WBR0071

Author	PageAuthor::Gerald Chi (Reviewed by Yazan Daaboul)
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Pulmonology
Prompt	[[Prompt::A 5-year-old boy is evaluated for his recurrent upper respiratory tract infections. His past history is notable for abdominal pain and 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::Reduced chloride absorption in sweat ducts is seen in patients with CF.
Answer B	AnswerB::Reduced sodium reabsorption by the sweat ducts
Answer B Explanation	AnswerBExp::In patients with CF, there is impaired reabsorption of chloride leading to restricted sodium reabsorption. Accordingly, sweat in patients with CF contains high levels of sodium.
Answer C	AnswerC::Decreased insulin release from the islets of Langerhans
Answer C Explanation	[[AnswerCExp::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::Hirschsprung's disease is characterized by the loss of migration of neurons to submucosa and muscularis propria of the colon.
Answer E	AnswerE::Acquired absence of the vas deferens
Answer E Explanation	[[AnswerEExp::The majority of male patients with CF are diagnosed with congenital bilateral absence of the vas deferens. It is a frequent finding in these patients and in most if not all children born with cystic fibrosis as well. In some males, this may be the only feature suggesting an underlying CFTR mutation.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Cystic fibrosis is caused by a mutation that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The protein is primarily expressed in epithelial and blood cells. It is part of the ATP-binding cassette (ABC), or traffic APTase, gene family. Thus, it characteristically contains 2 ATP hydrolysis domains and 12 membrane-spanning alpha helixes. Its main function is a chloride channel; however it also functions to inhibit sodium transporter through the epithelial sodium channel. The "low-volume" hypothesis states that CFTR impairment in the airways leads to loss of inhibition of epithelial sodium channels, causing excessive sodium and water reabsorption and dehydration in the airways. In contrast, a "high-salt" hypothesis suggests that excess sodium and chloride are retained in the airway surface liquid due to CFTR absence. Normally in sweat glands, sodium is reabsorbed from the ductular lumen via apical sodium channels and CFTR. This process is followed by a chloride counter-ion. In patients with CF, there is impaired reabsorption of chloride leading to restricted sodium reabsorption. Accordingly, sweat in patients with CF contains high levels of sodium. This is opposite to the "low-volume" model, but consistent with the "high-salt" model. Diagnosis of CF is suspected when newborns fail to pass meconium in the first 24-48 hours and thus suffer from meconium ileus. Nonetheless, some patients may remain undiagnosed until adulthood. Diagnosis is made when chloride sweat levels are elevated > 60 mmol/L (requiring pilocarpine iontophoresis and quantitative determination of chloride levels) for most patients and 2 disease-causing CFTR mutations are identified. Some patients, such as infants, may require less chloride concentrations to make the diagnosis. Although manifestations greatly vary, classically the liver, the pancreas (both exocrine and endocrine), the liver, and the genitals are involved. Although more than 1000 CFTR mutations have already been described, phenylalanine absence at position 508 accounts for the majority of mutations in Northern Europe and North America. Educational Objective: Normally in sweat glands, sodium is reabsorbed from the ductular lumen via apical sodium channels and CFTR. This process is followed by a chloride counter-ion. In patients with CF, there is impaired reabsorption of chloride leading to restricted sodium reabsorption. Accordingly, sweat in patients with CF contains high levels of sodium. References: Antunovic SS, Lukac M, Vujovic D. Longitudinal cystic fibrosis care. Clin Pharmacol Ther. 2013;93(1):86-97 Rigot JM, Lafitte JJ, Dumur V, et al. Cystic fibrosis and congenital absence of the vas deferens. N Engl J Med. 1991;325(1):64-5. O'Sullivan BP, Freedman SD. Cystic fibrosis. Lancet.373(9678):1891-1904. Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352:1992-2001.]]
Approved	Approved::No
Keyword	WBRKeyword::cystic, WBRKeyword::fibrosis, WBRKeyword::cystic fibrosis, WBRKeyword::sweat, WBRKeyword::duct, WBRKeyword::chloride, WBRKeyword::sodium, WBRKeyword::secretion, WBRKeyword::absorption, WBRKeyword::CFTR, WBRKeyword::gene, WBRKeyword::CFTR gene, WBRKeyword::congenital, WBRKeyword::vas, WBRKeyword::deferens
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