A case report on pseudohypoaldosteronism with a pathogenic mutation of CA12 causes autosomal recessive isolated hyperchlorhidrosis disorder

ABSTRACT

Pseudohypoaldosteronism (PHA) is a rare genetic condition characterized by the body’s inability to respond properly to the hormone aldosterone, which is essential for regulating sodium and potassium levels, as well as maintaining blood pressure. The aim is to present this case study on the mutation spectrum of the CA12 gene to help clinicians better recognize autosomal recessive isolated hyperchlorhidrosis disorder caused by CA12 gene mutations. An eight-month-old Jordanian boy presented with vomiting and diarrhea, initially treated for gastroenteritis with IV fluids and oral rehydration. Laboratory results revealed significant electrolyte imbalances, leading to a provisional diagnosis of pseudohypoaldosteronism. Genetic analysis later identified two heterozygous variants in the CA12 gene (c. 585C>A, p.(Tyr195Ter) and c. 635C>T, p.(Pro212Leu)), suggesting a link to autosomal recessive isolated hyperchlorhidrosis disorder. The patient was managed with NaCl supplements, showing improved and stable laboratory results over time. It is concluded that comprehensive genetic analysis is crucial in accurately diagnosing and managing complex electrolyte disorders. The discovery of CA12 gene mutations in this patient shifted the diagnosis from pseudohypoaldosteronism to autosomal recessive Isolated hyperchlorhidrosis disorder. This finding enabled targeted treatment with NaCl supplements, resulting in significant clinical and laboratory improvements.

Introduction

Pseudohypoaldosteronism (PHA) is a rare genetic condition characterized by the body’s inability to respond properly to the hormone aldosterone, which is essential for regulating sodium and potassium levels, as well as maintaining blood pressure.[1] This condition manifests in various forms, with differing underlying genetic causes and clinical presentations. One specific variant, pseudohypoaldosteronism type II (PHA II), also known as Gordon’s syndrome, is marked by hypertension, hyperkalemia (elevated blood potassium levels), and hyperchloremia (increased chloride levels in the blood).[2] Recent studies have identified pathogenic mutations in the CA12 gene as a causative factor for a novel autosomal recessive form of isolated hyperchlorhidrosis disorder associated with PHA.[3] The CA12 gene encodes carbonic anhydrase XII, an enzyme that plays a critical role in maintaining the acid–base balance in the body. Mutations in this gene disrupt normal enzyme function, leading to the dysregulation of electrolyte transport and acid–base homeostasis, thereby contributing to the clinical features observed in affected individuals.[4] PHA has an autosomal dominant mode of inheritance; however, its specific pedigree is different in cases of renal PHA.[5] Mineralocorticoids are unable to bind to the receptors because the individual carrying the diagnosis has a genetic mutation in the gene responsible for mineralocorticoid receptors.[6] Till date, it has been more than 50 genotypes but none of it reveals any correlation with the clinical characteristics of the disease. Its manifestation in the clinic differs a lot.[7,8]

The aim is to present this case study on the mutation spectrum of the CA12 gene to help clinicians better recognize autosomal recessive isolated hyperchlorhidrosis disorder caused by CA12 gene mutations.

Case Report

This describes the clinical journey of an eight-month-old Jordanian boy who was first admitted to Local hospital with “presentation” of diarrhea and vomiting. Initially, he was diagnosed with gastroenteritis (GE) accompanied by acute kidney injury (AKI). Prior to these symptoms, the infant had been healthy. Upon his first admission, laboratory tests revealed significant electrolyte imbalances: hyponatremia (Na 118 mmol/l), hyperkalemia (K 6.1 mmol/l), elevated creatinine (1.53 mg/dl), and blood urea nitrogen (BUN) levels (66 mg/dl). These results are detailed in Table 1. The medical team initiated hydration therapy and intravenous fluids (IVF), adjusting the fluid therapy over four days. The patient’s condition improved, with normalized electrolyte levels (Na 136 mmol/l, K 5 mmol/l) and renal function markers (creatinine 0.41 mg/dl, BUN 3 mg/dl) upon discharge. Other parameters, including glucose, pH, bicarbonate (HCO3), and carbon dioxide (CO2) levels, were within normal ranges, indicating resolution of dehydration and metabolic disturbances. However, three months later, the boy was admitted to our hospital with similar symptoms of diarrhea and vomiting that began the same day. The clinical examination was unremarkable, including no skin hyperpigmentation and normal male genitalia. Laboratory tests once again indicated hyponatremia and hypochloremia, raising the provisional diagnosis of pseudohypoaldosteronism (PHA). To identify the underlying cause, whole-exome sequencing (WES) was performed, revealing a combined heterozygous mutation in the CA12 gene, which had not been previously associated with the patient’s condition. The genetic workup identified two variants in the CA12 gene: c. 585C>A, p.(Tyr195Ter), classified as likely pathogenic, and c. 635C>T, p.(Pro212Leu), classified as a variant of uncertain significance (VOUS). These mutations in the CA12 gene were determined to cause autosomal recessive isolated hyperchlorhidrosis disorder, contributing to the patient’s clinical presentation.

Table 1.

