Transcript N - East Bay Newborn Specialists

Neonatology Genetics Topics
UCSF Benioff Children’s Hospital
Oakland Core NICU lectures
Genetics 101: Name the inheritance
pattern
Name the inheritance pattern
• Autosomal dominant
• With any disorder, can have incomplete
penetrance or variable expressivity
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
Name the inheritance pattern
Name the inheritance pattern
• Autosomal recessive
Name the inheritance pattern
Name the inheritance pattern
• X-linked dominant
Name the inheritance pattern
Name the inheritance pattern
• X-linked recessive
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
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)
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
Prader-Willi syndrome
Angelman syndrome
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
(uniparental disomy)
• Angelman - caused by deletion in maternal 15
or by paternal uniparental disomy
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
CHARGE syndrome
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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
VATER/VACTERL association
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V ertebral anomalies
A nal atresia
C ardiovascular anomalies
T racheoesophageal fistula
E sophageal atresia
R enal and/or radial anomalies
L imb defects
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
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
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
• C ardiac (tetralogy of Fallot)
• A bnormal facies
• T hymic aplasia
• C left palate
• H ypocalcemia/Hypoparathyroidism
• 22 q11.2 deletion (several genes in proximity)
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
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
Condition
AFP
Estriol
βhcG
Inhibin A
Trisomy 21
↓
↓
↑
↑
Trisomy 18
↓
↓
↓
No sig change
Trisomy 13
Not significantly helpful, slightly ↓ Estriol
Turner
↓
↓
↑
Smith-Lemli-Opitz
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↓
↓
Triploidy
↓
↑ if hydrops, ↓if not
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
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
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
Aneuploidy syndromes
• Conditions where number of chromosomes is
not an exact multiple of the monoploid
number
Name
Description
Monosomy
Lack of one chromosome of normal complement
Disomy
Two copies of a chromosome – normal in humans
Trisomy
Three copies of a chromosome
Tetrasomy/
Pentasomy
Four or five copies of a chromosome
• Name as many aneuploidy syndromes as you
can
Aneuploidy syndromes
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45, XO – Turner syndrome
47 XXY – Klinefelter syndrome
47, XYY
47, XXX
47, +13 – Patau syndrome
47, +18 – Edwards syndrome
47, +21 – Down syndrome
Trisomy 21/Down syndrome
• Name the common medical problems
associated with Down Syndrome
Trisomy 21/Down
syndrome
Taken from Clinical Report – Health Supervision
for Children with Down Syndrome. Pediatrics 2011
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
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
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
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
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
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
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
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)
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 is
A.diabetic embryopathy
B.Pierre Robin sequence
C.Stickler syndrome
D.Treacher Collins syndrome
E.22q11 deletion syndrome
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
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
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
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
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.depressed midface → 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
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
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
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
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
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