Genetics QOD

1. Genetics QOD

2. You are called to examine a newborn girl who has multiple congenital anomalies. On physical examination, you notice several "punched-out" scalp ulcers,bilateral cleft lip and palate, postaxial polydactyly (extra digit on the ring finger side) of the hands, and a small omphalocele.

3. Of the following, this infant's karyotype MOST likely is • 45,X • 45,X/47,XXX • 47,XX+13 • 47,XX+18 • 47,XX+21

4. Question 1 Answer C • The newborn described in the vignette has a 47,XX+13 karyotype consistent with trisomy 13. Her unusual features of "punched-out" scalp lesions (also known as "aplasia cutis"), bilateral cleft lip and palate, and polydactyly are present in at least 50% of newborns who have this diagnosis. Other common anomalies in affected individuals include holoprosencephaly (incomplete septation of the frontal lobes), microcephaly, and cardiac defects (80%). Trisomy 13 has a poor prognosis, with approximately 50% of affected individuals dying by 2 weeks of age and 90% dying by 1 year.Approximately 50% of individuals who have Turner syndrome have a 45,X karyotype; the remainder have a mosaic karyotype that includes a cell line consistent with Turner syndrome, such as 45,X/47,XXX, or a karyotype with 46 chromosomes wherein one of the X chromosomes is aberrant (eg, ring X, isochromosome Xq). Affected newborns may exhibit dysmorphisms or may appear completely normal. Unusual features include webbed neck with low posterior hairline, broad chest with widely spaced nipples, narrow and hyperconvex nails, and cardiac defects, most commonly bicuspid aortic valve.Individuals who have trisomy 18 usually have a 47,XX(or XY)+18 chromosome complement. Characteristic features include intrauterine growth restriction, prominent occiput, small facial features, clenched hands with overlapping of the second finger over the third and the fifth finger over the fourth, and hypertonia. Trisomy 18 has a poor prognosis; approximately 50% of affected individuals die by 2 weeks of age and 90% die by 1 year.47,XX(or XY)+21 is the most common karyotype seen in individuals who have Down syndrome. Affected newborns typically exhibit midface hypoplasia with epicanthal folds, upslanting palpebral fissures, small ears with overfolded pinnae, redundant nuchal skin, and hypotonia. Many affected individuals have fifth finger clinodactyly (in-curving) (Item C39), and almost 50% have a single transverse palmar crease. Approximately 45% of affected individuals have congenital heart defects.American Board of Pediatrics Content Specification: • Recognize the prominent features of trisomy 13 in a newborn infant

5. You care for a 5-year-old girl who recently received a diagnosis of neurofibromatosis type 1 (NF1). Her parents tell you that they have read that NF1 is associated with an increased risk for cancers, and they ask you for more information.

6. Of the following, the MOST accurate statement regarding cancers associated with NF1 is that • leukemia is an unlikely cancer type • Lisch nodules predispose to tumors of the eye • optic glioma most commonly presents at the onset of puberty • pheochromocytoma is common in early childhood • plexiform neurofibromas may show malignant transformation

7. Question 2 Answer E • Neurofibromatosis type 1 (NF1) is among the most common genetic conditions affecting humans, occurring in 1 in 3,000 births worldwide, regardless of ethnicity or geographic location. NF1 is caused by mutations in the NF1 gene on chromosome 17; this gene encodes the protein neurofibromin, which acts as a tumor suppressor by downregulating the ras signal transduction pathway. NF1 is an autosomal dominant condition, and 50% of cases are due to spontaneous gene mutations. Mutations in NF1 result in the production of cells that have only half the normal amount of intracellular neurofibromin. The subsequent somatic mutation of the normal NF1 gene leads to tumor formation in affected tissues.NF1 is a highly variable condition, even within families. Diagnosis is based on the finding of at least two features from the list of National Institutes of Health diagnostic criteria for NF1 (Item C87A). Using these criteria, approximately 95% of affected individuals can be diagnosed by age 11 years.Although most of the tumors associated with NF1 are benign (eg, cutaneous and subcutaneous neurofibromas), affected individuals are at increased risk for malignancy (approximately 35% to 37% lifetime risk versus approximately 30% risk in the general population). Plexiform neurofibromas, which occur in about 25% of individuals who have NF1, are a special type of neurofibroma that may exist largely beneath the skin's surface (Item C87B) or entirely internally. Plexiform neurofibromas undergo malignant transformation to neurofibrosarcomas in 10% to 15% of patients who have them. Signs of malignant transformation include the sudden onset of rapid tumor growth and pain at the site. Expeditious medical evaluation is warranted in such circumstances.Lisch nodules are hamartomas that resemble freckles and are located in the iris stroma (Item C87C). They can be appreciated in light-colored eyes with the use of a direct ophthalmoscope; a slitlamp is helpful for detecting them in darkly pigmented irises. Although not pathognomonic for NF1, the presence of two or more is a diagnostic criterion for the condition. They are benign and have no impact on vision.Optic glioma occurs in approximately 15% of individuals who have NF1 and typically develops before 6 years of age. Of note, optic glioma may be discovered at an older age upon head imaging performed for any purpose, but if it is not present by age 6 years, it typically does not occur. These benign tumors may cause problems due to their location along the optic nerves (Item C87D).Myeloproliferative and myelodysplastic leukemias are among the malignancies associated with NF1. Individuals who have NF1 have an increased incidence of pheochromocytoma, which typically occurs in adulthood. Individuals who have NF1 do not appear to be at increased risk for developing the common cancers affecting the breast, colon, and prostate.American Board of Pediatrics Content Specifications: • Know that neurofibromatosis is an autosomal dominant disease with extremely variable expression that produces tumors • Recognize that neurofibromatosis is inherited as an autosomal-dominant trait with a high spontaneous mutation rate

