Electrolyte Imbalance and Growth Failure: Unravelling the Connection to Infantile Hyponatremia

A 19-day-old girl born full-term via an uncomplicated vaginal delivery presents to the pediatrician with ongoing weight loss. She weighs 2.89 kg today, down by 15% from her birth weight of 3.39 kg. She has been exclusively breastfed, every 2 to 3 hours for 5 to 10 minutes per side. Her mother has also been pumping and storing the excess milk. Her newborn screen was normal, and there is no history of losses in the form of diarrhea/vomiting or other sick symptoms that can explain the weight loss. She continues to produce 5 to 6 wet diapers daily. Previously, at her 1-week health supervision visit, she had lost 540 g (16% loss from birth weight), and her pediatrician had recommended that she receive an additional 1 to 2 oz of expressed breast milk after each feed. Attempts had also been made to fortify breast milk to 22 kcal/oz; however, the baby seemed fussier with the fortified milk intake. On examination, she is afebrile with a heart rate of 161 beats/min, respiratory rate of 36 breaths/min, and blood pressure of 92/64 mm Hg. She appears well-hydrated with a capillary refill of less than 2 seconds. She is thin but overall, well-appearing without dysmorphic features or virilization, and the rest of the physical examination is normal. Laboratory studies obtained by the pediatrician reveal a sodium of 129 mEq/L, potassium of 7.5 mEq/L, chloride of 93 mEq/L, bicarbonate of 18 mEq/L, serum urea nitrogen of 23 mg/dL, creatinine of 0.31 mg/dL, glucose of 84 mg/dL, and calcium of 12.4 mg/dL. The pediatrician recommends admission to a children’s hospital for failure to gain weight and electrolyte abnormalities.On admission, she is resuscitated with intravenous fluids, and the endocrinology team is consulted based on a suspicion of adrenal insufficiency. A 125 μg cosyntropin stimulation test reveals a baseline cortisol of 17.7 ug/dl and a 60-minute peak of 73.5 ug/dl (normal response >18 ug/dl). This result, along with a negative newborn screen and normal appearing female external genitalia, makes congenital adrenal hyperplasia (CAH) highly unlikely. A nephrology consultation is obtained. Her urinalysis is unremarkable with no concern for urinary tract infection. Her spot urinary sodium is 45 mmol/L (10–20 mmol/L), and a renal ultrasonography reveals mild left-sided hydronephrosis. Renin and aldosterone levels are obtained, but do not result at the time of hospital discharge. As per the lactation service recommendations, breastfeeding frequency is increased to every 2 hours, along with fortification of expressed breast milk and addition of hydrolyzed 27 kcal/oz formula feeds. With increased caloric intake and fluid resuscitation, her sodium improves to 135 mEq/L, potassium decreases to 5.8 mEq/L, bicarbonate increases to 24 mEq/L, and calcium decreases to 11.4 mg/dl over the next 3 to 5 days. She has gained 250 g over 4 days and is discharged home on day of life 24 with instructions to continue fortified and frequent feedings.However, at a follow-up appointment with her pediatrician on day 26 of life, she had lost 96 g again despite adequate feeding, and her laboratory studies demonstrated hyponatremia and hyperkalemia (sodium 131 mEq/L, potassium 6.3 mEq/L, bicarbonate 22 mEq/L, serum urea nitrogen 17 mg/dL, creatinine 0.31 mg/dL). She is admitted to the hospital for a second time because of her persistent electrolyte abnormalities and inability to gain weight. During this hospital admission, the nephrology and endocrinology services are reconsulted. Previous laboratory studies revealed markedly elevated levels of renin at 218 ng/ml (normal range 0.25–5.82 ng/ml) and aldosterone at 1851 ng/dl (normal A, AG Acceptor) reported as likely pathogenic and confirmed the diagnosis of pseudohypoaldosteronism type 1a (PHA1a).Pseudohypoaldosteronism type 1 (PHA1) is characterized by a clinical picture of hyponatremia, hyperkalemia, and metabolic acidosis with unusually high serum aldosterone and renin levels. Based on the underlying genetic defect and presentation, it is classified into 2 forms: renal (PHA1a) and systemic (PHA1b). PHA1a (renal) is caused by autosomal dominant mutations in the NR3C2 gene encoding the mineralocorticoid receptor, resulting in aldosterone (mineralocorticoid) unresponsiveness and salt wasting in the kidneys.3 As PHA1a is restricted to the kidneys, it has a milder presentation that improves with age. In the systemic form, autosomal recessive mutations in ENaC cause defective sodium transport in