Download - Society for Maternal-Fetal Medicine

Fetal Anomalies:
What is the Diagnosis When the
Karyotype is Normal?
Mary E. Norton, MD
Regional Director, Perinatal
Genetic Services, Kaiser
Permanente, NCal
Clinical Professor, Stanford
University School of Medicine

Genetic evaluation of fetal
malformations
• Congenital anomalies are present in ~3% of
live births
• Many of these are identified prenatally
• Usual work up includes detailed ultrasound
and amniocentensis
• What then??

Genetic evaluation of fetal
malformations
• Amniocentesis (karyotype) does not tell you
everything about genetic disorders
• A fetus is not the same as a neonate
• The most important anomaly is the second
anomaly
• The key to diagnosis is often in the family
history

Making a precise diagnosis is
important for determining:
• Etiology
• Prognosis
• Recurrence risk
• Prevention / prenatal diagnosis
options in future pregnancies

An amniocentesis does not tell
you everything about genetic
diseases

Genetic Disease
• Chromosome abnormalities account for
about 20% of all genetic diseases
• Somewhat higher prenatally,
approximately one-third
• Only these abnormalities are diagnosed
by routine amniocentesis

Spectrum of Genetic Disease
Autosomal recessive
Autosomal dominant
X-linked
Congenital
malformations
Chromosomal

Amniocentesis
• Detects chromosomal abnormalities with
close to 100% accuracy
• Can diagnose other genetic diseases if the
DNA or biochemical basis is known and
specifically tested for
• A routinely processed amniocentesis will
not detect other genetic syndromes

Clues to determining the diagnosis
when the karyotype is normal
• Ultrasound findings
• Details of other imaging
• Gender
• Family history
• Family studies
• Additional studies on amniotic fluid
• Perinatal autopsy

Sometimes the ultrasound
diagnosis is obvious…

BWS case

What is the Diagnosis?

Beckwith Wiedemann Syndrome
Molecular studies done on amniotic fluid
confirmed hypomethylation of KCNQ1OT,
consistent with a diagnosis of BWS

Beckwith Wiedemann Syndrome
• Clinical features include omphalocele,
macroglossia, overgrowth, visceromegaly
• Hypoglycemia in neonatal period, various
malignancies in childhood
• Add’l ultrasound features: polyhydramnios
and large placenta
• ?associated with ART

Beckwith Wiedemann Syndrome
• Caused by variety of abnormalities involving
imprinted genes within the chromosome 11p15.5
region
• Different causes of maternal genomic imprinting
defect
• Translocation, mutation, deletion etc
• Overexpression of paternal allele
• Overgrowth and malignancies in BWS patients reflect
imbalance between paternal and maternal alleles

Etiology of BWS
Etiology
Mat translocation/inversion

Why Does it Matter?
• 10-20% of prenatally diagnosed
omphaloceles are due to BWS
• BWS should be considered whenever an
omphalocele is detected on prenatal US

Outcome of Prenatally Diagnosed
Omphalocele
Calvert et al, 2009: n=94
• Aneuploidy 43%
• Of euploid 53% other anomalies
• Of liveborn isolated 93% survived
28% postnatal anomalies
Porter et al, 2009: n=65
• Isolated defect or minor anomalies 29%
• Add’l findings at birth 25%
• PTD 37%

Outcome of Prenatally Diagnosed
Omphalocele
• Most children with BWS are neurologically
normal and do well
• There is a small increased risk of cancer,
although most children with BWS do not
develop cancer
‣Making this diagnosis can be reassuring and
allow more precise counseling when
omphalocele is detected prenatally

Often the salient findings are
difficult to detect…

Bilaterally enlarged lungs

Kidneys?

US Findings
• Oligohydramnios
• Enlarged,echogenic lungs (laryngeal
atresia)
• Ascites and body wall edema
• Bilateral renal agenesis?

