Gorlin Syndrome: More than skin deep Sherri J. Bale, Ph.D. Clinical Director GeneDx, Inc

Gorlin Syndrome:Gorlin Syndrome:More than skin deepMore than skin deep

Sherri J. Bale, Ph.D.Sherri J. Bale, Ph.D.

Clinical DirectorClinical Director

GeneDx, Inc.GeneDx, Inc.

►A multi-system genetic disorderA multi-system genetic disorder Skin, teeth (jaw)Skin, teeth (jaw) SkeletonSkeleton BrainBrain Growth and developmentGrowth and development ReproductiveReproductive

► InheritedInherited

Cardinal FeaturesCardinal Features

Multiple basal cell carcinomas, early onsetMultiple basal cell carcinomas, early onset

Odontogenic keratocystsOdontogenic keratocysts

Palmar and plantar pitsPalmar and plantar pits

Basal Cell CarcinomasBasal Cell Carcinomas

Odontogenic KeratocytsOdontogenic Keratocyts

Can you see jaw cysts Can you see jaw cysts without and x-ray?without and x-ray?

Palmar and Plantar PitsPalmar and Plantar Pits

Skeletal manifestations in Skeletal manifestations in NBCCNBCC

Rib anomaliesRib anomalies

Bifid RibBifid Rib

Polydactyly and SyndactylyPolydactyly and Syndactyly

Ectopic CacificationEctopic Cacification

Sprengel Deformity Sprengel Deformity (11%)(11%)

ScoliosisScoliosis

Pectus abnormalities Pectus abnormalities (13%)(13%)

Excavatum

Carinatum

Spade-shaped tuftsSpade-shaped tufts

NBCC can affect the brainNBCC can affect the brain

Macrocephaly

MedulloblastomaMedulloblastoma

►What is it?What is it? Brain tumor, arising from primitive brain cells Brain tumor, arising from primitive brain cells

very early in developmentvery early in development

► StatisticsStatistics Accounts for 20% of all childhood tumorsAccounts for 20% of all childhood tumors Incidence 1.5-2 cases per 100,000 personsIncidence 1.5-2 cases per 100,000 persons Occurs in about 5% of children with NBCCOccurs in about 5% of children with NBCC Usually presents between ages 3-8 yrs, but can Usually presents between ages 3-8 yrs, but can

occur at any age [in NBCC (my data) mean age occur at any age [in NBCC (my data) mean age at dx was 2.3 years (4 cases)]at dx was 2.3 years (4 cases)]

MedulloblastomaMedulloblastoma

► SymptomsSymptoms Early symptoms may occur up to 2 months Early symptoms may occur up to 2 months

before presentationbefore presentation Symptoms are due to increased pressure on the Symptoms are due to increased pressure on the

brain as a consequence of hydrocephalusbrain as a consequence of hydrocephalus► Increasing head circumferenceIncreasing head circumference►HeadacheHeadache►Vomiting (without nausea), usually early in the morningVomiting (without nausea), usually early in the morning►Visual, speech, ambulatory disturbanceVisual, speech, ambulatory disturbance►LethargyLethargy►Nystagmus (jerky eye movements)Nystagmus (jerky eye movements)►Stiff neck and head tilted to one side (torticollis) Stiff neck and head tilted to one side (torticollis)

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

Treatment of Treatment of Medulloblatoma:Medulloblatoma:

a special issue in NBCCa special issue in NBCC►Treatment may include surgery Treatment may include surgery

followed by radiation therapy and/or followed by radiation therapy and/or chemotherapychemotherapy

►Patients with NBCC can have serious Patients with NBCC can have serious complications from radiation therapy complications from radiation therapy Crops of hundreds of BCCs may occur in Crops of hundreds of BCCs may occur in

the radiation port, with a lag time of 6-18 the radiation port, with a lag time of 6-18 monthsmonths

SurveillanceSurveillance

►Baseline MRI in at-risk infants, at 6 Baseline MRI in at-risk infants, at 6 monthsmonths

►Yearly MRI until age 8Yearly MRI until age 8

FemalesFemales

• Ovarian FibromasOvarian Fibromas17% of females 17% of females (diagnosed at a mean (diagnosed at a mean age of 30 years)age of 30 years)

• Structural anomalies of Structural anomalies of the uterusthe uterus

• Effects?Effects?• Reduction in fertilityReduction in fertility

• SurveillanceSurveillancePelvic u/sPelvic u/sManual examManual exam

MalesMales

• Undescended testesUndescended testes• Inguinal herniasInguinal hernias

• TreatmentTreatment• SurgerySurgery

Growth and DevelopmentGrowth and Development

►Facial features characteristic of Gorlin Facial features characteristic of Gorlin syndrome syndrome

