Case presentation

An eight-year-old boy was referred for evaluation of chronic diarrhea and intermittent rectal bleeding that had been present since early infancy. His past medical history was notable for cow’s milk protein allergy diagnosed during infancy and orchidopexy for cryptorchidism at three months of age. Neurodevelopment was reported as normal, and toilet training was achieved at two years and two months. Family history was negative for IBD and positive for atopy.

From approximately two months of age, the child had recurrent blood-streaked stools, initially interpreted in the context of cow’s milk protein allergy. He remained exclusively breastfed until five months of age. Complementary feeding was introduced because of poor weight gain, but feeding difficulties persisted, with limited acceptance of textures and flavors. After weaning at two years of age, he transitioned to hypoallergenic formulas. Despite conventional allergy-directed dietary management, including avoidance of cow’s milk protein, he continued to have chronic loose stools, intermittent hematochezia, visible food fragments in stool, selective eating, and impaired chewing patterns.

At my first consultation with the patient, at approximately six years of age, the child passed two to three loose stools daily, sometimes associated with urgency and visible blood. Stools were described as foamy and disintegrating, with recognizable food fragments, including potato, corn, and fruits. Parents reported rapid swallowing, minimal chewing, and refusal of harder textures. There was little gas, no major abdominal distension, and episodic vomiting. He appeared thin for age but remained active. Dietary intake was heavily centered on refined carbohydrates and processed foods, including sandwiches, pizza, and baked goods, with limited fruit and vegetable acceptance.

The child lived with his family and had consistent parental involvement throughout the diagnostic and therapeutic process. The family’s main concern was the persistence of diarrhea and intermittent hematochezia despite long-standing dietary vigilance. Gastroenterological evaluation was pursued after colonoscopy described macroscopic findings compatible with IBD and suggestive of Crohn’s disease; however, histopathology showed mild chronic ileocolitis without granulomas or other definitive features sufficient to establish a diagnosis of Crohn’s disease. Because of concerns regarding long-term systemic corticosteroids, immunomodulators, and biologic therapy, the family declined systemic immunosuppressive treatment and elected close longitudinal monitoring with a structured, nonimmunosuppressive, gut-focused approach.

At the first clinical evaluation, the child weighed 22 kg and measured 122 cm in height, corresponding to a body mass index of 14.8 kg/m², approximately at the 30th-35th percentile for age and sex. He was clinically stable and afebrile. Abdominal examination was unremarkable, with no distension, focal tenderness, palpable masses, or signs of acute abdominal inflammation. Perianal examination was normal, without fissures, fistulas, abscesses, skin tags, or perianal ulceration. There were no oral aphthous ulcers and no extraintestinal manifestations suggestive of IBD, including arthritis, skin lesions, ocular inflammation, or unexplained fever. Orofacial myofunctional assessment identified a restrictive lingual frenulum with reduced tongue elevation and lateralization, consistent with impaired bolus manipulation and inefficient mastication.

Available growth and routine laboratory evaluations were within expected limits. C-reactive protein, erythrocyte sedimentation rate, albumin, hemoglobin, ferritin, vitamin D, vitamin B12/folate, and platelet count were within laboratory reference ranges, indicating no overt systemic inflammation, anemia, hypoalbuminemia, or clinically significant micronutrient deficiency at the time of assessment. Celiac disease was considered in the differential diagnosis; however, anti-tissue transglutaminase testing was normal, and upper gastrointestinal biopsies did not show histopathological features consistent with celiac disease.

Diagnostic assessment

Endoscopy and Histopathology

At six years and three months, colonoscopy performed for suspected IBD demonstrated aphthoid ulcers in the rectum, sigmoid, descending, and transverse colon, with intervening normal mucosa (Figure 1); the cecum and ascending colon appeared normal. The terminal ileum showed mild erythema. The endoscopic impression was compatible with IBD of Crohn's disease phenotype.