What is the Diagnosis?
Prenatal
• Oligohydramnios
• Enlarged,echogenic
lungs (laryngeal atresia)
• Ascites and body wall
edema
• Bilateral renal agenesis?
Postnatal
• Syndactyly
• Bilateral renal agenesis
• Cryptophthalmos
• Laryngeal atresia

Fraser Syndrome
• Autosomal recessive
• Clinical features include: bilateral renal
agenesis, largyngeal stenosis/atresia,
cryptophthalmos, syndactyly
• Some heterogeneity
• Should be considered in cases of bilateral
renal agenesis and/or laryngeal atresia

A careful history (medical
history, pregnancy history and
family history) is often the key to
the diagnosis

Family History
parents
partner
PATIENT
sibling
children

First Degree Relatives
parents
partner
PATIENT
sibling
children

Second & Third Degree Relatives
uncle
aunt
PATIENT
1 st cousins
nephew
niece

Second & Third Degree Relatives
Parent
Aunt
cousins

X-Linked
Disorders
1/2
1/4
Hemophilia
1/16

Case: Fetus with congenital
heart defect
• 29 yo G1P0 at 19 weeks
• Routine ultrasound suspected
congenital heart defect
• Level II and fetal echo

Fetal Heart Defect
Tetralogy of Fallot

Fetal Heart Defect
Cleft palate
Cleft palate
VSD
Developmental delay
Tetralogy of Fallot

What is the Diagnosis?

Congenital Heart Defects
• 5-10% of prenatally diagnosed heart
defects are caused by a microdeletion
of 22q
• Typically not visible by routine
karyotype, but CAN be detected with
FISH or microarray CGH

del(22)(q11.2q11.2) (D22S75-)
Chr 22
Log2 Mean Ave Raw Ratio
2
1.5
1
0.5
0
-0.5
-1
-1.5
-2
0 10000 20000 30000 40000 50000

22q Deletion Syndrome
Important prognostic implications:
• Many associated anomalies, including cleft
palate, developmental delay and psychiatric
disorders
• About 5% of cases inherited from
apparently normal parent
• If so, recurrence risk is 50% (vs 2-3% for
isolated heart defect)
• Prenatal diagnosis very accurate

Etiology of
Congenital Heart Defects
• Isolated birth defect (most common)
• Aneuploidy (trisomy 13, 18, 21, 45X)
• Single gene disorders
• Microdeletion syndromes (22q, others)
• Maternal diabetes
• Teratogen exposure

Etiology of Congenital Heart
Defects
McBrien et al, 2009
n=272 cases of congenital heart defects
• 73 diagnosed prenatally
• 30/73 (41%) died < 28 days
• Lethal trisomies
• 15% prenatal dx
• 2% postnatal dx

Tetralogy of Fallot
Poon et al, 2007
• N=129 cases of TOF in one center from 1998-
2005
• 65/129 other anomalies
• 112 fetuses with chromosomal analysis
• 55/112 (49%) abnormal
• 15/112 (13%) 22q11 microdeletion
• 77% survival in continuing pregnancies
• Prognosis for fetal cases much less favorable than
in postnatal series

Evaluation of
Congenital Heart Defects
• Level 2 OB Ultrasound
• Echocardiogram
• Karyotype (amnio or CVS)
• 22q microdeletion studies
(FISH vs aCGH)
• Evaluate family (AD disorders)
• Rule out maternal diabetes, other
teratogen exposure

Congenital Heart Defects
ETIOLOGY RR MANAGEMENT
Isolated CHD 3% NT/fetal echo
Trisomy 1% CVS/Amniocentesis
Diabetes Minimal Diabetic control
Ultrasound
Teratogens Varies Adjust medications
AD Form 50% Gamete donor
AmnioDNA testing
AR Syndromes 25% Gamete donor
AmnioDNA testing

Case: Anhydramnios
• 34 yo at 18 weeks gestation
• Referred for oligohydramnios

Bilateral Renal Agenesis
“Lying down adrenal”

