Gorlin Syndrome: More than skin deep

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Gorlin SyndromeMore than skin deep

• Sherri J. Bale, Ph.D.
• Clinical Director
• GeneDx, Inc.

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• A multi-system genetic disorder
• Skin, teeth (jaw)
• Skeleton
• Brain
• Growth and development
• Reproductive
• Inherited

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Cardinal Features

• Multiple basal cell carcinomas, early onset
• Odontogenic keratocysts
• Palmar and plantar pits

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Basal Cell Carcinomas
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Odontogenic Keratocyts
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Can you see jaw cysts without and x-ray?
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Palmar and Plantar Pits
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Skeletal manifestations in NBCC
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Rib anomalies
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Bifid Rib
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Polydactyly and Syndactyly
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Ectopic Cacification
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Sprengel Deformity (11)
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Scoliosis
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Pectus abnormalities (13)
Excavatum
Carinatum
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Spade-shaped tufts
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NBCC can affect the brain
Macrocephaly
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Medulloblastoma

• What is it?
• Brain tumor, arising from primitive brain cells
  very early in development
• Statistics
• 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)

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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)

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• CT scans and MRI are used to diagnose the
  presence of a medulloblastoma

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Treatment of Medulloblatomaa 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

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Surveillance

• Baseline MRI in at-risk infants, at 6 months
• Yearly MRI until age 8

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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

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Males

• Undescended testes
• Inguinal hernias
• Treatment
• Surgery

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Growth and Development

• Facial features characteristic of Gorlin syndrome
  
• Issues of height and head circumference

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Measurements
OFC head circumference Eye measurements
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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

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Facial features
macrocephaly
synophrys
Mandibular prognathism
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Facial Features Dental
Class III malocclusion With open bite
Cleft lip/palate
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Facial features Ocular
strabismus
Retained epicanthal folds
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Generalized Overgrowth
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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

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How can you say its autosomal dominant? Im the
only person in my family with this disorder!
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Mutations in the PTCH geneCause 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

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The PTCH gene codes for a protein that sits
within the cells membrane
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How do we find mutations in the PTCH gene?

• A sample of a patients 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

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A cheek swab or blood sample is collected
at home, a lab, or doctors office and sent to
a genetics laboratory for analysis.
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When the brushes arrive in the lab, DNA is made
from the cells.
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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.
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The fragments of PTCH gene DNA are loaded on a
DNA sequencing machine.
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The DNA sequence is read as a series of letters
(G,A,T,C) for each fragment of the PTCH gene.
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The sequence of the PTCH gene from a patient is
compared to the normal sequence of the gene
and any difference (mutation) is identified.
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So what is a mutation, anyway?
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What can you do with the information about your
PTCH sequence?
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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

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Ultrasound scanner
Amnion
Fetus
Cervical Canal
Uterus
Catheter
Chorion
Vagina
CVS (chorionic villus sample) is taken at about
10 weeks.
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Ultrasound scanner
Syringe to Remove AF
Syringe to Remove AF
Abdominal Wall
Chorion
Amniotic Fluid
Fetus
Uterus
Vagina
Chorion
Amniotic Fluid Samples are taken at about
14-16 Weeks of pregnancy
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Results of Prenatal Diagnosisare available in lt2
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)

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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

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