Figure 1: Colonoscopic appearance before and after treatment(A) Pretreatment image showing erythematous, granular mucosa with focal whitish punctate lesions suggestive of erosions or aphthoid ulcers and a reduced vascular pattern. (B) Posttreatment image showing endoscopic mucosal healing, with a smoother mucosal surface and no visible erosions in the field shown

Histopathology reported mild chronic ileitis and mild chronic colitis with lymphoid hyperplasia, with mild chronic nonspecific inflammation in rectal mucosa. There were no granulomas, no crypt abscesses, no cryptitis, and no architectural distortion. Upper gastrointestinal biopsies showed mild chronic gastritis without Helicobacter pylori.

Stool Inflammatory Markers, Digestive Profile, Microbiome, Infectious, and Histamine-Pathway Assessment

The rationale for the expanded diagnostic assessment was the coexistence of chronic diarrhea, intermittent hematochezia, prior allergic history, selective eating, poor mastication, visible undigested food fragments, and inflammatory stool biomarkers in a child with endoscopic findings suggestive of IBD. Because standard anatomical and histopathological evaluation did not fully explain the clinical complexity, additional stool, infectious, digestive, microbiome, and histamine-pathway assessments were pursued to characterize potentially modifiable contributors, including impaired digestion, altered intestinal barrier activity, microbial imbalance, occult infection, and histamine-related mechanisms.

A comprehensive stool, serum, microbiome, infectious, and histamine-pathway assessment was performed by Lemos Laboratory, Minas Gerais, Brazil, as part of the clinical diagnostic work-up. Fecal calprotectin, lactoferrin, zonulin, and secretory IgA were measured using automated enzyme immunoassay-based methods. Fecal histamine and fecal melatonin were quantified by liquid chromatography-mass spectrometry coupled to high-performance liquid chromatography. Qualitative and functional stool digestion analysis was performed using optical microscopy combined with an automated microscopy system. Fecal microbiota composition was assessed by 16S rRNA sequencing. Stool antigen testing for _Giardia _and _Clostridium _was performed using solid-phase chromatography. Histamine-pathway genetic testing, including amine oxidase copper-containing 1 (AOC1)/diamine oxidase (DAO), histamine N-methyltransferase (HNMT), monoamine oxidase B (MAOB), methylenetetrahydrofolate reductase (MTHFR), and aldehyde dehydrogenase 2 (ALDH2), was performed by real-time polymerase chain reaction. Serum DAO concentration and functional histamine degradation capacity were assessed using automated enzyme immunoassay-based methods.

The comprehensive stool panel obtained after colonoscopy showed increased inflammatory markers, including elevated fecal calprotectin and markedly elevated fecal lactoferrin (Table 1). Barrier-related markers were also increased, with elevated fecal zonulin and secretory immunoglobulin A (IgA). Fecal histamine was elevated, whereas fecal melatonin was reduced (Table 1). Qualitative digestive assessment identified undigested starch, digestible cellulose, and muscle fibers, consistent with impaired digestion and/or inadequate mastication.

Stool marker | Unit | Baseline (pretreatment) | After 18 months (posttreatment) | Reference interval
Fecal calprotectin | µg/g | 318 | 54 | <200
Fecal lactoferrin | µg/mL | 28,106 | 8,427 | <7,200
Fecal zonulin | µg/mL | 153 | 130 | <80
Fecal secretory IgA | mg/dL | 722 | 5 | 51-204
Fecal histamine | µg/g | 752 | 143 | <500
Fecal melatonin | pg/mL | 9 | 149 | 15-297
Qualitative digestive assessment | Qualitative | Undigested starch; digestible cellulose; muscle fibers | Some undigested muscle fibers | Not applicable

Fecal 16S rRNA microbiome analysis showed reduced diversity and depletion of genera commonly considered beneficial or barrier-supportive, including Akkermansia, Faecalibacterium, and Bifidobacterium, with overrepresentation of taxa often associated with inflammatory or dysbiotic intestinal states. Stool antigen testing for _Giardia _and Clostridium was positive. Because these findings were identified and treated during the multimodal intervention sequence, infection- and overgrowth-directed therapy represents an important confounder and may have contributed to the observed clinical and biomarker improvement.

