Transcript Getting to the Roof of our Problem: Human Malformations of the Mid

Prenatal diagnosis for Joubert
syndrome:
Challenges and Possibilities
Ian A. Glass, MB ChB, MD, FACMG
Associate Professor of Pediatrics and Medicine
Prenatal Diagnosis (PND)
Topics for this seminar
• Goals of PND in general
• Methods of PND
• PND in Joubert syndrome
• Strengths/weaknesses of PND for JS
• Future directions for PND of JS
Goals of PND
• Facilitate informed reproductive choices
• Reduce anxiety in high-risk groups
• Enable prenatal treatment, if available
• Ensure the birth of unaffected infants
(termination of affected fetus)
• Enable preparations for the birth of an
affected child
• Medical care
• Psychological preparations
Indications for PND
• Screening of high risk groups
• Advanced Maternal Age (AMA)
• Particular ethnic groups
• Cystic fibrosis in Caucasians
• Sickle cell anemia in African-Americans
• Specific prenatal testing
• Family history of prior affected child
• Muscular dystrophy
• Joubert syndrome
Reproductive options for couples
who have a child with JS
• Accept the risk without PND
• Accept the risk and consider PND imaging:
– To be prepared for an affected child
– To terminate an affected fetus
• Sperm or egg donor to reduce risk
• Choose to adopt
• Choose not to have additional children
ALL of these choices are valid!
Methods of PND
• Non-invasive
testing
• serum markers
• imaging by ultrasound, fetal-MRI
• Invasive testing
• amniocentesis
• chorionic villus sampling (CVS)
Non-invasive testing: Imaging
• Ultrasound (US)
• Fetal MRI
• Screening for high risk groups (e.g. AMA)
• Directed diagnostic imaging for:
• Fetuses with abnormalities
• Family history of birth defect
• Post-natal correlations to confirm PND prediction
• Postnatal follow-up exam and/or testing
• Fetal autopsy if demise or termination
Correlations often not performed !!!
Normal Fetal Hand:
3D US
Polydactyly:
3D US
Normal Face:
2D and 3D US
Non-invasive testing: Imaging
Prenatal Hydrocephalus on US
Imaging: Post-natal correlation
Hydrocephalus on MRI after birth
Invasive testing: Amniocentesis
Test
• Amniocentesis
Risk of Loss
1/200
Timing
Result
16 wk
18-22wk
Invasive testing: Chorionic villus sampling
Test
• CVS
Risk of Loss
1/100
Timing
Result
11 wk
11-12wk
PND in Joubert syndrome
The flow of genetic information:
Chromosomes  Genes (DNA)  Message (RNA)
Protein
Gene made of DNA
Cell
Nucleus
Chromosomes
RNA
Protein
Testing Opportunities
Family with a child with JS
?
Diagnosis: JS
+ MTS
RR = 25%
What prenatal testing
is available?
Methods for PND in JS
• Invasive testing
Useful for JS?
• amniocentesis
• chorionic villus sampling (CVS)
Maybe*
Maybe*
• Non-invasive testing
• serum markers (triple screen, AFP)
• imaging by ultrasound, fetal-MRI
No
YES
Most of these methods are not useful because chromosomal, DNA*
and protein markers for JS are not available
*If a known mutation in a JS gene
Is DNA testing currently available for JS?
• Best situation: one gene causes all JS cases
–But we have at least 5 JS genes known/mapped
already
• Goal: direct DNA testing once JS genes are known
• 2006: Only two direct DNA tests are clinically
“available” for JS for the NPHP1 and AHI1 genes,
accounting for <15% of JS
• Specific gene testing may be indicated if an older
sibling has a mutation in a known JS gene
What is available now?
• Prenatal imaging by ultrasound scanning
(considerable experience)
• Prenatal imaging by fetal MRI scanning
(increasing experience)
PND of JS
Family History is Key
Characteristic
MTS
Small vermis /large cisterna
magna
Hypotonia
Ataxia
Abnormal Eye Movements
Developmental Delay
Irregular breathing pattern
Polydactyly
Encephalocele
Abnormal kidneys
Postnatal
Prenatal
+
+
?
+/-
+
+
+
+
+
+
+
+
+/+
+
+/-
Molar Tooth Sign
deep interpeduncular fossa
thick, elongated SCPs
cerebellar vermis hypoplasia
Cerebellar vermis in utero
Normal
Normal
Hypoplastic
JS in utero:
absence of cerebellar vermis
Ultrasound
MRI
JS: enlarged cisterna magna
Ultrasound
MRI
JS in utero:
polydactyly
3 2
4
1
5
6
Aslan et al. 2002
JS in utero:
encephalocele
Wang et al. 1999
US for PND: promise and perils
• Advantages:
–
–
–
–
–
Non-invasive
Can see important structures: brain, fingers, kidneys
Can be repeated throughout pregnancy
Relatively inexpensive
Standardized measurements
• Disadvantages:
–
–
–
–
Technician-dependent: angle of transducer
Observer-dependent: experience in looking at brain
May not see subtle abnormalities
Timing is crucial: defects may not be visible early
For couples who desire prenatal imaging
• 11-12 wks: baseline US for dates, nuchal fold
• 16 wks: US for cranial views, skull, fingers,
kidney
• 18 wks: US to confirm cerebellar growth
• 20-22 wks: US for above + fetal MRI
• Further imaging, dependent on prior findings
• If possible, review by an experienced radiologist,
or perinatologist in evaluations of the posterior
fossa
Improving PND of JS
• Systematic review of prenatal imaging
• Correlation with outcomes
• Follow ongoing pregnancies with imaging studies
• Hypothesis: Systematic review of ultrasound and/or
fetal MRI imaging will improve diagnosis of JS and
generate guidelines for prenatal monitoring of at-risk
pregnancies
JS PND Summary
• Can we diagnose JS prenatally given a prior
family history?
– Sometimes, but the reliability is unknown
• Can we diagnose JS prenatally without a prior
family history?
– Almost never, if at all
• Improved PND is needed, imaging is our best
option at this time
Making an informed choice
• A Genetic Counselor or Geneticist can help
– Discuss options
– Provide resources and support
• When possible, get information prior to
getting pregnant (preconception counseling)
• www.genetests.org or www.nsgc.org for a
list of local genetic counselors
Current Research Efforts
• Linkage and other methods to locate new
genes
• Structural and functional MRI imaging
• Improved clinical understanding (JSF
Registry, Biobank)
• Accurate prenatal diagnosis
• Recommendations for medical management
How to participate in Joubert
research
• Contact us:
– Dana Knutzen, MS, GC and Melissa Parisi, MD, PhD
[email protected]
[email protected]
800-246-6312, 206-987-3832
– Ian A. Glass, MD and Dan Doherty, MD, PhD
[email protected]
[email protected]
206-987-5142
206-987-2489
Acknowledgments
UW Joubert Center
• Phillip Chance, MD
• Jon Adkins, BS
• Craig Bennett, PhD
• Daniel Doherty, MD, PhD
• Ian Glass, MD
• Nick Gorden, BS
• Dana Knutzen, MS
Research Collaborators
• William Dobyns, MD
• Joseph Gleeson, MD
• Friedhelm Hildebrandt, MD
• Bernard Maria, MD
• David Nyberg, MD
• Hamit Ozyurek, MD
• Joseph Pinter, MD
• Dennis Shaw, MD
• Other collaborators!
You! Children with JSRD and their Families
JSF & RCD