8. You are seeing a 4-year-old boy who is new to your practice for a health supervision visit. While reviewing the family history, you learn that his father has neurofibromatosis type 1 (NF1). Careful examination of the boy's skin using a Woods lamp reveals six café au lait macules measuring at least 5 mm, but no other lesions.

9. Of the following, the MOST likely feature(s) of NF-1 to develop next in this boy is (are) • cutaneous neurofibromas • Lisch nodules • plexiform neurofibroma • pseudarthrosis of the tibia • skinfold freckling

10. Question 3 Answer E • Neurofibromatosis type 1 (NF1) is among the most common genetic disorders in humans, occurring in approximately 1 in 3,000 individuals worldwide. The diagnosis is based on clinical criteria established by the National Institutes of Health Consensus Development Conference in 1987 (Item C215A). To meet the diagnostic criteria for NF1, a person must have at least two of the criteria listed.Typically, the first feature to appear is café au lait macules (Item C215B), as described for the boy in the vignette. The diagnosis should be considered in any prepubertal child who has six or more café au lait macules measuring at least 5 mm at their greatest dimension. The macules may be present at birth or appear in infancy. Approximately 80% of individuals who have NF1 have at least 6 café au lait macules by age 5 years. These may be difficult to see initially, and a Woods lamp may be helpful. Sun exposure causes them to darken.It is important to recognize that the appearance of the diagnostic features of NF1 is largely age-dependent. This fact, together with the extreme variability of the condition at any age, can make the diagnosis challenging. Most commonly, the second feature to appear is skinfold freckling (Item C215C), usually in the axillae and groin; this commonly occurs between ages 3 and 5 years. Cutaneous or subcutaneous neurofibromas are often the third feature to appear, and they typically herald the onset of puberty. Lisch nodules, frecklelike hamartomas (Item C215D) in the iris stroma, may not be evident until early adulthood.Plexiform neurofibromas occur in approximately 25% of individuals who have NF1 and are often congenital (Item C215E). They can remain quiescent for indefinite periods of time, grow steadily, or grow intermittently. These lesions can be disfiguring.Tibial pseudarthrosis is either congenital or occurs following fracture due to congenital tibial bowing (Item C215F). Children who have tibial dysplasia should be referred promptly for orthopedic care.Although genetic testing is available for NF1, implementation is not often necessary. By the age of 11 years, 95% of affected individuals meet clinical diagnostic criteria.American Board of Pediatrics Content Specifications: • Know the clinical features of neurofibromatosis • Know that six or more café au lait spots >.5 cm in diameter suggest the diagnosis of neurofibromatosis. • Be aware that neurofibromas usually do not appear until after puberty

11. You are asked to consult on a baby in the neonatal intensive care unit who has severe respiratory distress and unusual physical features. The baby is receiving maximum ventilatory support, but his oxygen saturation is in the 80s. His nose is deviated to one side, his ears are overfolded, and his hands and feet are unusually positioned. You review his chest radiographs and note bilateral pulmonary hypoplasia.

12. Of the following, the test that is likely to be MOST helpful in determining the cause of this infant's abnormalities is • chromosome analysis • Echocardiography • head magnetic resonance imaging • renal ultrasonography • toxicology screen

