WBR0071

Author	PageAuthor::Gerald Chi
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics, MainCategory::Pathology
Sub Category	SubCategory::Endocrine, SubCategory::Gastrointestinal, SubCategory::Genitourinary, SubCategory::Pulmonology, SubCategory::Reproductive
Prompt	[[Prompt::A 5-year-old male child is evaluated for his recurrent upper respiratory tract infections. His past history is notable for vomiting due to failure to pass his first stool as a newborn. Genetic analysis reveals a homozygous deletion of three nucleotides coding for phenylalanine at amino acid position 508. At his present age, which of the following conditions is most likely to be associated with the gene defect?]]
Answer A	AnswerA::Reduced chloride secretion by the sweat duct
Answer A Explanation	[[AnswerAExp::A. Reduced chloride secretion by the sweat duct is incorrect Reduced chloride absorption in sweat ducts is seen in patients with CF. In the absence of chloride flow in cystic fibrosis, sodium ions do not flow through ENaC despite upregulation of the ENaC channel, leading to greater salt and water loss. As such, patients' skin tastes salty, and this is commonly used to help diagnose the disease.]]
Answer B	AnswerB::Reduced chloride secretion by the intestinal epithelium
Answer B Explanation	[[AnswerBExp::B. Reduced chloride secretion by the intestinal epithelium is correct Reduced chloride secretion with augmented sodium absorption resulting in water retention in the intestinal epithelium is seen in patients with CF.]]
Answer C	AnswerC::Decreased insulin release from the islets of Langerhans
Answer C Explanation	[[AnswerCExp::C. Decreased insulin release from the islets of Langerhans is incorrect The thickened secretions from the pancreas block the exocrine movement of the digestive enzymes into the duodenum and result in irreversible damage to the pancreas. This causes atrophy of the exocrine glands and progressive fibrosis. However, the endocrine pancreas might also be damaged at the advanced stage of the disease. The median age at diagnosis of cystic fibrosis-related diabetes (CFRD) is 21 years.]]
Answer D	AnswerD::Loss of migration of neurons to submucosa and muscularis propria of the colon
Answer D Explanation	[[AnswerDExp::D. Loss of migration of neurons to submucosa and muscularis propria of the colon is incorrect During normal fetal development, cells from the neural crest migrate into the colon to form Auerbach's plexus and Meissner's plexus. In Hirschprung's disease, the migration is not complete and part of the colon lacks these nerve bodies that regulate the activity of the colon. The affected segment of the colon cannot relax and may lead to meconium ileus.]]
Answer E	AnswerE::Congenital absence of the vas deferens
Answer E Explanation	[[AnswerEExp::E. Congenital absence of the vas deferens is incorrect Obstructive azoospermia and infertility are found in 95% of the affected CF males who survive to adulthood; bilateral absence of the vas deferens is a frequent finding in these patients. In some males, this may be the only feature suggesting an underlying CFTR mutation.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Cystic fibrosis (CF) is an autosomal recessive genetic disorder that affects the lungs, pancreas, liver, and intestine. It is characterized by abnormal transport of chloride and sodium across an epithelium, leading to thick, viscous secretions. CF is caused by mutation of the gene CFTR (cystic fibrosis transmembrane conductance regulator) which encodes a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. The encoded protein functions as a chloride channel and controls the regulation of other transport pathways. ΔF508 is the most common type of mutation within the CFTR gene. The mutation is a deletion of the three nucleotides that comprise the codon for phenylalanine (F) at position 508. A person with the CFTRΔF508 mutation will produce an abnormal CFTR protein that lacks this phenylalanine residue. This protein does not escape the endoplasmic reticulum for further processing and fails to be translocated to the epithelial surface, rendering epithelial membranes relatively impermeable to chloride ions. In sweat ducts, there is decreased absorption of chloride through CFTR with decreased absorption of sodium through epithelial sodium channel (ENaC) which results in production of hypertonic sweats. In the gastrointestinal tract, there is decreased secretion of chloride through CFTR with increased absorption of sodium through ENaC which leads to production of dehydrated mucus. In the airways, the absence of functional CFTR causes upregulation of the ENaC channel which further decreases salt and water secretion by reabsorbing sodium ions. As such, the respiratory complications in cystic fibrosis are not solely caused by the lack of chloride secretion, but instead by enhanced reabsorption of sodium and water. Educational Objective: References: ]]
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