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Congenital myenteric hypoganglionosis is a rare developmental disorder characterized clinically by severe and persistent neonatal intestinal pseudoobstruction. The diagnosis is established by the prevalence of small myenteric ganglia composed of closely spaced ganglion cells with sparse surrounding neuropil. In practice, the diagnosis entails familiarity with the normal appearance of myenteric ganglia in young infants and the ability to confidently recognize significant deviations in ganglion size and morphology. We review clinical, histologic, and immunohistochemical findings from 12 patients with congenital myenteric hypoganglionosis in comparison with similar data from age-matched controls and clearly delineate the diagnostic features of the condition. Practical guidelines are provided to assist surgical pathologists, who are likely to encounter this condition only infrequently. The diagnosis typically requires full-thickness intestinal biopsy as the abnormality is confined to the myenteric plexus in many patients. Immunohistochemistry for Hu C/D may be used to confirm hypoganglionosis. Reduced staining for calretinin and NeuN implicates a selective deficiency of intrinsic primary afferent neurons in this disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Surgical management of Hirschsprung disease requires resection of the aganglionic bowel and transition zone, a length of ganglionic bowel, immediately proximal to the aganglionic segment, with neuropathologic features that seem to correlate with dysmotility. Pathologists must be able to recognize histopathologic features of the transition zone in hematoxylin and eosin-stained sections in order to interpret intraoperative frozen sections and ensure adequate resection. The proximal ganglionic portions of colonic resection specimens from 59 patients with distal aganglionosis were analyzed with closely spaced transverse sections to map the distribution of the 3 most commonly referenced features of transition zone (partial circumferential aganglionosis, myenteric hypoganglionosis, and submucosal nerve hypertrophy). Each of these "primary" findings was restricted to a region ≤5 cm proximal to the aganglionic segment in the overwhelming majority of patients. Exceptions were more common with longer aganglionic segments. Three other neuroanatomic phenotypes (gangliosclerosis, ectopic myenteric ganglia, and eosinophilic ganglionitis) of uncertain clinical significance were distributed more irregularly and often over much longer distances. Routine resection of at least 5 cm of ganglionic bowel proximal to the aganglionic segment may reduce the incidence of transition zone pull-through. However, routine intraoperative frozen section examination of the proximal resection margin to exclude the 3 primary forms of hematoxylin and eosin neuropathology described in this study is strongly advised.

Alpers disease is a recessive mitochondrial disorder caused by mutations in POLG1 and characterized primarily by progressive neurological and hepatic degeneration. Intestinal dysmotility is a frequent symptom, but it is often overshadowed by other clinical manifestations. The onset and progression of Alpers disease vary; however, most patients die during childhood, often before a specific diagnosis has been established. The gastrointestinal neuromuscular pathology of 4 patients, obtained largely from postmortem specimens, showed distinctive eosinophilic cytoplasmic granules in a subset of enteric ganglia and patchy atrophy of small intestinal muscularis externa. The cytoplasmic inclusions corresponded to abnormal mitochondria, which have been reported previously in another mitochondrial disorder (mitochondrial neurogastrointestinal encephalomyopathy) but not in Alpers disease. Recognition of these distinctive light microscopic findings, in an appropriate clinical setting, should prompt the evaluation of an underlying primary mitochondriopathy.

X-linked intestinal pseudo-obstruction, a rare disorder caused by mutations in FLNA, the gene encoding the cytoskeletal protein filamin A, has been regarded as a hereditary enteric neuropathy largely on the basis of sparse and incomplete pathologic studies. Diffuse abnormal layering of small intestinal smooth muscle (DAL) is a rare malformation, which has only been described in 4 patients (all male, 3 in the same family) with intestinal pseudo-obstruction. We report DAL in 5 male patients (2 families) with intestinal pseudo-obstruction and mutations in FLNA. Light microscopic, ultrastructural, and immunohistochemical studies showed abnormal lamination of the small intestinal muscularis propria with associated absent or severely reduced FLNA immunoreactivity. Intestinal samples from the oldest patient in the series, a teenager, showed multinucleate myocytes in small and large intestine, along the submucosal surface of the muscularis propria. As neither DAL nor the pattern of myocyte multinucleation observed in our patients have been described outside the context of X-linked intestinal pseudo-obstruction, these histopathologic features may be specific for this hereditary disorder and suggest an underlying myopathic basis for dysmotility in affected patients.