Diagnostic and management considerations in pseudohypoaldosteronism type 1b

Abstract

Pseudohypoaldosteronism type 1B is a rare autosomal recessive disorder caused by dysfunction of amiloride-sensitive epithelial sodium channels (ENaCs). We present the case of a neonate with cardiogenic shock after cardiac arrest due to profound hyperkalaemia. Genetic testing revealed a novel homozygous variant in SCNNIA. We review diagnostic considerations including the molecular mechanisms of disease, discuss treatment approaches and highlight the possible significance of the diversity of pulmonary ENaCs.

Background

Aldosterone plays a central role in regulating sodium and potassium homeostasis through its effects on the distal nephron. It facilitates potassium excretion by stimulating the basolateral sodium-potassium-ATPase and by increasing the potassium permeability of the luminal membrane.¹ Conversely, it induces the kidney-specific Ser/Thr kinase WNK1, leading to increased amiloride-sensitive epithelial sodium channel (ENaC)-mediated sodium reabsorption.¹ In pseudohypoaldosteronism (PHA), the distal nephron fails to respond to stimulation by aldosterone, resulting in hyponatraemia and hyperkalaemia.² PHA can be subdivided based on presentation and underlying aetiology: type 1 is characterised by hyponatraemia, hyperkalaemia and metabolic acidosis with increased serum aldosterone levels; type 2, also known as Gordon syndrome, presents with hyperkalaemia and hypertension; and type 3 is an acquired defect in the setting of chronic kidney disease.^{3 4} PHA type 1 (PHA1) can be further subclassified into PHA type 1A (PHA1A (Mendelian Inheritance in Man (MIM) number: 177 735)), an autosomal dominant renal form due to heterozygous mutations in the mineralocorticoid receptor, and PHA type 1B (PHA1B (MIM: 264 350)), an autosomal recessive condition that affects multiple organs. PHA1B can lead to severe life-long disease characterised by recurrent salt-wasting episodes and pulmonary infections.⁵ We present the case of a neonate who witnessed an at-home cardiac arrest.

Case presentation

Our patient is the product of a dizygotic twin pregnancy born via caesarean section at 37 weeks of gestation. She was born to non-consanguineous parents of Asian descent. She had an uncomplicated initial hospital stay. Her parents report that after leaving the hospital, she struggled with establishing good oral intake. There is no family history of sudden death in infancy and the patient’s fraternal twin sister has no medical issues. In the first week of life, her father noted a brief episode of apnoea and loss of tone that self-resolved. Later that week, the patient had a nighttime episode of non-bloody, non-bilious emesis. When her father checked on the patient 3 hours after this event, he noted she had decreased responsiveness and apnoea. Emergency medical services (EMS) were called, and her father performed cardiopulmonary resuscitation until EMS arrival. EMS administered epinephrine and the infant was taken to a local emergency department where she was intubated and resuscitated. Initial blood gas evaluation revealed a pH of 6.7 and a base deficit of 33. Further biochemical assessment revealed a serum sodium concentration of 119 mmol/L and a serum potassium concentration above the limit of detection (>9 mmol/L).

On physical examination, congenital abnormalities and hyperpigmentation were absent and the infant had normal female external genitalia without virilisation or palpable gonads. An echocardiogram revealed no anatomical cardiac abnormalities. ECG findings were consistent with hyperkalaemia.

Investigations

A random serum cortisol concentration was appropriately elevated at 42.9 µg/dL. Renal ultrasound was significant for elevated parenchymal resistive indices, a non-specific finding, but otherwise unremarkable. Urine and blood cultures were obtained and remained sterile.

A serum aldosterone level collected at presentation was profoundly elevated at 1328 ng/dL (reference range, 5.0–102.0 ng/dL) consistent with PHA. The newborn screen was unremarkable, including a normal 17-hydroxyprogesterone.

A rapid PHA type 1 panel was completed at Prevention Genetics and included the genes NR3C2, SCNN1A, SCNN1B and SCNN1G. This panel was performed using next-generation sequencing and exome capture probes for these genes. This analysis included 100% coverage of all coding exons including 10 bases of flanking non-coding DNA in all available transcripts along with other non-coding regions in which prior pathogenic variants have been identified in these genes. This test identified a homozygous variant of uncertain significance (c.684G>T; p.=) in SCNN1A. This genetic evidence along with the clinical presentation confirmed the diagnosis of PHA1B.

