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 Scoliosis

Pectus abnormalities (13%) Excavatum Carinatum

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 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 Ovarian Fibromas 17% of females (diagnosed at a mean age of 30 years) Structural anomalies of the uterus Structural anomalies of the uterus Effects? Effects? Reduction in fertility Reduction in fertility Surveillance Surveillance Pelvic u/s Manual exam

Males Undescended testes Undescended testes Inguinal hernias Inguinal hernias Treatment Treatment Surgery 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 strabismusRetained 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 CVS Amniocentesis Amniocentesis

Catheter Vagina Uterus Fetus Chorion Amnion Cervical Canal Ultrasound scanner CVS (chorionic villus sample) is taken at about 10 weeks.

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 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