First biochemical and venous blood gases investigation report on the day of admission and day of discharge

Measured parameter	Day of admission result (units)	Normal range	Day of discharge results
Blood urea nitrogen (BUN)	66.00 Mg/dl	5.1–16.8	3
Calcium	10.00 Mg/dl	9–11	-
Random blood sugar	105.00 Mg/dl	70–140	-
Creatinine	1.53 Mg/dl	0.6–1.4	0.41
Sodium (Na)	118.00 mmol/L	139–146	136
Potassium (K)	6.10 mmol/L	4.1–5.3	5.1
Chloride (CL)	82.00 mmol/L	98–107	-
Venous blood gases pH	7.31	7.32–7.42	7.41
Venous blood gases SO2	63.00%		96
Venous blood gases HCO3	15.60 mmol/L	22–28	21.8
Venous blood gases PO2	38.80 mmHg	35–50	77.0
Venous blood gases PCO2	30.50 mmHg	41–51	34.1

For the past three months, the patient had been treated for gastroenteritis (GE) with oral rehydration solution (ORS) and had no complications or associated symptoms, like, fever, hypoglycemia, or skin pigmentation abnormalities.

Upon admission, initial laboratory results showed:

• Potassium: 7.8 mmol/L (normal: 4.1–5.3 mmol/L)

• Sodium: 123 mmol/L (normal: 139–146 mmol/L)

• Elevated 17-hydroxyprogesterone (17-OH) on June 10, 2023, 14.1 nmol/l (<6 nmol/l).

Follow-up results were as follows:

• June 11, 2023: Sodium: 136.0 mmol/L, potassium: 4.2 mmol/L, chloride: 109 mmol/L

• June 12, 2023: All parameters normal

• June 13, 2023: Sodium and chloride normal, potassium slightly high

• January 19, 2023 (discharge): All parameters normal except slightly low sodium.

Treatment: IV fluids, sodium chloride, salbutamol, calcium gluconate, and calcium resonium for hyperkalemia, hydrocortisone, and fludrocortisone 0.1 mg PO daily.

Monitoring: Regular checks of renin, aldosterone, and electrolytes.

Discharge: On sodium chloride NACL, fludrocortisone was stopped after confirmation of elevated aldosterone levels as mentioned below:

• Aldosterone: >132 ng/dl

• Renin: >550 uIU/mL.

Follow-up laboratory results

• One Month After Stopping Fludrocortisone:

  • Na: 138 mmol/L

  • K: 4.5 mmol/L

  • Cl: 111 mmol/L

  • 17-OH: 1 nmol/l

  • DHEA: 0.011 umol/L

  • Cortisol: 131.6 nmol/L

  • ACTH: 5.46 pmol/L

  • Renin: 132.3 uIU/mL

  • Aldosterone: 43.8 ng/dl.

• Two Months Later:

  • Na: 138 mmol/L

  • K: 3.9 mmol/L

  • Cl: 107 mmol/L

  • 17-OH: 0.72 nmol/L

  • Renin: 75 uIU/mL

  • Aldosterone: 10.7 pmol/L

  • Cortisol: 536 nmol/L

  • ACTH: 4.2 pmol/L.

Genetic analysis

• Identified Variants:

  • Variant 1: Chr15:63632923G > T, NM_001218.4

    0.585C > A, p.(Tyr195Ter) (likely pathogenic)

  • Variant 2: Chr15:63632599G > A, NM_001218.4

    0.635C > T, p.(Pro212Leu) (variant of uncertain significance, VOUS).

The genetic analysis revealed combined heterozygous variants in the CA12 gene. The first variant, c. 585C > A, p.(Tyr195Ter), is likely pathogenic, while the second variant, c. 635C > T, p.(Pro212Leu), is classified as a variant of uncertain significance. These findings suggest a potential link to the patient’s condition, as pathogenic mutations in the CA12 gene are associated with autosomal recessive isolated hyperchlorhidrosis. This explains the patient’s electrolyte imbalances and supports the diagnosis beyond pseudohypoaldosteronism, highlighting a genetic basis for the disorder.

The following relevant variants related to the clinical indication have been identified in this case:

CA12 Gene variant 1

This mutation introduces a premature stop codon in the CA12 gene, leading to a truncated protein. Such a truncated protein might be nonfunctional or have reduced functionality, which can contribute to disease phenotypes.

CA12 Gene variant 2

This mutation causes a single amino acid change from proline to leucine. This type of missense mutation can affect the protein’s structure and function, depending on the roles of the involved amino acids. Informed consent was taken from the patient [Figure 1].

Figure 1.

Mutation in CA12 creates a single AA change in normal protein

Limitations

There are some limitations of this study also, first it is a case report and based on the findings of a single patient. It limits the generalizability of conclusions and results. Genetic and phenotypic variability among individuals may mean that other cases with similar mutations could present differently. The study also lacks a larger control group or comparisons with similar disorders, restricting the ability to isolate the effects of the CA12 mutation from other potential contributing factors.

Conclusion

In conclusion, CA12-related isolated hyperchlorhidrosis is rare and difficult to diagnose. It is concluded that comprehensive genetic analysis is crucial in accurately diagnosing and managing complex electrolyte disorders. The discovery of CA12 gene mutations in this patient shifted the diagnosis from pseudohypoaldosteronism to autosomal recessive isolated hyperchlorhidrosis disorder. This finding enabled targeted treatment with fludrocortisone and NaCl supplements, resulting in significant clinical and laboratory improvements.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.