multiple organs such as the lungs, kidneys, colon, salivary, and sweat glands, resulting in a more severe and lifelong condition.4 Both forms present with salt wasting, hyperkalemia, and metabolic acidosis in the neonatal period, but PHA1b patients additionally exhibit severe respiratory symptoms, failure to gain weight, and recurrent pulmonary infections due to abnormal sodium transport in the lungs.5 Laboratory findings show elevated plasma renin activity and aldosterone levels in both types, with the multiorgan involvement in PHA1b. Genetic testing provides definitive confirmation of the diagnosis, but treatment should be initiated immediately based on clinical and laboratory findings, as the therapeutic response is typically rapid and can be lifesaving while simultaneously supporting the diagnostic impression.Treatment of PHA1 focuses on managing electrolyte imbalances and preventing salt-wasting crises with marked differences between the 2 forms.6,7 PHA1a responds well to salt supplementation and often improves with age, allowing weaning of therapy. PHA1b requires lifelong intensive management, including high-dose salt supplementation, potassium-binding resins, and aggressive pulmonary care with chest physiotherapy and prompt infection treatment. PHA1a has a favorable prognosis, while PHA1b carries higher morbidity and mortality risks, especially in neonates. In PHA1a, the cornerstone of management is high-dose oral sodium chloride supplementation, often requiring 3 to 20 mEq/kg/d (daily need is 1–3 mEq/kg/d) or more, which can be administered through a specially prepared formula in infants or the addition of sodium chloride (NaCl) to breast milk.8 NaCl is available in liquid and tablet formulations, with table salt as an alternative when less precise dosing is acceptable. In older infants, where the diet includes foods with higher sodium content, the need for additional sodium supplementation is less essential. Potassium management involves dietary restriction and sometimes the use of cation exchange resin, such as polystyrene sulfonate. Sodium bicarbonate may be needed to correct metabolic acidosis. Fludrocortisone is typically ineffective because of aldosterone resistance.The infant responded well to salt supplementation. Treatment consisted of sodium chloride supplementation (4 mEq/kg/d) administered in breast milk, divided into 2 to 3 doses daily. The patient responded remarkably well, requiring neither potassium-lowering interventions nor acidosis management. Fortification of breastmilk with formula was tapered as consistent weight gain was achieved. She has since been growing and developing well on the 3 to 4 mEq/kg/d of sodium. Currently aged at 9 months, she has achieved the 60th percentile for weight (see Figure 2) and has been switched to standard table salt for supplementation (quarter teaspoon of table salt, which was equivalent to 3 mEq/kg/d for her). This approach allows for more flexible dosing and easier integration into meals. While precise measurement is less crucial now, we continue to monitor the child's overall salt intake and clinical status. In terms of genetic counseling, it was performed by the geneticist, and parents declined further familial genetic testing, citing completed family planning.9 Interestingly, a retrospective history revealed that the patient's older siblings have always preferred salty foods. This likely reflects the lack of genotype- phenotype correlation and phenotypic variability seen in this condition, with the presumption that the siblings have the same variant as our case but did not experience similar symptoms. Given that most children aged 3 years with isolated PHA1a outgrow the condition, we plan to closely monitor our patient over time while gradually weaning off supplementation.Have a high index of suspicion of pseudohypoaldosteronism (type 1a and 1b) as a cause of failure to gain weight in infants with clinical presentation of hyponatremia, hyperkalemia, and metabolic acidosis.10Urinary tract infections, renal tubular acidosis, and adrenal disorders such as CAH and adrenal hypoplasia congenita are primary considerations in the differential diagnosis of PHA1.Paradoxically high aldosterone levels despite hyponatremia are a key diagnostic clue for PHA (pseudohypoaldosteronism)Targeted genetic testing, if available, is a valuable tool to confirm diagnosis, assess prognosis, and aid in management.11Treatment requires aggressive sodium supplementation and close electrolyte monitoring during infancy. Systemic PHA type 1b requires lifelong management.