Abstract
Congenital chloride diarrhea (CCD) is a rare genetic disorder characterized by persistent watery diarrhea and electrolyte imbalances. Herein, we report the case of a 6-year-old girl with a significantly delayed diagnosis of CCD, who had been misdiagnosed with Bartter syndrome since infancy due to atypical symptoms. Notably, the patient presented with rare gastrointestinal complications, including colonic ulcerations and an active perianal fistula. While the colonic ulcerations resolved under standard conservative medical treatment, the concurrent perianal fistula completely healed using an innovative, non-surgical approach consisting of local rectal antibiotic application (cefdinir powder) and antiseptic sitz baths. This case demonstrates that CCD can present with unusual structural complications. Crucially, although CCD typically manifests in early infancy, clinicians should consider this genetic metabolic disorder even in older children presenting with chronic diarrhea and recurrent electrolyte disturbances.
Introduction
Congenital chloride diarrhea (CCD) is a rare autosomal recessive disorder characterized by persistent secretory diarrhea with high stool chloride (Cl⁻) concentrations. Driven by mutations in the SLC26A3 gene (, ), which encodes an apical intestinal epithelial chloride/bicarbonate (Cl⁻/HCO₃⁻) exchanger from the SLC26 sulfate permease/anion transporter family, this life-threatening electrolyte imbalance stems from a profound transport defect. Specifically, functional impairment of SLC26A3 disrupts the coupled sodium/hydrogen (Na+/H+) transport system, resulting in failed ileal and colonic absorption of Cl⁻ and sodium (Na+). The consequent massive intestinal loss of sodium chloride (NaCl) presents clinically as voluminous, acidic diarrhea (, ).
The clinical phenotype of CCD evolves distinctly across developmental stages. Prenatal manifestations typically include premature birth, maternal polyhydramnios, and dilated fetal bowel loops (). Following birth, the disorder presents as profuse watery diarrhea that consistently leads to secondary hypochloremia, hypokalemia, metabolic alkalosis, and failure to thrive (, ). Due to the severity of these confounding electrolyte derangements, CCD is most commonly misdiagnosed as Bartter syndrome ().
Definitive diagnosis of CCD relies on a synthesis of clinical presentations, characteristic biochemical derangements, and pathogenic genetic mutations. Management centers on lifelong oral salt replacement with sodium chloride (NaCl) and potassium chloride (KCl). Although timely intervention usually secures a favorable long-term prognosis, chronic sequelae—including chronic kidney disease, hyperuricemia, spermatoceles, and inflammatory bowel disease (IBD)—can still emerge (). We present a rare pediatric case of CCD that followed an insidious clinical course, posing substantial diagnostic challenges. The patient, a school-age girl, presented with a history of mild, atypical chronic diarrhea that remained unrecognized for several years. Her diagnosis at age 6 was severely confounded by a complex clinical dyad of extensive colonic ulcerations and an active perianal fistula. This atypical presentation underscores the need to maintain clinical vigilance for underlying genetic metabolic disorders in school-age children to avoid protracted diagnostic delays.
Case presentation
A 6-year-4-month-old female was admitted to our department with a 2-month history of persistent perianal fistula and frequent watery diarrhea, averaging 6 to 7 episodes daily and accompanied by periumbilical pain. Notably, fecal matter was observed leaking from the sinus tract of the fistula (Figure 1); however, she exhibited no fever, dehydration, or other systemic symptoms, and the stool contained no gross blood or mucus. The patient was born vaginally at 36 weeks and 4 days of gestation (birth weight: 2,800 g) following a pregnancy complicated by maternal polyhydramnios. Her medical history was notable for a hospitalization for pneumonia at 6 months of age, during which Bartter syndrome was suspected due to recurrent hypochloremia, hypokalemia, hyponatremia, and metabolic alkalosis. However, this diagnosis was never definitively confirmed, and subsequent intermittent oral electrolyte supplementation (KCl and NaCl) was severely hindered by poor compliance. Her family history was unremarkable.
Figure 1
Physical examination on admission revealed profound growth restriction, with both weight (17 kg) and height (105 cm) well below the 3rd percentile. Her blood pressure was stable at 92/53 mmHg. Perianal inspection identified a solitary, superficial, low-lying right-sided fistula, notably lacking deep induration or surrounding tissue inflammation. Laboratory workup uncovered severe electrolyte and acid-base derangements, characterized by marked hypochloremia (88.5 mmol/L), hyponatremia (133.7 mmol/L), hypokalemia (3.0 mmol/L), and profound metabolic alkalosis (pH 7.760, base excess 25.8 mmol/L). Concurrently, significant renal impairment was evident, with serum creatinine and blood urea nitrogen elevated to 203 μmol/L and 23.80 mmol/L, respectively. A complete blood count showed mild anemia (hemoglobin 104 g/L). Although fecal screening was positive for Clostridium difficile (C. difficile) toxin, microscopic stool examination identified no erythrocytes, leukocytes, or pyocytes; due to technical limitations, stool and urine electrolyte profiles were not obtained.
