From crisis to catch-up: Reversing salt-wasting in an Indian infant with CMO II deficiency – A case report

INTRODUCTION

Aldosterone synthase (CYP11B2, corticosterone methyl oxidase [CMO]) is the only enzyme responsible for aldosterone production in the body. The CYP11B2 enzyme is expressed in the zona glomerulosa of the adrenal cortex, where it catalyzes the 11 and 18-hydroxylation (by CMO I) and 18-oxidation (by CMO II) of deoxycorticosterone.^[1] Isolated aldosterone deficiency, due to CYP112 gene mutations, is an uncommon but important differential in infants with salt-wasting, dehydration, and growth failure. Clinical presentation in both CMO I and II deficiencies is similar, with undetectable aldosterone. 18-hydroxycorticosterone is decreased in CMO I deficiency, while elevated in the other.^[2] Early diagnosis and mineralocorticoid replacement lead to excellent outcomes.^[3] In India, genetically confirmed cases of aldosterone synthase deficiency (ASD), particularly CMO II deficiency, remain rare due to limited awareness and access to advanced diagnostics. Only a handful of cases have been published, highlighting the importance of clinical suspicion in infants with unexplained electrolyte imbalances.

CASE REPORT

A 7-month-old Indian male infant presented with vomiting, failure to thrive, and developmental delay. He was born at term with a birth weight of 2.7 kg to non-consanguineous parents, with a short neonatal intensive care unit (NICU) stay for neonatal jaundice. The perinatal period was uneventful. Family history was non-contributory. He had a prior hospital admission at 24 days of life with similar complaints of vomiting, but no definitive diagnosis was made.

The mother observed progressive lethargy, poor feeding, persistent vomiting, and reduced activity levels. There was no history of loose stools, fever, respiratory distress, seizures, or hypoglycemic episodes. Importantly, signs and symptoms typically associated with electrolyte imbalances—such as irritability, poor weight gain, failure to thrive, and hypotonia —were evident. However, symptoms of hypoglycemia (such as jitteriness, apnea, or altered consciousness) were not observed.

On physical examination, the child was dehydrated and underweight (4.3 kg, Z-score −5.81), with hypotonia and global developmental delay. Length (61.5 cm, Z-score −3.53) and head circumference (40.2 cm, Z-score −3.07) were also <3^rd percentile. No dysmorphic features, hyperpigmentation, or external genital abnormalities were present. Blood pressure was 76/48 mm Hg, suggestive of volume depletion— below the 5^th percentile for age, consistent with hypotension due to intravascular volume depletion from salt wasting.

Initial laboratory investigations revealed hyponatremia (Na 124.7 mmol/L), hyperkalemia (K 5.92 mmol/L), hypochloremia (Cl 82 mmol/L), elevated blood urea nitrogen (121.6 mg/dL), normal creatinine (0.4 mg/dL), and metabolic acidosis (pH 7.33, HCO₃ 13.6 mmol/L). Blood glucose, liver functions, and calcium levels were normal. 17-hydroxyprogesterone was also normal (0.2 ng/mL). Renal ultrasonography showed increased echogenicity of both renal parenchyma without obstructive uropathy.

At the nephrology clinic, the child was managed with potassium-lowering agents, 3% sodium chloride supplementation (3 mmol/kg/day), and sodium bicarbonate to correct the electrolyte and acid–base disturbances. Genetic testing was sent, and these measures were continued until the report was available. The whole exome sequencing revealed two known compound heterozygous mutations in CYP11B2. Next-generation sequencing (Whole exome sequencing, Orion® panel, Neuberg Center for Genomic Medicine) detected two compound heterozygous variants in the CYP11B2 gene (NM_000498.3) —c.554C>T (p.Thr185Ile) in exon 3 and c.1342C>T (p.Arg448Cys) in exon 8. Both are missense variants located within catalytic domains of aldosterone synthase, previously reported as pathogenic/likely pathogenic in CMO type II deficiency. The p.Thr185Ile variant is classified as pathogenic and has been functionally shown to impair enzyme activity, while the p.Arg448Cys variant is classified as likely pathogenic. Zygosity was confirmed as heterozygous for each variant, consistent with an autosomal recessive inheritance pattern. Parental testing was recommended to confirm the phase of the variants.

