FG Syndrome (FGS) 40 –Year Retrospective · 3 FGS: DEFINITION The FGS syndromes constitute a:...

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FG Syndrome (FGS)FG Syndrome (FGS)40 40 ––Year RetrospectiveYear Retrospective

Lucia Santoro, James F. Smith, Lucia Santoro, James F. Smith, Gary Gary HedlundHedlund, John M. Opitz, John M. Opitz

Urology and RadiologyUrology and RadiologyUniversity of Utah Health Sciences CenterUniversity of Utah Health Sciences Center

European Course on Clinical European Course on Clinical DysmorphologyDysmorphologyRome, ItalyRome, Italy

March 28 March 28 –– 29, 200829, 2008

Cathedral St. HelenaHelena, Montana, USA

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FGS: DEFINITIONFGS: DEFINITION

•• CommonCommon

•• HeterogeneousHeterogeneous

•• MCA/DD syndromesMCA/DD syndromes

•• XX--linked, incompletely recessivelinked, incompletely recessive

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The FGS syndromesThe FGS syndromes constitute a:constitute a:

CharacteristicCharacteristic combination of minor combination of minor

anomalies, malformations, abnormal growth, anomalies, malformations, abnormal growth,

health problems, and CNS and GI dysfunctions.health problems, and CNS and GI dysfunctions.


PrenatalPrenatal

Reduced fetal movements, polyReduced fetal movements, poly-- (rarely (rarely

oligooligo--) ) hydramnioshydramnios, , prematurityprematurity, fetal , fetal

distress, Cdistress, C--sections, intrauterine growth sections, intrauterine growth

retardation with retardation with ““big headbig head””, large anterior , large anterior

fontanelle.fontanelle.


NeonatalNeonatal

Hypotonia, difficulties with feeding and Hypotonia, difficulties with feeding and

neonatal adaptation (temperature); neonatal adaptation (temperature); icterusicterus, ,

hypoglycemia, reflux (GER), failure to thrive hypoglycemia, reflux (GER), failure to thrive

(FTT); multiple congenital anomalies; (FTT); multiple congenital anomalies;

autonomic instability.autonomic instability.

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InfancyInfancyGERGER: With aspiration: With aspiration bronchoscopybronchoscopy to to rule out laryngeal cleft. rule out laryngeal cleft. NissenNissen fundoplicationfundoplication

FTTFTT: Gastrostomy: GastrostomyMultiple ear/sinus infections: Multiple ear/sinus infections: PETsPETs, , tonsil/adenoidectomytonsil/adenoidectomy


Infancy, contInfancy, cont’’dd

Reactive airway disease Reactive airway disease –– asthmaasthma

Abnormal sensory integration (DSI)Abnormal sensory integration (DSI)

Constipation and/or diarrheaConstipation and/or diarrhea

Shortness of stature, Shortness of stature, megalencephalymegalencephaly

Immune abnormalities, SIDSImmune abnormalities, SIDS

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FGS: DEFINITIONFGS: DEFINITIONChildhoodChildhood

DD: Speech delay > motor delay, frustration DD: Speech delay > motor delay, frustration with with ““meltdownsmeltdowns””. Mental retardation not . Mental retardation not obligatory.obligatory.

DSI: e.g. DSI: e.g. taglesstagless shirts, bolting of food.shirts, bolting of food.

Behaviors: Mechanical fascinations, attentionBehaviors: Mechanical fascinations, attention--seeking, seeking, ““affableaffable””, OCD, ODD, aggression; , OCD, ODD, aggression; bipolar disorderbipolar disorder

““AspergerAsperger””, , ““PDDPDD--NOSNOS””, , ““autismautism””

FGS: DEFINITIONFGS: DEFINITIONCNSCNS

Small head (metopic suture Small head (metopic suture synostosissynostosis))

Seizures (uncommon), staring spells, generally Seizures (uncommon), staring spells, generally benign coursebenign course

Visceral (abdominal) migraineVisceral (abdominal) migraine

Chiari I/tethered cord manifestationsChiari I/tethered cord manifestations

SensoriSensori--neural hearing loss (cochlear implant)neural hearing loss (cochlear implant)

Sleep disturbanceSleep disturbance


Childhood Childhood –– AdolescenceAdolescence

May develop obesity, decreased physical and May develop obesity, decreased physical and

mental function with sleep apnea. Sleep clinic. mental function with sleep apnea. Sleep clinic.

