Genetics Metro NY

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Question 1: In the NICU, you've just examined a newborn with hypotonia and dysmorphic features that included epicanthal folds, upward slanting of the palpebral fissures, flat nasal bridge with anteverted nares and midface hypoplasia. Among the following, the medical complication that is MOST likely to present in the newborn period in this infant is:A.atlantoaxial instabilityB.hypothyroidismC.leukemiaD.obstructive bowel diseaseE.seizures.

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Genetics Metro NY

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1. Genetics Metro NY/NJ Pediatric Board Review Course Joy M. Samanich, M.D. Robert W. Marion, M.D. Albert Einstein Col of Med/ Children’s Hosp at Montefiore

3. Question 1: Preferred Response: D The baby has features of Down syndrome. He should be observed for: Obstructive gi tract abnormalities (~10%) including duodenal atresia, annular pancreas, anal atresia, and TEF. Cardiac anomalies (~40%) including ECCD. ALL INFANTS WITH DS SHOULD HAVE ECHO-CARDIOGRAM BEFORE DISCHARGE FROM THE NURSERY! Polycythemia and leukemoid reaction (which can look like leukemia but is self-limited); ALL INFANTS WITH DS SHOULD HAVE A CBC! Congenital hypothyroidism (~1%)

4. Question 1: Preferred Response: D (GI obstruction) Atlantoaxial instability, which can lead to compression of the cord, occurs in ~10%, but is not a problem in the newborn period. Neck films (lateral in neutral, flexion and extension) should be performed after age 3. Pts with DS have a higher incidence of leukemia, which approaches 1% (but is also not a problem in the NB). Seizures occur in a small number of patients with DS . All patients with DS display cognitive impairment, (most with IQs in the mod MR range). Early intervention to maximize development in early childhood is recommended. HE SHOULD ALSO HAVE CHROMOSOME TESTING:

6. Question 2: Preferred Response: B Following the clinical diagnosis of Down syndrome, it’s essential to obtain a karyotype, which will provide information about parental risks in future pregnancies. In DS: 95% are due to trisomy 21 (46,XY,+21 or 46,XX+21) 3% are due to unbalanced Robertsonian translocations involving an acrocentric chromosome (13, 14,15, 21, or 22) ; ie: 46, XY, -14. t (14q21q) 2% are due to mosaicism If the condition is caused by trisomy, the recurrence risk for any trisomy is 1%

7. Question 2: Preferred Response: B If the condition is due to an unbalanced translocation, it is necessary to do a karyotype on the parents. In these cases: 2/3 are de novo (both parents have normal karyotypes). RR is ~1% 1/3 result from unbalanced segregation of a balanced Robertsonian translocation in one of the parents. If mother is the translocation carrier (45,XX,-14,-21, t(14q21q), RR=10-15% If father is the translocation carrier (45,XY,-1`4,-21,t(14q21q), RR=2-5%. If the balanced translocation involves one chromosome 21 attached to the other (ie. 45,XY, -21,-21, t(21q21q), all progeny will have Down syndrome! Once a balanced translocation is found, other family members should be tested

9. Question 3: Preferred Response: B Isolated CL+/-P is inherited as a multifactorial (MF) trait, caused by the interplay of genetic and environmental factors. Disorders showing MF inheritance occur more commonly in individuals in a particular family than in the general population, but at a lower rate than would be expected for single gene traits. RR for MF traits have been derived by analysis of many families that express the trait. For CL+/-P, RR for a family in which neither parent is affected and only one child is affected is 2-5%. MF inheritance is seen in many common birth defects (CHD, CDH, NTDs, pyloric stenosis, hypospadias, etc). In general, the RR for all of these disorders is between 2 and 5%. MF inheritance is also the cause of most disease of childhood and adulthood, ie. asthma, DM, hypertension, cancer, alcoholism, coronary artery disease, etc.

10. Question 3: Preferred Response: B RR of MF traits is altered by a # of factors, including the number of family members who are affected. The RR for subsequent sib of a child who has clubfoot is 3%. However, if one parent also had clubfoot, RR is 10-15%. To provide accurate information about RR, a careful exam should be done to identify additional anomalies. The possibility that the most obvious defect is part of a genetic syndrome, which may carry a higher risk, must be considered . In general, chromosome analysis should be obtained in pts with two or more major abnormalities (eg, clefting, congenital heart disease) or one major anomaly and two or three minor defects (eg, epicanthal folds, simian line). Accordingly, chromosome analysis would not be indicated for an infant with an isolated cleft lip and palate.

