Adrenal Insufficiency in Peroxisomal Disorders: A Single Institution Case Series

Abstract

Introduction: There are two major categories of peroxisomal disorders (PD): Peroxisomal biogenesis disorders (PBD) due to defects in peroxisomal (PEX) genes and deficiency of other peroxisomal enzymes (such as D-bifunctional enzyme deficiency due to HSD17B4). PD are characterized by abnormal elevations of very long-chain fatty acids (VLCFA). We aim to evaluate the clinical phenotype of adrenal insufficiency in patients with PD and to assess any genotype-phenotype correlations with adrenal insufficiency. Methods: We performed a retrospective electronic medical record review at a single University Medical Center, of data over 12 years and identified seven patients with PD. Cases: Of the seven patients identified, six 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: three, out of the four, patients had elevated baseline ACTH. Three patients failed to have increased response after Cortrosyn™ stimulation test. Three patients were on daily hydrocortisone replacement and one patient was on stress dose hydrocortisone only as needed. Specific genetic variant analysis revealed that, all the three patients with PBD and adrenal insufficiency who were on steroid supplementation had compound heterozygous pathogenic variant in exon 13 of PEX1 c.2097dupT (p.Ile700Tyrfs*42) and c.2528G>A (p.Gly843Asp) while the one 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 three PBD patients without adrenal insufficiency did not have a PEX1 variant. Conclusions: Primary adrenal insufficiency is common in patients with peroxisomal disorder. 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.

Addison’s Disease: Diagnosis and Management Strategies

“…51 Another single-center, retrospective study included data regarding peroxisomal diseases of patients who were followed for 12 years and identified peroxisomal biogenesis disorders in 6 individuals and one person with peroxisomal enzyme deficiency HSD17B4 (overall average age at diagnosis of 0.61 years); AD was identified in 4/7 individuals, requiring either daily glucocorticoids replacement in 3 subjects or hydrocortisone in stress circumstances in one case; the authors concluded that heterozygous PEX1 variants of exon 13 (c.2097dupT and c.2528G>A) are at higher risk for clinical manifestations as AD. 52 A retrospective, single-center study (Northern China, between 2015 and 2021) on 16 pediatric patients with non-CAH AD showed through a next-generation sequencing analysis that 87.5% of them had a gene mutation, ABCD1 being the most frequent (37.5%) followed by NR0B1 (25.0%), NR5A1 (12.5%), and 6.25% for each AAAS, and NNT. 53 An interesting analysis on reported cases included 55 patients with sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) harboring SGPL1 mutations; 71.2% of patients had AD and 32.7% had hypothyroidism with kidney disorders affecting 80% of them; among 30 SGPL1 mutations, the most frequent was c.665G > A (p.Arg222Gln) in onefifth of cases.…”