13. Question 4 Answer D • In 1946, Potter described the clinical features associated with bilateral renal agenesis. Subsequently, fetuses and infants that had similar findings were referred to as having "Potter syndrome." More recently, however, it has been recognized that the constellation of features associated with Potter syndrome actually are caused by a cascade of effects due primarily to oligohydramnios, and the term "oligohydramnios sequence" has come into favor.The term "oligohydramnios tetrad" sometimes is used to refer to the four primary clinical features associated with a prolonged reduction in amniotic fluid: abnormal, "pugilistic" facies; lung hypoplasia; limb deformation; and renal agenesis or, variably, fetal growth deficiency. In fact, renal agenesis is not necessary for oligohydramnios sequence to occur; any circumstance that leads to significant, longstanding oligohydramnios, such as renal dysplasia with reduced urinary output, posterior urethral valve, and chronic leakage of amniotic fluid, can be causative. Reduction in amniotic fluid volume before, or beginning at the middle, of the second trimester interferes with normal fetal "breathing," resulting in lung hypoplasia. Affected newborns cannot be ventilated adequately, and pulmonary insufficiency usually is the cause of death. Reduced amniotic fluid also leads to fetal constraint that, in turn, causes facial deformities (compression of the nose, overfolding of the ears) and unusual positioning (deformation) of the limbs.The physical findings described for the infant in the vignette are consistent with oligohydramnios sequence, and the most appropriate next step in management is evaluation of the urinary tract by renal ultrasonography. If the imaging indicates renal agenesis, supportive care can be offered. If a urinary tract outflow obstruction is present, the clinician must determine whether surgical correction would offer benefit.It is important to consider that this infant could have a chromosome abnormality underlying his anomalies and might have other birth defects affecting the heart or brain. However, absent or dysplastic kidneys or other genitourinary tract anomaly is likely to be the direct cause of his presentation. In addition, he may have been exposed to substances prenatally that have affected his genitourinary system, such as cocaine or angiotensin-converting enzyme inhibitors, but such knowledge has no impact on immediate medical management.American Board of Pediatrics Content Specification: • Know that any infant with features of the oligohydramnios tetrad (Potter facies) warrants a detailed evaluation of the genitourinary system

14. A couple comes to you for counseling following the delivery of a stillborn fetus that had multiple anomalies 1 year ago. They would like to have another baby, but they are concerned about the possibility of recurrence. The couple declined autopsy after the fetus was delivered, but they bring you photos for review. You note a cleft extending diagonally across the face, a constriction ring around one arm, and multiple digital amputations on the ipsilateral hand with attached strands of tissue.

15. Of the following, the MOST accurate statement regarding this condition is that it stems from an abnormality that usually occurs • at conception • in association with amniocentesis • in association with chorionic villus sampling • in the first trimester • in the second or third trimester

16. Question 5 Answer D • The infant described in the vignette has amniotic band sequence (also known as amniotic rupture sequence and amniotic band disruption sequence); the strands of tissue attached to the hand with digital amputations are important clues to the diagnosis. Amniotic band sequence refers to the fetal anomalies that can occur as a result of early amnion rupture. Once this diagnosis is established, it is appropriate to tell the parents that this is a sporadic occurrence, and recurrence risk for future pregnancies is negligible.Although multiple theories have been proposed about the cause of this phenomenon, one of the most widely held is that it is due to early, primary rupture of the amnion before 12 weeks' gestation. Prior to 12 weeks' gestation, the amnion and chorion are separate membranes, making the amnion more susceptible to rupture. Fetal entrapment can occur any time throughout the remainder of the pregnancy. Following rupture, strands of amnion can wrap around developing fetal structures, leading to constriction and reduced distal blood flow that results in hypoplasia, syndactyly, or amputation. The tissue strands also can transect the body and head, resulting in abdominal wall defects and facial clefts, respectively. Furthermore, amniotic bands may cause changes, such as limitation of movement, that lead to unusual fetal position and result in fetal deformation. It is important to look for evidence of amniotic bands in the newborn who has limb deficiencies; they often are washed away with the first bath. Examination of the placenta also may allow for confirmation of amniotic rupture.There are rare reports of amniotic bands occurring in association with maternal trauma such as a bad fall within the first 12 weeks of pregnancy, resulting in amniotic rupture. Amniotic bands are not associated with procedures such as chorionic villus sampling or amniocentesis.American Board of Pediatrics Content Specification: • Know that amniotic bands can become adherent to any part of the fetal body, thereby causing a variety of disruptions (eg, ring-like constrictions of limbs, amputation of digits, disruptive cleft of the face)

17. The parents of one of your patients, who has spina bifida, would like to have a second child. They want to do everything possible to reduce the risk of having another baby affected by a neural tube defect. You discuss the benefits of maternal folic acid supplementation, citing the recommendations from the Centers for Disease Control and Prevention.

