Clinical Manifestations of Pseudohypoaldosteronism with Genotype-phenotype Correlation. A Single Center Experience, A Retrospective Cohort Study.
Authors: Bin-Abbas Bassam , Aljaser Alhanouf , AlSagheir Afaf , Joueidi Faisal , Sayed Ahmed Gamal 
Published: April 2024

Background:
Pseudohypoaldosteronism (PHA) is a rare endocrine disorder characterized by unresponsiveness, multi-organ involvement affecting sodium salt wasting, poor renal excretion, and severe volume depletion resulting in electrolyte imbalance (hyponatremia, hyperkalaemia, and metabolic acidosis) and further classified into type 1 and 2. Ali et al. reported that PHA1b geno-phenotype correlation has not been well described. As such, in our study, we propose how the clinical behaviour of this subtype can be predictable. Moreover, the diagnosis of any of the PHA types is made by the clinical presentation and laboratory findings during a clinical suspicion setting.
Methods:
A descriptive retrospective study includes 22 patients diagnosed with PHA during 2023 in the endocrine subdivision of paediatric service in KFSHRC. The informed consent was obtained from either the patients or their guardians.
Results:
Of a total of 22 patients, ages ranged between 3 days to 2 years at presentation, 95% of them presented with vomiting, 63.3% had respiratory symptoms, 50% had hypotension 31% had dermatitis, and 31% had polyurea, 27% had HTN, 22% had UTI only one patient had arrhythmia, none of them had gallstone. Labs were Lowest Na; 110–132 Lowest Cl: 81–108 Lowest HCO3: 10–18 Highest K: 5.5-8 Aldosterone: 7510 − 1659, half of the patient did not do Aldosterone level. Renin: 50–751 Number of admissions: range from 0 to 20 times. Treatment: NaCl dose range (2-480 meq/kg/day) NaHCO3 (1–34 meq/kg/day) Kayexalate (0.5–45 g/kg/day) One patient needed a gastrostomy tube. One patient was off treatment at the age of 6 years. Severity at presentation ranges from very severe to 4 severe, Then improved with age to range between very mild to moderate.
Discussion:
PHA1a has a heterogeneous inactivating mutation in the NR3C2 gene; it encodes for a mineralocorticoid receptor responsible for aldosterone binding. Therefore, mutations are associated with a phenotype restricted to the kidneys. As a course, this disease has an early life onset, which is almost always in the neonatal period, presenting with fever, feeding difficulties, nausea, vomiting, weight loss, recurrent pulmonary infection, and sudden cardiac arrest alongside laboratory findings in the form of electrolyte imbalance which includes hyponatremia, hyperkalaemia and salt wasting with elevated plasma renin and aldosterone levels. On the other hand, PHA1b is multi-systemic and mainly caused by mutations in the ENaC channel, affecting sodium reabsorption in the body. It manifests in the first week of life with electrolyte imbalance with nonspecific symptoms such as nausea and vomiting alongside hypotension, with salt-wasting episodes. It has been demonstrated that PHA1b usually presents with a more severe clinical phenotype than PHA1a. Furthermore, complications with the PHA1b subtype are more prone to develop.
Conclusion:
PHA is a rare genetic endocrine disorder that needs awareness by the endocrinologist of its existence. It is a clinical diagnosis that requires monitoring, follow-up, and close observation of affected patients. Hence, this is because pheno-genotype correlation is an expandable process in the endocrine medical literature. Our single-centre experience gives an insight into the predictable clinical behaviour of this under-diagnosed condition to improve further the physicians related to the paediatric population's understanding of the PHA natural course. Also, to have a better provisional plan and management care for affected individuals to increase the likelihood of a better prognosis further, better quality of life, and survival.