WBR0073

Author	PageAuthor::Anonymous (reviewed by Will Gibson and Yazan Daaboul)
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Endocrine
Prompt	[[Prompt::A newborn male is evaluated for vomiting due to failure to pass his first stool within 48 hours of birth. The vomit is approximately two teaspoons in volume, green-brownish in color, and without bloody contents. His abdomen is distended and digital rectal examination elicits massive passage of gas and stools. Diagnosis is confirmed with rectal biopsy that demonstrates lack of migration of ganglion cells due to mutation of a proto-oncogene. Which of the following conditions is associated with mutation of this gene?]]
Answer A	AnswerA::Café au lait macules
Answer A Explanation	AnswerAExp::Café au lait macules may be associated with a wide variety of diseases including neurofibromatosis type I, McCune–Albright syndrome, and Fanconi anemia.
Answer B	AnswerB::Cutaneous angiofibroma
Answer B Explanation	AnswerBExp::Angiofibromas are reddish brown subcentimetric papules that present over the sides of the nose and the medial portions of the cheeks. It may be associated with multiple endocrine neoplasia type 1 (MEN1) .
Answer C	AnswerC::Medullary thyroid carcinoma
Answer C Explanation	[[AnswerCExp::Medullary thyroid cancer (MTC) is a neuroendocrine tumor that originates from the parafollicular cells (C-cells) which produce calcitonin (CT). Medullary thyroid carcinoma may be associated with multiple endocrine neoplasias (MEN) type 2A and 2B.]]
Answer D	AnswerD::Pituitary prolactinoma
Answer D Explanation	[[AnswerDExp::Pituitary prolactinoma is a benign tumor of the pituitary gland. It is the most common type of pituitary tumor. Symptoms of prolactinoma are caused by hyperprolactinemia or by pressure of the tumor on surrounding tissues. It may be associated with type 1 multiple endocrine neoplasia.]]
Answer E	AnswerE::Vasoactive intestinal peptide secreting tumor
Answer E Explanation	[[AnswerEExp::A VIPoma is an endocrine tumor usually originating from non-beta islet pancreatic cells. They produce vasoactive intestinal peptide (VIP). VIP secretion causes: Watery Diarrhea, Hypokalemia, and Achlorhydria (known as WDHA syndrome). Additionally, VIP secretion causes vasodilation, hypercalcemia, and hyperglycemia. Although rare, it may be associated with multiple endocrine neoplasia type 1.]]
Right Answer	RightAnswer::C
Explanation	[[Explanation::The patient is most likely diagnosed with Hirschsprung's disease. It is a congenital aganglionosis of the submucosal (Meissner's) and the myenteric (Auerbach's) neural plexuses that affect the rectosigmoid or rectal portions of the GI tract. The pathophysiology of the disease is thus linked to the absence of autonomic neural crest-derived ganglion cells in the terminal hindgut. Failure to pass the first stool postnatally after the first 24-48 hours is consistent with the diagnosis of Hirschsprung's disease. Failure to pass stools is characterized by intestinal obstruction, abdominal distension, and bilious vomiting that occur soon after birth. In patients with Hirschsprung's disease, patients eventually pass a meconium plug followed by sparse bowel movements. Barium enema often shows small-to-normal aganglionic bowel of normal diameter with proximal dilated bowels, termed megacolon. Failure of passage of meconium may be also be associated with cystic fibrosis. Abdominal radiographs in these patients reveals distended bowels with few air-fluid levels, and presence of "ground-glass" appearing meconium mixed with air. In contrast, a microcolon is observed on barium enema. On barium enema. The normal function of RET (REarranged during Transfection) proto-oncogene is the encoding of a receptor tyrosine kinase that plays a role in activation of signalling pathways via phosphorylation of tyrosine residues. RET proto-oncogene mutation is associated with MEN 2A and 2B, Hirschsprung's disease, and Neuroblastoma. While loss of function mutations of RET are observed in Hirschsprung's disease, gain of function is associated with MEN 2A, 2B, and medullary thyroid carcinoma. MEN 2A syndrome: Parathyroid tumor Medullary thyroid cancer Pheochromocytoma MEN 2B syndrome: Oral/intestinal ganglioneuromas Medullary thyroid cancer Pheochromocytoma Educational Objective: RET is a proto-oncogene whose mutation can give rise to Hirschsprung's disease or multiple endocrine neoplasia (MEN). Medullary thyroid carcinoma may be associated with multiple endocrine neoplasias type 2A and 2B. References: Chernyavsky VS, Farghani S, Davidov T, et al. Calcitonin-negative neuroendocrine tumor of the thyroid: a distinct clinical entity. Thyroid. 2011;21(2):193-6. Chen F, Winston JH, Jain SK et al. Hirschsprung's disease in a young adult: report of a case and review of the literature. Ann Diagn Pathol. 2006;10(6):347-51. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature. 1994;367:378-380. Loening-Baucke V, Kimura K. Failure to pass meconium: diagnosing neonatal intestinal obstruction. Am Fam Physician. 1999;60(7):2043-2050 Martucciello G, Lerone M, Bricco L, et al. Multiple endocrine neoplasia type 2B and RET proto-oncogene. Ital J Pediatr. 2012. 38:9 First Aid 2014 page 329]]
Approved	Approved::Yes
Keyword	WBRKeyword::Gastrointestinal, WBRKeyword::GI, WBRKeyword::Motility, WBRKeyword::Meconium, WBRKeyword::Endocrine, WBRKeyword::Multiple endocrine neoplasia, WBRKeyword::Cancer, WBRKeyword::Thyroid, WBRKeyword::Genetics
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