18. Of the following, the percent reduction in neural tube defects that has occurred since implementation of these recommendations is CLOSEST to • 5% to 15%   • 15% to 25%   • 25% to 50%   • 50% to 70%   • 70% to 90%

19. Answer C • Neural tube defects (NTDs) are among the most common of the birth defects, with a worldwide incidence of 1 per 1,000 births. They are caused by both environmental and genetic factors. Of the environmental factors that play a role in neural tube closure, folic acid has proven to be the most significant thus far.Folic acid is a water-soluble B vitamin (vitamin B9) that is essential to humans and is abundant in leafy, green vegetables; legumes (such as peas and beans); and some seeds (such as sunflower). Folate, the naturally occurring form of folic acid, plays an important role in conditions involving rapid cell division, such as pregnancy. Folate also is important in purine production, which is required for DNA and RNA synthesis and repair, as well as other biochemical pathways.Numerous well-designed studies have shown that oral supplementation with 0.4 mg/day of folic acid from 1 month prior to conception through the first trimester in women who have not had a previous child affected by an NTD reduces the current fetus' NTD risk by up to 75%. For women who have had a previously affected child, a dose of 4.0 mg/day is recommended for the same time period and reduces the recurrence risk by up to 75%.

20. Despite the previously cited recommendations for supplementation, the expected decline in NTD rate did not occur, and in 1998, mandatory fortification of cereal grain products with folic acid went into effect in the United States. Unfortunately, the hoped-for reduction in NTD rate has not occurred since that time. Instead, the reduction in rate of NTDs has been approximately 25% to 50%. Factors contributing to this lower reduction rate include lack of patient education, reduced patient compliance, and barriers to prenatal care.NTD research continues, with a focus on genes and epigenetic (factors that influence gene expression) variables that play a role in NTDs. The role(s) of folic acid in these processes largely remain(s) a mystery.American Board of Pediatrics Content Specification(s): Understand the role of folic acid in the prevention of neural tube defects

21. A 4-year-old girl presents to your clinic for evaluation of developmental delays and dysmorphic features. On physical examination, you document unusual facial features and multiple major anomalies. Review of a recent developmental evaluation reveals significant global delays. Family history is negative for any individuals who have birth defects or intellectual deficits. You consult a medical geneticist, who does not recognize a pattern to this child's features and recommends genetic testing. The high-resolution chromosome analysis yields normal results.

22. Of the following, the testing strategy that is MOST likely to be helpful in determining the cause of this child's anomalies is • comparative genomic hybridization   • DNA testing for fragile X syndrome   • fluorescence in situ hybridization   • urine organic acid analysis   • X-inactivation studies

23. Answer A • Genetic testing for individuals who have intellectual disabilities, multiple anomalies, and dysmorphic features is evolving rapidly. High-resolution chromosome analysis, which requires dividing cells, has a resolution of 5 to 19 megabases (Mb), making it impossible to detect deletions, duplications, or rearrangements that could contain hundreds of genes. Therefore, additional testing is required for the girl described in the vignette.Fluorescence in situ hybridization (FISH), which uses fluorescently labeled DNA probes that hybridize to dividing or resting cells, has a higher resolution than chromosome analysis and is excellent in detecting missing, extra, or relocated chromosomal regions. However, it does not detect single-gene mutations, and it requires that the physician request testing for a specific region, or regions, of interest. Without a recognized pattern to the features for the child in the vignette, a specific request is not possible. FISH is useful for identifying contiguous gene deletions, as can be seen in Prader-Willi, Angelman, Williams, Smith-Magenis, and Miller-Dieker syndromes. The combined diagnostic yield of chromosome analysis and targeted FISH testing approaches 10% in children who have intellectual disabilities and dysmorphisms.

24. Microarray-based comparative genomic hybridization (CGH) is a revolutionary testing strategy for the detection of DNA copy number variations throughout the human genome that may be associated with disease. Depending on the platforms used, which vary largely according to the size of the probes used (the smaller the probe, the greater the resolution) and the amount of the genome covered, microarray CGH can detect clinically significant abnormalities in up to 20% of individuals who have unexplained intellectual disability. Therefore, it is the most helpful choice for determining the cause of this child's anomalies. It is important to note, however, that this modality also detects variations of unclear clinical significance as well as variations of no clinical significance.The array CGH procedure employs thousands to millions of probes (synthetic DNA sequences that hybridize with genomic DNA) that are affixed to glass or silicon wafers (chips) or beads. Added to this matrix are a sample of the patient's DNA labeled with a green dye, for example, and a sample of reference DNA labeled with a red dye, for example. Following hybridization of the samples to the chip, sophisticated equipment is used to interpret the results. Simply speaking, wherever there are equal amounts of patient DNA and reference DNA on the chip, a yellow color is present. If there is excess patient DNA on a probe, the region appears green, and if there is excess reference sample on a probe, the region appears red.

