An infant born to a 26-year-old woman is evaluated shortly after delivery. Birth weight and length are at the 10th and 15th percentiles, respectively. Vital signs are normal. Physical examination shows a protruding tongue, excessive skin at the nape of the neck, and upslanting palpebral fissures. The startle reflex is symmetric and weak. Cardiac auscultation reveals a harsh, III/VI systolic murmur heard best over the lower left sternal border. The patient has normal external female genitalia. Review of maternal medical records shows a past history of 2 spontaneous abortions in the last 3 years. Echocardiography confirms the presence of a ventricular septal defect. Which of the following karyotypes is most likely to be found in this infant?
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Down syndrome is most commonly caused by random meiotic nondisjunction, an abnormality that correlates with increasing maternal age and results in 3 complete copies of chromosome 21 (47, XX, +21).
Translocation Down syndrome, which is less common, can be inherited from an unaffected parent with a balanced translocation. Robertsonian translocations occur between 2 acrocentric, nonhomologous chromosomes (eg, 14 and 21). The resultant translocated chromosomes are the fusion of 2 long arms (eg, 14q and 21q [red arrow]) and the fusion of 2 short arms (eg, 14p and 21p); the latter usually contains nonessential genetic material and is lost after several cell divisions. The affected parent is asymptomatic because they have a normal (albeit rearranged) genetic complement. However, when an ovum containing the translocated chromosome and a normal chromosome 21 is fertilized with a sperm containing a normal set of chromosomes (ie, 1 copy of chromosome 21), the resultant fetus has an unbalanced Robertsonian translocation with 46 chromosomes and 3 effective copies of chromosome 21 [46,XX, t(14;21)]. Another possible maternal gamete includes 0 copies of chromosome 21, which increases the rate of miscarriages in balanced Robertsonian translocation carriers.
Dysmorphic features of Down syndrome include epicanthal folds, upslanting palpebral fissures, a protruding tongue, and excessive skin at the nape of the neck. Birth weight and length are often below average, and hypotonia and a weak startle (Moro) reflex are characteristic. Cardiac defects are present in >50% of cases.
(Choice A) Turner syndrome (45,XO) presents with low-set ears, a webbed neck, wide-spaced nipples, and cardiac defects (eg, aortic coarctation). Most cases are due to absence of the paternally contributed X chromosome.
(Choice B) DiGeorge syndrome, caused by sporadic 22q11 deletions, presents with hypertelorism, micrognathia, cleft palate, and cardiac defects (eg, interrupted aortic arch, Tetralogy of Fallot).
(Choice C) The Philadelphia chromosome is a balanced translocation between chromosomes 9 and 22 that produces an oncogenic fusion gene (BCR-ABL) associated with chronic myelogenous leukemia.
(Choice E) Trisomy 18 (47, XX, +18), or Edwards syndrome, usually arises secondary to meiotic nondisjunction with maternal age >35. Findings include dysmorphic facies (eg, micrognathia, low-set ears), clenched hands with overlapping fingers, and hypertonia.
Educational objective:
Unbalanced Robertsonian translocations account for a minority of Down syndrome cases. Karyotyping shows 46 chromosomes with a translocation between 2 acrocentric nonhomologous chromosomes [eg, 46, XX, t(14;21)].