► Issues of height and head Issues of height and head circumferencecircumference

MeasurementsMeasurementsOFC = head circumferenceEye measurements

Facial Features in Gorlin Facial Features in Gorlin SyndromeSyndrome

► Relative macrocephaly (50%)Relative macrocephaly (50%)►Hypertelorism (42%)Hypertelorism (42%)► Retained epicanthal foldsRetained epicanthal folds► Frontal & bi-parietal bossingFrontal & bi-parietal bossing►Mandibular prognathismMandibular prognathism► SynophrysSynophrys►Dental malocclusionDental malocclusion► Cleft lip/palateCleft lip/palate

Facial featuresFacial features

macrocephaly

synophrys

Mandibular prognathism

Facial Features: DentalFacial Features: Dental

Class III malocclusionWith open bite

Cleft lip/palate

Facial features: OcularFacial features: Ocular

strabismus Retained epicanthal folds

Generalized OvergrowthGeneralized Overgrowth

The Genetics of Gorlin SyndromeThe Genetics of Gorlin Syndrome

► Inherited in an autosomal dominant Inherited in an autosomal dominant mannermanner

►Due to mutation in the PTCH geneDue to mutation in the PTCH gene►Mutations can be detected in the Mutations can be detected in the

laboratory in the majority of patientslaboratory in the majority of patients►Once you know the mutation in a Once you know the mutation in a

family, there are many options for family, there are many options for family planning availablefamily planning available

How can you say its How can you say its autosomal dominant? I’m autosomal dominant? I’m

the only person in my family the only person in my family with this disorder!with this disorder!

Mutations in the PTCH geneMutations in the PTCH geneCause Gorlin SyndromeCause Gorlin Syndrome

►The gene is on chromosome 9The gene is on chromosome 9► It is very largeIt is very large►Mutations can occur anywhere in this Mutations can occur anywhere in this

very large genevery large gene►Most mutations are “private”Most mutations are “private”►The best way to find a mutation in The best way to find a mutation in

PTCH is to sequence the entire genePTCH 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 How do we find mutations in the PTCH gene?the PTCH gene?

►A sample of a patient’s DNA is needed:A sample of a patient’s DNA is needed: From bloodFrom blood From cheek swabsFrom cheek swabs OtherOther

►The sample is sent to a labThe sample is sent to a lab►The PTCH gene is sequencedThe PTCH gene is sequenced►The results are reported to the The results are reported to the

referring physician/genetic counselorreferring physician/genetic counselor

A cheek swab or blood sample is collected athome, a lab, or doctor’s office and sent to agenetics laboratory foranalysis.

When the brushesarrive in the lab,DNA is made fromthe cells.

By a technique called PCR, the PTCHgene is broken into many pieces andmany copies of each piece are madein preparation for sequencing.

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

The DNA sequence isread as a series of letters (G,A,T,C) foreach fragment of thePTCH gene.

The sequence of the PTCHgene from a patient is compared to the normalsequence of the gene andany difference (mutation)is identified.

So what is a mutation, So what is a mutation, anyway?anyway?

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

Prenatal DiagnosisPrenatal Diagnosis

If you know your mutation and are If you know your mutation and are concerned about having children with concerned about having children with Gorlin Syndrome you can have Gorlin Syndrome you can have prenatal diagnosis once you have prenatal diagnosis once you have achieved a pregnancy.achieved a pregnancy.

• CVSCVS• AmniocentesisAmniocentesis

Catheter

Vagina

Uterus

Fetus

Chorion

Amnion

CervicalCanal

Ultrasoundscanner

CVS (chorionic villus sample) is taken at about 10 weeks.

Vagina

Uterus

Fetus

Chorion

AmnioticFluid

Ultrasoundscanner

Chorion

Syringe to Remove AFSyringe toRemove AF

AbdominalWall

Amniotic Fluid Samples are taken at about 14-16Weeks of pregnancy

Results of Prenatal DiagnosisResults of Prenatal Diagnosisare available in <2 weeksare available in <2 weeks

►Decision to continue or terminate Decision to continue or terminate pregnancy based on the information pregnancy based on the information receivedreceived

► If the fetus is found to have inherited If the fetus is found to have inherited Gorlin Syndrome and you choose to Gorlin Syndrome and you choose to continue the pregnancycontinue the pregnancy Doctors should be informed of issues that Doctors should be informed of issues that

may present at birth may present at birth ►Hydrocephalus, macrocephaly, cleft lip/palateHydrocephalus, macrocephaly, cleft lip/palate►Develop surveillance plan (scheduled MRI, watch Develop surveillance plan (scheduled MRI, watch

head circumference carefully)head circumference carefully)

Other OptionsOther Options

►Pre-implantation genetic diagnosis Pre-implantation genetic diagnosis (PGD)(PGD) In-vitro fertilizationIn-vitro fertilization Testing of resulting embryos for PTCH Testing of resulting embryos for PTCH

mutationsmutations Implantation in uterus only of embryos Implantation in uterus only of embryos

without the PTCH mutationwithout the PTCH mutation

►AdoptionAdoption