25. Microarray CGH does NOT replace high-resolution chromosome analysis for identifying all genetic abnormalities of clinical significance. Abnormalities that can be detected on chromosome analysis but not on microarray CGH at the time of this writing include balanced chromosomal rearrangements (that theoretically can transect a gene and may have reproductive significance for parents of the proband who are potential carriers of the rearrangement), free-standing trisomy versus translocation-related trisomy, and low-level chromosomal mosaicism.Fragile X syndrome typically is not associated with multiple major anomalies and is seen most commonly in boys. Organic acid analysis is most helpful in the evaluation of children who have metabolic derangements, which are not part of this child's presentation. Finally, X-inactivation studies generally are used if a girl is believed to have a presentation typically only seen in a boy who has an X-linked disorder, in which case she may have preferential inactivation of the X chromosomes containing the normal copy of the gene in question.American Board of Pediatrics Content Specification(s): Understand that comparative genomic hybridization has replaced high-resolution chromosome analysis to screen patients suspected of having a chromosome abnormality • Know the common gene defects that can be diagnosed with fluorescence in situ hybridization

26. A couple comes to you with questions following the diagnosis of trisomy 21 in their now 18-week fetus. They ask what medical problems may be anticipated for a child who has Down syndrome.

27. Of the following, the medical problem that is encountered MOST frequently in infants who have trisomy 21 is • a cardiac defect   • duodenal atresia   • hypotonia   • polycythemia   • strabismus

28. Answer C • A syndrome is a recognizable pattern of features owing to a specific cause. Down syndrome (DS) is caused by trisomy for all, or a critical portion of, chromosome 21. Almost 99% of affected individuals have extra chromosome 21 material in every cell in their bodies; approximately 1% have a mosaic chromosome complement (46,XX/47,XX+21 or 46,XY/47,XY+21). Chromosome 21 is composed of about 400 genes. An extra copy of some or all of these genes causes a variety of potential medical problems, which should be discussed with the parents who are expecting an affected baby. It is important to note that each child who has DS is unique, and there is a spectrum of potential outcomes. Of note, individuals who have mosaic DS are anticipated to have similar features/cognitive ability to those who have full trisomy 21 because it is not possible to know which tissues contain the abnormal chromosome complement. If these individuals are affected more mildly than the typical person who has DS, this fact becomes evident over time.Hypotonia is one of the most common abnormalities in babies who have DS, occurring in up to 90%. The degree of hypotonia varies from child to child, but usually it is not so severe as to interfere with feeding in the newborn period, and most babies who have DS are able to breastfeed effectively (assuming there is not a cardiac abnormality that precludes this). Early intervention programs should address hypotonia by offering appropriate therapies. The natural history of low muscle tone in DS is that it improves over time.

29. Approximately 12% of children who have DS are born with anomalies of the gastrointestinal tract, including Hirschsprung disease, esophageal atresia, tracheoesophageal fistula, and pyloric stenosis. Duodenal atresia occurs in approximately 4%.Cardiac abnormalities are present in approximately 45% of newborns who have DS. Most are atrioventricular canal defects (almost 50%), followed by ventricular septal defects (~33%), but a variety of anomalies can occur. All newborns who have DS should undergo echocardiography, regardless of their physical examination findings.Polycythemia is a complication during the newborn period in approximately 18% of individuals who have DS. Polycythemia can interfere with oxygenation, and sometimes partial exchange transfusion is recommended for treatment. Otherwise, this problem typically is self-limiting.Problems affecting the eye occur in approximately 60% of children who have DS and include cataracts, lacrimal duct stenosis, nystagmus, and refractive errors. Strabismus occurs in up to 50%. Direct ophthalmoscopic examination should be performed regularly during pediatric visits, with referral to a pediatric ophthalmologist for baseline evaluation between 6 and 12 months of age. Ophthalmology follow-up is tailored to the child's needs but should take place at least every 2 years.American Board of Pediatrics Content Specification(s): Know the associated medical problems in children with Down syndrome

30. You have sent one of your patients, who has achondroplasia, for follow-up evaluation in the genetics clinic. When discussing achondroplasia with the medical student after the evaluation, the medical geneticist points out that approximately 80% of individuals who have this diagnosis have spontaneous mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.

31. Of the following, the mutation that causes achondroplasia MOST commonly is a(n) • autosomal recessive trait   • contiguous gene deletion   • deletion of FGFR3 only   • duplication of FGFR3 • single base-pair substitution