Based on these clinical findings, the differential diagnosis primarily included infectious enteritis (induced by C. difficil or other pathogens) and IBD. To establish a definitive diagnosis, a thorough diagnostic workup was performed. Extensive pathogen screening—encompassing enterovirus, cytomegalovirus, Mycobacterium tuberculosis, rubella virus, Toxoplasma gondii, herpes simplex virus, and human immunodeficiency virus—yielded uniformly negative results. Furthermore, systemic inflammatory markers remained within their respective reference ranges; these included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and a comprehensive cytokine panel consisting of interleukin (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-α (TNF-α), and interferon-α. Immunological assessments of both cellular and humoral immunity revealed no abnormalities. Additionally, a contrast-enhanced computed tomography scan of the abdomen and pelvis demonstrated no significant masses or organic lesions. Notably, the perirectal and pelvic fat planes appeared clear, showing only mild soft tissue thickening in the right perianal region. While gastroscopy showed no remarkable abnormalities, colonoscopy revealed scattered ulcerations throughout the colonic mucosa (Figure 2). Histopathological analysis of colonic biopsies demonstrated mild, non-specific superficial chronic active inflammation, notably lacking granulomas, crypt distortion, or cryptitis. Finally, both aerobic and anaerobic stool cultures were negative.
Figure 2
A comprehensive therapeutic regimen was implemented to address the patient's complex clinical status. Systemic management included oral metronidazole to target the C. difficil infection, oral rehydration salts to correct electrolyte imbalances, and montmorillonite powder for symptomatic relief from diarrhea. To manage the mucosal inflammation, mesalazine suppositories were initiated. Management of the perianal fistula prioritized structured conservative management. In addition to systemic therapy, a targeted topical intervention was implemented: cefdinir powder (0.1 g) was instilled rectally every night to achieve a high local antimicrobial concentration directly at the internal orifice of the fistula. This intervention was complemented by daily sitz baths using a 1:20 diluted povidone-iodine solution to ensure regional antisepsis.
A follow-up assessment was performed 2 months post-intervention. The perianal fistula had completely healed, and C. difficil toxin was no longer detectable in the stool. Additionally, renal function and serum electrolyte levels had normalized. However, despite these therapeutic successes, the patient experienced persistent watery diarrhea (3–4 episodes per day) of an unresolved etiology. Because infectious enteritis and IBD had been definitively excluded, and given the documented electrolyte imbalances dating back to 6 months of age, an underlying congenital disorder was highly suspected. To establish a definitive diagnosis, whole-exome sequencing was performed, which identified a homozygous frameshift mutation within the SLC26A3 gene (c.269_270dup: p.G91Kfs*3). This mutation was biparentally inherited, with both parents confirmed as heterozygous carriers.
Retrospective re-evaluation of the patient's medical history subsequently confirmed persistent watery diarrhea (3–4 episodes per day) since birth, which was initially misattributed to a cow's milk protein allergy. Although the family had attempted substituting breast milk with an amino acid-based formula, this dietary trial proved ineffective. Furthermore, the electrolyte abnormalities at 6 months of age, which had initially raised suspicion of Bartter syndrome, were managed only with intermittent oral KCl and NaCl supplementation. Throughout this period, the persistent watery diarrhea remained mild, thereby eluding significant clinical and parental attention. Based on the molecular genetic findings, a definitive diagnosis of CCD was established, and the management strategy was optimized exclusively to targeted KCl and NaCl supplementation.
At the latest follow-up assessment, performed at 6 years and 9 months of age, the patient experienced persistent watery diarrhea, although the frequency had markedly reduced to 2–3 episodes per day. Concurrently, she demonstrated progressive catch-up growth, with her height reaching 107.5 cm (placing her at the 3rd percentile) and her weight increasing to 18 kg (advancing to the 10th percentile).
Discussion
CCD is a rare autosomal recessive disorder that exhibits marked geographical variation in its global incidence. Epidemiological studies report a relatively high prevalence of CCD in Finland, Poland, and certain Arab nations, a phenomenon largely driven by high rates of consanguinity within these populations (, 9). Conversely, the incidence of CCD in East Asia remains poorly defined due to the scarcity of documented cases (, 10).