Differential diagnosis

The triad of hyperkalaemia, hyponatraemia and acidosis without evidence of cortisol deficiency found in our patient suggests an absolute or relative mineralocorticoid deficiency, of which the most common form presenting in infancy is salt-wasting congenital adrenal hyperplasia. Given our patient’s presentation, we initiated treatment with fludrocortisone just above the range recommended for treatment of salt-wasting congenital adrenal hyperplasia (0.05–0.2 mg/day).⁶ However, both the robust serum cortisol level during acute illness, along with 17-OH progesterone levels from the newborn screen, and lack of virilisation noted on physical examination excluded this diagnosis.

While we were unable to obtain enough blood to run this test at presentation, obtaining a renin level may indicate whether the aldosterone pathway is being appropriately stimulated. Obtaining levels of 11-deoxy-corticosterone, corticosterone, 18-OH corticosterone and aldosterone ensures adequate aldosterone synthesis or, if abnormal, can help locate the level of the defect. A significantly increased aldosterone level without appropriate renal response as seen in our patient is diagnostic for aldosterone resistance of PHA.

Treatment

Hyperkalaemia was treated with sodium bicarbonate, albuterol, insulin and furosemide. Fludrocortisone treatment was initiated at 0.1 mg via nasogastric tube every 8 hours (0.11 mg/kg/day or 0.3 mg/day) based on concern for mineralocorticoid deficiency. Over the following days, due to persistent hyperkalaemia, the fludrocortisone dose was increased to 0.3 mg every 6 hours (0.44 mg/kg/day or 1.2 mg/day).

Outcome and follow-up

The patient was successfully extubated to non-invasive support by the end of her first week in the hospital and weaned to room air by the end of week 3.

Discussion

PHA1B is a multisystem disease caused by dysfunction of the ENaC.³ In humans, ENaCs are made up of a combination of subunits α, β, γ and/or δ.⁷ These subunits are encoded by SCNN1A on chromosome 12p, SCNN1B and SCNN1G on chromosome 16p, and SCNN1D on chromosome 1p.⁷ The specific subunits expressed and combined to make up an ENaC vary between tissues. To date, mutations in SCNN1A, SCNN1B and SCNN1G but not SCNN1D have been associated with PHA1B.⁷ This observation is consistent with the expression pattern found in humans; SCNN1A, SCNN1B and SCNN1C are expressed in the kidney, lung, salivary gland, skin and colon, while SCNN1D is expressed mostly in the brain, pancreas and testis.⁷

Our patient was found to be homozygous for a variant of unknown significance within the SCNN1A gene, 684G>T, located within exon 3 of the gene. While this variant is not expected to result in an amino acid substitution, it is expected to abolish the canonical donor splice site (as predicted by Alamut Visual V.2.11) as this variant impacts the last nucleotide of the exon bordering the neighbouring intron. Of note, this variant is not present in the large human population control database GnomAD, which can be consistent with frequency for a pathogenic-acting variant in a recessive condition.⁸ Similar splice site variations have been reported in association with SCNN1A-related PHA1B in patients, supporting splice site variations as a mechanism of disease.⁹ Homozygous loss of exon 3 of the SCNN1A gene is consistent with loss of function of ENaC activity, leading to disruption of sodium absorption and potassium excretion across the apical epithelium of the kidney.¹⁰ The implications of this genotype were discussed with the family by our genetic team. As PHA1B is an autosomal recessive disease, the 25% recurrence risk should be explained at diagnosis and prenatal diagnostic tests should be offered during future pregnancies.

Initial management for PHA1 is supportive and aimed at controlling serum potassium levels to prevent life-threatening arrythmias. To this end, administration of calcium gluconate to prevent cardiac arrythmias, insulin and albuterol to shift potassium intracellularly, and loop diuretics and potassium binding resins are frequently used. Given the severity of our patient’s initial presentation, the choice was made to refrain from initiation of potassium-binding resins due to concern for intestinal ischaemia. Given ongoing hyperkalaemia, the patient was started on fludrocortisone. This was weaned after the diagnosis of PHA1B was made because of the lack of data supporting its use in these patients. Surprisingly, the patient consequently developed worsening hyperkalaemia. It seems most likely that this was due to concurrent changes to the patient’s parenteral nutrition. However, because of this episode the patient currently remains on fludrocortisone 0.2 mg two times per day (0.025 mg/kg/dose or 0.05 mg/kg/day). There is one reported case of an early adolescent male with PHA1 who seemed to have responded to fludrocortisone. However, the authors were unable to explain why this same patient had no response to high-dose fludrocortisone in infancy, and no disease-causing mutation was found in their patient.¹¹ After initial stabilisation and diagnosis, long-term sodium replacement and potassium monitoring are required. Sodium replacement should be titrated to effect, and doses up to 45 g/day have been reported.⁵ Potassium-binding resins are used for long-term potassium control.² Specifically, in a recent cohort study, sodium resonium was helpful in obtaining hyperkalaemia control and was initiated as early as the neonatal period.¹² Furthermore, a written emergency treatment plan should be frequently reviewed with the family and available for the family to share with emergency services as required.