Renal Agenesis
• Most commonly isolated
• Can occur as part of some genetic
syndromes (Fraser syndrome)
• Can also be autosomal dominant,
sometimes with co-existing maternal
Mullerian (uterine) anomalies
• In 9% of cases, a 1st degree relative will
have unilateral renal agenesis

Left Kidney
Maternal evaluation

Right
Maternal evaluation

Renal Agenesis
• Empiric recurrence risk of BRA is 3-4%
• With obligate heterozygote parent (eg
unilateral renal agenesis, Mullerian
anomalies), recurrence risk estimated at
15-20%
• Some familial cases are autosomal
dominant with variable penetrance

Case: Fetal Hydrops
• 29 y.o. G1P0 at 18 weeks
• Initially seen for abnormal quad screen
(1/53 chance of DS)
• Ultrasound demonstrated hydrops
• Counseled about grim prognosis,
termination offered
‣Second opinion requested

Hydrops

MCA Peak Systolic Velocity>1.55 MoM

Fetal Hydrops
Evaluation:
• US: structurally normal fetus with
hydrops
• O positive, Antibody screen negative
• SE Asian MCV 92
• History of exposure to 2 nephews with
Fifth’s disease ~ 1 month prior

Fetal Hydrops
Evaluation:
• US: structurally normal fetus with
hydrops
• O positive, Antibody screen negative
• SE Asian MCV 92
• History of exposure to 2 nephews with
Fifth’s disease ~ 1 month prior

Nonimmune Hydrops
ETIOLOGY PROGNOSIS RR
Chromosomal Poor ~ 1%
Cardiac Poor 2-3%
Other Structural Poor varies
Hematologic Poor 25%
(e.g. thalassemia)
Metabolic Poor 25%
Parvovirus UsuGood ~ 0%

Follow-up US

A fetus is not the same as a
neonate
=

A fetus is not the same as a
neonate
The prognosis is typically worse due to:
• Undetected, additional anomalies
• More likely to be syndromic
• More likely to be associated with aneuploidy
• Hidden mortality of most severe cases

Chromosome abnormalities are
more common with prenatal vs
postnatal malformations
• Dysmorphism and other anomalies that are
not identified prenatally
• In utero mortality of aneuploidy syndromes
• DS: 30%
• T18: 70%

In Utero Mortality of Aneuploidy

A fetus is not the same as a
neonate
The prognosis in some cases is better:
• Sex chromosome aneuploidy
• Better prognosis prenatally due to postnatal
ascertainment bias

The most important anomaly is
the second anomaly

The hardest anomaly to detect is
the second anomaly

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia and
mild ventriculomegaly

Mild Ventriculomegaly
• Ventricles typically 7 mm
• Mild VM: 10-15 mm
• Usually normal outcome
when isolated, esp in males,
with vents

Fryns Syndrome
• Autosomal recessive disorder
• Clinical features:
• Congenital diaphragmatic hernia (>80%)
• Distal digital hypoplasia
• Facial dysmorphism
• Heart defects, clefts, renal anomalies, CNS
abnormalities

Fryns Syndrome
Important diagnosis to make!!
• Survival is rare
• Autosomal recessive: 25% RR
• Can have Fryns syndrome without CDH
• Recurrence may be difficult to detect
• All survivors have mental retardation

CDH: Outcomes of Prenatal vs
Postnatal Cases
Abdullah et al 2009
• 2173 CDH cases repaired in US
• Survival 90%
Logan et al, 2007
• 763 prenatal cases in 11 centers in US
• Survival 79%
Bianco et al, 2005
• N=149 cases referred to UCSF
• Survival 58%

Survival of CDH Cases
Logan et al, J Perinatol, 2007
• Review of 13 reports from 11 centers
• Survival rates:
• Overall 603/763 79%
• Isolated 560/661 85%
• Other abn 43/102 40%

Survival of fetuses with CDH
Author prenatal postnatal isolated other
dx dx anomalies
Witters(‘01) 31% -- 52% 7%
Wenstrom(‘91) 55% 6%
Cannon(‘96) 35% 78% 76% 38%

Congenital diaphragmatic hernia
• Survival in postnatal series is greater than
prenatal
• Largely due to undetected syndromic
prenatal cases
• For many, additional findings may be
difficult to detect prenatally
‣What constitutes a second anomaly?

