Long‐term clinical trajectory of microvillus inclusion disease associated with STXBP2‐related familial hemophagocytic lymphohistiocytosis type 5: A case report

Abstract

Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin‐binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long‐term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22‐year‐old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long‐term follow‐up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long‐term extrahematopoietic phenotype of STXBP2‐related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.

INTRODUCTION

Familial hemophagocytic lymphohistiocytosis is caused by pathogenic variants in genes encoding proteins associated with the perforin‐dependent cytolytic pathway of CD8‐positive T cells and natural killer cells, resulting in impaired cytolytic activity and persistent immune activation. ¹ Familial hemophagocytic lymphohistiocytosis is classically categorized into five subtypes, and hematopoietic cell transplantation remains the only curative treatment. ¹ Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic loss‐of‐function variants in STXBP2, which encodes syntaxin‐binding protein 2 (STXBP2), a key regulator of membrane fusion and vesicle exocytosis. ² STXBP2 interacts with syntaxin‐11 and plays an essential role in both hematopoietic cells and polarized epithelial cells at the intestinal and renal brush border. ² , ³

In addition to immune dysfunction, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea, which persists after hematopoietic cell transplantation. ³ , ⁴ Previous reports have demonstrated that these patients can exhibit ultrastructural features resembling microvillus inclusion disease, a congenital enteropathy characterized by defective intracellular trafficking and loss of apical microvilli in enterocytes. ⁵ , ⁶ Although several cases of microvillus inclusion disease associated with familial hemophagocytic lymphohistiocytosis type 5 have been reported, long‐term outcomes are poorly described, and prolonged nutritional support has often been required in reported cases. ³

Here, we report a 22‐year‐old male with familial hemophagocytic lymphohistiocytosis type 5 who was diagnosed with microvillus inclusion disease 16 years after bone marrow transplantation. This patient provides a long‐term clinical trajectory of microvillus inclusion disease associated with familial hemophagocytic lymphohistiocytosis type 5.

CASE PRESENTATION

The patient was a 22‐year‐old male, the fourth child of nonconsanguineous parents. He was diagnosed with hemophagocytic lymphohistiocytosis at 2 months of age and underwent bone marrow transplantation from a sibling at 6 months of age. Because his older sister had died at 2 months of age due to multiple organ failure, familial hemophagocytic lymphohistiocytosis was suspected based on the family history. In addition to familial hemophagocytic lymphohistiocytosis, he had persistent severe diarrhea and failure to thrive since infancy. These symptoms were initially attributed to graft‐versus‐host disease. From the age of 6, he underwent repeated endocrine and gastrointestinal evaluations due to significant growth retardation. At 6 years of age, growth hormone replacement therapy was initiated for growth hormone deficiency, followed by levothyroxine treatment for hypothyroidism at 7 years of age. To investigate persistent diarrhea, colonoscopy was performed at 11 years of age, which revealed only mild findings suggestive of graft‐versus‐host disease; no definitive cause of diarrhea was identified. At 12 years of age, due to severe growth retardation, he was started on home parenteral nutrition via a central venous catheter. Since then, he has continued to receive home parenteral nutrition three days per week; however, his height and weight have remained below −2.0 standard deviations (SD) on the growth chart (Figure 1). At 17 years of age, he had not developed puberty and was started on human chorionic gonadotropin and recombinant follicle‐stimulating hormone replacement therapy for central hypogonadism.

Figure 1.

Growth chart of the patient plotted using the reference data provided by the Japanese Society for Pediatric Endocrinology. Following intensification of total parenteral nutrition at 17 years of age, both height and weight demonstrated catch‐up growth, accompanied by improved pituitary function. BMT, bone marrow transplantation; hCG, human chorionic gonadotropin; HPN, home parenteral nutrition; rFSH, recombinant follicle‐stimulating hormone.

At 17 years of age, he was admitted for hypokalemia (K: 1.9 mmol/L) and metabolic acidosis, which were incidentally detected during routine follow‐up. Parenteral nutrition was discontinued at the patient's request, and oral potassium supplementation was initiated. However, metabolic acidosis and hypokalemia persisted, and additional abnormalities, including hyponatremia, hypomagnesemia, and hypophosphatemia, became evident. These abnormalities were considered to be exacerbated by the coexistence of malabsorption due to severe diarrhea and Fanconi syndrome, which was diagnosed based on elevated tubular markers and low‐molecular‐weight proteinuria. After resuming intravenous supplementation of potassium, sodium, magnesium, and phosphate, metabolic acidosis rapidly resolved. This indicated that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalances. Further investigations were performed to determine the underlying cause of his chronic diarrhea and Fanconi syndrome. Gastroscopy, colonoscopy, and small bowel evaluation by capsule endoscopy revealed only mild inflammation, mucosal edema, and villous hypertrophy, without identifying a specific cause. Fecal analysis showed no excess fat or starch, and technetium‐99m scintigraphy demonstrated no abnormal accumulation, indicating no evidence of protein‐losing gastroenteropathy. Renal biopsy revealed no significant pathological findings, including on electron microscopy. Although he had not been genetically diagnosed initially, he was later confirmed to have familial hemophagocytic lymphohistiocytosis type 5 with compound heterozygous pathogenic variants in STXBP2 [c.88‐1 G > A and c.303_305del, p.(Ala102del)]. ⁷ A previous report demonstrated that the c.88‐1 G > A variant caused aberrant splicing, producing two aberrant cDNA fragments on RT‐PCR analysis. Sequence analysis showed that the larger fragment retained the entire intron 2, whereas the smaller fragment showed skipping of exon 3. ⁷ Based on genetic diagnosis, microvillus inclusion disease was suspected to be the cause of chronic diarrhea. Periodic acid–Schiff staining and CD10 immunohistochemistry were performed on duodenal biopsy specimens, which demonstrated Periodic acid–Schiff‐ and CD10‐positive intracytoplasmic granules consistent with microvillus inclusion disease, leading to the diagnosis of microvillus inclusion disease (Figure 2).

