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Background <p>Primary adrenal insufficiency (PAI) in children, outside of congenital adrenal hyperplasia (CAH), represents a rare and genetically diverse group of disorders often leading to diagnostic delays. Advances in molecular genetics have uncovered a wide spectrum of non-CAH etiologies, yet real-world data from pediatric cohorts remain limited.</p> Methods <p>We retrospectively reviewed 11 children diagnosed with non-CAH PAI at a single tertiary care center between March 2015 and December 2024. Clinical, biochemical, and genetic findings were evaluated using targeted Sanger sequencing or next-generation sequencing panels. Variants were classified according to ACMG/AMP criteria.</p> Results <p>Pathogenic or likely pathogenic variants were identified in <i>MC2R</i> (<i>n</i> = 3), <i>NR0B1</i> (<i>n</i> = 2), <i>ABCD1</i> (<i>n</i> = 2), <i>MRAP</i> (<i>n</i> = 1), <i>AIRE</i> (<i>n</i> = 1), and <i>AAAS</i> (<i>n</i> = 1) genes, while one patient remained genetically undiagnosed. In total, five novel variants were identified: one in <i>MC2R</i> (shared by two siblings), and one each in NR0B1, <i>ABC</i>D1, and <i>AAAS</i>. Clinical presentations ranged from neonatal adrenal crisis to later-onset symptoms such as fatigue, hyperpigmentation, or hypoglycemia. Consanguinity was present in 45% of cases. One <i>MC2R</i> case required only stress-dose glucocorticoid therapy, while most others required lifelong hormone replacement. Notably, we describe the first homozygous <i>MC2R</i> p.Arg128His variant causing partial adrenal insufficiency without long-term glucocorticoid treatment, and a unique case of PAI co-occurring with genetically confirmed Marfan syndrome.</p> Conclusion <p>This single-center cohort underscores the clinical and genetic heterogeneity of pediatric non-CAH PAI. The identification of five novel variants expands the mutational spectrum and provides new insights into genotype–phenotype correlations, reinforcing the importance of early genetic testing for optimal management.</p>

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The pivotal role of etiology in managing Non-CAH primary adrenal insufficiency in pediatric and adolescent populations: A Single-Center study

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • Emrullah Arslan,
  • Aslı Ece Solmaz,
  • Deniz Özalp Kızılay,
  • Haluk Akın,
  • Hanife Gül Balkı,
  • Arzu Jalilova,
  • Ruhsar Damla Gökşen,
  • Şükran Darcan,
  • Samim Özen

摘要

Background

Primary adrenal insufficiency (PAI) in children, outside of congenital adrenal hyperplasia (CAH), represents a rare and genetically diverse group of disorders often leading to diagnostic delays. Advances in molecular genetics have uncovered a wide spectrum of non-CAH etiologies, yet real-world data from pediatric cohorts remain limited.

Methods

We retrospectively reviewed 11 children diagnosed with non-CAH PAI at a single tertiary care center between March 2015 and December 2024. Clinical, biochemical, and genetic findings were evaluated using targeted Sanger sequencing or next-generation sequencing panels. Variants were classified according to ACMG/AMP criteria.

Results

Pathogenic or likely pathogenic variants were identified in MC2R (n = 3), NR0B1 (n = 2), ABCD1 (n = 2), MRAP (n = 1), AIRE (n = 1), and AAAS (n = 1) genes, while one patient remained genetically undiagnosed. In total, five novel variants were identified: one in MC2R (shared by two siblings), and one each in NR0B1, ABCD1, and AAAS. Clinical presentations ranged from neonatal adrenal crisis to later-onset symptoms such as fatigue, hyperpigmentation, or hypoglycemia. Consanguinity was present in 45% of cases. One MC2R case required only stress-dose glucocorticoid therapy, while most others required lifelong hormone replacement. Notably, we describe the first homozygous MC2R p.Arg128His variant causing partial adrenal insufficiency without long-term glucocorticoid treatment, and a unique case of PAI co-occurring with genetically confirmed Marfan syndrome.

Conclusion

This single-center cohort underscores the clinical and genetic heterogeneity of pediatric non-CAH PAI. The identification of five novel variants expands the mutational spectrum and provides new insights into genotype–phenotype correlations, reinforcing the importance of early genetic testing for optimal management.