WBR0103

Author	[[PageAuthor::William J Gibson (reviewed by Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Endocrine, SubCategory::Musculoskeletal/Rheumatology
Prompt	[[Prompt::A 28-year-old man with dwarfism recently married a woman of normal stature. Neither of his parents had dwarfism, nor did any of his two siblings. Further questioning reveals that his parents conceived him when his father was 52 years old and his mother was 28. The patient and his wife are interested in having children and seek genetic counseling. Which of the following statements is most likely true?]]
Answer A	AnswerA::The patient’s condition is caused by inactivating mutations in the ''FGFR3'' gene; and his children have a near 0% chance of developing dwarfism.
Answer A Explanation	[[AnswerAExp::While achondroplasia is caused by mutations of the FGFR3 gene, they are mutations that cause hyperactive signaling of this receptor. Since achondroplasia is an autosomal dominant genetic disorder with complete penetrance, there is 50% chance the mutant allele is transmitted to the offspring.]]
Answer B	AnswerB::The patient’s condition is caused by inactivating mutations in the ''FGFR3'' gene; and his children have a 50% chance of developing dwarfism.
Answer B Explanation	[[AnswerBExp::While achondroplasia is caused by mutations of the FGFR3 gene, they are mutations that cause hyperactive signaling of this receptor.]]
Answer C	AnswerC::The patient’s condition is caused by activating mutations in the ''FGFR3'' gene; and his children have a near 0% chance of developing dwarfism.
Answer C Explanation	AnswerCExp::Since achondroplasia is an autosomal dominant genetic disorder with complete penetrance, there is 50% chance the mutant allele is transmitted to the offspring.
Answer D	AnswerD::The patient’s condition is caused by activating mutations in the ''FGFR3'' gene; and his children have a near 25% chance of developing dwarfism.
Answer D Explanation	[[AnswerDExp::Since achondroplasia is an autosomal dominant genetic disorder with complete penetrance, there is 50% chance the mutant allele is transmitted to the offspring. Had the disease been transmitted by an autosomal recessive pattern, the patient's offspring would have had a 25% chance of developing dwarfism.]]
Answer E	AnswerE::The patient’s condition is caused by activating mutations in the ''FGFR3'' gene; and his children have a near 50% chance of developing dwarfism.
Answer E Explanation	[[AnswerEExp::The patient in this vignette most likely has achondroplasia, the most common cause of dwarfism. Achondroplasia is a fully penetrant autosomal dominant disease.]]
Right Answer	RightAnswer::E
Explanation	[[Explanation::Achondroplasia is caused by mutations in the FGFR3 gene located at the distal short arm of chromosome 4. It is characterized by a glycine-to-arginine substitution at position 380 (G380R). The mutation affects the transmembrane domain of the tyrosine kinase fibroblast growth factor receptor (FGFR) activated receptor continually signals for bone to cease growing. Longitudinal bone growth is primarily affected as a result of defective endochondral (cartilage-mediated) ossification. Because membranous ossification is not affected, these patients often have large heads relative to the size of their limbs. Prognosis of achondroplasia is good, with patients generally having a normal life span. 80% of achondroplasia cases are caused by sporadic mutations that may be associated with advanced paternal age at conception. Other cases may be inherited with a fully penetrant autosomal dominant pattern. In this case, the patient will transmit his altered FGFR3 gene with 50% probability, meaning that his children have a 50% chance of developing dwarfism. Educational Objective: Achondroplasia is caused by activating mutations in the FGFR3 gene and is transmitted in an autosomal dominant pattern. References: First Aid 2014 page 419]]
Approved	Approved::Yes
Keyword	WBRKeyword::Achondroplasia, WBRKeyword::Dwarfism, WBRKeyword::Genetics, WBRKeyword::Autosomal dominant
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