Given its rarity, CCD was carefully differentiated from its mimics. Bartter syndrome was excluded by the absence of renal chloride wasting (11), while congenital sodium diarrhea and cystic fibrosis were ruled out by the presence of metabolic alkalosis and the lack of respiratory or pancreatic involvement. Furthermore, despite the patchy colonic ulcers and perianal fistula, Crohn's disease was excluded because the patient lacked mucus or bloody stools, and the fistula was solitary and highly superficial. Additionally, other systemic inflammatory markers (including CRP, ESR, and a cytokine panel) were entirely normal, though fecal calprotectin was unavailable due to laboratory limits. Most importantly, pathology showed only non-specific inflammation that resolved rapidly without IBD-targeted therapies. Ultimately, the detection of the homozygous SLC26A3 mutation definitively confirmed CCD.
The primary novelty of this case lies in the exceptionally late age of diagnosis compared to most previously reported cases (12, 13); specifically, our patient remained undiagnosed until six years of age. She had sustained chronic watery diarrhea (3–4 episodes daily) since birth, which went undetected prior to the current presentation. At six months of age, she received a misdiagnosis of Bartter syndrome due to the coexistence of hypochloremia, hypokalemia, hyponatremia, and metabolic alkalosis, leading to long-term conservative management under this incorrect clinical classification. During her current hospitalization, she experienced an exacerbation of diarrhea, and colonoscopy revealed scattered ulcerations within the colonic mucosa. Concurrently, fecal evaluation detected C. difficil toxin. Although a combination of systemic metronidazole and mesalazine suppositories successfully resolved the mucosal ulcerations, the frequent watery diarrhea persisted. Because of the recurrent electrolyte imbalances, we could not rule out genetic metabolic diseases, prompting next-generation sequencing. This analysis ultimately confirmed a homozygous mutation within the SLC26A3 gene (c.269_270dup: p.G91Kfs*3), which represents the most prevalent allele identifier among Chinese patients with CCD ().
Within the context of this retrospective case study, a notable limitation was the absence of classical biochemical confirmations, specifically including baseline electrolyte measurements obtained from stool and urine samples, because rapid genetic sequencing directly broke the diagnostic deadlock. Crucially, a recent report by Sadagah et al. (14) further illustrates this diagnostic challenge by documenting the case of a 28-year-old adult who was misdiagnosed with Bartter syndrome during childhood and presented with concurrent intestinal ulcerations. Based on this clinical course, we emphasize that when encountering atypical school-age or older patients, evaluating fecal and urinary electrolytes is essential to provide preliminary clues. Furthermore, clinicians should promptly consider genetic sequencing to establish a definitive diagnosis, thereby preventing prolonged misdiagnoses such as Bartter syndrome.
Patients with CCD generally achieve a favorable long-term prognosis when timely therapeutic intervention follows an early diagnosis (). However, long-term clinical follow-up has increasingly identified several intestinal and extraintestinal complications, including IBD, chronic kidney disease, hyperuricemia, and spermatoceles (, , , 15). In contrast to the historically reported literature, our case presents a unique constellation of clinical complications featuring extensive colonic ulcerations and an active perianal fistula.
Initially, colonoscopy revealed significant mucosal damage characterized by scattered ulcerations within the colonic mucosa. We hypothesize that multifactorial mechanisms drive this clinical manifestation, specifically mechanical epithelial damage secondary to persistent watery diarrhea, alongside localized mucosal inflammation and exacerbated epithelial sloughing induced by the concurrent C. difficile infection. Furthermore, mutations within the SLC26A3 gene may modulate intestinal inflammatory pathways. Ding et al. (16) demonstrated an association between a lack of SLC26A3 protein expression and the upregulation of TNF-α within the intestinal mucosa, a mechanism that potentially stimulates regional inflammatory cascades. Concurrently, researchers have recognized SLC26A3 as a susceptibility locus for ulcerative colitis in Japan (17) and consider it an IBD susceptibility gene (18). Additionally, evidence suggests that SLC26A3 protein is essential for colonic mucus expansion, and its loss of function directly attenuates the thickness of the protective mucosal barrier (19). Nonetheless, these potential pathways remain hypothetical and warrant prospective experimental validation.
