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Primary adrenal insufficiency: New genetic causes and their long-term consequences.

ABSTRACT: Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1). Reaching a specific diagnosis can have life-long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, "Addison's disease."

SUBMITTER: Buonocore F

PROVIDER: S-EPMC6916405 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Primary adrenal insufficiency: New genetic causes and their long-term consequences.

Buonocore Federica F Achermann John C JC

Clinical endocrinology 20191030 1

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about ...[more]

PMID: 31610036

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Project description:BackgroundPrimary adrenal insufficiency (PAI) is life-threatening, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features.MethodsSeventy children were enrolled in this cross-sectional study. Clinical information was collected, and combined genetic tests were performed according to the children's manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants.ResultsAmong the 70 children, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2-21.3) and five novel variants, including 2 in the NR0B1 gene (c.323-324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein.ConclusionsWe found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.

Project description:Abstract OBJECTIVE: Several biomarkers for glucocorticoid (GC) sensitivity have been proposed relevant for the inter-individual variation seen in treatment response and side effects to GC treatment. Four single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene have been associated with increased (Bcl1 and N363S) or decreased (9β and ER23/23EK) GC sensitivity. We investigated the influence of these proposed biomarkers for GC sensitivity on GC-induced adrenal insufficiency. SUBJECTS AND METHODS: We included 239 patients receiving long-term prednisolone treatment for rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) / giant cell arteritis (GCA), or after renal transplantation (RTx). Four GR gene SNPs (Bcl1 rs41423247; 9β rs6198; N363S rs56149945; ER22/23EK rs6189 + rs6190) were sequenced by Sanger sequencing. Adrenal function was evaluated by a 250 µg corticotropin stimulation test. To compare allele frequencies with background population, two control groups were generated from two regional whole-genome databases. We downscaled each genome dataset to 239 individuals/group to balance statistical analysis. RESULTS: In total 239 patients were genotyped and 178 of these (RA n=103, PMR/GCA n=47, RTx n=28) treated with a median current dose of 5 mg prednisolone/day (interquartile range 5-7 mg) and a median treatment duration of 48 months (interquartile range 22-111 months) completed the corticotropin test. Seventy-three (41%, CI95%: 34-48%) patients had an insufficient response to the corticotropin test. Neither the risk of adrenal insufficiency, unstimulated nor stimulated P-cortisol levels were directly associated with any of the GR SNPs. However, for both insensitive SNPs 9β and ER23/23EK the effect of current prednisolone dose on stimulated P-cortisol was smaller (higher dose did not suppress the cortisol level as much) in carriers vs. non-carriers (p=0.035 and p=0.0075). The same sensitivity-associated tendency was seen for the N363S, but not the Bcl1 SNP. The Bcl1 SNP occurred more frequently in our cohort compared with control groups (63% vs. 40%, p<0.0001). The same trend was seen for the other sensitive but less frequent SNP N363S. The 9β SNP also occurred more frequently in our cohort (18% vs. 13%, p=0.029), but depending on regional sub cohorts in one control group. CONCLUSION: The GR SNPs did not directly associate to the risk of adrenal insufficiency, unstimulated nor stimulated cortisol levels, respectively. However, the effect of prednisolone dose on stimulated cortisol depended on the GR SNPs: Cortisol was less suppressed with higher current prednisolone dose in patients carrying the insensitive SNPs. The substantially higher frequency of the Bcl1 SNP is remarkable even with modest n=239. It questions whether there is an association between carrying the sensitive GR SNPs and inability to taper GC treatment ending up in this cohort of long-term treated patients.

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Primary adrenal insufficiency: New genetic causes and their long-term consequences.

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Primary adrenal insufficiency: New genetic causes and their long-term consequences.

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