A 4-year-old boy is brought to the office due to a progressively worsening cough for the past 2 days that is productive of yellow sputum. A year ago, he was found to have bilateral lower-lobe pulmonary infiltrates on chest x-ray and was diagnosed with pneumonia. The patient has since had 2 additional episodes of pneumonia, each requiring antibiotics for improvement of symptoms. His current chest x-ray again reveals bilateral lower lobe infiltrates. Further testing shows a high chloride content in his sweat. Which of the following abnormalities is most likely to be seen in this patient?

Question

A 4-year-old boy is brought to the office due to a progressively worsening cough for the past 2 days that is productive of yellow sputum.  A year ago, he was found to have bilateral lower-lobe pulmonary infiltrates on chest x-ray and was diagnosed with pneumonia.  The patient has since had 2 additional episodes of pneumonia, each requiring antibiotics for improvement of symptoms.  His current chest x-ray again reveals bilateral lower lobe infiltrates.  Further testing shows a high chloride content in his sweat.  Which of the following abnormalities is most likely to be seen in this patient?

Quizplus · Accepted Answer

11ec160b_3787_f12a_9249_4789a484041d_MD0001_00 This patient most likely has cystic fibrosis (CF), an autosomal recessive disease characterized by recurrent sinopulmonary infections, pancreatic insufficiency, and malabsorption. It is caused by several different mutations that affect the CF transmembrane conductance regulator (CFTR) gene. The most common CFTR gene mutation (found in approximately 70% of cases) is a 3-base pair deletion of phenylalanine at amino acid position 508 (ΔF508). This mutation causes impaired post-translational processing (eg, improper folding and glycosylation) of CFTR, which is detected by the endoplasmic reticulum. As a result, the abnormal protein is targeted for proteasomal degradation, preventing it from reaching the cell surface. Certain drugs (eg, lumacaftor) can partially correct this folding defect, leading to expression of functional CFTR. (Choice B) Decreased production of functionally normal CFTR (eg, reduced messenger RNA or protein stability) often causes a milder form of the disease with normal sweat chloride levels that may not be diagnosed until adulthood. (Choice C) Mutations affecting regulation of chloride ion conduction through a CFTR protein also result in CF. However, they result in decreased chloride conductivity and are less common than the ΔF508 mutation. (Choice D) Mutations causing premature termination of the transmembrane protein (eg, nonsense, frameshift) also lead to a complete absence of membrane-bound CFTR as the truncated protein is typically recognized and degraded. These mutations are more common in the Ashkenazi Jewish population. (Choice E) CFTR is an ATP-gated chloride channel activated by cAMP-mediated phosphorylation. Mutations that reduce the ability of the channel to open can also cause CF. The ΔF508 mutation, in addition to preventing proper trafficking to the cell surface, also reduces the regulatory effects of ATP and cAMP on channel opening. Educational objective: Cystic fibrosis (CF) is most commonly due to a 3-base pair deletion in the CF transmembrane conductance regulator (CFTR) gene at amino acid position 508 (ΔF508). This mutation impairs post-translational processing of CFTR, resulting in shunting of CFTR toward the proteasome, with complete absence of the protein on the cell surface. Elevated sweat chloride concentrations are found in most patients with CF. __________ References: Protein processing and inflammatory signaling in cystic fibrosis: challenges and therapeutic strategies. (http://www.ncbi.nlm.nih.gov/pubmed/20205681) The pore architecture of the cystic fibrosis transmembrane conductance regulator channel revealed by co-mutation in pore-forming transmembrane regions. (http://www.ncbi.nlm.nih.gov/pubmed/27070741)

A 4-Year-Old Boy Is Brought to the Office Due to a Progressively