Another distinctive feature of our case is the active perianal fistula, as this clinical manifestation remains previously undocumented within the context of CCD. We postulate that chronic mucosal irritation induced by persistent watery diarrhea, alongside localized tissue infection, triggered the development of this fistula. Notably, the concurrent C. difficile infection required the utmost caution regarding the selection and administration of broad-spectrum antibiotics—particularly via the intravenous route—to prevent further disruption of the intestinal microbiota. Consequently, we managed the perianal fistula using an innovative, non-surgical multimodal approach not previously reported in the literature. This protocol involved the nightly rectal administration of cefdinir powder (0.1 g) to target the perianal fistula locally, complemented by daily sitz baths with a 1:20 diluted povidone-iodine solution to maintain regional antisepsis.
Although applied topically, this micro-dosage offered an inherently conservative strategy for a pediatric patient. A daily total of 0.1 g is substantially below the standard oral dose recommended for a 6-year-old child, thereby ensuring clinical safety while avoiding systemic side effects. This targeted regimen achieved complete clinical resolution, successfully obviating the need for invasive surgical intervention. Finally, although pelvic magnetic resonance imaging is generally preferred for detailed anatomical assessment, we did not pursue it because the contrast-enhanced computed tomography confirmed a superficial, simple fistula that responded rapidly to our conservative therapy.
The primary therapeutic strategy for CCD relies on adequate, lifelong supplementation with NaCl and KCl to maintain electrolyte and acid-base homeostasis (13, 20). Clinical practice necessitates a gradual transition from neonatal intravenous administration to oral rehydration formulations, a strategy that actively promotes physiological intestinal development. The specific recommended weight-based dosages for chloride supplementation are delineated as follows: 6–8 mmol/(kg·d) (NaCl:KCl = 3:1) for neonates; 6 mmol/(kg·d) (NaCl:KCl = 2:1) for infants; and 3–5 mmol/(kg·d) (NaCl:KCl = 6:5) for young children (12). Additionally, clinicians may utilize adjunctive therapies—including omeprazole, cholestyramine, and butyrate—to reduce diarrhea frequency, although these agents exhibit substantial inter-individual variability in therapeutic efficacy (21).
In conclusion, CCD is a rare congenital autosomal recessive disorder that clinicians frequently confound with renal salt-wasting conditions, such as Bartter syndrome, particularly when diarrheal symptoms are subtle or unrecognized by parents. In the absence of an early diagnosis and timely intervention, patients may develop unusual gastrointestinal complications, including colonic ulcerations and a perianal fistula. Therefore, although CCD typically manifests in early infancy, this case underscores the critical need to maintain a high index of suspicion for underlying genetic metabolic disorders in older pediatric patients presenting with persistent diarrhea and recurrent electrolyte disturbances, especially when they exhibit atypical or mild clinical phenotypes.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by the ethics committee of West China Second University Hospital, Sichuan University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.
Author contributions
WL: Writing – original draft, Writing – review & editing, Data curation. XG: Data curation, Writing – review & editing, Writing – original draft. YX: Conceptualization, Visualization, Writing – review & editing, Funding acquisition.
Funding
The author(s) declared that financial support was received for this work and/or its publication. Sichuan Science and Technology Program (General Program of Natural Science Foundation, No. 2024NSFSC0633) The Fundamental Research Funds for the Central Universities (SCU2022F4080).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Abbreviations
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; CCD, Congenital chloride diarrhea; Cl⁻, Chloride; SLC26A3, Solute carrier family 26 member 3; HCO₃⁻, Bicarbonate; Na+, Sodium; H+, Hydrogen; NaCl, Sodium chloride; KCl, Potassium chloride; IBD, Inflammatory bowel disease; C. difficile, Clostridium difficile; IL-1β, Interleukin-1β; TNF-α, Tumor necrosis factor-α.
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Summary
Keywords
child, colonic ulcers, congenital chloride diarrhea, hypochloraemia, hypokalaemia, metabolic alkalosis, perianal fistula
Citation
Li W, Guo X and Xie Y (2026) Case Report: Congenital chloride diarrhea in a prepubertal girl with perianal fistula and colonic ulcers. Front. Pediatr. 14:1720572. doi: 10.3389/fped.2026.1720572
Received
08 October 2025
Revised
06 July 2026
Accepted
07 July 2026
Published
23 July 2026
Volume
14 - 2026
Edited by
Andrew S. Day, University of Otago, New Zealand
Reviewed by
Bruno Martinez-Leo, IMSS, Mexico
Saqib Hassan, Sathyabama Institute of Science and Technology, India
Updates
Copyright
© 2026 Li, Guo and Xie.
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*Correspondence: Yongmei Xie yongmeixiescu@163.com
† These authors have contributed equally to this work.
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.