12. Question 4: Preferred Response: C As noted in the last question, CL+/-P can occur in isolation or as part of a multiple malformation syndrome. Syndromes (groups of malformations caused by a single identifiable etiology) can occur due to a chromosomal abnormality, a single gene mutation, or as the result of exposure to a teratogen. In the present patient, the pattern of findings is most consistent with trisomy 13. Trisomy 13 (47,XX or Y,+13) occurs in 1 in 5-10,000 liveborns. Most affected infants die in the newborn period; 5% survive to 6 months. It is associated with advanced maternal age. Associated features include holoprosencephaly, severe MR; microcephaly; microphthalmia; coloboma; CL+/-P; ear anomalies; distinctive scalp defects in the occipital area; CHD; postaxial polydactyly and cryptorchidism in males.

13. Question 4: Preferred Response: C Peripheral blood karyotype should be performed to document dx and help provide genetic counseling about future risks. In particular, it’s important to determine if the child has a translocation inherited from one parent which would increase the RR (see previous case). Fetal valproate syndrome results in CHD, NTDs and unusual facial features (narrow bifrontal diameter, high forehead and epicanthi) as well as limb defects. Retinoic acid embryopathy results in facial asymmetry, microtia or anotia, & CHD. Trisomy 18 is characterized by growth deficiency, prominent occiput, low-set ears, micrognathia, clenched hand, and structural defects of the heart and kidney. Microphthalmia and clefting are not prominent features.

15. Question 5: Preferred Response: D The Pierre-Robin malformation sequence (PRMS) is characterized by: (1) micrognathia, (2) glossoptosis; and (3) a U-shaped cleft of the palate. The initial event in the sequence is failure of mandibular growth in the 1st tri-mester. This results in displacement of the tongue & failure of the palatal shelves to close, causing the U-shaped cleft. PRMS may occur in isolation or as part of a syndrome. Associated ones include Stickler and velocardiofacial syndromes and CHARGE association. In infants, the glossoptosis may occlude the airway, especially when they are supine. Obstructive apnea with desaturation is by far the most serious complication that may develop within the first days of life. Such obstruction may be severe enough to cause ischemic encephalopathy.

16. Question 5: Preferred Response: D Feeding difficulties are common in children with PRMS. Posterior displacement of the tongue and the cleft may contribute to a poor suck. In most cases, though, oral feeding, including breastfeeding, is successful. Although OM is quite common among children who have cleft palate, it typically does not cause problems in early infancy. PRMS is a medical emergency in the newborn! The infant should be placed in the prone position, which allows the tongue to fall forward, relieving the obstruction. But this is only a temporary measure: definitive treatment is essential to assure that the airway remains open. Placement of a nasopharyngeal tube should occur, followed by surgical management.

18. Question 6: Preferred Response: E Malformations are defined as abnormalities of form or function that are caused by alterations in the tissue primordia that forms a structure; as such, malformations occur in the first trimester, can range from mild to severe, and usually require surgical correction. They occur in ~3% of newborns. Deformations result from abnormal external forces acting on normally formed tissue. Unlike malformations, deformations develop after the first trimester, are frequently mild, and usually improve spontaneously once the external force has been removed. One to 2% of neonates have one or more deformations.

19. Question 6: Preferred Response: E The infant described has multiple features suggestive of a deformation sequence due to intrauterine compression. The most important factor contributing to deformation is the restriction of fetal movement, which can be caused by mechanical forces, malformations, or functional abnormalities. However, mechanical causes are the most common etiology. Frequently, more than one deformation is present because the mechanical force exerts an adverse effect on multiple body parts. 1/3 of all deformations occur in infants who present in the breech position. A chromosomal abnormality or teratogen exposure associated with the multiple defects described for this infant would be expected to cause malformations of internal organ systems as well as external findings

21. Question 7: Preferred Response: E NTDs result from failure of the neural tube to close prior to the 27th postconceptional day. Closure proceeds from mid-cervical area caudally and rostrally. Anterior closure defects result in anencephaly; posterior defects result in meningocele or myelomeningocele.. Before 1990, NTDs occurred in 1 in 1,000 births. Etiology is hetero- geneous, including chromosome anomalies (trisomy 18), single gene defects (Meckel-Gruber), and teratogenic exposures (Valproic acid). Isolated NTDs exhibit MF inheritance. RR is 2-4%; such couples should be offered prenatal monitoring in future pregnancies. Isolated NTDs are more common in individuals from the British Isles and less common in Asians; in NA, births of infants with NTDs cluster in the late fall and early winter. This has led to the discovery that periconceptual folic acid supplementation can decrease the risk of having a child with NTD by 70%. This diminution in risk exists for both women who have had a previous affected child as well as those who have not had an affected child.