Targeted single nucleotide polymorphism (SNP) analysis of histamine- and methylation-related pathways identified selected variants of potential functional relevance, including heterozygous variants in AOC1/DAO, HNMT, and MTHFR, as well as a reported MAOB variant interpreted according to the laboratory report. These findings were considered susceptibility-related context involving histamine degradation, methylation, and biogenic amine handling, rather than diagnostic or causal markers. They were interpreted alongside the child’s allergic history, elevated fecal histamine, dietary pattern, impaired oral-phase processing, and Crohn-like inflammatory findings.

Serum DAO concentration was in the low-normal range. A separate functional histamine degradation assay was interpreted as showing reduced histamine degradation capacity.

Timeline Summary

Symptoms began in early infancy with hematochezia and suspected cow’s milk protein allergy. Chronic loose stools and intermittent bleeding persisted into early childhood. At age six years and three months, colonoscopy and histology supported a Crohn-like inflammatory phenotype. A gut-focused multimodal protocol was implemented without systemic immunosuppression and continued over approximately 18-24 months. At age eight years, symptoms and stool inflammatory markers had improved substantially, and at age eight years and 10 months, repeat colonoscopy showed near-complete mucosal healing (Figure 2).

Figure 2: Clinical timeline, key findings, and nonimmunosuppressive managementImage credit: created by the author using BioRender

Diagnostic challenges

Diagnostic challenges included the clinical overlap between pediatric IBD (PIBD), chronic allergic or food-sensitive colitis, infectious/parasitic colitis, histamine-related symptom amplification, microbiota disruption, and oral-phase digestive dysfunction. The absence of granulomas, crypt abscesses, cryptitis, architectural distortion, perianal disease, and extraintestinal manifestations made definitive classification as classic Crohn's disease less certain at baseline. In addition, no systematic monogenic IBD or immunologic workup was available in the clinical records, which limited etiologic stratification. No formal pediatric disease activity index or prognostic staging score was available retrospectively; therefore, prognosis was assessed longitudinally using clinical course, growth trajectory, fecal inflammatory biomarkers, and follow-up colonoscopy.

Diagnostic Considerations and Differential Diagnosis

The clinical phenotype and initial endoscopic findings raised concern for PIBD, particularly colonic-predominant Crohn's disease or IBD-unclassified, given the chronic diarrhea, hematochezia, segmental aphthoid ulceration, mild terminal ileal erythema, mild chronic ileitis/colitis, and elevated fecal inflammatory biomarkers. However, several findings argued against a classic, clearly progressive Crohn's disease phenotype at that time, including the absence of granulomas, crypt abscesses, cryptitis, architectural distortion, perianal disease, oral aphthous ulcers, unexplained fever, or extraintestinal manifestations.

The differential diagnosis also included chronic allergic or food-sensitive colitis, given the history of cow’s milk protein allergy, family history of atopy, selective diet, and possible food-related immune activation. Infectious or parasitic colitis was also considered because stool antigen testing was positive for _Giardia _and Clostridium, which informed subsequent infection- and overgrowth-directed treatment. Eosinophilic gastrointestinal disease was considered within the broader differential diagnosis; however, the available histopathology did not describe eosinophil-predominant inflammation. Celiac disease was considered less likely based on negative serologic testing and the absence of supportive histopathologic findings in the available records. Inborn errors of immunity or monogenic IBD were also considered as part of the broader differential diagnosis for early-onset intestinal inflammation; however, no systematic immunologic or monogenic IBD work-up was available in the clinical records.

Taken together, the available clinical, endoscopic, histologic, and fecal inflammatory biomarker findings supported a Crohn-like chronic inflammatory colitis within the PIBD spectrum. However, the absence of granulomas, crypt abscesses, cryptitis, architectural distortion, perianal disease, oral aphthous ulcers, unexplained fever, and extraintestinal manifestations made definitive classification as classic Crohn's disease less certain at baseline. Therefore, the case was interpreted conservatively as an IBD-spectrum/Crohn-like inflammatory phenotype with overlapping allergic, infectious/overgrowth, histamine-related, microbiota-related, and oral-phase digestive contributors, requiring longitudinal clinical, biomarker, and endoscopic follow-up.

