ABSTRACT

Pseudohypoaldosteronism (PHA) is a rare disorder that, if not promptly recognized and treated, can lead to life-threatening hyperkalemia resulting in cardiac arrest and death. Systemic PHA is caused by variants that deactivate the epithelial sodium channel subunits. Management is challenging due to high-dose oral replacement therapy, and patients with systemic PHA require lifelong treatment. Here, we present the clinical course of a newborn diagnosed with PHA at seven days of age due to severe dehydration, inadequate feeding, vomiting, and lethargy. The infant was found to be homozygous for the variant c.1234dup (p.Glu412Glyfs*39) in exon 8 of the SCNN1B gene. The patient had multiple hospitalizations during follow-up and died at the age of 10 months due to pneumonia. Maintaining a high clinical suspicion for PHA is crucial for initiating treatment and preventing potential cardiac arrest and death in these patients. Further research is needed to determine the significance of such novel mutations in this disease.

Introduction

Pseudohypoaldosteronism (PHA) is a rare, salt-wasting syndrome characterized by marked resistance to aldosterone in peripheral target tissues. There are two main types of PHA: type 1 PHA and type 2 PHA. Type 1 PHA may be inherited in an autosomal dominant (AD) or autosomal recessive (AR) manner. The AD form (renal form) is associated with mutations affecting the mineralocorticoid receptor (MR) in principal cells of the kidney, affecting sodium transport. The AR form (systemic form), on the other hand, is linked to mutations in the epithelial sodium channel (ENaC), expressed in various organs including renal tubules, lungs, colon, sweat glands, and salivary glands, which can exacerbate the severity of this form (1). The systemic form, which requires lifelong management, tends to have a more severe course while the renal form often improves within the first two years of life. Type 1 PHA typically presents with symptoms of salt wasting, growth retardation, hyperkalemia, and acidosis, similar to those seen in infants diagnosed with congenital adrenal hyperplasia (CAH) (2). Decreased sodium reabsorption from epithelial cells and the cortical collecting duct leads to volume depletion, thereby reducing the electrochemical gradient that normally supports potassium and hydrogen ion secretion. Besides renal dysfunction, the systemic form of Type 1 PHA is also associated with respiratory tract infections and a positive sweat test (3). Type 2 PHA, known as Gordon syndrome or familial hyperkalemic hypertension, is characterized by hypertension, hyperkalemia, metabolic acidosis, normal kidney function, low-normal plasma renin activity, and aldosterone concentration (4). Type 2 PHA exhibits AD inheritance.

This article discusses our experience in managing a patient with PHA due to an SCNN1B variant, highlighting the challenges encountered in clinical management.

Case Report

A 7-day-old female infant, born via repeat cesarean section from the second pregnancy of a 23-year-old mother, presented to the hospital with symptoms of vomiting, pallor, lethargy, poor feeding, and sleepiness. The infant was born at term, weighing 3500 grams (between the 50^th and 90^th percentile), with a length of 51 cm (50^th percentile) and a head circumference of 36 cm (50^th percentile). Due to the findings of hyponatremia and hyperkalemia upon initial evaluation, a preliminary diagnosis of CAH was considered, prompting referral to our center. There is a history of consanguinity (second-degree cousins) between the mother and father. The infant has a healthy 3.5-year-old male sibling.

