Research Explained: Adrenal Hypoplasia: A Diagnostic and Clinical Challenge

Authors: Sara Geraldes Paulino, Alice Porto Guerra Vasconcelos, Sofia Ferreira, Carla Costa, Rita Santos Silva, Cintia Castro-Correia

Written by: Tierney Baum, PhD, Strategic R&D Consultant

Edited by: Gabrielle Rushing, PhD, Chief Scientific Officer, CSNK2A1 Foundation

Link to Publication: https://www.cureus.com/articles/334386-adrenal-hypoplasia-a-diagnostic-and-clinical-challenge#!/

Research Explained Summary

This study presents the case of a 17-year-old male patient that had a complex diagnosis of two different rare disorders, OCNDS and congenital adrenal hyperplasia, which were initially misdiagnosed during infancy. The patient had a normal birth but quickly developed signs of adrenal insufficiency (AI), with abnormally low sodium and high potassium levels in his blood, as well as high blood acidity. AI is a potentially life-threatening condition with low secretion of specific hormones (glucocorticoid and/or mineralocorticoid) by the adrenal cortex. The patient was subsequently diagnosed with congenital adrenal hypoplasia (CAH) – a genetic disorder caused by deficiencies in various enzymes. This is the most common type of AI, accounting for about 95% of cases in children.

By 22 months of age, the patient had symptoms that did not align with a CAH diagnosis, including hyperpigmentation of the skin and mucous membranes. Genetic sequencing of the patient found no variants in the gene associated with CAH (CYP21A2); however, by 15 years of age repeat genetic testing discovered a heterozygous deletion of the entire CSNK2A1 gene and a pathogenic variant in the NROB1 gene (c.1273A>G, Arg425Gly). The CSNK2A1 deletion was found to be inherited from the patient’s father and the NROB1 variant was de novo. Due to the presence of these variants the patient was diagnosed with both OCNDS and X-linked adrenal hypoplasia congenita (OMIM #300200).

The deletion of the CSNK2A1 gene is likely the cause of the patient’s short stature, two-year delay in bone age, mild intellectual development disorder, and facial dysmorphisms including a broad nasal bride, upturned nose, and epicanthal folds. The variant in the NROB1 gene is associated with the AI and low sex hormone levels in the patient resulting in delayed onset of puberty. At 15 years of age the patient started on treatment with testosterone and steroids typically used to treat AI. By 17 years of age the patient had started puberty and had a significant increase in growth rate with no symptoms of AI.

This study highlights the complexity of diagnosing a patient that shows symptoms from multiple disorders. The clinicians in this study advocate for comprehensive clinical, biochemical, and genetic assessment for complex endocrine disorders to avoid the misdiagnosis of patients.