© The Children’s Mercy Hospital, 2017
Susan Starling Hughes, MS, CGC
Certified Genetic Counselor
The Genetics of Cleidocranial
Dysplasia Spectrum Disorders
©The Children's Mercy Hospital, 2015
No disclosures.
OBJECTIVES
o The role of RUNX2 gene in human development.
o Genetic testing for CCD Spectrum Disorders.
o Patterns of inheritance.
o Variability in clinical presentation.
o Resources and support.
RUNX2
RUNX2• The RUNX2 gene provides
instructions for making a protein that is
involved in the development and
maintenance of the teeth, bones, and
cartilage.
• Researchers believe that the RUNX2
protein acts as a "master switch,"
turning on and off a cascade of other
genes required to build bones and
develop teeth.
6
≠NORMAL
CARTILAGE
≠NORMAL
BONEX
X X X
X
GENETIC TESTINGThe evolution of
8
Types of Genetic Testing
• Karyotype
• Microarray
• Targeted Gene Sequencing, Deletion/Duplication Analysis
• Whole Exome/Genome Sequencing
9
KaryotypeChromosomes are like the books that hold all
of the genetic instructions. A karyotype looks
at the books lined up on a shelf and can
detect large changes or rearrangements.
MicroarrayA microarray can detect missing or extra
chapters or paragraphs. Will look through the
entire collection of books for missing or extra
chromosome material.
Next Generation
Genes are like the sentences within each
book. NGS spellchecks each sentence, letter
by letter, to look for misspelled words
(variants). Variants can sometimes be of
unclear clinical significance.
Sequencing (NGS)
Possible Results
• Positive: A likely pathogenic or pathogenic change (variant) is detected that fits with the
patient’s clinical features
• Negative: No variants were found or only benign/likely benign variants were detected.
• Variant of Uncertain Significance (VUS): A change was found in a gene that could be related
to a patient’s clinical features or could be a harmless change; not enough information known to
classify
Detection Rate
• Gene testing for RUNX2 sequence
variations will be positive in 60-70% of
individuals with a clinical diagnosis of
CCD.
• Deletions of all or part of the
RUNX2 gene, which would not be
detected by sequencing, may be present
in ~10% of all patients with CCD.
12
• Important to identify a unifying diagnosis for a
patient’s symptoms
– Guide medical management
– Manage a family’s expectations
– Accurately assess a recurrence risk
• Skeletal survey including the hands/feet
• DXA scan for those in early adolescence
and older
• Dental evaluation
• Audiologic evaluation
• Consultation with a genetic counselor
14
Genetic Counseling
• Review new diagnosis and associated
medical management.
• Family history
• Recurrence risk
– Prenatal recommendations
15
Prenatal Recommendations• Meet with a prenatal genetic counselor prior to or early in
a future pregnancy
• Prenatal testing options
– Invitro fertilization with preimplantation genetic diagnosis
(IVF/PGD)
– Prenatal Screening versus diagnostic testing
• Pregnant women with CCD spectrum disorders should be
monitored closely for cephalopelvic disproportion
– The primary cesarean section rate among women with a
CCD spectrum disorder is 69%
16
INHERITANCEAUTOSOMAL DOMINANT
17
Autosomal Dominant Inheritance
• Typically, with AD disorders, we expect a
positive family history with multiple affected
generations.
– However, de novo (new) mutation rate in
CCD is high.
• Recurrence risk for an affected person is
50%. Can affected males or females.
• If parents have been tested and are
negative, then recurrence risk is low, but not
zero (<1%)
18
19
VARIABLE EXPRESSIVITYA CASE EXAMPLE OF
20
Variable Expressivity
• Individuals with pathogenic variants have different features of the
disorder, ranging from mild to more significant.
– Can occur both within and between families
• CCD spectrum disorder is present at a frequency of one in
1,000,000 individuals worldwide.
– 0.12 per 10,000 individuals in the Utah (USA) population, suggesting that the
frequency may be higher than previously recognized.
21
SM• SM presented to our clinic as a
4 month old male.
• His pediatrician noted large
soft spots, in both the front and
the back (anterior and
posterior fontanelles).
• Prior to our evaluation, he saw
Neurology and Plastic Surgery,
where an MRI of the brain and
lab work was negative.
22
SM• PRENATAL HISTORY:
Delivered at 39 weeks gestation by
vaginal delivery. Normal birth weight
and length. Fontanelles were noted to
be large at birth. He also had an extra
(supernumerary) tooth, which was
later removed.
• DEVELOPMENTAL HISTORY:
No concerns; he had a social smile at
1 month, rolled over at 4 months. No
intervention therapies.
23
SM
• PHYSICAL EXAMINATION:
HEAD CIRCUMFERENCE:
43.5 cm (63rd percentile)
CRANIUM: Frontal bossing. Generous anterior (~4 cm) and posterior (2-3 cm)
fontanelle. Prominent veins on forehand.
TEETH: No teeth currently. Supernumerary tooth pulled.
THORAX: Normal sternum. Normal nipples.
Hypoplastic clavicles to palpation.
24
25
SM
• Clinical and family history consistent with a clinical
diagnosis of CCD
• RECOMMENDATIONS:
– RUNX2 gene sequencing, reflex to deletion/duplication studies,
if negative.
– Skeletal survey
– Sleep study, given concerns for apnea
26
27
RUNX2
RESOURCESSUPPORT AND
30
31
ccakids.org faces-cranio.org
32www.globalgenes.org
POPS ProgramChildren’s Mercy Kansas City
• Parents Offering Parents Support
– A program that helps parents connect
with each other.
• A way for parents whose child has a
chronic medical or a life-limiting
condition to talk with someone who
has had similar experiences.
33