32. Answer E Achondroplasia, the most common form of dwarfism, is an autosomal dominant condition. In 99% of affected individuals, it is caused by a single base-pair change (guanine-to-adenine or guanine-to-cytosine) at nucleotide 1138 in the fibroblast growth factor receptor 3 gene (FGFR3). Both of these changes result in the substitution of an arginine for a glycine in the encoded protein, leading to increased activation of the growth factor receptor. Because the normal action of the receptor is to reduce bone growth, its increased activity leads to shorter bones and smaller stature. It is important to note that DNA point mutations (substitutions, deletions, or insertions of a single base-pair) can cause a wide range of outcomes, some of which are dramatic. Point mutations can result in the production of nonfunctional proteins (nonsense mutations), different amino acids than expected (missense mutations), and alterations in the amino acid or protein that have no functional significance (silent mutations). One of the best known examples of a point mutation causing severe disease is that seen in sickle cell disease (SCD). SCD is caused by a single base-pair substitution in the beta-globin gene, resulting in the production of a valine instead of a glutamic acid in the protein. The resultant hemoglobin molecule is malformed, such that it cannot carry oxygen effectively. Although contiguous gene deletions, as well as gene deletions and duplications, are associated with numerous genetic disorders, they do not play a significant role in causing achondroplasia.American Board of Pediatrics Content Specification(s): Understand that a single base pair substitution or deletion can lead to a gene defect with major consequences

33. The attending neonatologist notifies you that she is caring for a newborn boy in your practice who has multiple congenital anomalies. The baby was transferred from the newborn nursery to the intensive care unit due to cyanosis. Echocardiography reveals findings consistent with tetralogy of Fallot. The infant has a cleft palate. Chest radiographs show multiple thoracic hemivertebrae. Renal ultrasonography documents unilateral renal agenesis. On physical examination, the infant has hypoplastic thumbs. The baby is normally grown and vigorous.

34. Of the following, the MOST likely diagnosis for this infant is • CHARGE syndrome   • Fanconi anemia   • trisomy 18   • 22q11 deletion syndrome   • VACTERL association

35. Answer D • The combination of tetralogy of Fallot, hypoplastic thumbs, cleft palate, and a renal abnormality described for the infant in the vignette is highly suspicious for 22q11 deletion syndrome. This syndrome can be diagnosed by fluorescence in situ hybridization or comparative genomic hybridization microarray. The incidence of 22q11 deletion syndrome is believed to be approximately 1 in 4,000, making it one of the most common multiple congenital anomaly syndromes. Fanconi anemia is an autosomal recessive condition that is extremely rare (1 in 100,000 to 1 in 350,000) and is associated with physical abnormalities (thumb hypoplasia, heart defect, renal anomalies, and more) in 60% of affected individuals as well as bone marrow failure and significant cancer risk. It is more common among persons of Ashkenazi Jewish heritage.Trisomy 18 occurs in approximately 1 in 3,000 births. Affected infants may share a number of the features with the infant in the vignette, but they typically are small for gestational age and usually are feeble. In medical genetics, the term "association" is used to describe abnormalities that occur together more than would be expected by chance but that do not have a common cause. Probably the most well known of these is the VATER association, where V=vertebral anomalies, A=anal atresia, TE=tracheoesophageal fistula, and R=renal anomalies (Item C183). The VATER association has been expanded since its original description to "VACTERL" association, wherein C=cardiac defects, and L=(radial)limb anomalies. To consider VACTERL association as a possibility, at least one anomaly in each of three geographic regions of involvement (pelvis/lower abdomen, limb, and thorax) is deemed necessary, but no official minimum criteria are established.

36. It is important to recognize that associations are better classified as descriptions than as diagnoses. For an infant to receive the label of VACTERL association, all other reasonable possibilities should be ruled out, including chromosomal and microarray abnormalities, teratogenic exposures, and syndromic diagnoses.CHARGE (C=coloboma, H=heart, A=atresia choanae, R=retardation of growth and/or development, G=genital anomalies, E=ear anomalies) was considered an association until it was described in more detail and ultimately discovered to be caused by alterations in the CHD7 gene in 2006. It is now appropriately called "CHARGE syndrome," and the features that are most consistent with this diagnosis have been delineated even further. For example, cranial nerve dysfunction and internal ear anomalies are more prevalent than once thought, and intelligence often is normal.American Board of Pediatrics Content Specification(s): Recognize multiple congenital anomaly associations such as VATER, CHARGE • Recognize the clinical manifestations of genetic associations (eg, CHARGE, VACTERL, VATER)

37. You are called to the newborn nursery to evaluate a term female infant who has dysmorphic facial features. She was born to a woman who received no prenatal care. Labor and delivery were uncomplicated. The infant has normal weight, length, and head circumference. On physical examination, you document notched lower eyelids, hypoplastic zygomatic arches, malar hypoplasia, a hypoplastic ear on one side with two preauricular tags on the same side, and retrognathia. The remainder of the findings are normal.