22. Question 7: Preferred Response: It has been hypothesized that FA prevents NTDs by stimulating certain enzymes (eg, methionine synthetase) that otherwise are present in reduced levels in susceptible women. It’s recommended that all women take folic acid: women who have had a previously affected child are given a dose of 4 mg/day; all others receive 0.4 mg/day. RR in families in which there is a child who has an NTD does not depend significantly upon the ethnic group. The location of the defect along the neural axis also does not influence RR. If the NTD is part of a syndrome, the specific RR for the syndrome should be discussed.

24. Question 8: Preferred Response: D Fetal sonography performed between 12 and 24 weeks of pregnancy is most useful for detection of structural anomalies such as NTDs. Its sensitivity and specificity can be substantially improved if performed by an experienced sonographer. It’s noninvasive, safe, & accurate in experienced hands. Advantages of early fetal sonography include improved dx of multiple gestation and accurate dating of the pregnancy. Although levels of AFP in amniotic fluid are increased in the fetus who has open NTDs, this test has limited sensitivity & specificity for the dx of a myelomeningocele. Early amnio (between 12 & 14 weeks) is most useful for detecting fetal chromosomal abnormalities (ie trisomy 21) & genetic defects .

25. Question 8: Preferred Response: D CVS, which entails biopsy of the placenta between 8 and 11 weeks, is not useful for diagnosing NTDs. It’s most helpful for detecting cytogenetic abnormalities, but it is an invasive procedure and has risks. Cordocentesis (aspiration of fetal blood by direct puncture of the umbilical cord under sonographic guidance) is not useful for the diagnosis of NTDs. It can aid in diagnosing conditions such as coagulation disorders, blood cell abnormalities, and congenital infections such as toxoplasmosis. This invasive procedure has a great many risks. We’ll discuss maternal serum AFP screening in the next question:

27. Question 9: Preferred Response: B AFP, the fetal equivalent of albumin, is produced only during fetal life; thereafter, AFP is found only in the serum of pregnant women and adults with liver disease (hepatoma). Since the 1960s, an association between NTDs & elevated levels of AF-AFP has been noted. The defect in the fetal skin causes AFP to pass between the fetal circulation and the amniotic fluid. Elevated AF-AFP levels also occur in fetuses with omphalocele, gastroschisis, bladder exstrophy, cystic hygroma, as well as in multiple gestations, impending fetal death, etc. Since 1970s, the association between these defects and elevated levels of MSAFP was also noted. Measuring MSAFP between the 16th and 22nd week of gestation has become a standard screening test throughout the world. As noted above, an elevated MSAFP level is not pathognomonic for exposed neural tissue. It is not, however, elevated with most birth defects. And trisomy 13, 18 and 21 are all associated with an MSAFP level that is less than expected.

28. Question 9: Preferred Response: B A positive MSAFP requires confirmatory testing, including sonogram (to verify dates and identify defects) and amniocentesis (for chromosome analysis or acetylcholinesterase activity). The concentration of AFP in the maternal serum is an order of magnitude lower than that in the amniotic fluid; thus, it is more difficult to measure. The development and refinement of obstetric sono-graphy has led some authorities to question whether this might be an adequate screening tool for NTDs. However, ultrasonography will fail to detect some flat or low myelomeningoceles.

30. Question 10: Preferred Response: D This child has features of NF-1. The diagnosis of NF-1 is made on the basis of having two of the following 7 criteria: Café au lait spots: 6 or more of >0.5 cm in diameter for prepubertal children or >1.5 cm post pubertally Axillary and/or inguinal freckles Neurofibromas: 2 or more, or 1 plexiform Optic glioma Lisch nodules Skeletal abnormalities, including scoliosis, pseudarthrosis, sphenoid wing dysplasia Family history of a 1st degree relative with NF-1, diagnosed using these criteria.

31. Question 10: Preferred Response: D NF-1 is an autosomal dominant disorder and one of the most common single-gene defects. The gene, NF-1, which is on chromosome 17, produces neurofibronin, an inhibitor of nerve growth factor. The gene is huge, one of the largest in the human genome; there are no “common mutations.” As such, molecular diagnosis depends on sequencing the entire gene, a strategy that is not practical. In about half of cases, the condition occurs as a spontaneous mutation.

