Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.

BARTTER SYNDROME (BS), first described and named by Bartter et al. in 1962, is a group of syndromes characterized by hypokalemia, metabolic alkalosis, hyperreninemic hyperaldosteronism, and hyperplasia of the juxtaglomerular apparatus [1]. Based on the gene mutations involved, BS is currently classified into five different subtypes: Type 1 is caused by mutations in the SLC12A1 gene encoding NKCC2 (Na-K-2Cl cotransporter) [2]; Type 2 is caused by mutations in the KCNJ1 gene encoding ROMK (K+ channel) [3]; Type 3 is caused by mutations in the CLCNKB gene encoding ClC-Kb (Cl- channel) [4]; Type 4a is caused by mutations in the BSND gene encoding barttin (a subunit for ClC-Ka and ClC-Kb) [5]; Type 4b is caused by mutations in both the CLCNKA and CLCNKB genes encoding ClC-Ka and ClC-Kb [6]; and Type 5 is caused by mutations in the MAGED2 gene encoding MAGE-D2 [7]. Most patients with BS present clinical symptoms prenatally, especially in Types 1, 2, 4a, 4b and 5. Type 3 (also known as classic BS) occurs in infancy or early childhood [8]; patients with adult-onset are less common [9]. This case report describes a classic BS with onset in adults and summarizes all cases of adult-onset BS Type 3 to better understand this disease.

A 25-year-old man was admitted to our hospital with bilateral lower limb paralysis, numbness, and weakness. The patient reported no history of diarrhea, vomiting, excessive alcohol consumption, or drug use (including laxatives or diuretics). Pertinent history included an episode of muscle paralysis due to a severe hypokalemia (K⁺ 1.82 mmol/L) at the age of 20 years. The patient was apparently healthy before 5 years, with no retardation in growth. No history of premature or maternal polyhydramnios was reported. The family history was unrevealing; the father was 168 cm tall, and the mother was 158 cm tall.

On physical examination, the patient had a temperature of 36.0°C, blood pressure of 110/69 mmHg, heart rate of 80 bpm, respiratory rate of 20 bpm. The patient weighed 65 kg and was 164 cm tall, with an abdominal circumference of 85 cm, and a BMI of 24.2 kg/m². Muscle strength in both lower limbs was diminished, and the remainder of the physical examination results was normal. Similar episode has been reported two times previously, and laboratory biochemical tests showed severe hypokalemia, hyperkaliuria, metabolic alkalosis, and high renin and aldosterone levels (Table 1).

Although the U wave was initially visible on the electrocardiogram, it disappeared with the improvement in treatment. Renal ultrasonography revealed no renal stones or nephrocalcinoses. Abdominal ultrasonography revealed non-alcoholic fatty liver disease. Cortisol and thyroid function, adrenal computed tomography (CT) , and electromyography results of the lower limbs were normal.

Because the hypokalemia was of adult-onset, without growth retardation or increased urinary calcium excretion, similar to that of Gitelman’s syndrome (GS), we performed genetic testing to further distinguish it. We detected a homozygous variation in the CLCNKB (OMIM 602023 NM_000085) gene, which was c.1052G>T; p.Arg351Leu; EX11; Hom:missense. SIFT and PolyPhen software predicted its protein function, and both the results were deleterious. Furthermore, Sanger sequencing of the parents showed that the father was heterozygous, and the mother did not carry the gene (Fig. 1).

Fig. 1

The sanger sequencing map of this patient’s family. (A) The patient’s homozygous variation CLCNKB gene, which was c.1052G>T; (B) The sanger results of his father; (C) The sanger results of his mother.

Based on the clinical manifestations and genetic diagnosis, the patient was finally diagnosed with classic BS, or BS Type 3. Spironolactone and potassium chloride were then administered to supplement potassium throughout the disease course to maintain serum potassium levels. Serum potassium levels improved to a maximum of 4.1 mmol/L; however, owing to gastrointestinal adverse reactions and breast development (Fig. 2), the dosage could not be continued, and serum potassium levels could not be maintained above 3.0 mmol/L, subsequently leading to another attack of lower limb paralysis. Fig. 3 shows the fluctuations in serum potassium levels during the entire treatment course.

Fig. 2

Two years after oral administration of spironolactone, the patient developed bilateral mammary gland hyperplasia (A) shows the positive position, (B) shows the side

Fig. 3

Improvement in serum potassium levels after oral potassium chloride supplements, spironolactone and indomethacin.

Interestingly, when a symptomatic hypokalemia attack recurred in the fifth year after the patient was diagnosed with BS, hyperglycemia and hyperuricemia occurred simultaneously. Normal levels of serum uric acid and blood glucose were restored when the potassium ion level recovered (Table 1). During this process, the patient developed “acute appendicitis” and underwent surgery. This could be attributed to the low potassium levels, which led to reverse peristalsis of the intestinal tract, thereby pushing the fecal stones of the intestinal tract into the appendix.

To ascertain whether the patient had diabetes, an oral glucose tolerance test and simultaneous insulin release test was performed after recovery. Although the results were not indicative of diabetes, the patient exhibited impaired glucose tolerance and insulin resistance (Table 2).

