|Year : 2022 | Volume
| Issue : 3 | Page : 61-63
Applied genetics in pediatric practice: Case series on pseudohypoaldosteronism
M Shagufa1, Preetha Remesh2, MR Anand2, PT Vishnu Mohan2, Divya Pachat3
1 Department of Paediatrics, Malabar Institute of Medical Sciences, Calicut, India
2 Department of Neonatology, Malabar Institute of Medical Sciences, Calicut, India
3 Medical Genetics, Malabar Institute of Medical Sciences, Calicut, Kerala, India
|Date of Submission||09-Mar-2023|
|Date of Decision||05-Apr-2023|
|Date of Acceptance||16-Apr-2023|
|Date of Web Publication||29-Aug-2023|
Dr. M Shagufa
Department of Paediatrics and Neonatology, Aster Malabar Institute of Medical Sciences, Calicut 673016, Kerala
Source of Support: None, Conflict of Interest: None
Systemic pseudohypoaldosteronism (PHA) type I is a rare genetic disorder resulting from mutations in the subunits of the epithelial sodium channel that manifests as severe salt wasting, hyperkalemia, and metabolic acidosis in infancy. In this article, we report two cases with systemic PHA presented as a shock in the early neonatal period. They were found to have a known mutation in the SCNN1A gene and subsequently required long-term treatment with high-dose fludrocortisone, antihyperkalemic measures, and added salt in diet. In any neonate who presents with hyponatremia, hyperkalemia, metabolic acidosis, dehydration, shock, and failure to thrive, pediatricians should consider the possibility of PHA as it could be potentially lethal if the diagnosis is delayed. It is also important to differentiate such cases from congenital adrenal hyperplasia.
Keywords: Pseudohypoaldosteronism, salt-wasting crisis, hyperkalemia in infancy
|How to cite this article:|
Shagufa M, Remesh P, Anand M R, Vishnu Mohan P T, Pachat D. Applied genetics in pediatric practice: Case series on pseudohypoaldosteronism. Pediatr Companion 2022;1:61-3
| Introduction|| |
Type 1 pseudohypoaldosteronism (PHA) is a rare hereditary disorder characterized by generalized resistance to actions of aldosterone. This condition typically presents in the neonatal period with sodium wasting, hypovolemia, hyperkalemia, and metabolic acidosis. There are two forms, a relatively mild autosomal dominant form caused by mutations in the NR3C2 gene encoding human mineralocorticoid receptor and a more severe autosomal recessive form due to homozygous mutation in the subunits of the epithelial sodium channel.
When faced with a combination of hyponatremia and hyperkalemia, one must consider not only the commoner congenital adrenal hyperplasia but also its mimics like type 4 renal tubular acidosis (RTA), aldosterone synthase deficiency, and PHA.
Here, we present two cases of systemic PHA type I presented as shock in the early neonatal period.
| Case history|| |
Eleven days old baby presented with a history of poor activity and poor feeding from day of life 9. The baby was born full term by vaginal delivery with a birth weight of 3.15 kg to a third-degree consanguineous marriage with a maternal history of hypothyroidism. Examination showed the baby in profound shock and needed resuscitation with invasive positive pressure ventilation, fluid boluses, inotropes, and steroids.
The baby had normal female genitalia; lab investigations revealed hyponatremia, hyperkalemia, and marked metabolic acidosis. The baby had normal sugars and negative septic screening. ultrasound abdomen abdomen, serum 17-hydroxyprogesterone, and renal function tests were normal.
Further evaluation showed both plasma aldosterone and plasma renin activity far above its normal range. Clinical profiles with corroborative lab reports favor the possibility of PHA. Once the acute crisis was tided over, the baby was stabilized on oral hydrocortisone, high-dose fludrocortisone, added salt in diet, and oral antihyperkalemic measures. No history of similar illness in the family.
Genetic evaluation detected a likely pathogenic homozygous splicer donor variant in SCNN1A (ENaC alpha), a known gene of PHA type 1.
