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Gorlin Syndrome Powerpoint Presentation Transcript

  • 1. Gorlin Syndrome: More than skin deep Sherri J. Bale, Ph.D. Clinical Director GeneDx, Inc.
  • 2.
    • A multi-system genetic disorder
      • Skin, teeth (jaw)
      • Skeleton
      • Brain
      • Growth and development
      • Reproductive
    • Inherited
  • 3. Cardinal Features
      • Multiple basal cell carcinomas, early onset
      • Odontogenic keratocysts
      • Palmar and plantar pits
  • 4. Basal Cell Carcinomas
  • 5. Odontogenic Keratocyts
  • 6. Can you see jaw cysts without and x-ray?
  • 7. Palmar and Plantar Pits
  • 8. Skeletal manifestations in NBCC
  • 9. Rib anomalies
  • 10. Bifid Rib
  • 11. Polydactyly and Syndactyly
  • 12. Ectopic Cacification
  • 13. Sprengel Deformity (11%)
  • 14. Scoliosis
  • 15. Pectus abnormalities (13%) Excavatum Carinatum
  • 16. Spade-shaped tufts
  • 17. NBCC can affect the brain Macrocephaly
  • 18. 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)]
  • 19. 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)
  • 20.
    • CT scans and MRI are used to diagnose the presence of a medulloblastoma
  • 21. 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
  • 22. Surveillance
    • Baseline MRI in at-risk infants, at 6 months
    • Yearly MRI until age 8
  • 23. 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
  • 24. Males
    • Undescended testes
    • Inguinal hernias
    • Treatment
      • Surgery
  • 25. Growth and Development
    • Facial features characteristic of Gorlin syndrome
    • Issues of height and head circumference
  • 26. Measurements OFC = head circumference Eye measurements
  • 27. 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
  • 28. Facial features macrocephaly synophrys Mandibular prognathism
  • 29. Facial Features: Dental Class III malocclusion With open bite Cleft lip/palate
  • 30. Facial features: Ocular strabismus Retained epicanthal folds
  • 31. Generalized Overgrowth
  • 32.  
  • 33.  
  • 34. 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
  • 35.  
  • 36.  
  • 37. How can you say its autosomal dominant? I’m the only person in my family with this disorder!
  • 38.  
  • 39. 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
  • 40. The PTCH gene codes for a protein that sits within the cell’s membrane
  • 41. 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
  • 42. A cheek swab or blood sample is collected at home, a lab, or doctor’s office and sent to a genetics laboratory for analysis.
  • 43. When the brushes arrive in the lab, DNA is made from the cells.
  • 44. 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.
  • 45. The fragments of PTCH gene DNA are loaded on a DNA sequencing machine.
  • 46. The DNA sequence is read as a series of letters (G,A,T,C) for each fragment of the PTCH gene.
  • 47. The sequence of the PTCH gene from a patient is compared to the normal sequence of the gene and any difference (mutation) is identified.
  • 48. So what is a mutation, anyway?
  • 49. What can you do with the information about your PTCH sequence?
  • 50. 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
  • 51. Catheter Vagina Uterus Fetus Chorion Amnion Cervical Canal Ultrasound scanner CVS (chorionic villus sample) is taken at about 10 weeks.
  • 52. Vagina Uterus Fetus Chorion Amniotic Fluid Ultrasound scanner Chorion Syringe to Remove AF Syringe to Remove AF Abdominal Wall Amniotic Fluid Samples are taken at about 14-16 Weeks of pregnancy
  • 53. 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)
  • 54. 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
  • 55.