32. Question 10: (continued) Other tumors that occur in pts with NF-1 include: plexiform NFs (usually evident in the first 2 yrs of life). These tumors, in ~5%, can undergo sarcomatous change and frequently present a surgical challenge because of their extensive vascular supply. CNS tumors, including optic gliomas, occur in 2-3% of affected individuals. Overall, the lifetime risk for the development of a malignancy in patients who have NF-1 is ~5% (NOT 50%!). Acoustic neuromas are a prominent feature of NF-2. They are bilateral in ~ 85% of patients and unilateral in ~6%. In NF-2, cutaneous findings are not as prominent. Pheochromocytoma is a rare tumor in NF-1 (<1% of patients), but it is common in patients who have von Hippel-Lindau disease.

34. Question 11: Preferred Response: A Molecular technology allows us to prenatally diagnose mutations leading to Factor XIII and Factor IX hemophilia in > 95% of families. The genes for both diseases are located near the terminus of Xq. Hemophilia occurs in ~1 in 5,000 individuals in the general population, with 80-85% of patients having factor VIII deficiency hemophilia (hemophilia A) and 10-15% having factor IX deficiency (hemophilia B). Neither disorder has apparent racial or ethnic predilection.

35. Question 11: Preferred Response: A The factor VIII gene is much larger, more complex, and has a strong predisposition to spontaneous mutation: ~1/3 of affected individuals have no family history and appear to represent new mutations. More than 200 different mutations have been identified, with the most common being a gene inversion in the tip of Xq, which accounts for ~45% of cases of severe hemophilia A and always is associated with the severe form of the disease. Other mutations account for the remaining cases of severe disease and most cases of moderate or mild disease. The factor IX gene is considerably smaller and less complex. >400 mutations have been identified. Because the gene is smaller, DNA sequencing can be employed to identify mutations and can be used for carrier detection and prenatal dx. There is a very low rate of spontaneous mutation, so the family history almost always is positive.

37. The answer is E A describes Beckwith Wiedemann syndrome B describes Angelman syndrome C describes diGeorge (aka velocardiofacial, Shprintzen, or 22q11.2 deletion syndrome) D describes Fragile X syndrome Children with PWS have a characteristic history: Hypotonia in infancy, with poor sucking and FTT Improvement in muscle tone by age 1 year Development of a voracious, insatiable appetite Development of obesity and related problems

38. PWS results from deficiency of the gene product of the SNRPN gene. SNRPN (15q11) is only expressed in the chromosome 15 inherited from the father. Thus, PWS results when a copy of paternal chromosome 15 is missing. This can be caused by: Deletion of pat 15q11.2 (seen in 60-70%): Use FISH to diagnose Maternal uniparental disomy of chromosome 15 (yielding two copies of maternal chromosome 15 and no copies of paternal chromosome 15) (seen in 20%)

40. The answer is D WS is caused by deletion of 7q11.2 (use FISH to make diagnosis) Occurs in 1 in 5,000 births Features include all those listed in question except for short philtrum (which is seen in fetal alcohol syndrome). Heart disease occurs in 80%, with SVAS in 67%

42. The answer is A Noonan syndrome is caused by a mutation in the PTPN11 gene on chromosome 12. Occurs in 1 in 10,000 births Features include all those listed in question except for AR inheritance 50% also have Factor 11 deficiency causing prolonged PTT.

44. The answer is E Esophageal atresia, occurring alone or as part of a TEF, can be isolated or part of a syndrome or association. The most common association is VACTERL. Association: a group of malformations that occur more commonly together than would be expected by chance, but for which no etiology can be identified. Features of VACTERL include: Vertebral anomalies Anal anomalies (imperforate, stenotic, etc) Cardiac anomalies (VSD, ASD most common) Tracheo-Esophageal Fistula Renal anomalies Limb anomalies (specifically radial ray defects)

46. The answer is D Osteoporosis is seen in osteogenesis imperfecta. Hypotrichosis occurs in anhidrotic ectodermal dysplasia. Large head and short extremities describes achondroplasia. Ehlers Danlos is a disorder of collagen that leads to: Joint laxity Spontaneous joint dislocation Hyperelastic skin Poor scar formation (“cigarette paper” scars) Easy bruisability


49. Preferred Response: B TSD, an AR inherited inborn error of metabolism, results from absence of HexA, a lysosomal enzyme. Parents of an affected child are obligate carriers and together, have a RR of 25% for subsequent pregnancies. HexA activity can be measured in fetal cells obtained by CVS, performed as early as 10 weeks gestation, or via amnio (14-16 weeks). Carrier frequency for TSD is highest in Ashkenazi Jews and French Canadians, although the mutation can occur in any ethnic group. Among Ashkenazim, the carrier frequency is ~1 in 25. Screening programs to identify carriers have been conducted since the 1970s. These programs, relying on the measurement of hex activity in serum or isolated leukocytes, have virtually eradicated the disease among this population. In the past 10 years most infants dx’d with TSD have been non-Jewish or have had one Jewish and one non-Jewish parent. Thus, screening of couples in whom one member is Ashkenazi Jewish is recommended.

