypic of endocrine disorders than is currently recognized.


Recently, biallelic loss-of-function variants in polymerase epsilon-1 (POLE1, Pol ε) have been reported to cause an IMAGe-like syndrome, in children with growth restriction and adrenal hypoplasia (with variable salt-loss), together with variable immune dysfunction and distinctive facial features.[54] A small proportion of children have preserved adrenal function. POLE1 is a key DNA leading-strand polymerase, and most subjects reported to date have a heterozygous intronic variant (c.1686 + 32C>G) together with a disruptive loss-of-function variant in the other allele. POLE1 plays an important role in DNA replication by binding to PCNA and extending DNA synthesis in the replisome. Loss of POLE1 disrupts this mechanism and is associated with delayed S-phase progression and cell division, although the exact mechanism is unclear.