Key result
Primary adrenal insufficiency was present in 66.7% of patients with peroxisomal biogenesis disorders, correlating with compound heterozygous PEX1 pathogenic variants in exon 13.
Observational (n=7)
No
Primary adrenal insufficiency is common in patients with peroxisomal disorders, particularly those with specific compound heterozygous PEX1 pathogenic variants.
Supports adrenal evaluation in peroxisomal biogenesis disorders; leaves open whether PEX1 variants predict insufficiency in larger cohorts.
INTRODUCTION: There are two major categories of peroxisomal disorders (PDs): peroxisomal biogenesis disorders (PBDs) due to defects in peroxisomal (PEX) genes and deficiency of other peroxisomal enzymes (such as D-bifunctional enzyme deficiency due to HSD17B4). PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA). We aimed to evaluate the clinical phenotype of adrenal insufficiency in patients with PD and to assess any genotype-phenotype correlations with adrenal insufficiency. CASE PRESENTATION: We performed a retrospective electronic medical record review at a single university medical center, of data over 12 years and identified 7 patients with PD. Of the 7 patients identified, 6 patients had a diagnosis of PBD and one had a single peroxisomal enzyme deficiency, HSD17B4. The average age of the patients at diagnosis were 0.61 ± 0.66 years. Four patients (66.7%) had primary adrenal insufficiency: 3, out of the 4, patients had elevated baseline ACTH. Three patients failed to have increased response after the Cortrosyn™ stimulation test. Three patients were on daily hydrocortisone replacement, and 1 patient was on stress-dose hydrocortisone only as needed. Specific genetic variant analysis revealed that all the 3 patients with PBD and adrenal insufficiency who were on steroid supplementation had the compound heterozygous pathogenic variant in exon 13 of PEX1 c.2097dupT (p.Ile700Tyrfs*42) and c.2528G>A (p.Gly843Asp), while the 1 patient with peroxisomal enzyme deficiency and adrenal insufficiency had compound heterozygous pathogenic variants in HSD17B4 c.1369A>T (p.Asn457Tyr) and c.1210 - 1G>A (splice acceptor). Two of these patients with PEX1 variants also required mineralocorticoid supplementation. The 3 PBD patients without adrenal insufficiency did not have a PEX1 variant. DISCUSSION/CONCLUSION: Primary adrenal insufficiency is common in patients with PD. Based on our data, patients with the compound heterozygous PEX1 pathogenic variants of exon 13 (c.2097dupT and c.2528G>A) tend to have adrenal insufficiency. Aldosterone deficiency, though rare, can occur in PD.
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Gagnon et al. (2023) conducted an observational in Peroxisomal disorders (n=7). Peroxisomal disorders was evaluated on Primary adrenal insufficiency. Primary adrenal insufficiency was present in 66.7% of patients with peroxisomal biogenesis disorders, correlating with compound heterozygous PEX1 pathogenic variants in exon 13.
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