Abstract | CONTEXT: PATIENT: We present the case of a 10-year-old child who presented with CS at an early age due to bilateral adrenocortical hyperplasia (BAH). The patient was placed on low-dose ketoconazole (KZL), which controlled hypercortisolemia and CS-related signs. Discontinuation of KZL for even 6 weeks led to recurrent CS. RESULTS: Screening for known genes causing cortisol-producing BAHs (PRKAR1A, PRKACA, PRKACB, PDE11A, PDE8B, ARMC5) failed to identify any gene defects. Whole-exome sequencing showed a novel KCNJ5 pathogenic variant (c.506T>C, p.L169S) inherited from her father. In vitro studies showed that the p.L169S variant affects conductance of the Kir3.4 channel without affecting its expression or membrane localization. Although there were no effects on steroidogenesis in vitro, there were modest changes in protein kinase A activity. In silico analysis of the mutant channel proposed mechanisms for the altered conductance. CONCLUSION: We present a pediatric patient with CS due to BAH and a germline defect in KCNJ5. Molecular investigations of this KCNJ5 variant failed to show a definite cause of her CS. However, this KCNJ5 variant differed in its function from KCNJ5 defects leading to PA. We speculate that GIRK4 (Kir3.4) may play a role in early human adrenocortical development and zonation and participate in the pathogenesis of pediatric BAH.
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Authors | Christina Tatsi, Andrea G Maria, Cole Malloy, Lin Lin, Edra London, Nick Settas, Chelsi Flippo, Meg Keil, Fady Hannah-Shmouni, Dax A Hoffman, Constantine A Stratakis |
Journal | The Journal of clinical endocrinology and metabolism
(J Clin Endocrinol Metab)
Vol. 106
Issue 6
Pg. 1606-1616
(05 13 2021)
ISSN: 1945-7197 [Electronic] United States |
PMID | 33630995
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Intramural)
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Copyright | Published by Oxford University Press on behalf of the Endocrine Society 2021. |
Chemical References |
- G Protein-Coupled Inwardly-Rectifying Potassium Channels
- KCNJ5 protein, human
- Ketoconazole
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Topics |
- Cells, Cultured
- Child
- Cushing Syndrome
(drug therapy, genetics)
- Dose-Response Relationship, Drug
- Female
- G Protein-Coupled Inwardly-Rectifying Potassium Channels
(genetics)
- HEK293 Cells
- Humans
- Ketoconazole
(administration & dosage)
- Mutation, Missense
- Treatment Outcome
- United States
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