38. Of the following, the condition with which this infant's features are MOST consistent is • diabetic embryopathy   • Pierre Robin sequence   • Stickler syndrome   • Treacher Collins syndrome   • 22q11 deletion syndrome

39. Answer D • The infant described in the vignette has features of mandibulofacial dysostosis, a description that applies to a group of disorders in which there is underdevelopment of the mandible and variable facial and ear anomalies. The best characterized of the mandibulofacial dysostoses is the Treacher Collins syndrome (TCS).TCS is an autosomal dominant condition that is highly variable and is caused by spontaneous gene mutations in 60% of affected individuals. Unusual features associated with TCS include downslanting eyes with lower lid coloboma (notching) and absent eyelashes medial to the notch, malar hypoplasia, hypoplastic/malformed external ears with conductive and/or sensorineural hearing loss, and microretrognathia that has the potential to compromise the airway. Features may be highly variable, even within the same family.TCS is known to be associated with only one gene, TCOF1, and most individuals who meet clinical diagnostic criteria for TCS have detectable mutations in this gene. Clinical molecular testing is available and may serve to establish recurrence risk for very mildly affected or apparently unaffected individuals.

40. The management of TCS is supportive. Special attention should be given to the airway because of the potential for choanal stenosis/atresia or glossoptosis (posterior displacement of the tongue). The newborn should be examined carefully for cleft palate and swallowing difficulties. Formal audiologic evaluation is important to establish a baseline and to detect possible hearing loss. Ophthalmology referral is indicated in early infancy due to increased risk for corneal damage, strabismus, and refractive errors. Craniofacial computed tomography scan with three-dimensional reconstruction may be indicated in the first 6 months to define anatomy better in anticipation of future treatments such as plastic surgery.Diabetic embryopathy can include malformation/hypoplasia of the ears. However, affected individuals do not have notched lower eyelids or malar hypoplasia, as seen in TCS, and they frequently have heart defects and other anomalies.Pierre Robin sequence (retrognathia, retroglossia, and cleft palate) may be isolated or may be part of a bigger picture, such as Stickler (Item C199) and 22q11 deletion syndromes. In each case, there is marked retrusion of the mandible, but the eye findings associated with TCS are not present, and although the ears may be unusual in 22q11 deletion, typically they are not severely malformed.American Board of Pediatrics Content Specification(s): • Know the clinical features of Treacher Collins syndrome and that it is due to a single gene defect

41. You are called to the newborn nursery to evaluate an infant who has had two dusky episodes unrelated to feedings. Serum glucose values are normal. Oxygen saturation on pulse oximetry is 98% with the infant sleeping comfortably on her side. Cardiac examination yields normal results. You notice features consistent with Pierre Robin sequence (PRS)

42. Of the following, the series of events that MOST commonly causes PRS is • cleft palate → glossoptosis → airway obstruction   • depressed midface → choanal stenosis → airway obstruction   • glossoptosis → cleft palate → cleft larynx → airway obstruction   • macroglossia → cleft palate → airway obstruction   • retrognathia → glossoptosis → cleft palate → airway obstruction

43. Answer E • A sequence is a cascade of events that occurs subsequent to a primary abnormality in the developing embryo/fetus. One of the best known of these is the Pierre Robin sequence (PRS), also called "Robin sequence". It is named after the French physician who, in 1933, described the pattern of micrognathia, glossoptosis (posterior displacement of the tongue), and cleft palate.The primary cause of PRS is believed to be hypoplasia of the mandible before 9 weeks' gestation. At 9 weeks, the palatal shelves, which "hang down" on either side of the tongue, normally swing up and close, anteriorly to posteriorly. If the mandible is small (micrognathia) or posteriorly placed (retrognathia), the tongue is pushed back and mounded up, making it impossible for the palatal shelves to "clear" the tongue as they try to close over it.There are myriad causes of PRS, including uterine constraint, single gene disorders, chromosome abnormalities, teratogenic exposures, disruptions, and unknown reasons. It is incumbent upon the physician caring for the child who has PRS to investigate underlying causes because a unifying diagnosis is important in defining a management strategy, the natural history of the disorder, and recurrence risk.

44. The clinical presentation of PRS varies. Some affected individuals have relatively mild micrognathia, a small and soft palatal cleft, and minimal-to-no difficulties with feeding and breathing. Some have oxygen desaturations that can be treated effectively with side or prone positioning. Others are severely affected and have marked micrognathia, large palatal clefts, and severe glossoptosis, leading to airway compromise and frequent cyanotic spells. Furthermore, there may be swallowing difficulties. Medical intervention is required in these cases and includes feeding tubes (usually nasogastric) and various methods of maintaining airway integrity, including tongue-lip adhesion, intubation, tracheostomy, and mandibular traction.Of note, some studies have shown that infants and children who have PRS may have oxygen saturations less than 90% for prolonged periods without evidence for airway obstruction. They are at increased risk for pulmonary hypertension that ultimately can cause cor pulmonale and failure to thrive. Although no formal recommendations exist for surveillance in PRS, it may be prudent to monitor oxygen saturations and refer for echocardiography at regular intervals.American Board of Pediatrics Content Specification(s): Know that upper airway obstruction caused by glossoptosis may cause cor pulmonale in infants with Pierre-Robin sequence • Know that the features of Pierre-Robin sequence are secondary to micrognathia

45. The parents of a 12-year-old boy bring him to the clinic because they are concerned about his lack of interest in socializing and physical activity. He was held back in school this year due to learning problems, primarily in reading and writing. He has no close friends, and his favorite activity is watching television. On physical examination, the pleasant and attractive youngster converses with you easily. His weight is at the 50th percentile and his height at the 95th percentile. He wears thick glasses due to high myopia. He has mild scoliosis in the thoracic spine. He shows no signs of puberty. Using a Woods lamp, you identify five café au lait macules on his trunk and extremities.

