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Gorlin Syndrome: More than skin deep

Gorlin Syndrome: More than skin deep. Sherri J. Bale, Ph.D. Clinical Director GeneDx, Inc. A multi-system genetic disorder Skin, teeth (jaw) Skeleton Brain Growth and development Reproductive Inherited. Cardinal Features. Multiple basal cell carcinomas, early onset

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Gorlin Syndrome: More than skin deep

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  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. 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

  33. How can you say its autosomal dominant? I’m the only person in my family with this disorder!

  34. 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

  35. The PTCH gene codes for a protein that sits within the cell’s membrane

  36. 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

  37. A cheek swab or blood sample is collected at home, a lab, or doctor’s office and sent to a genetics laboratory for analysis.

  38. When the brushes arrive in the lab, DNA is made from the cells.

  39. 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.

  40. The fragments of PTCH gene DNA are loaded on a DNA sequencing machine.

  41. The DNA sequence is read as a series of letters (G,A,T,C) for each fragment of the PTCH gene.

  42. The sequence of the PTCH gene from a patient is compared to the normal sequence of the gene and any difference (mutation) is identified.

  43. So what is a mutation, anyway?

  44. What can you do with the information about your PTCH sequence?

  45. 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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