A boy is admitted to the neonatal intensive care unit shortly after being born to a 28-year-old woman who had poor prenatal care. His temperature is 37.2 C (99 F), blood pressure is 70/30 mm Hg, pulse is 128/min, and respirations are 40/min. Pulse oximetry shows 85% on room air. Physical examination is significant for orbital hypertelorism, a submucous cleft palate, and bifid uvula. An echocardiogram reveals right ventricular hypertrophy, pulmonary stenosis with ventricular septal defect, and overriding aorta. The patient's diagnosis is eventually confirmed by fluorescence in situ hybridization. These findings are most consistent with which of the following mechanisms?

Question

A boy is admitted to the neonatal intensive care unit shortly after being born to a 28-year-old woman who had poor prenatal care.  His temperature is 37.2 C (99 F), blood pressure is 70/30 mm Hg, pulse is 128/min, and respirations are 40/min.  Pulse oximetry shows 85% on room air.  Physical examination is significant for orbital hypertelorism, a submucous cleft palate, and bifid uvula.  An echocardiogram reveals right ventricular hypertrophy, pulmonary stenosis with ventricular septal defect, and overriding aorta.  The patient's diagnosis is eventually confirmed by fluorescence in situ hybridization.  These findings are most consistent with which of the following mechanisms?

Quizplus · Accepted Answer

11ec160b_377f_dacb_9249_815607b39079_MD0001_00 Chromosome 22q11.2 microdeletion involves deletion of genes residing in adjacent loci. This results in variable phenotypes including DiGeorge syndrome (cardiac anomalies, hypoplastic/absent thymus, hypocalcemia) and velocardiofacial syndrome (cleft palate, cardiac anomalies, dysmorphic facies); the latter is exemplified in this patient. Defective neural crest migration into derivatives of the third and fourth pharyngeal pouches results in maldevelopment of the thymus and parathyroid as well as subsequent T-cell deficiency and hypocalcemia. Cardiac defects include interrupted aortic arch and tetralogy of Fallot (described in this patient). Dysmorphic facial features include orbital hypertelorism, short palpebral fissures and short philtrum, cleft palate, and bifid uvula. In fluorescence in situ hybridization (the gold standard test), genes of interest are hybridized with fluorescently labeled DNA probe. Lack of fluorescent signal is indicative of a microdeletion. (Choice A) Kartagener syndrome results from immotile cilia due to an autosomal recessive microtubular defect in the dynein arm. It results in infertility, situs inversus, chronic sinusitis, and bronchiectasis. (Choice C) Marfan syndrome, a fibrillin defect, causes cystic medial necrosis of the aorta and joint hyperextensibility. It is not associated with a cleft palate, but rather with a high-arched palate with crowded teeth and a narrow face. (Choice D) Microdeletion syndrome due to genomic imprinting includes Prader-Willi syndrome (PWS) and Angelman syndrome (AS). In PWS, paternal genes are deleted (15q-) and maternal genes are silenced, resulting in short stature, obesity, hypotonia, and hypogonadism. In AS, maternal genes are deleted (15q-) and paternal genes are silenced. Patients have microcephaly, ataxia, hand flapping movements, and frequent laughter ("happy puppet"). (Choice E) Tuberous sclerosis involves defective tumor suppressor gene-coded proteins hamartin (TSC1) and tuberin (TSC2), and is characterized by cutaneous angiofibromas, brain hamartomas, and cardiac rhabdomyomas. (Choice F) Friedrich ataxia (GAA repeat) is characterized by spinocerebellar degeneration and spinal ataxia. It is not associated with facial or palatal malformations. Other examples of trinucleotide repeats include Fragile X (CGG) and myotonic dystrophy (CTG). Educational objective: Chromosome 22q11.2 microdeletion results in DiGeorge syndrome (cardiac anomalies, hypoplastic or absent thymus, and hypocalcemia) and velocardiofacial syndrome (cleft palate, cardiac anomalies, dysmorphic facies). Fluorescence in situ hybridization is the "gold standard" for detecting a microdeletion. __________ References: 22q11.21 deletion syndromes: a review of proximal, central, and distal deletions and their associated features. (http://www.ncbi.nlm.nih.gov/pubmed/26278718) Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. (http://www.ncbi.nlm.nih.gov/pubmed/17950858)

A Boy Is Admitted to the Neonatal Intensive Care Unit