A term neonate, appropriate for gestational age, presented with unresponsiveness on day 8 of life. The baby was born to a third-degree consanguineous marriage by lower segment caesarean section with no maternal comorbidities. Examination showed the baby in near cardiac arrest, in profound shock, resuscitated with multiple fluid boluses, invasive positive pressure ventilation, inotropes, iv calcium, and steroids. Postresuscitation showed ill-looking, pale, severely dehydrated baby with feeble peripheral pulses.
Lab investigations showed life-threatening hyperkalemia with hyponatremia and marked metabolic acidosis. Peritoneal dialysis was initiated as serum potassium levels continued to be high despite stringent antihyperkalemic measures. The baby had normal female genitalia, renal ultrasound, renal function tests, and 17-hydroxyprogesterone levels were normal. No similar family history.
Further evaluation showed markedly high-serum aldosterone along with a similar elevation in plasma renin activity. Considered the possibility of PHA and baby stabilized with high-dose mineralocorticoids along with anti hyperkalemic measures and added salt in diet.
Genetic studies confirmed the diagnosis of PHA, likely a pathogenic homozygous splice-donor variant in SCNN1A (ENaC alpha) was detected.
| Discussion|| |
Systemic PHA typically presents in the neonatal period with severe salt-wasting crisis with hyponatremia, hyperkalemia, acidosis, and dehydration.
Initial presentation may be confused with salt-wasting congenital adrenal hyperplasia or RTA type IV. Salt wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency leads to cortisol and aldosterone deficiency, leading to the same presenting symptoms as aldosterone resistance that is characteristic of systemic PHA type 1. Females with salt-wasting congenital adrenal hyperplasia are born with virilized genitalia due to elevated androgen levels and high-serum 17 hydroxy progesterone levels. RTA type IV typically presents with mild hyponatremia, hyperkalemia, and metabolic acidosis with aldosterone deficiency. Hence, laboratory workup should include serum aldosterone as well as renin levels to differentiate among them.
Two different modes of inheritance have been described for PHA. Autosomal recessive PHA type 1, involving the epithelial sodium channel (ENaC), in which the defect is permanent and affects all aldosterone target organs. Autosomal dominant or sporadic PHA type 1, which is due to heterozygous pathogenic variants in the NR3C2 gene coding for the mineralocorticoid receptor, in which the defect is limited to the kidney. Both of our babies likely had pathogenic splice-donor variants in SCNN1A gene. This variant is likely disease causing because minor allele frequency is extremely rare, and CADD prediction score is relatively high. They had no similar family history, nor their parental genetic evaluation was done.
Our patients with autosomal recessive PHA type I had a difficult clinical course, requiring intensive support for the stabilization of electrolytes. Recurrent salt-wasting crisis and severe hyperkalemia can lead to life-threatening cardiac arrhythmias and cardiac arrest. After recovery from acute crisis, infants can be managed with high dose of oral salt supplements for hyponatremia, oral sodium bicarbonate for metabolic acidosis as well as chronic ion exchange resin therapy for hyperkalemia.
An autosomal recessive form of PHA Type I is more severe as salt loss is not confined to kidney but instead occurs from most epithelia. It is often difficult to control electrolyte abnormalities leading to frequent hospitalizations and a need for close clinical monitoring. It is noteworthy that signs & symptoms of aldosterone deficiency tend to remit as the patient gets older, particularly in the autosomal dominant form.
| Conclusion|| |
These case series highlight the nonspecific nature of clinical presentation, in systemic PHA type 1, which results in delayed diagnosis and an increased chance of mortality.
Even though the clinical diagnosis is certain in many disorders, molecular diagnosis is important because the type of variant may affect the disease severity and aids in appropriate disease prognostication.
It is essential for the treating pediatrician to do genetic counseling along with molecular testing for the index baby so that the family can be benefitted during subsequent pregnancy, as done in both of our cases.
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Conflicts of interest
There are no conflicts of interest.
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