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A Case of MIRAGE Syndrome with SAMD9 Mutation and Refractory Infantile Diarrhea: Endoscopic Biopsy Evaluation via
Kevin Emil Bove1, Oscar Lopez-Nunez1, Jiri Bedrnicek2
1Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Abstract:
An infant with intrauterine growth restriction, suspected of having MIRAGE syndrome based on prenatal ultrasound, presented with genital ambiguity, adrenal insufficiency, intractable diarrhea from birth, and a pathogenic SAMD9 mutation (c.1376G>A, p.R459Q). Endoscopic biopsies of the duodenum revealed complex light and electron microscopic abnormalities. Hypoplastic villi without signs of enteritis suggests a disorder of mucosal growth with reduced absorptive surface area contributes to intractable diarrhea. Ultrastructural study showed prominent dilated endoplasmic reticulum, abnormalities of Golgi morphology, specialized granule, and mucin processing. We hypothesize that the SAMD9 mutation alters mucosal growth, and the processing of mucin, Paneth and neurosecretory granules, with premature degradation of specific granules in enterocyte lysosomes. These distinctive morphological findings support the idea that multisystem manifestations of MIRAGE syndrome are due to a primary disorder of microsomal trafficking.
Insights
MIRAGE syndrome, a rare genetic disorder, is linked to a SAMD9 mutation causing genital ambiguity and adrenal insufficiency. This mutation also impacts intestinal mucosal growth and granule processing, leading to severe diarrhea.
Area of Science:
- Genetics and Molecular Biology
- Gastroenterology
- Pediatric Endocrinology
Background:
- MIRAGE syndrome is a rare genetic disorder characterized by Myeloid hyperplasia, Adrenal insufficiency, Gastric issues, Enteric dysfunction, and Ambiguous genitalia.
- Mutations in the SAMD9 gene are implicated in MIRAGE syndrome, but the precise mechanisms underlying its multisystemic manifestations remain incompletely understood.
Purpose of the Study:
- To investigate the cellular and molecular basis of intractable diarrhea in an infant with MIRAGE syndrome.
- To correlate the identified SAMD9 mutation with observed gastrointestinal and systemic abnormalities.
Main Methods:
- Clinical presentation analysis of an infant with intrauterine growth restriction, genital ambiguity, adrenal insufficiency, and intractable diarrhea.
- Genetic sequencing to identify pathogenic mutations in SAMD9.
- Light and electron microscopic examination of duodenal endoscopic biopsies.
Main Results:
- A pathogenic SAMD9 mutation (c.1376G>A, p.R459Q) was identified in the affected infant.
- Duodenal biopsies revealed hypoplastic villi and significant ultrastructural abnormalities, including dilated endoplasmic reticulum and altered Golgi morphology.
- Evidence of abnormal mucin, Paneth, and neurosecretory granule processing, with premature lysosomal degradation, was observed in enterocytes.
Conclusions:
- The SAMD9 mutation in MIRAGE syndrome appears to disrupt intestinal mucosal growth and the processing of key cellular granules.
- These findings suggest that altered microsomal trafficking is a primary mechanism contributing to the multisystemic features of MIRAGE syndrome, particularly intractable diarrhea.
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