Neonatology Genetics Topics

1. Neonatology Genetics Topics UCSF Benioff Children’s Hospital Oakland Core NICU lectures

2. Genetics 101: Name the inheritance pattern

3. Name the inheritance pattern • Autosomal dominant • With any disorder, can have incomplete penetrance or variable expressivity

4. Genetics 101 continued • Penetrance: proportion of individuals with a gene that express the trait (phenotype) • Expressivity: Variations in a phenotype among individuals carrying a genotype

5. Name the inheritance pattern

6. Name the inheritance pattern • Autosomal recessive

7. Name the inheritance pattern

8. Name the inheritance pattern • X-linked dominant

9. Name the inheritance pattern

10. Name the inheritance pattern • X-linked recessive

11. Genetics 201 • Multifactorial inheritance – many factors (genetic and environmental) are involved in the causation of the disorder • Ex diabetes, cancer, cleft lip/palate, club foot, pyloric stenosis • Genetic anticipation – genetic disorder becomes apparent at an earlier age as it’s passed on to the next generation • Common in trinucleotide repeat disorders where each generation has more repeats and presents earlier/more severely • Fragile X, Huntington’s disease, myotonic dystrophy

12. Mitochondrial inheritance • Mitochondrial genome is transmitted from mother to child • Males and females affected but always maternally inherited (Leigh subacute sclerosing encephalopathy, Leber’s hereditary optic neuropathy and others)

13. Genomic Imprinting • Phenomenon where certain genes are expressed in parent of origin manner • If allele inherited from dad is imprinted, it’s silenced and only the one from mom is expressed Angelman syndrome Prader-Willi syndrome

14. Imprinting examples • Prader-Willi – 70% cases occur when segment of paternal chromosome 15 is deleted and the genes on the maternal copy are imprinted (inactive) • 25% of cases, a patient has 2 copies of chromosome 15 inherited from their mother (uniparentaldisomy) • Angelman - caused by deletion in maternal 15 or by paternal uniparentaldisomy

15. Genetic Associations • Occurrence (more often than can be explained by chance) of two or more traits in a population of individuals • At least one trait is known to be genetic • Name some Genetic association syndromes

16. CHARGE syndrome • C oloboma/CNS • H eart defects • A tresia of the choanae • R etardation of growth/development • G enital and/or urinary defects • E ar anomalies

17. VATER/VACTERL association • V ertebral anomalies • A nal atresia • C ardiovascular anomalies • T racheoesophageal fistula • E sophageal atresia • R enal and/or radial anomalies • L imb defects

18. You are asked to evaluate a 2-day-old baby who was born at term and was admitted to the neonatal intensive care unit due to respiratory distress. Anteroposterior chest radiography reveals multiple butterfly vertebrae (Item Q103). On physical examination, the baby is normally grown and formed except for hypoplastic thumbs. You request echocardiography, which reveals a large ventricular septal defect. The baby is feeding and stooling well.Of the following, the recommendation that is MOST helpful in guiding further management for this infant is A. fluorescence in situ hybridization B. hematology consultation C. renal ultrasonography D. serum calcium quantitation E. urine organic acid analysis

19. C. renal ultrasonography • Infant has VACTERL (Vertebral, anal, cardiac, TE fistula, Renal, Limb) • Diagnosis of exclusion • FISH uses fluorescent labied DNA probes to detect specific regions on genome (faster than chromosome analysis) • Used for such things as FISH for 22q11 deletion • Hypoplstic thumbs can have blood dyscrasias (TAR) • Serum Ca can be low in infants with 22q11 deletion

20. Contiguous gene syndromes • Clinical phenotype caused by deletion or duplication that removes several genes lying in close proximity to one another on a chromosome • Velocardiofacial/DiGeorge syndrome • Cardiac (tetralogy of Fallot) • Abnormalfacies • Thymic aplasia • C left palate • Hypocalcemia/Hypoparathyroidism • 22 q11.2 deletion (several genes in proximity)

21. Prenatal Screening – Non invasive • 1st trimester • Pregnancy-associated plasma protein A (PAPP-A) not as elevated in T21 or T18, done 10-13 weeks • Combined with maternal age, can detect 60-65% T21 • Nuchal translucency test • Between 11-13 weeks gestation, normal is 0.5-2mm, >3mm is abnormal • With maternal age and 1st trimester screening, can detect 78-89% of T21, 91% of T18 • Cell free DNA • Maternal serum taken and fetal cells isolated after 10 weeks of gestation evaluates for trisomies