BS is a rare disease predominantly reported in Asia, particularly in China [18]. Type 3, the most common type of BS, occurs mostly in children and infants. A French cohort study [9] reported a 74% incidence in children, while a Chinese cohort study [19] found that almost 100% of cases occurred in children. Adult-onset Type 3 BS is rare, and a definitive diagnosis is primarily based on clinical, biochemical, and sonographic findings. For the initial diagnostic workup, the ERKNet Working Group recommends the following: 1. Evaluation of medical history, including polyhydramnios, premature birth, growth failure, and family history; 2. Biochemical parameters: serum electrolytes (sodium, chloride, potassium, calcium, and magnesium), acid-base status, renin, aldosterone, creatinine, fractional excretion of chloride, and urinary calcium/creatinine ratio; 3. Renal ultrasound to detect medullary nephrocalcinosis and/or kidney stones; 4. Genetic analysis is recommended to confirm the clinical diagnosis of BS whenever possible [20]. This study summarized all the case reports and case series of adult-onset with relatively complete data that can be retrieved from PubMed in the past 10 years and listed their genotype and phenotypic characteristics (Table 3). The age of onset varied from 19 to 72 years, and the sex ratio was approximately 1:1. No specific correlation was observed between disease severity and genotype. However, the lower the serum potassium concentration at onset, the more complex the treatment strategy, and the more difficult it is for serum potassium to reach the standard value. Simultaneously, we found that adults with BS had no growth retardation and less nephrolithiasis, contrary to those in children with BS.

This was the first study to report a case of adult-onset BS Type 3, with a homozygous genotype (c.1052g>T; p.Arg351Leu). Clinical findings indicated hypokalemic paralysis without growth retardation or kidney stones. Sanger sequencing confirmed that the patient’s father had a single heterozygous mutation in one allele with no clinical phenotype. However, the heterozygous mutation of this gene reported by Han Y [21] had a clinical phenotype, which may be related to the fact that the other allele of the father was normal, whereas that of the child reported by Han Y had another gene mutation.

The patient had an early onset of the disease with no hypercalciuria, which was difficult to distinguish from GS (Table 4). Multiplex ligation-dependent probe amplification, whole exome sequencing, or genome-wide second-generation sequencing are effective means of identifying the two. Compared with most adult-onset GS cases, the patient’s potassium ion level at the onset of the disease was lower and required more potassium supplementation during treatment. In the present study, merely increasing the potassium content of the preparation had negligible effect; spironolactone and indomethacin had to be added to reach the treatment objective (potassium levels ˃ 3.0 mmol/L). Because K-sparing diuretics may worsen salt wasting and risk critical hypovolemia, they are not recommended routinely in BS; however, their usage is considered in certain patients with severe symptoms from electrolyte abnormalities, despite the maximization of routine treatment with nonsteroidal anti-inflammatory drugs and salt supplements [20]. Similar to our patient and our summarized cases, plasma potassium levels improved only with the help of spironolactone. To avoid insufficient blood volume, amount of spironolactone administered was controlled with close monitoring of blood pressure. Although no clinical manifestations of insufficient blood volume were observed in our patient, long-term use of spironolactone induced breast hyperplasia, which had a negative impact on the patient’s self-esteem and quality of life. Spironolactone can be substituted with eplerenone; however, it is not commercially available in China.

Moreover, during the follow-up at five years after the onset of the disease, the patient experienced components of metabolic syndrome, such as abnormal glucose tolerance, hyperuricemia, and non-alcoholic fatty liver disease, which are similar to those in patients with GS and are prone to problems of glucose metabolism [22-24], possibly due to the reduction of insulin secretion due to long-term hypokalemia [24, 25]. Additionally, in adult men, the inhibition of androgens by spironolactone may also increase disorders of glucose and lipid metabolism, leading to abnormal glucose metabolism and even diabetes.

In summary, the use of gene sequencing to differentiate Bartter and Gitelman syndromes is of great significance in clinical decision-making. Treatment for BS is currently lacking; therefore, adherence to medications to maintain potassium levels close to the normal range is an effective means of delaying complications. Discontinuation of medication can not only result in the recurrence of paralysis but also in other metabolic disorders. Regular follow-up is necessary for early detection of complications and timely intervention. Potassium supplements, indomethacin, and spironolactone are still the mainstream treatment options; however, the gastrointestinal side effects of indomethacin limit its usage, and spironolactone should be used with great caution owing to the potential risk of hypovolemia. For BS with severely low potassium, increasing the potassium level to 3 mmol/L is difficult. An effective therapeutic regimen is being explored [26], and whether highly selective mineralocorticoid receptor antagonists developed for patients with diabetic nephropathy, such as fenneridone, can replace spironolactone in patients with BS warrants further validation.

We would like to thank the patient and his family members and appreciate all the members of the Department of Endocrinology at the Inner Mongolia Autonomous Region People’s Hospital for their assistance.

All authors declare that they have no potential competing interests.

The patient provided written informed consent for using his medical records, the publication of this study and its accompanying images. The identity of the patient has been protected.

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