Therapeutic intervention

The family expressed reluctance to long-term systemic corticosteroids, immunomodulators, or biologic therapy. A stepwise nonimmunosuppressive, gut-focused multimodal plan was implemented and adjusted according to clinical response, stool findings, and tolerability.

Dietary and Allergen-Load Interventions

Dietary management was individualized under nutritional supervision. Cow’s milk protein and foods identified as poorly tolerated or associated with hypersensitivity were excluded. Additional restrictions included selected highly fermentable foods, foods rich in antinutritional compounds such as phytates, oxalates, and tannins, and dietary components considered potential intestinal triggers, including gluten, casein, added sugars, ultra-processed foods, artificial colorants, preservatives, and monosodium glutamate. A strict low-histamine diet was followed for approximately 2 months, after which the intervention shifted to reduction of total dietary histamine load. Nutritional adequacy was supported through the progressive introduction of tolerated foods, including acacia gum, hydrolyzed beef protein, sources of mono- and polyunsaturated fatty acids, and antioxidant-rich foods. Food preparation and cooking methods were adapted to enhance digestibility and texture tolerance.

Mastication and Oral-Phase Feeding Therapy

The child was referred for feeding therapy twice monthly and orofacial myology/speech therapy twice weekly for 8 weeks, targeting chewing efficiency, bolus formation, tongue lateralization, and progressive expansion of texture tolerance. During the therapeutic course, a restrictive lingual frenulum was identified as a potential anatomic contributor to reduced tongue mobility, impaired bolus manipulation, and inefficient mastication. Lingual frenectomy was performed in approximately March 2025 (Figure 3), followed by continued orofacial myology and feeding therapy focused on tongue mobility, chewing efficiency, bolus formation, and texture progression.

Figure 3: Pre- and postfrenectomy intraoral findings(A) Preoperative intraoral image showing a restrictive lingual frenulum with visible anterior tethering and reduced tongue elevation. (B) Postoperative intraoral image following lingual frenectomy, showing release of the tethered tissue and the immediate postoperative healing area

Digestive Support and Histamine-Load Mitigation

Pancrelipase was used as digestive enzyme support based on qualitative stool evidence of maldigestion and visible undigested food fragments, without implying a diagnosis of pancreatic exocrine insufficiency unless supported by pancreatic function testing. Pancrelipase delayed-release capsules (Creon 10,000) were administered with each main meal. Exogenous DAO supplementation was used before main meals at a dose of 2.1 mg, up to three times daily, particularly when meals were expected to carry a higher histamine load. Nutritional cofactor support for methylation and homocysteine metabolism was provided with a commercially available methylation-support supplement containing riboflavin-5′-phosphate 25 mg, pyridoxal-5′-phosphate 15 mg, 5-methyltetrahydrofolate 800 µg, vitamin B12 as methylcobalamin/adenosylcobalamin 1000 µg, and trimethylglycine 700 mg per capsule. This was used as supportive nutritional therapy in the context of the patient’s histamine- and methylation-pathway variants, without implying that the variants were diagnostic or directly causal.

Microbiota Modulation and Infection/Overgrowth Treatment

Based on stool and microbiome findings, targeted probiotic therapy was implemented, including a commercial Lactobacillus rhamnosus GG preparation (Culturelle). Akkermansia muciniphila supplementation (1 billion TFU) was later added for 2 months, given the baseline depletion of beneficial taxa. There was no prior systematic deworming early in the course. For a 22-kg child, nitazoxanide 200 mg twice daily with food for 3 days was prescribed for Giardia infection, followed by metronidazole suspension 40 mg/kg/day divided three times daily for 21 days, targeting suspected Clostridium-associated overgrowth based on stool antigen findings and clinical context. Stool reassessments and clinical response informed subsequent adjustments.

No systemic corticosteroids, thiopurines, methotrexate, biologics, or small-molecule immunosuppressants were used during follow-up. A summary of the therapeutic sequence, including the main interventions, rationale, and approximate timing, is provided in Table 3.