On physical examination, her general condition was fair to poor, with altered skin turgor and milia and pustular erythematous rash on her face and neck. There were no ambiguous genitalia or hyperpigmentation noted. Examination of other systems was unremarkable. The patient’s laboratory test results are shown in Table 1. Venous blood gas analysis showed a pH of 7.36, bicarbonate (HCO₃) of 11.5 mmol/L, and base excess (BE) of -11.3 mmol/L. Due to hyperkalemia, the patient was started on appropriate fluid therapy and received treatments including calcium gluconate, glucose-insulin infusion, NaHCO₃ infusion, and inhaled salbutamol. A 25-mg loading dose of IV hydrocortisone was administered, followed by 5 mg of IV stress dosing every 6 hours. In addition, fludrocortisone 0.1 mg twice daily was initiated. However, despite these interventions, the patient’s hyperkalemia and hyponatremia remained resistant. Oral calcium polystyrene sulfonate at a dose of 1 g/kg/day and oral salt supplementation (4x1 g/day) were gradually increased. Laboratory findings upon admission to our clinic included spot urine analysis showed sodium levels of 156 mEq/L (normal range: 54-150 mEq/L) and potassium levels of 3.5 mEq/L (normal range: 6.7-21.3 mEq/L) concurrent with serum sodium of 118 mmol/L and potassium of 9.8 mmol/L. The calculated transtubular potassium gradient was low. Based on these laboratory results, hydrocortisone therapy was halted. Fludrocortisone therapy was continued but did not provide benefit. Considering the patient’s presentation in the neonatal period, laboratory findings of hyponatremia and hyperkalemia with increased urinary sodium excretion, elevated aldosterone levels, and normal blood pressure, systemic PHA was suspected. Secondary PHA was ruled out based on normal urine analysis, urine culture, and urinary system ultrasonography. Despite increasing the dose of calcium polystyrene sulfonate to 4 g/kg/day and other conventional treatments, the patient’s hyperkalemia persisted, necessitating peritoneal dialysis. Potassium levels decreased from 8.2 mmol/L pre-dialysis to 4.3 mmol/L on follow-up. The patient remained stable on treatment with 4x1 g oral salt and 10 g/day of calcium polystyrene sulfonate. She gained 1360 grams during hospitalization, weighing 4620 grams at discharge on the 37^th day, with treatment being appropriately managed.

This infant was diagnosed with electrolyte imbalance at two months of age, pneumonia at 3.5 months, and again with electrolyte imbalance at six months, requiring hospitalization and treatment each time.

At eight months of age, the patient was brought to the emergency department due to vomiting and diarrhea. Initial tests upon arrival showed sodium at 123 mmol/L and potassium at 10.7 mmol/L. Due to respiratory distress and desaturation, the patient underwent endotracheal intubation and was admitted to the pediatric intensive care unit. Following 55 days of hospitalization for pneumonia, the patient passed away at 10 months of age (Figure 1).

Considering the clinical and laboratory findings suggestive of systemic type 1 PHA, the patient’s related genes were examined using next-generation sequencing. Informed consent was obtained from the parents for this study. A homozygous variant c.1234dup (p.Glu412Glyfs*39) in exon 8 of the SCNN1B gene was identified in the infant. This variant, a nucleotide duplication, has not been reported in population genetics studies and is classified as “likely pathogenic” according to ACMG (American College of Medical Genetics) criteria (21). We plan to conduct genetic testing for the patient’s family as well, but this remains outstanding at the time of writing.

Discussion

In this article, we present our observations and the challenges encountered during the treatment process of a newborn with multisystem PHA type 1. Systemic Type 1 PHA is a rare, life-threatening condition. In the neonatal period, salt-wasting syndromes present with various clinical manifestations. Patients may present with nonspecific symptoms such as vomiting, weakness, feeding difficulties, failure to thrive, and increased tendency to sleep, or severe dehydration leading to shock (5). Typically, neonates presenting with these symptoms may initially be misdiagnosed with conditions such as CAH due to 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase deficiency, or primary hypoaldosteronism causing salt loss in the neonatal period. The diagnosis of type 1 PHA relies on high plasma aldosterone and renin levels, especially when high-dose mineralocorticoid therapy fails to correct potassium and salt imbalance. Moreover, measurements of 17-hydroxyprogesterone, adrenocorticotropin hormone, cortisol, renin, and aldosterone levels provide clues to distinguish between CAH and type 1 PHA (6). Our patient presented with hyponatremia and hyperkalemia alongside normal genitalia. Hydrocortisone and fludrocortisone were initiated until adrenal androgen results were obtained. The diagnosis of systemic type 1 PHA was confirmed as adrenal hormone levels remained within normal ranges during follow-up. Differential diagnosis in our case included transient aldosterone resistance secondary to urinary tract infection, which was ruled out due to normal urine analysis, urine culture, and urinary system ultrasonography. The co-occurrence of high aldosterone levels with hyponatremia and hyperkalemia supported renal aldosterone resistance guiding our patient’s treatment.

