WBR0311

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::General Principles
Prompt	[[Prompt::A 5-month-old girl is evaluated in a well child visit. The child was born without complications via normal vaginal delivery to a G2P2 42-year-old woman. On physical examination, the child has skin folds of the upper eyelid that cover the inner angles of the eyes, upslanted palpebral fissures, a flat nasal bridge, and a small chin. She also has a low set of small ears, furrowed tongue, and short broad hands. Her feet are pictured below. Which of the following diseases is mostly associated with this child's condition? ]]
Answer A	AnswerA::Acute Lymphoblastic Leukemia
Answer A Explanation	[[AnswerAExp::Patients with Down syndrome are at an increased risk of leukemias, including ALL. The precise reasons why Down syndrome increases the probability of developing ALL is unknown. Cases of ALL arising in Down syndrome children share a similar set of genomic alterations as cases arising in children with euploid genomes.]]
Answer B	AnswerB::Atherosclerosis
Answer B Explanation	AnswerBExp::Down syndrome patients tend to have a decreased risk of atherosclerosis. Other cardiovascular abnormalities are associated with Down syndrome including endocardial cushion defects, AV canal, VSD, and ASD.
Answer C	AnswerC::Crohn’s disease
Answer C Explanation	AnswerCExp::Down syndrome is not associated with an increased risk of Crohn’s disease. Other gastrointestinal abnormalities are associated with Down syndrome including duodenal atresia, annular pancreas, celiac disease, and imperforate anus.
Answer D	AnswerD::Lung cancer
Answer D Explanation	AnswerDExp::Down syndrome patients have a markedly decreased risk of most solid tumors except for testicular cancer.
Answer E	AnswerE::Folate deficiency
Answer E Explanation	AnswerEExp::Patients with Down syndrome are not at increased risk of folate deficiency.
Right Answer	RightAnswer::A
Explanation	[[Explanation::Down syndrome is the most common chromosomal abnormality that is compatible with life. It is caused by an extra copy of chromosome 21 (trisomy 21). Down syndrome is typically associated with physical growth delays, unique facial dysmorphism, and intellectual disability. Some of the physical characteristics that are associated with Down syndrome include: Short neck Abnormally small chin Flat nasal bridge Upslanting of palprebral fissures Epicanthic fold (skin folds of the upper eyelid that cover the inner angles of the eyes) A protruding, furrowed tongue Abnormal teeth and narrow palate Low set of small or dysplastic ears Short broad hands Single palmar fold (simian crease) Sandal gap (excessive space between the large toe and second toe, as pictured above) Down syndrome is most often caused by meiotic nondisjunction, which occurs during meiosis I. Approximately 2-3% of cases are caused by Robertsonian translocation. On quad screen, Down syndrome is associated with decreased AFP, increased beta-HCG, decreased estriol, and increased inhibin A. Of note non-invasive tests using fetal DNA detected in maternal blood are beginning to replace the quad screen for aneuploidy testing. Down syndrome is associated with the development of several diseases, including cardiac diseases (Endocardial cushion defect, AV canal, VSD, ASD, Tetralogy of Fallot, and PDA), pulmonary diseases (asthma and sleep apnea), GI diseases (Hirschsprung disease, annular pancreas, imperforate anus, esophageal or duodenal atresia, celiac disease, and tracheoesophageal fistula), skin disorders (hyperkeratosis and dermatitis), hypospadias, cryptorchidism, testicular cancer, leukemias, immunodeficiency syndromes, endocrinopathies (type I diabetes mellitus and hypothyroidism), hearing impairment, ocular disorders (Brushfield spots of the iris, refractive errors, strabismus, nystagmus), and Alzheimer's disease at a young age. Educational Objective: Down syndrome is associated an increased risk of leukemia. References: Mullighan CG, Collins-Underwood JR, Phillips LA, et al. Rearrangement of CRLF2 in B-progenitor–and Down syndrome–associated acute lymphoblastic leukemia. Nat Genet. 2009; 41(11):1243-6. Nikolaev SI, Garieri M, Santoni F, et al. Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations. Nat Commun. 2014; 5:4654. Image: Attribution to "Feet of a boy with Down Syndrome.JPG" uploaded by user:Loranchet licensed under the Creative Commons Attribution 3.0 Unported license. commons.wikimedia.org. Retrieved Jan 9 2015. First Aid 2014 page 90 ]]
Approved	Approved::Yes
Keyword	WBRKeyword::Down syndrome, WBRKeyword::Cancer, WBRKeyword::Leukemia, WBRKeyword::Acute Lymphocytic Leukemia, WBRKeyword::Chromosome, WBRKeyword::Genetics, WBRKeyword::Trisomy 21, WBRKeyword::Epicanthic folds, WBRKeyword::Sandal gap, WBRKeyword::Toes
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