Period | Intervention | Rationale | Dose/frequency/duration
Baseline/early phase | Dairy/cow’s milk protein exclusion | Prior cow’s milk protein allergy and possible food-sensitive colitis | Continuous during follow-up
Early phase | Reduction of high-histamine and ultra-processed foods | To reduce dietary histaminergic amine load and processed-food exposure | Progressive implementation under nutritional supervision
Early phase | Pancrelipase | Visible food fragments and qualitative stool evidence of maldigestion | Pancrelipase delayed-release capsules, Creon 10,000, with main meals
Early phase | DAO supplementation | Elevated fecal histamine and reduced functional histamine degradation capacity | 2.1 mg before main meals, up to three times daily
Microbiota phase | Lactobacillus rhamnosus GG | Microbiota modulation | 5 × 10⁹ CFU daily; continued during follow-up
Microbiota phase | Akkermansia muciniphilaAKK1 | Baseline depletion of beneficial taxa, including Akkermansia | 1 × 10⁹ AFU daily for 2 months
Infection/overgrowth phase | Nitazoxanide | Positive stool antigen testing for Giardia | 200 mg twice daily with food for 3 days
Infection/overgrowth phase | Metronidazole | Suspected Clostridium-related overgrowth signal based on stool testing and clinical context | 40 mg/kg/day divided three times daily for 21 days
Oral-phase intervention | Feeding therapy and orofacial myology | Inefficient mastication, impaired bolus formation, and limited tongue mobility | Feeding therapy twice monthly; orofacial myology twice weekly for 8 weeks
Surgical/oral-motor phase | Lingual frenectomy | Restrictive lingual frenulum with impaired tongue mobility and bolus manipulation | Performed in March 2025; followed by continued orofacial myology and feeding therapy

Follow-up and outcomes

Clinical improvement occurred progressively rather than immediately after a single intervention. Early management focused on dairy exclusion, reduction of high-histamine and ultra-processed foods, digestive enzyme support, DAO supplementation, and probiotic therapy. Persistent oral-phase dysfunction and visible food fragments in stool prompted structured feeding and orofacial myology therapy, followed by lingual frenectomy in March 2025. Over the subsequent months, the parents reported greater chewing efficiency, broader texture acceptance, reduced stool urgency, and gradual resolution of visible rectal bleeding. Because the intervention was multimodal and sequential, the relative contribution of each component cannot be determined.

Over approximately 18-24 months, bowel frequency decreased to 1-2 formed or softly formed stools per day, and visible blood resolved. Parents reported reduced urgency, improved appetite, broader food repertoire, and better energy and mood. Growth trajectory was reported as appropriate, without weight loss.

Repeat stool testing at age eight years demonstrated substantial improvement in inflammatory and histamine-related markers compared with baseline. Fecal calprotectin decreased to a near-normal range, and fecal lactoferrin decreased markedly, although it remained elevated. Fecal zonulin remained elevated, suggesting persistent barrier-related abnormalities, while secretory IgA decreased to a low level. Fecal histamine normalized, and fecal melatonin also returned to the expected range. Some undigested muscle fibers persisted on qualitative digestive assessment; however, the overall inflammatory, histamine-related, and digestive profile showed meaningful improvement compared with baseline (Table 1).

A second colonoscopy at age eight years and 10 months performed for monitoring showed normal mucosa throughout the colon and terminal ileum (Figure 1). No macroscopic features of active Crohn's disease were reported. The patient remained off systemic immunosuppression and continued nutritional and gastroenterological follow-up.

Adherence, tolerability, and adverse events

Adherence was assessed through serial clinical follow-up, parental reports, review of dietary implementation, and monitoring of symptom evolution during the therapeutic sequence. The family reported consistent adherence to dairy exclusion, progressive reduction of high-histamine and ultra-processed foods, digestive support, microbiota-directed supplementation, and feeding/orofacial therapy. No serious adverse events were reported during the follow-up period. No complications related to lingual frenectomy were documented in the available clinical records. Transient gastrointestinal discomfort related to dietary changes, supplementation, or antimicrobial therapy was not reported as clinically significant.