Diagnostic pitfalls in aldosterone defects: a 9-year follow-up of early-onset pseudohypoaldosteronism type 2
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Mevra Cay
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Bahriye Atmıs
Abstract
Objectives
Pseudohypoaldosteronism type 2 (PHA2) is a rare autosomal dominant electrolyte disorder characterized by hypertension, hyperkalemia, metabolic acidosis, and suppressed renin activity, usually with preserved renal function. Pathogenic variants in WNK1, WNK4, KLHL3, and CUL3 have been identified, with CUL3 mutations particularly associated with early-onset and severe phenotypes. Thiazide diuretics are effective in correcting both electrolyte imbalance and hypertension.
Case presentation
We report a pediatric patient with early-onset PHA2 caused by a de novo splice-site variant (c.1207-2A>C) in the CUL3 gene. The patient, first evaluated at 2 years and 7 months of age for recurrent vomiting, was found to have hyponatremia, hyperkalemia, and metabolic acidosis, initially treated with fludrocortisone. On referral, significant hypertension, hyperkalemia, and suppressed renin and aldosterone were observed. Initiation of low-dose thiazide therapy led to normalization of blood pressure and electrolytes. Long-term follow-up confirmed clinical stability, normal growth, and appropriate developmental milestones.
Conclusions
Aldosterone pathway defects may be misdiagnosed during the initial clinical assessment. This underscores the importance of a comprehensive diagnostic approach incorporating biochemical profiling and genetic testing to ensure accurate identification. Next-generation sequencing has emerged as a valuable tool for establishing a definitive diagnosis, particularly in cases with aldosterone defects. Timely and accurate diagnosis of PHA2 is critical, as persistent metabolic acidosis and hypertension may lead to significant growth and developmental impairments in pediatric patients. Despite the potential severity of clinical manifestations associated with CUL3-related PHA2, it is noteworthy that treatment with thiazide diuretics alone can effectively restore electrolyte balance and support normal growth and development.
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Research ethics: Ethical Approval was not required for this case report, in accordance with the policies of our institution.
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Informed consent: Informed consent for publication of case details was obtained from the patient’s parents.
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Author contributions: Mevra Cay: Collected clinical data, performed literature review, and drafted the initial manuscript. Ihsan Turan: Conceptualized the study, supervised clinical management, and critically revised the manuscript. Bahriye Atmıs: Contributed to patient evaluation and interpretation of clinical data. Leman Damla Kotan: Assisted in data collection and literature review. Sukriye Tugce Celebi: Participated in patient follow-up and data collection. Ayse Merve Cimen: Assisted in data acquisition and clinical evaluation. Eda Mengen: Contributed to literature review and editing of the manuscript. Aysun Karabay Bayazıt: Provided nephrology expertise, supervised clinical interpretation, and revised the manuscript. Bilgin Yuksel: Contributed to study design, supervised the project, and approved the final version of the manuscript. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.”
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Use of Large Language Models, AI and Machine Learning Tools: Not used.
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Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Research funding: The authors declared that this study received no financial support.
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Data availability: Not applicable. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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