Type 1 PHA is classified into renal (OR) and systemic (OD) forms based on mutations in the NR3C2 gene encoding MR or SCNN1A, SCNN1B, and SCNN1G genes encoding ENaC subunits. The systemic form of type 1 PHA leads to systemic salt loss involving kidneys, colon, sweat, and salivary glands (7). In the presented case, a homozygous variant c.1234dup (p.Glu412Glyfs*39) was identified in exon 8 of the SCNN1B gene. The SCNN1B gene, comprising 13 exons and encoding a transmembrane protein with two transmembrane segments totaling 640 amino acids (8), has been associated with pathogenic variants linked to type 1 PHA and Liddle syndrome. It is anticipated that the identified homozygous variant in the SCNN1B gene at nucleotide position 1234, a duplication variant, affects protein functions. This variant has not been previously reported in the literature.

A case with a homozygous mutation detected in the promoter region of the ENaC in the SCNN1B gene also exhibited recurrent lung infections, similar to our patient. However, in this case, over time, the frequency and severity of these respiratory illnesses showed a tendency to decrease, and the lung condition stabilized after the age of six years (9). In another study reporting a case with a mutation detected in the SCNN1B gene, additional clinical features included persistent clear nasal discharge, frequent lower respiratory tract infections associated with wheezing, and developmental delay. This case, which required a gastrostomy at 14 months, showed a significant reduction in hospital admissions (1-2 per year) following the gastrostomy, although recurrent lower respiratory tract infections were still reported despite being four years old when reported (10). Similarly, another case reported recurrent chronic bronchitic attacks during childhood (11). In another case with a homozygous c.1266-1G > C variant mutation in intron 8 of the SCNN1B gene, vomiting and feeding difficulties similar to those observed in our patient were reported (12). The skin findings observed in our patient, which persisted despite treatment, have also been observed in other patients with mutations in the SCNN1B gene. Belot et al. (13) observed bullous dermatitis, while Gopal-Kothandapani et al. (8) reported severe eczema. Similarly, another case with a homozygous mutation in the SCNN1B gene presented with features mimicking pustular miliaria rubra, crystal deposition on the forehead, Meibomian gland swelling on the eyelids, and dental-like protrusions (11). These skin and ocular findings can aid in distinguishing type 1 PHA from other conditions causing salt loss, like CAH, prompting the evaluation of serum electrolytes through blood tests (14). In the literature, gastrostomy has been required in four cases due to salt loss (10, 11, 13, 15). Although not needed in our patient, during episodes of vomiting, an orogastric tube was used to administer oral therapies. Hyperkalemia can be life-threatening due to the risk of cardiac arrhythmias. Publications have reported peritoneal dialysis being performed to correct hyperkalemia, as required in the present case (6, 8, 16, 17, 18, 19).

Since systemic Type 1 PHA can be more refractory to treatment, it is essential to learn from less commonly known approaches. Further guidance for sodium polystyrene sulfonate (brand name: Kayexalate, kalexate, and kionex; molecular weight 70,000 atomic mass units; concentration 15 g/60 mL) administration in neonates and infants under the care of endocrinology is necessary (20). There is limited guidance in the literature on specifically how to give sodium polystyrene sulfonate to neonates and infants, specifically the optimally safe method of transitioning from decanting formula to giving it directly. Sodium polystyrene sulfonate dosing in several children between the ages of 1.75 and 3.25 years old ranged from 0.4 to 3.4 g/kg/day; however, the dosing and method of administration varied (2). Initial direct administration is not always feasible in neonates, to minimize risks such as gastrointestinal bleeding (2). Sodium polystyrene sulfonate can effectively treat hyperkalemia in type 1 PHA, but it is not routinely available in our country. Therefore, we used calcium polystyrene sulfonate in the treatment of our patient.

Conclusion

Clinical suspicion of PHA, aggressive treatment with IV hydration, sodium and bicarbonate supplementation, and correction of hyperkalemia are crucial. Publishing patients’ clinical symptoms and genetic changes, and establishing clearer links between reported mutations and clinical outcomes, will lead to earlier clinical diagnosis and effective genetic counseling for families affected by PHA.