Genetic primary adrenal insufficiency in children: a narrative review.
- 1Department of Surgical Intensive Care Unit, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China.
Abstract
Pediatric primary adrenal insufficiency (PAI) beyond common 21-hydroxylase deficiency comprises rare monogenic disorders affecting adrenal development, steroidogenesis, adrenocorticotropic hormone (ACTH) signaling, or cellular stress responses. Clinical overlap is substantial, but associated features such as disorders of sex development, hypogonadism, alacrima and achalasia, neurologic disease, growth restriction, or immunodeficiency can guide etiologic testing. This review summarizes the molecular basis, genotype-phenotype relationships, diagnostic approach, and emerging therapies for these disorders. Literature from 2015 to 2025 was retrieved from PubMed using keywords: pediatric adrenal insufficiency; non-congenital adrenal hyperplasia; monogenic endocrine disorders; steroidogenesis; next-generation sequencing. Papers were filtered by pre-set inclusion and exclusion criteria. This review synthesizes current diagnostic algorithms, highlighting the critical integration of baseline biochemical profiling with high-throughput next-generation sequencing (NGS) and whole-exome sequencing (WES) to achieve precise molecular characterization and mitigate missed diagnoses. Severe loss-of-function variants in genes required for adrenal development or steroidogenesis generally present early with combined glucocorticoid and mineralocorticoid deficiency, whereas hypomorphic variants may cause later-onset or isolated glucocorticoid deficiency. Extra-adrenal findings narrow the differential diagnosis and should determine the first genes analyzed. Biochemical phenotyping remains essential, but targeted panels or WES improve diagnostic yield when presentations overlap. Hormone replacement prevents mortality but does not reproduce physiologic cortisol exposure or treat the neurologic, reproductive, or immune components of syndromic disease. Diagnosis should integrate the age at onset, pattern of steroid deficiency, associated phenotype, and molecular testing rather than rely on a single clinical feature. Current limitations include incomplete genotype-phenotype prediction, variants of uncertain significance, uneven access to functional testing, and limited pediatric outcome data for modified-release or infusion-based hydrocortisone. Near-term priorities are prospective registries, standardized variant interpretation, and genotype-stratified studies. Gene editing, gene replacement, and cell-based adrenal restoration remain experimental and should be matched to the affected tissue and mutation mechanism; hematopoietic transplantation can treat selected immune or neurologic complications but does not restore adrenal steroidogenesis.
Related
- Primary Adrenal Insufficiency in a Patient with Mosaic Klinefelter Syndrome
- Autoimmune-mediated Primary Adrenal Insufficiency After Covid-19
- Chromosomal and genetic causes of primary ovarian insufficiency in the Utah population
- Expanding the Knowledge of the Genetic Spectrum of Primary Ovarian Insufficiency Using a Cohort of 118 Chinese Cases
- Long-term cyclic ectopic adrenocorticotropic hormone syndrome with extreme fluctuations and adrenal insufficiency
BibTeX
@article{dai2026genetic,
title = {{Genetic primary adrenal insufficiency in children: a narrative review.}},
author = {Lingling Dai and Yiyao Bao and Lei Hu},
journal = {Translational pediatrics},
year = {2026},
month = sep,
doi = {10.21037/tp-2026-0707},
url = {https://europepmc.org/article/MED/42996728},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Genetic primary adrenal insufficiency in children: a narrative review.
AU - Lingling Dai
AU - Yiyao Bao
AU - Lei Hu
PY - 2026
DA - 2026/09/29
JO - Translational pediatrics
DO - 10.21037/tp-2026-0707
UR - https://europepmc.org/article/MED/42996728
AB - Pediatric primary adrenal insufficiency (PAI) beyond common 21-hydroxylase deficiency comprises rare monogenic disorders affecting adrenal development, steroidogenesis, adrenocorticotropic hormone (ACTH) signaling, or cellular stress responses. Clinical overlap is substantial, but associated features such as disorders of sex development, hypogonadism, alacrima and achalasia, neurologic disease, growth restriction, or immunodeficiency can guide etiologic testing. This review summarizes the molecular basis, genotype-phenotype relationships, diagnostic approach, and emerging therapies for these disorders. Literature from 2015 to 2025 was retrieved from PubMed using keywords: pediatric adrenal insufficiency; non-congenital adrenal hyperplasia; monogenic endocrine disorders; steroidogenesis; next-generation sequencing. Papers were filtered by pre-set inclusion and exclusion criteria. This review synthesizes current diagnostic algorithms, highlighting the critical integration of baseline biochemical profiling with high-throughput next-generation sequencing (NGS) and whole-exome sequencing (WES) to achieve precise molecular characterization and mitigate missed diagnoses. Severe loss-of-function variants in genes required for adrenal development or steroidogenesis generally present early with combined glucocorticoid and mineralocorticoid deficiency, whereas hypomorphic variants may cause later-onset or isolated glucocorticoid deficiency. Extra-adrenal findings narrow the differential diagnosis and should determine the first genes analyzed. Biochemical phenotyping remains essential, but targeted panels or WES improve diagnostic yield when presentations overlap. Hormone replacement prevents mortality but does not reproduce physiologic cortisol exposure or treat the neurologic, reproductive, or immune components of syndromic disease. Diagnosis should integrate the age at onset, pattern of steroid deficiency, associated phenotype, and molecular testing rather than rely on a single clinical feature. Current limitations include incomplete genotype-phenotype prediction, variants of uncertain significance, uneven access to functional testing, and limited pediatric outcome data for modified-release or infusion-based hydrocortisone. Near-term priorities are prospective registries, standardized variant interpretation, and genotype-stratified studies. Gene editing, gene replacement, and cell-based adrenal restoration remain experimental and should be matched to the affected tissue and mutation mechanism; hematopoietic transplantation can treat selected immune or neurologic complications but does not restore adrenal steroidogenesis.
SN - 2224-4336
SN - 2224-4344
ER -