Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations

Abstract

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene are a rare cause of congenital enteropathy that can result in significant morbidity. TTC7A deficiency leads to disruption of the intestinal epithelium. The histopathology of this condition has been partly described in case reports and clinical studies. This manuscript describes an in-depth investigation of the pediatric gastrointestinal pathology of the largest histologically examined cohort with confirmed TTC7A mutations reported to date and, for the first time, compared the findings to age-matched and sex-matched control patients with intestinal atresia not thought to be associated with TTC7A mutations. Hematoxylin and eosin-stained slides of endoscopically obtained mucosal biopsies and surgical resection specimens from 7 patients with known TTC7A mutations were examined retrospectively. The microscopic findings were found to be on a spectrum from atresia-predominant to those with predominantly epithelial abnormalities. Several unique histopathologic characteristics were observed when compared with controls. These included neutrophilic colitis and prominent lamina propria eosinophilia throughout the gastrointestinal tract. Striking architectural abnormalities of the epithelium were observed in 4 of the 7 patients. The 5 patients with intestinal atresia demonstrated hypertrophy and disorganization of the colonic muscularis mucosae accompanied by bland spindle cell nodules within the intestinal wall. The components of the latter were further elucidated using immunohistochemistry, and we subsequently hypothesize that they represent obliterated mucosa with remnants of the muscularis mucosae. Finally, atrophic gastritis was noted in 4 patients. In conclusion, the unique histopathologic characteristics of TTC7A mutation-associated enteropathy described herein more fully describe this novel disease entity in infants who present with congenital enteropathy or enterocolitis.

Society for Pediatric Pathologists Abstracts of the 2023 Fall Meeting October 6-8, 2023 Hybrid Meeting

“…However, the histologic findings in this specimen were classic for KHE, as shown in the figures above. Following this debridement, the patient was started on sirolimus, which has been shown to be efficacious in the management of KHE in recent studies [11 . Despite initial improvements, his symptoms have recurred with continued limited mobility of the wrist and increasing pain levels.…”

“…2,7 Histopathologic findings of MIA-SCID can be heterogenous, but some combination of the following is frequently seen: intestinal fibrosis at sites of atresia, apoptotic enterocolitis with mucosal ulceration and regenerative changes, crypt drop-out and distortion, villous blunting of the small bowel, neutrophilic and eosinophilic infiltration of the lamina propria, and decreased plasma cells. 2,[8][9][10][11] Thickened fibrotic bowel wall with calcifications and reduced lymphoid follicle size may also be seen. 12 A recent study comparing the gastrointestinal histopathology of patients with TTC7A germline mutations to a control group of patients with intestinal atresia and clinicopathologic findings incompatible with TTC7A mutation noted several of these findings.…”

The genetics of monogenic intestinal epithelial disorders

“…Consequently, loss-of-function mutations in TTC7A lead to profound abnormalities in intestinal epithelial polarity and lumen formation. This results in a highly architecturally distorted epithelium particularly in the colon characterized by stratified or pseudostratified epithelium, formation of crypt glands with multiple lumens, and mis-localization of apical and basolateral markers (Bigorgne et al 2014 ; Jardine et al 2018 ; Dannheim et al 2022 ). In addition to epithelial polarity defects, TTC7A also plays a role in stabilization of the Akt survival signaling pathway (Jardine et al 2018 ).…”

“…For most disorders, diarrhea is the predominant symptom with minimal or no inflammatory component present in the intestinal mucosa. However, loss of epithelial barrier function or disruption of normal mucosal architecture, for example in TTC7A deficiency (Dannheim et al 2022 ) or alteration of normal host–microbiome responses (e.g., SLC9A3 deficiency (Kini et al 2022 )) can result in a secondary mucosal inflammatory response. This contrasts and can be distinguished from monogenic causes of very-early-onset inflammatory bowel disease such as IL10 mutations or other primary immune deficiencies with intestinal involvement such WAS mutations (Wiskott-Aldrich) or FOXP3 mutations (IPEX) that primarily affect immune cell function, or development (Nambu and Muise 2020 ).…”

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease

“…VEOIBD from TTC7A deficiency results in profuse bloody diarrhea shortly after birth, usually necessitating parenteral nutrition (39)(40)(41). Intestinal disease is microscopically characterized by atresias, architectural distortion, crypt degeneration, pronounced apoptosis, hypertrophy of the muscularis mucosa and spindle cell nodules (42). While all patients present with intestinal manifestations (MIA or VEOIBD, with or without CID), it remains unclear what drives the phenotypic variability.…”