46. Of the following, the MOST likely diagnosis for this boy is • Asperger syndrome • Klinefelter syndrome • Marfan syndrome • neurofibromatosis • Stickler syndrome

47. Answer B • The combination of poor social interaction with same-age peers, a tendency to be a loner, difficulties with reading and writing, and tall stature described for the boy in the vignette should raise suspicion for the diagnosis of Klinefelter syndrome (KS). KS typically is associated with a 47,XXY karyotype, although the term applies to boys who have at least one extra X chromosome or a mosaic chromosome complement with at least one cell line having more than one X.KS is relatively common, with a birth incidence of 1.2 per 1,000 males. There are three times in the lifespan when KS is likely to be diagnosed: 1) prenatally, on amniocentesis performed due to advanced maternal age; 2) in adolescence, due primarily to gynecomastia (present in one third of affected boys); and 3) in adulthood, due to infertility.Boys who have KS typically do not have dysmorphisms. They are tall compared with their chromosomally normal siblings, and they often have mild skeletal differences, such as an increased carrying angle or gynecoid pelvis. Scoliosis is common in boys who have KS. Puberty usually is delayed, and after puberty, affected boys may have reduced facial or body hair, gynecomastia, and small testes. Obesity and poor muscular development may be evident. Elevations in luteinizing hormone and follicle-stimulating hormone are associated with reduced testicular function and lack of feedback inhibition by testosterone. In adulthood, individuals who have KS are at increased risk for Leydig cell neoplasia, and a history of gynecomastia is associated with a 20- to 50-fold increased risk for breast cancer compared with the general male population.

48. From developmental and behavioral standpoints, there is wide variation among boys who have KS, but common problems include delays in motor skills, speech and language, and reading. A commonly described feature is the "the tip of the tongue" phenomenon, wherein the boys are unable to retrieve the correct phrase or response to a question. The boys tend to be immature, to adapt poorly to unfamiliar situations, and possibly to be inappropriately aggressive. Inattentiveness may be a problem, and social skills are often lacking, although the boys may relate better to adults than to their peers. Intelligence quotient (IQ) is usually within the normal range, although the average IQ is typically 10 to 20 points less than in otherwise healthy siblings.Asperger syndrome (AS) is a multifactorial autism spectrum disorder associated with deficits in social interaction that involves relative preservation of language and cognitive function. AS has an estimated incidence of 1 in 5,000. Affected individuals are not typically tall, and they have an unusual conversational style, sometimes speaking in a monotone, showing few facial movements, or displaying restricted body movements.Marfan syndrome is an autosomal dominant connective tissue disorder associated with tall stature and skeletal abnormalities, including arachnodactyly, pectus deformity, and scoliosis as well as dilation of the aortic root and subluxed lenses of the eye. Thus far, an association with learning problems is not documented. Socialization is average for age.

49. Stickler syndrome is an autosomal dominant connective tissue disorder that may have skeletal features overlapping with Marfan syndrome in childhood. Cardinal features are prominent eyes and malar hypoplasia as well as rapidly progressive high myopia. Scoliosis is a complication of the disorder. Learning problems are not part of the picture, and socialization is normal.Neurofibromatosis (NF) type 1 is an autosomal dominant neurocutaneous syndrome that has an incidence of 1 in 3,500. Café au lait macules (CALMs) typically are the first sign to appear, and six or more CALMs measuring at least 5 mm in diameter in a prepubertal child should raise suspicion for this diagnosis. Individuals who have NF1 are at increased risk for intellectual and learning disabilities. NF1 is not associated with tall stature, and socialization typically is normal.American Board of Pediatrics Content Specification(s): Know the major clinical manifestations of Klinefelter syndrome

50. The parents of a 6-month-old boy in your care are concerned because his development seems to be slowing. They also say that he has begun to startle easily to loud noises, and he is less attentive than he once was. On physical examination, he appears normally grown and has no dysmorphisms. He displays some roving eye movements and has reduced tone compared with his previous examination at 4 months of age. You refer the infant for an ophthalmology evaluation, which reveals cherry-red spots of the maculae. Blood analysis of hexosaminidase A activity reveals that it is undetectable.