22. Second trimester • Quadruple screen done at 14-20 weeks • Maternal AFP: least sensitive, produced by yolk sac then the liver and GI tract • Maternal unconjugated estriol (produced by placenta from precursors by fetal adrenals + liver) • Maternal βhcG: most sensitive for T21 • Inhibin A: produced by placenta and ovaries

23. Fetal ultrasonography • Pregnancy can be diagnosed by US by 5th week post menses • 80% of major fetal abnormalities are detected by 2nd trimester US Ventriculomegaly

24. Invasive prenatal testing • Chorionic villus sampling • Earliest technique with biopsy of CV at 10-13 weeks, chromosomal analysis of trophoblast • 1.5% fetal loss above baseline • Amniocentesis • 15-20 weeks (20-30mL amniotic fluid) aspirated • Measure chromosomal analysis (from fetal skin cells), bilirubin, fetal lung maturity, or infection • 0.5% loss above baseline • PUBS (Percutaneous umbilical blood sampling) • >19 weeks gestation, insert needle into umbilical vein • Fast chromosomal analysis (24-72 hours), Hgb, antibody levels, transfusions can be given, fetal drug therapy • 1.4% fetal loss above baseline

25. Postnatal testing • Karyotype – number and appearance of chromosomes in nucleus  can’t exclude subtle chromosome abnormalities (resolution 5-15megabases) • FISH – fluorescence in-situ hybridisation – using probes to localize specific RNA targets (can only detect deltions or duplications of regions targeted) • Comparative Genomic Hybridization Microarray – method for analyzing copy number variations (Deletion/duplication) with resolution of 100 kilobases cannot detect balanced structural changes

26. Aneuploidy syndromes • Conditions where number of chromosomes is not an exact multiple of the monoploid number • Name as many aneuploidy syndromes as you can

27. Aneuploidy syndromes • 45, XO – Turner syndrome • 47 XXY – Klinefelter syndrome • 47, XYY • 47, XXX • 47, +13 – Patau syndrome • 47, +18 – Edwards syndrome • 47, +21 – Down syndrome

28. Trisomy 21/Down syndrome • Name the common medical problems associated with Down Syndrome

29. Trisomy 21/Down syndrome Taken from Clinical Report – Health Supervision for Children with Down Syndrome. Pediatrics 2011

30. Translocation • Chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes • Can be balanced or unbalanced • Robertsonian translocation is a break at or near the centromere of two acrocentric chromosomes • Reciprocal exchange gives rise to a large metacentric chromosome and a small one that may be lost • Recurrence rate for Down Syndrome is much higher if the result of a Robertsonian translocation

31. You are called to examine a newborn girl who has multiple congenital anomalies. On physical examination, you notice several "punched-out" scalp ulcers (Item Q39A), bilateral cleft lip (Item Q39B) and palate, postaxial polydactyly (extra digit on the ring finger side) of the hands (Item Q39C), and a small omphalocele.Of the following, this infant's karyotype MOST likely is A. 45,X B. 45,X/47,XXX C. 47,XX+13 D. 47,XX+18 E. 47,XX+21

32. C. 47,XX+13 Trisomy 13/Patau • (aplasia cutis), cleft lip/palate, polydactyl are in 50% of infants with Trisomy 13 • Also seen are holoprosencephaly, microcephaly, cardiac defects • Midline defects, VSD • 50% of infants die by 2 weeks, 90% by 1yr • 80% with complete trisomy and remainder with translocation • 95% of trisomy 13 conceptions lead to spontaneous abortion

33. Turner Syndrome • 50% are 45, X • 30-40% mosaics • 10-20% from deletions of X chromosome • Majority of fetuss undergo spontaneous abortion • Associated with coarctation of the aotrta, bicuspid aortic valve, cystic hygroma, webbed posterior neck, congenital lymphydema, short stature, wide spaced nipples

34. Klinefelter syndrome • 47, XXY (equally derived from maternal or paternal errors) • Associated with mitral valve prolapse, ToF, ASD, long arms and legs, 5th finger clinodactyly, hypogonadism, hypogenitalia, gynecomastia, behavioral issues

35. Edward’s Syndrome/Trisomy 18 • 1/6000 births, 90% mortality in first year of life • >95% with complete trisomy • Females> males • 95-99% with cardiac (VSD, PDA, bicuspid aortic valve, pulm stenosis, CoA) • Clenched hand, overlapping of 2nd finger over 3rd, rocker bottom feet, micrognathia, small mouth, cryptorchidism, hypertonia after neonatal period, short sternum