50. Preferred Response: B The deficiency of HexA activity results in accumulation of GM2 gangliosides in the CNS, liver, and spleen. Following a 6 to 9 month period of normal development, affected infants present with hypotonia, apathy, developmental delay, and an exaggerated startle response. Exam reveals a cherry red spot in the maculae, which represents lipid accumulation in the ganglion cells (cherry red spots are also seen in Type I GM1 gangliosidosis and Niemann-Pick disease). Macrocephaly is common after age 1. The disease progresses rapidly, with death occurring by 5 years. The genes encoding HexA has been mapped, and specific mutations have been identified, including several that are common among Ashkenazim.

52. Preferred Response: E Organ & bone marrow transplantation (BMT) may halt progression of some metabolic disorders. Because more effective immunosuppressants have been developed & there are no other effective treatment strategies, BMT has been used increasingly. Each case must be considered individually and parents must be provided with detailed info about associated morbidity and mortality to permit them to make an informed decision. Sometimes, BMT is undertaken to provide a source of enzyme that’s not produced in sufficient quantities. For example, it’s been used successfully in pts with ADA deficiency. Sometimes, organ tx replaces an organ that’s been damaged by the disease process (ie liver tx. in alpha-1-antitrypsin deficiency, and renal tx in cystinosis).

53. Preferred Response: E BMT in pts with inherited metabolic disorders carries the same risks as when performed for other indications. Risks include: infection; graft-versus-host disease; and rejection. Identifying a histocompatible donor frequently requires that a donor from within the family be considered. Because most inherited metabolic disorders are transmitted as AR traits, the parents of affected children are obligate carriers, and unaffected siblings have 2/3 chance of being carriers. Carriers are acceptable donors. Because BMT is associated with high rates of morbidity and mortality, selection of appropriate candidates is important. In particular, there has been controversy over whether patients with metabolic disorders that include neurologic symptoms should be candidates. Recent studies with Hurler patients (MPS-IH) indicate that BMT can be beneficial despite the presence of adverse neurologic symptoms. Particularly when the diagnosis is made early and the transplantation is carried out shortly thereafter, improved neurologic function and increased survival have been reported.

55. Preferred Response: A This clinical presentation is typical of one of the fatty acid oxidation defects, AR traits that represent defects in mitochondrial beta-oxidation of fatty acids (MBOFA) and include defects in plasma membrane carnitine transport; carnitine palmityl transferase I and II deficiency (CPTI, CPTII); and long-chain, medium-chain, and short-chain acyl CoA dehydrogenase deficiencies. Of these, MCAD (medium-chain acyl CoA dehydrogenase deficiency) is most common. Pts usually presents by age 2 with lethargy after fasting, typically associated with a URI or AGE. Lab findings during illness include hypoketotic hypoglycemia and hyperammonemia. Definitive dx requires that the plasma acylcarnitine profile be determined. Because dx is complex, consultation with a biochemical geneticist is recommended. MBOFA includes > 20 steps and requires metabolism of carnitine for the transport of LCFA into mitochondria. Because MBOFA for the production of energy is only required during periods of fasting, clinical manifestations do not become apparent unless substantial fasting has occurred. Thus, there can be great heterogeneity in clinical course.

56. Preferred Response: A Between episodes of illness, affected pts are normal. Unfortunately, the 1st episode may result in death and is frequently mis-dx’d as Reye syndrome or SIDS. Correct dx is essential for both proper Rx and genetic counseling. Treatment includes avoidance of fasting, carnitine supplementation, and dextrose during acute episodes. Molecular diagnosis of MCAD is available; > 90% of mutant alleles are accounted for by a single point mutation in the MCAD gene. Wrong answers: An organic acidemia should be suspected in pts presenting with hypoglycemia and hyperammonemia in the presence of metabolic acidosis. Plasma insulin levels should be obtained in a child suspected of having hyperinsulinemia, which may cause hypoglycemia but usually is not associated with hyperammonemia. Urine and stool porphyrin analysis is useful in the diagnosis of the porphyrias, Acetylsalicylic acid poisoning usually presents with hyperventilation and dehydration, but hyperammonemia is not typical.

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