© 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

Thank you!

Questions?sshughes@cmh.edu