Download The PTCH gene and Gorlin Syndrome

Gorlin Syndrome:
More than skin deep
Sherri J. Bale, Ph.D.
Clinical Director
GeneDx, Inc.
►A
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multi-system genetic disorder
Skin, teeth (jaw)
Skeleton
Brain
Growth and development
Reproductive
► Inherited
Cardinal Features
 Multiple basal cell carcinomas, early onset
 Odontogenic keratocysts
 Palmar and plantar pits
Basal Cell Carcinomas
Odontogenic Keratocyts
Can you see jaw cysts without
and x-ray?
Palmar and Plantar Pits
Skeletal manifestations in NBCC
Rib anomalies
Bifid Rib
Polydactyly and Syndactyly
Ectopic Cacification
Sprengel Deformity
(11%)
Scoliosis
Pectus abnormalities
Excavatum
Carinatum
(13%)
Spade-shaped tufts
NBCC can affect the brain
Macrocephaly
Medulloblastoma
► What
is it?
 Brain tumor, arising from primitive brain cells very early
in development
► Statistics
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Accounts for 20% of all childhood tumors
Incidence 1.5-2 cases per 100,000 persons
Occurs in about 5% of children with NBCC
Usually presents between ages 3-8 yrs, but can occur at
any age [in NBCC (my data) mean age at dx was 2.3
years (4 cases)]
Medulloblastoma
► Symptoms
 Early symptoms may occur up to 2 months before
presentation
 Symptoms are due to increased pressure on the brain
as a consequence of hydrocephalus
► Increasing
head circumference
► Headache
► Vomiting
(without nausea), usually early in the morning
► Visual, speech, ambulatory disturbance
► Lethargy
► Nystagmus (jerky eye movements)
► Stiff neck and head tilted to one side (torticollis)
► CT
scans and MRI are used to diagnose the
presence of a medulloblastoma
Treatment of Medulloblatoma:
a special issue in NBCC
► Treatment
may include surgery followed by
radiation therapy and/or chemotherapy
► Patients
with NBCC can have serious
complications from radiation therapy
 Crops of hundreds of BCCs may occur in the
radiation port, with a lag time of 6-18 months
Surveillance
► Baseline
MRI in at-risk infants, at 6 months
► Yearly MRI until age 8
Females
•
•
•
Ovarian Fibromas
17% of females
(diagnosed at a mean age
of 30 years)
Structural anomalies of the
uterus
Effects?
• Reduction in fertility
•
Surveillance
Pelvic u/s
Manual exam
Males
•
Undescended testes
Inguinal hernias
•
Treatment
•
• Surgery
Growth and Development
► Facial
features characteristic of Gorlin
syndrome
► Issues
of height and head circumference
Measurements
OFC = head circumference
Eye measurements
Facial Features in Gorlin Syndrome
► Relative
macrocephaly (50%)
► Hypertelorism (42%)
► Retained epicanthal folds
► Frontal & bi-parietal bossing
► Mandibular prognathism
► Synophrys
► Dental malocclusion
► Cleft lip/palate
Facial features
macrocephaly
synophrys
Mandibular
prognathism
Facial Features: Dental
Class III malocclusion
With open bite
Cleft lip/palate
Facial features: Ocular
strabismus
Retained epicanthal folds
Generalized Overgrowth
The Genetics of Gorlin Syndrome
► Inherited
in an autosomal dominant manner
► Due to mutation in the PTCH gene
► Mutations can be detected in the laboratory
in the majority of patients
► Once you know the mutation in a family,
there are many options for family planning
available
How can you say its autosomal
dominant? I’m the only person
in my family with this disorder!
Mutations in the PTCH gene
Cause Gorlin Syndrome
► The
gene is on chromosome 9
► It is very large
► Mutations can occur anywhere in this very
large gene
► Most mutations are “private”
► The best way to find a mutation in PTCH is
to sequence the entire gene
The PTCH gene codes for a protein that
sits within the cell’s membrane
How do we find mutations in the
PTCH gene?
►A
sample of a patient’s DNA is needed:
 From blood
 From cheek swabs
 Other
► The
sample is sent to a lab
► The PTCH gene is sequenced
► The results are reported to the referring
physician/genetic counselor
A cheek swab or blood
sample is collected at
home, a lab, or doctor’s
office and sent to a
genetics laboratory for
analysis.
When the brushes
arrive in the lab,
DNA is made from
the cells.
By a technique called PCR, the PTCH
gene is broken into many pieces and
many copies of each piece are made
in preparation for sequencing.
The fragments of PTCH gene DNA are
loaded on a DNA sequencing machine.
The DNA sequence is
read as a series of
letters (G,A,T,C) for
each fragment of the
PTCH gene.
The sequence of the PTCH
gene from a patient is
compared to the normal
sequence of the gene and
any difference (mutation)
is identified.
So what is a mutation, anyway?
What can you do with
the information about
your PTCH sequence?
Prenatal Diagnosis
If you know your mutation and are concerned
about having children with Gorlin Syndrome
you can have prenatal diagnosis once you
have achieved a pregnancy.
• CVS
• Amniocentesis
Ultrasound
scanner
Amnion
Cervical
Canal
Catheter
Vagina
Fetus
Uterus
Chorion
CVS (chorionic villus sample) is taken at about 10 weeks.
Ultrasound
scanner
Abdominal
Wall
Amniotic
Fluid
Syringe
Syringe to
to
Remove AF
AF
Remove
Chorion
Fetus
Uterus
Vagina
Chorion
Amniotic Fluid Samples are taken at about 14-16
Weeks of pregnancy
Results of Prenatal Diagnosis
are available in <2 weeks
► Decision
to continue or terminate pregnancy
based on the information received
► If the fetus is found to have inherited Gorlin
Syndrome and you choose to continue the
pregnancy
 Doctors should be informed of issues that may
present at birth
►Hydrocephalus,
macrocephaly, cleft lip/palate
►Develop surveillance plan (scheduled MRI, watch
head circumference carefully)
Other Options
► Pre-implantation
genetic diagnosis (PGD)
 In-vitro fertilization
 Testing of resulting embryos for PTCH
mutations
 Implantation in uterus only of embryos without
the PTCH mutation
► Adoption