* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download The PTCH gene and Gorlin Syndrome
Zinc finger nuclease wikipedia , lookup
Fetal origins hypothesis wikipedia , lookup
Genome evolution wikipedia , lookup
Gene desert wikipedia , lookup
Population genetics wikipedia , lookup
Epigenetics of neurodegenerative diseases wikipedia , lookup
Gene expression programming wikipedia , lookup
Gene nomenclature wikipedia , lookup
No-SCAR (Scarless Cas9 Assisted Recombineering) Genome Editing wikipedia , lookup
Oncogenomics wikipedia , lookup
Genetic engineering wikipedia , lookup
Neuronal ceroid lipofuscinosis wikipedia , lookup
History of genetic engineering wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Nutriepigenomics wikipedia , lookup
Genome (book) wikipedia , lookup
Gene therapy wikipedia , lookup
Cell-free fetal DNA wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
Genome editing wikipedia , lookup
Saethre–Chotzen syndrome wikipedia , lookup
Therapeutic gene modulation wikipedia , lookup
Helitron (biology) wikipedia , lookup
Frameshift mutation wikipedia , lookup
Artificial gene synthesis wikipedia , lookup
Designer baby wikipedia , lookup
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 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 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