With potassium-lowering therapies as outlined above and aggressive sodium replacement, the patient’s electrolytes stabilised. The patient was discharged home on day of life (DOL) 47. The cardiology service was consulted in the care of this patient, and since discharge the patient has experienced no further clinically significant cardiac arrythmias. The patient has experienced two brief hospitalisations at 2 months and 3 months of age for hyperkalaemia requiring adjustments in her nutritional regimen. She is currently meeting her developmental milestones despite some increased muscular spasticity and is working closely with physical therapy. She is also followed by both endocrinology and nephrology services and remains on sodium chloride (3 mEq/kg/day) and sodium citrate (3 mEq/kg/day).

In addition to severe electrolyte abnormalities, some patients with PHA1B suffer from frequent pulmonary infections.⁴ This is thought to be due to the loss of normal ENaC transport, leading to increased airway surface liquid (ASL).⁷ This situation contrasts with cystic fibrosis (CF (MIM: 219 700)) in which CFTR dysfunction leads to decreased inhibition of ENaCs, thereby decreasing the amount of ASL.⁷ The end result, however, is similar to decreased ciliary function due to the lack of correct ASL regulation leading to recurrent lower airway infections both in CF and in PHA1B.⁷ Of note, for some unknown reason, chronic lung disease and bronchiectasis seen in CF have not been reported in PHA1B.¹³ No clear correlation between the genotype and pulmonary phenotype has been described to date.⁵

It is worth noting that in many tissues, ENaCs are thought to be highly selective for sodium over potassium transport and have a trimeric structure composed of an α-subunit, β-subunit and γ-subunit^{14 15} However, specifically in lung tissue, ENaCs with a different composition play a role in non-selective cation transport.¹¹ It has been suggested that a channel that does not distinguish between sodium and potassium transport may be formed by either three α-subunits or two α-subunits in combination with a β-subunit or a γ-subunit.¹⁶ The importance of this alternative configuration is underscored by the observation that neonatal mice lacking β-subunits or γ-subunits are able to clear fetal lung fluid, although slowly, while those lacking the α-subunit are completely unable to do so.¹⁷ Given this, one might expect that those patients with no residual functional α-subunits would be especially predisposed for pulmonary complications; indeed, initially, it was suggested that pulmonary complications may be limited to those with mutations in the SCNN1A gene.¹³ While our patient had no respiratory distress in the postnatal period, she did develop a wet cough in the first weeks of life that has persisted despite initiation of chest physical therapy two times a day to help augment her airway clearance. Over the next few months, this wet cough resolved. To date, our patient has not developed any significant pulmonary infections. While the lack of evidence for any significant benefit to chest physical therapy has been discussed with the family, they have so far elected to continue administering it two times a day hoping to help prevent possible future infections.

β-agonists are known to increase transepithelial sodium transport in the lung.¹⁸ Specifically, terbutaline has been shown to enhance the expression of the ENaC α-subunit, an effect that is blocked by propranolol.¹⁹ The clinical relevance of this observation is supported by increased fluid clearance by human tissue seen after stimulation with salmeterol.²⁰ While to our knowledge no clinical data are available, it may be reasonable to trial β-agonists in patients with PHA1B with significant pulmonary symptoms to optimise any residual ENaC function. To date, our patient has not experienced significant pulmonary complications warranting a trial of β-agonists.

Learning points.

• In newborns with hyperkalaemia, hyponatraemia and acidosis, hyperaldosteronism without appropriate renal response is diagnostic for pseudohypoaldosteronism type 1 (PHA1). Genetic testing can help distinguish dominant and localised PHA1A from the recessive and systemic PHA1B

• Initial management of PHA1B aims to rapidly decrease serum potassium levels to prevent life-threatening arrythmias. This follows the traditional approach of shifting potassium intracellularly and using potassium-binding resins. However, there are currently no data to support the use of fludrocortisone in this population.

• Long-term management includes sodium supplementation and preventing pulmonary infections as these infections can become a frequent cause of morbidity and mortality in PHA1B. There is a diversity of pulmonary epithelial sodium channels, and the α-subunit may be especially important in pulmonary physiology.

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