CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy
Madori Osawa1, Yumi Ogura, Kiyoshi Isobe
1Department of Pediatrics, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359-8513, Japan.
Insights
Pseudohypoaldosteronism type II (PHA-II) in a child was linked to a novel CUL3 gene mutation. Early genetic testing and treatment with trichlormethiazide improved electrolyte balance and growth.
Area of Science:
- Genetics
- Pediatrics
- Endocrinology
Background:
- Pseudohypoaldosteronism type II (PHA-II) is a rare genetic disorder affecting electrolyte balance.
- Four genes are known to cause PHA-II, aiding molecular diagnostics.
Purpose of the Study:
- To report a novel CUL3 gene mutation causing PHA-II in a pediatric patient.
- To highlight the importance of early diagnosis and intervention for PHA-II.
Main Methods:
- Clinical presentation and genetic analysis of a 1-year-old boy with PHA-II symptoms.
- Identification of a de novo CUL3 mutation affecting mRNA splicing.
- Treatment with trichlormethiazide, a sodium-chloride co-transporter inhibitor.
Main Results:
- The patient presented with hyperkalemia, metabolic acidosis, hyperchloremia, growth delay, and hypertension.
- A novel mutation in the CUL3 splice acceptor site caused exon 9 skipping in CUL3 mRNA.
- Treatment with trichlormethiazide successfully corrected electrolyte imbalances and improved homeostasis.
Conclusions:
- Novel CUL3 mutations can cause severe PHA-II phenotypes in infants.
- Early genetic diagnosis of CUL3 mutations is crucial for timely intervention.
- Prompt treatment can prevent long-term complications like growth and developmental delays.
Background:
Four genes responsible for pseudohypoaldosteronism type II (PHA-II) have been identified, thereby facilitating molecular diagnostic testing.
Case-Diagnosis/Treatment:
A 1-year-old boy with prolonged hyperkalemia, metabolic acidosis, hyperchloremia, growth delay, and mild hypertension was diagnosed with PHA-II based on the detection of exon 9 skipping in CUL3 mRNA. The impaired splicing was the result of a de novo, previously unreported single nucleotide substitution in the splice acceptor site of CUL3 intron 8. Among the four genes reported to be involved in PHA-II, CUL3 was the primary suspect in our patient because in patients with the CUL3 mutation, the onset of disease is often early in infancy and the phenotypes of PHA-II are more severe. Our patient was treated with trichlormethiazide, which inhibits the function of the sodium-chloride co-transporter (NCC), and the outcome was favorable, with correction of body fluids and blood electrolyte homeostasis.
Conclusion:
Since chronic acidosis and hypertension associated with PHA-II can result in delayed growth and development in pediatric patients, genetic analysis to detect the CUL3 mutation and to enable intervention early in the disease course would be beneficial for infants with suspected PHA-II.
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