Genetic diagnosis of primary adrenal insufficiency in children and adolescents can establish a specific etiology and assist in managing this condition, according to the results of a study published in the Journal of the Endocrine Society.
Researchers reported on the findings of a genetic analysis of children and adolescents with primary adrenal insufficiency of unknown etiology at 3 major research centers in the United Kingdom in order to provide a combined analysis of experiences in diagnosing this and related conditions during a 25-year period.
The patient cohort included 155 children and adolescents (102 boys) with primary adrenal insufficiency of unknown etiology referred for genetic analysis with a genetic diagnosis made from 1993 to 2018. The cohort included 16 sibling or familial pairs, 3 trios, and 1 extended family with 7 affected members.
All study participants had provisional diagnoses of adrenal hypoplasia, familial glucocorticoid deficiency/adrenocorticotropic hormone resistance, triple A syndrome/Allgrove syndrome, or primary adrenal insufficiency. All participants underwent standard clinical and biochemical analyses for diagnostic purposes.
From 1993 to 2012, genetic analysis was conducted via Sanger sequencing using a candidate gene approach, analyzing the MC2R, MRAP, AAAS, NNT, NR0B1 (DAX-1), NR5A1 (SF-1), CDKN1C, STAR, and CYP11A1 genes. Since 2013, a next-generation sequencing (NGS) strategy was employed in an attempt to reach a specific genetic diagnosis.
Of the cohort, 66.5% of the children received a specific genetic diagnosis, and 30.3% had no specific genetic diagnosis (29 NGS, 18 candidate gene sequencing). Adrenal insufficiency resolved in 3.2% of the children, and steroid replacement treatment was withdrawn during the course of the study. No genetic causes were found in this group. Overall, 11 different genes were identified with pathogenic variants.
Familial glucocorticoid deficiency type 1 was one of the most prevalent conditions due to disruption of the adrenocorticotropic hormone receptor, melanocortin receptor-2. This pathogenic variant was identified in 19.4% (n=30) of the cohort; in 20 of these patients, it was due to the p.S74I variant found in those with Irish and Scottish ancestry. Most of these patients were treated with glucocorticoids alone; 7 were treated with additional mineralocorticoids.
NR0B1 (DAX-1) disruption causing X-linked adrenal hypoplasia congenita was identified in 7.7% of study participants. This presentation was primarily during the newborn period. The researchers identified an additional 51 boys from 42 families with pathogenic NR0B1 variants through clinical testing pathways. Overall, 63 of 154 children with a positive genetic diagnosis had a diagnosis of X-linked adrenal hypoplasia congenita, representing the largest diagnostic group overall (40.9%).
Of the study participants, 7.7% had CYP11A1 mutations in the form of partial loss of CYP11A1 activity that often presented in childhood through signs of glucocorticoid insufficiency, such as ketotic hypoglycemia. Triple A syndrome was identified in 7.1% of the cohort; these children typically developed mid-childhood adrenal insufficiency in addition to features like alacrima and achalasia, as well as neurologic symptoms. Half of these patients required treatment with glucocorticoids plus mineralocorticoids.
Nicotinamide nucleotide transhydrogenase defects were identified in 6.5% of children aged between 4 months and 2.5 years. Three of these children experienced early puberty. Melanocortin 2 receptor-associated protein was identified in 4.5% of the patients, usually presenting during the neonatal period or the first 3 months of life. An additional 4.5% of patients had adrenal insufficiency due to a homozygous stop gain mutation in TXNRD2. No pathogenic TXNRD2 variants were found in other patients.
Severe disruption of steroidogenic acute regulatory proteins was diagnosed in a girl with 46,XY disorders of sexual development with early-onset, salt-losing adrenal insufficiency that resulted from a homozygous frameshift mutation. An additional 5 patients presenting at 9 months and 4 years of age with a predominant glucocorticoid insufficiency had nonclassic, congenital lipoid adrenal hyperplasia.
Five children presented with de novo gain-of-function mutations in SAMD9; all were born preterm and had fetal growth restriction. Only 1 participant had a pathogenic variant in NR5A1; this child presented with salt loss and a female phenotype. No NR5A1 variants caused primary adrenal insufficiency alone.
An analysis of sex differences identified an “excess” of boys in the UK cohort (102 of 155 patients), which persisted even when those with X-linked adrenal hypoplasia were removed from the analysis (91 of 143 participants). These sex differences were “even more marked” in the undiagnosed group, as well as in the group of participants in whom primary adrenal insufficiency had resolved.
Study limitations included the lack of generalizability of the cohort, which included children and families sent for genetic analysis; per the researchers, this did not represent a cross- sectional cohort. Additional limitations included a lack of adrenal imaging, which may have led to potential underdiagnosis.
“In summary, this retrospective observational study shows that genetic analysis can help reach a specific diagnosis in almost 70% of children and young people with [primary adrenal insufficiency] of unknown etiology, with potential implications for long-term counseling and management,” the researchers reported. “Taken together with [congenital adrenal hyperplasia] and other established causes of adrenal dysfunction, it is now likely that a specific diagnosis can be reached in the vast majority of children and young people with [primary adrenal insufficiency].”
“The adoption of [primary adrenal insufficiency] into clinical genetic testing platforms in countries such as the UK should help considerably in improving the speed and rate of diagnosis for these conditions in the future,” they concluded.
Buonocore F, Maharaj A, Qamar Y, et al. Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years’ experience in the UK. Published online May 12, 2021. J Endocrine Society. doi:10.1210/jendso/bvab086