• c.554C>T (p.Thr185Ile)^[4]

• c.1342C>T (p.Arg448Cys)^[3]

This confirmed CMO II deficiency, a subtype of ASD. Urine sodium and serum aldosterone could not be measured at the time of diagnosis.

The child was started on fludrocortisone 100 µg twice a day. Alongside fludrocortisone, oral sodium chloride supplementation (3 mmol/kg/day) was continued during the initial stabilization phase and, with serial monitoring, gradually tapered off over 2 weeks as electrolyte imbalances normalized. Good catch-up in growth and development was observed [Table 1]. Subsequently, the infant was maintained on oral fludrocortisone and multivitamin supplements.

DISCUSSION

ASD is a rare but potentially life-threatening disorder of mineralocorticoid biosynthesis. It results from mutations in the CYP11B2 gene, which encodes the aldosterone synthase enzyme responsible for the terminal steps of aldosterone production. In this process, corticosterone is converted into 18-hydroxycorticosterone and then to aldosterone by the sequential actions of CMO I and CMO II enzymatic activities, both governed by CYP11B2.^[1] Deficiencies in either of these enzymatic steps manifest as aldosterone deficiency, with CMO II deficiency being associated with elevated 18-hydroxycorticosterone.^[2]

Our patient presented with hallmark features of salt-wasting: vomiting, failure to thrive, poor weight gain, and developmental delay. Notably, the clinical course showed an initial transient improvement with nutritional therapy at 5 months, which may have obscured the underlying endocrine etiology. However, the rapid decline following cessation of therapeutic feeds, along with persistent biochemical disturbances—including hyponatremia, hyperkalemia, hypochloremia, and metabolic acidosis— prompted a more thorough investigation. These biochemical imbalances are characteristic of mineralocorticoid deficiency and indicate impaired sodium retention and potassium excretion at the renal level due to inadequate aldosterone action.

Genetic testing played a pivotal role in establishing a definitive diagnosis. The availability and affordability of next-generation sequencing have revolutionized the diagnosis of rare monogenic endocrine disorders, enabling early detection and precise classification.^[5] Although plasma renin was measured 1 month after starting fludrocortisone, it was mildly elevated (3.39 ng/mL/h), supporting the underlying diagnosis of mineralocorticoid deficiency.

The therapeutic response to fludrocortisone, a synthetic mineralocorticoid, was rapid and dramatic. Initiation of fludrocortisone at 100 μg twice daily led to improvement in both anthropometric parameters and neurodevelopmental milestones. These outcomes affirm the crucial role of aldosterone in maintaining electrolyte balance, blood pressure, extracellular fluid volume, and indirectly, nutritional status and brain development in infancy.^[2,6] It is important to note that while dietary supplementation and symptomatic treatments can temporarily stabilize such patients, only specific hormonal therapy addresses the root biochemical defect.

Importantly, as mineralocorticoid sensitivity improves with age—due to maturation of renal tubules and an evolving sodium-rich diet—dosage reduction of fludrocortisone is often necessary.^[7] Many children do not require therapy for long. Long-term follow-up is essential, not only to titrate therapy but also to monitor linear growth, pubertal development, and screen for potential complications. Genetic counseling and testing the parents is important for affected families, particularly for future reproductive planning, as most genetic defects follow an autosomal recessive inheritance pattern.^[3,5]

This case adds to the limited but growing literature on ASD and CMO II deficiency from the Indian subcontinent. It reinforces the need for pediatricians to be vigilant for endocrine causes in infants who do not respond adequately to nutritional interventions and exhibit persistent electrolyte abnormalities. Raising awareness among frontline clinicians, especially in resource-limited settings, can facilitate early recognition and timely intervention—factors that are pivotal in ensuring optimal growth, neurodevelopmental outcomes, and quality of life for affected children. Compared to the only other genetically suspected Indian case of congenital ASD—reported in a 4-month-old infant in Chennai^[8]—our case was genetically identified earlier, allowing for timely treatment and resulting in significant growth and developmental catch-up.

CONCLUSION

ASD should be considered in infants presenting with unexplained hyponatremia and hyperkalemia without signs of glucocorticoid deficiency. Genetic confirmation and appropriate mineralocorticoid therapy result in significant clinical improvement. Our case illustrates that prompt diagnosis and targeted treatment of CMO II deficiency can lead to reversal of growth and developmental delays, offering a favorable long-term prognosis.