36. You are called to the newborn nursery to evaluate a baby who is having difficulty with feedings. He seems ravenously hungry when given the nipple but becomes fretful and cries after sucking for more than a few seconds. Nurses have noticed that he becomes dusky when sleeping, but when he wakes and cries, his color improves. Echocardiography reveals a structurally normal heart. You suspect that the baby has choanal atresia.Of the following, the MOST likely associated condition in this child is A. Achondroplasia B. Crouzon syndrome C. Down syndrome D. fetal alcohol syndrome E. Prader-Willi syndrome

37. B. Crouzon syndrome • Other info: bilateral atresia is associated with the symptoms described • Unilateral atresia may be associated only with mucous discharge on affected side • Male to female 1:2, uni:bilateral 2:1 • CHARGE is associated with choanal atresia • Any condition that causes depression of the nasal bridge or midface retraction (Crouzon, Pfeiffer, Antley-Bxler)

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

39. D) Treacher Collins syndrome • Patient with mandibulofacial dystosis (syndromes including Treacher Collins) • TCS is AD condition, highly variable, spontaneous gene mutations in 60% • Lower lid coloboma (notching), absent eyelashes medial to notch, malar hypoplasia, hypoplastic/malformed external ears, hearing loss, microretrognathia • Associated with gene TCOF1 • Management is supportive (especially airway) • Ophthalmology referral is indicated in early infancy • Eye findings not found in PRS, Stickler, or 22q11 deletion

40. Sequences • Series of ordered consequences due to a single cause • More predictable than a syndrome  A causes B, B causes C, C causes D • D is not seen if C is not seen

41. Oligohydramnios sequence • Renal disease or urinary obstruction in fetus  oligohydramnios  pugilistic facies, aberrant hand/foot positioning, fetal growth deficiency, pulmonary hypoplasia Flattened nose, prominent epicanthal folds, low set ears

42. Management • Renal ultrasound to evaluate cause of oligohydramnios • Potential dialysis if renal failure/agenesis • Respiratory support for possible pulmonary hypoplasia and pulmonary hypertension • Orthopedics involvement for any limb deformations

43. 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) (Item Q215).Of the following, the series of events that MOST commonly causes PRS is A.cleft palate → glossoptosis → airway obstruction B.depressedmidface → choanal stenosis → airway obstruction C.glossoptosis → cleft palate → cleft larynx → airway obstruction D.macroglossia → cleft palate → airway obstruction E.retrognathia → glossoptosis → cleft palate → airway obstruction

45. E) Retrognathia  glossoptosis  cleft palate  airway obstruction • Glossoptosis = posterior displacement of tongue • Causes of PRS  uterine constraint, single gene disorders, chromosome abnormalities, teratogenic exposure, disruptions • Presentations varies (minimal to no difficulties with feeding/breathing, O2 desats improved with prone/side, or severe with airway compromise and cyanotic spells) • May be swalloing difficulties • Intervention is feeding tubes, tongue-lip adhesion, intubation, tracheostomy, distraction • Infants may have PRS with O2 sats <90% for prolonged periods without evidence for airway obstruction  pulm hypertension, cor pulmonale, FTT

46. Pierre Robin Sequence • Congenital condition of facial abnormalities • Sometimes part of an underlying syndrome (Stickler, Velocardiofacial, Treacher Collins, fetal alcohol syndrome) • Micrognathia  Glossoptosis (posterior displacement of tongue)  upper airway obstruction and cleft palate

47. Management • Airway support (prone positioning, oral airway, intubation) • Feeding support (NG or gastrostomy tube if needed) • ENT and craniofacial evaluations • Genetics evaluations if other findings • Potential mandibular distraction or tracheostomy

48. 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 (Item Q71A), his ears are overfolded, and his hands and feet are unusually positioned (Item Q71B). You review his chest radiographs and note bilateral pulmonary hypoplasia.Of the following, the test that is likely to be MOST helpful in determining the cause of this infant's abnormalities is A. chromosome analysis B. Echocardiography C. head MRI D. renal ultrasonography E. toxicology screen

49. D. renal ultrasonography • Symptoms suggest “Potter syndrome” • Cascade of effects ude to oligohydramnios  pugilistic facies, lung hypoplasia, limb deformation, renal agenesis, growth deficiency • Infant could have chromosome abnormalities underlying anomalies • Absent or dysplastic kidneys is likely to be direct cause • May have been exposed to cocaine or ACE inhibitors but wouldn’t affect treatment