Figure 2.

CD10 immunostaining (A, B, and D) and periodic acid‐Schiff (PAS) staining (C) of duodenal biopsies from the patient. (A) Unaffected duodenal mucosa showing linear staining along the apical surface, indicating an intact brush border structure. (B) Affected duodenal mucosa showing loss of the brush border structure. (C) PAS‐positive cytoplasmic granules in the apical pole of enterocytes (black arrow and circle). (D) CD10‐positive cytoplasmic granules in the apical pole of enterocytes (red arrows).

Following the diagnosis, a multidisciplinary team comprising pediatric hematologists, endocrinologists, nephrologists, and surgeons was assembled to manage the patient. Intensified parenteral nutrition and small bowel transplantation were considered as potential treatment options. Therefore, after careful discussion with the patient and family regarding the benefits and risks of parenteral nutrition, including infection and vascular access complications, we re‐emphasized the need for parenteral nutrition and initiated daily parenteral nutrition. Furthermore, the Wechsler Intelligence Scale for Children–Fourth Edition revealed a full‐scale IQ of 59, indicating mild intellectual disability, and appropriate social support was arranged. At 22 years of age, his growth showed catch‐up, and his growth hormone deficiency, hypothyroidism, and hypogonadism had improved; Fanconi syndrome had also improved (Figure 1).

DISCUSSION

In this report, we described a 22‐year‐old male with microvillus inclusion disease associated with familial hemophagocytic lymphohistiocytosis type 5. To our knowledge, this patient represents one of the oldest reported survivors and provides a long‐term clinical trajectory of microvillus inclusion disease associated with familial hemophagocytic lymphohistiocytosis type 5. Chronic diarrhea persisting after hematopoietic cell transplantation has been reported as a characteristic extra‐immune manifestation of familial hemophagocytic lymphohistiocytosis type 5, and some patients require long‐term parenteral nutrition. ³ , ⁴ STXBP2 interacts with STX3 and is involved in vesicle trafficking; therefore, STXBP2 dysfunction can produce a microvillus inclusion disease‐like enteropathy. ⁶ , ⁸ , ⁹ Long‐term observations such as the present case are important for clarifying the phenotypic variability of STXBP2‐associated microvillus inclusion disease.

Fanconi syndrome was another key feature in this patient and provided important insight into the condition. To our knowledge, only one case of Fanconi syndrome in a patient with familial hemophagocytic lymphohistiocytosis type 5 has been reported. ³ The previously reported patient was similar to ours, with onset after hematopoietic cell transplantation and comparable renal biopsy findings showing preserved brush border morphology; however, renal imaging in that patient revealed multiple small cysts, suggesting a potentially distinct underlying renal pathology. In contrast, in our patient, Fanconi syndrome showed partial improvement following intensification of parenteral nutrition, which may account for the observed differences between the two patients. Fanconi syndrome has also been reported in several patients with microvillus inclusion disease associated with MYO5B variants. ¹⁰ In those patients, no significant renal pathological findings were observed, and the symptoms improved after intestinal transplantation. These patients and our observations suggest that intestinal‐specific factors or nutritional status may contribute to the renal manifestations.

In addition, the patient had growth retardation, growth hormone deficiency, hypothyroidism, and hypogonadism. These conditions were considered likely secondary to undernutrition, as parenteral nutrition intensification led to catch‐up growth and improvement in both endocrine function and Fanconi syndrome. These findings suggest that optimization of nutritional status is the most important aspect of managing this condition. Adequate parenteral nutrition may be an effective means of achieving this; however, long‐term parenteral nutrition carries various risks and, therefore, requires shared decision‐making with the patient and family.

CONCLUSION

Familial hemophagocytic lymphohistiocytosis type 5 causes chronic diarrhea that persists after hematopoietic cell transplantation. The clinical course of microvillus inclusion disease associated with familial hemophagocytic lymphohistiocytosis type 5 remains poorly characterized, as few patients survive beyond early childhood. Although adequate parenteral nutrition may be effective, careful follow‐up is important for manifestations related to malabsorption and undernutrition due to microvillus inclusion disease. In addition, the pathophysiology of microvillus inclusion disease is not fully understood, and the extent to which enteral intake can be tolerated should be assessed on an individual basis. Therefore, regular clinical monitoring is crucial for optimal management.

AUTHOR CONTRIBUTIONS

Hiroyuki Tanaka, Mariko Sekiguchi, and Yuko Kajiho contributed to the conception and design of the research. All authors contributed to the acquisition, analysis, and interpretation of the data. Hiroyuki Tanaka and Mariko Sekiguchi drafted the manuscript. All authors critically revised the manuscript, agreed to be fully accountable for ensuring the integrity and accuracy of the work, read and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

The patient and mother provided written informed consent, and the study was approved by the Ethics Committee of The University of Tokyo (Approval No. 2701‐(7)).