Fryns syndrome cases at UCSF
Congenital diaphragmatic hernia and…
• Mild ventriculomegaly
• Single umbilical artery
• Unilateral renal agenesis

Survival of Fetuses with CDH
and Second Anomalies
Anomaly Survival p-value vs isolated
Isolated 87/149 (58%)
SUA 1/5 (20.0 %) 0.08
Other 7/30 (23.3 %) 0.001
Cardiac 1/6 (16.6 %) 0.04
GI 0/1 (0 %) 0.23
Renal 5/10 (50.0 %) 0.60
Bianco et al, UCSF, 2005

Congenital Diaphragmatic Hernia
and Associated Abnormalities
Stoll et al, 2008
• N= 115 births with CDH noted
• 70 (61%) had associated malformations
• Chromosomal abnormalities (n = 21, 18%)
• Non-chromosomal syndromes (n=30, 26%)
• Fryns syndrome, fetal alcohol syndrome, De Lange
syndrome, CHARGE syndrome, Fraser syndrome,
Goldenhar syndrome, Smith-Lemli-Opitz syndrome,
multiple pterygium syndrome, Noonan syndrome, and
spondylocostal dysostosis); malformation sequences
(laterality sequence, ectopia cordis); malformation
complexes (limb body wall complex) and non
syndromic multiple congenital anomalies (MCA)

Case: Mild ventriculomegaly
• 30 yo G1P0
• Mild ventriculomegaly on routine 18
wk scan

Agenesis of corpus callosum

Female fetus

Agenesis of corpus
callosum
Normal corpus callosum

Diagnoses on US & Fetal MRI
Mild ventriculomegaly
Agenesis of corpus callosum
Subependymal heterotopia
Frontal dysplasia
Dysplastic cerebellum
Microphthalmia

What is the Diagnosis?

Diagnosis: Aicardi Syndrome
• Multiple anomalies, particularly CNS
• Severe neurologic impairment
• X-linked dominant, lethal in males
• All cases due to new mutations
• minimal recurrence risk
• MRI changed counseling about
prognosis and recurrence risk

MRI for CNS abnormalities
Levine et al, Obstet Gynecol, 1999
• 66 confirmed CNS abnormalities by sonogram
• MRI findings changed diagnosis in 26/66 (40%)
Simon et al, A J Neuroradiol 2000
• 66 cases of fetal MRI for CNS abnormalities
• 24/52 (46%) managed differently based on MRI
findings

MRI for CNS abnormalities
MRI findings not detected by ultrasound included
(Levine et al):
• Partial or complete agenesis corpus callosum
• Porencephaly
• Hemorrhage
• Tethered cord
• Cortical gyral abnormality
• Cortical cleft
• Midbrain abnormality
• Partial or complete absence of septum pellucidum

Mild Ventriculomegaly
• Associated with increased risk of other
anomalies
• Usually normal outcome when
ISOLATED
• Early manifestation of other CNS
anomalies, in some cases
• Broad spectrum of outcomes

Evaluation of Mild VM
• Level 2 OB Ultrasound
• R/O other anomalies
• Gender ?
• Family History
• Amniocentesis
• Karyotype
• Viral studies (Toxoplasmosis, CMV)
• MRI
• R/O other CNS abnormalities
• Subtle anomalies not detectable by US

Perinatal Autopsy
• Perinatal autopsy has been demonstrated to
provide further diagnostic information in
40-50% of cases
• MRI may be useful as an adjunct to autopsy
in some situations
Antonsson et al, 2008; Amini et al, 2006

Take Home Messages
• Even if US anomaly is felt to be lethal,
a full evaluation is important!
• New genetic tests become available
almost daily