CPAP. Nutritional management.CPAP. Nutritional management.

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MRIMRI•• Increased Increased subarachnoidsubarachnoid fluid spacesfluid spaces

•• Delayed/defective Delayed/defective myelinationmyelination ((““PVLMPVLM””))

•• Abnormal/absent corpus callosumAbnormal/absent corpus callosum

•• Abnormal cerebral veinsAbnormal cerebral veins

•• Posterior fossa cyst (Posterior fossa cyst (““BlakeBlake’’s pouchs pouch””))


MRIMRI•• PeriventricularPeriventricular nodular nodular heterotopiaheterotopia (PVNH)(PVNH)

•• Chiari I anomalyChiari I anomaly

•• SyringomyeliaSyringomyelia

•• Tethered cordTethered cord

•• Cervical/LS vertebral anomaliesCervical/LS vertebral anomalies

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CraniofacialCraniofacial•• Small OFC: metopic suture Small OFC: metopic suture synostosissynostosis

•• Coloboma eye; palpebral fissuresColoboma eye; palpebral fissures

•• Choanal atresiaChoanal atresia

•• Cleft palate/uvula (Cleft palate/uvula (““nevernever”” of lip)of lip)

•• Narrow ear canalsNarrow ear canals


HeartHeart•• PFO, PDA, ASD, VSDPFO, PDA, ASD, VSD

•• Persistent left superior vena cavaPersistent left superior vena cava

•• Occasional valve defectsOccasional valve defects

•• Rare peripheral Rare peripheral pulmonicpulmonic stenosisstenosis

•• Severe CHD rare!Severe CHD rare!

FGS: DEFINITIONFGS: DEFINITIONGIGI•• Cleft palate, grade 1 laryngeal cleftCleft palate, grade 1 laryngeal cleft

•• Occasional pyloric stenosisOccasional pyloric stenosis

•• MidgutMidgut volvulusvolvulus

•• Diaphragmatic herniaDiaphragmatic hernia

•• Rectal/anal stenosis, atresiaRectal/anal stenosis, atresia

•• Dental/enamel defectsDental/enamel defects

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GUGU•• HypospadiasHypospadias, , ““banana signbanana sign””

•• Short Short perinealperineal bodybody

•• Inguinal Inguinal herniaeherniae

•• CryptorchidismCryptorchidism

•• Renal malformations; stonesRenal malformations; stones


LimbsLimbs•• BrachyclinodactylyBrachyclinodactyly (Dubois)(Dubois)

•• Rare Rare oligo/ectrodactylyoligo/ectrodactyly

•• Rare polydactylyRare polydactyly

•• Flat feet; plantar fat padFlat feet; plantar fat pad


DysplasiasDysplasias•• Common pigmentary Common pigmentary dysplasiasdysplasias –– initial initial

suspicion of NF1, multiple pigmented nevi suspicion of NF1, multiple pigmented nevi (may be pre(may be pre--melanomatousmelanomatous))

•• LymphohemangiomataLymphohemangiomata, cavernous or , cavernous or capillary capillary hemaniomatahemaniomata

•• Gastrointestinal Gastrointestinal dysganglionesesdysganglioneses

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Minor anomaliesMinor anomalies•• HighHigh--broad foreheadbroad forehead

•• Cowlicks/hair whorlsCowlicks/hair whorls

•• Hypertelorism, Hypertelorism, palppalp. . fissfiss. slant and opening . slant and opening

•• Short, thick nasal septumShort, thick nasal septum

•• Prominence lower lipProminence lower lip

•• Narrow ear canalsNarrow ear canals

FGS: DEFINITIONFGS: DEFINITIONMinor anomaliesMinor anomalies•• SternalSternal anomaliesanomalies

•• Persistent fingertip pads and other signs Persistent fingertip pads and other signs of congenital lymphedemaof congenital lymphedema

•• PalmarPalmar creasescreases

•• Broad thumbs and Broad thumbs and halluceshalluces

•• Curved (Curved (““roundround””) (2) (2ndnd) toenails) toenails

•• PilonidalPilonidal dimpledimple


CarriersCarriers•• Apparently Apparently ““completelycompletely”” normal or normal or

manifesting any or all FGS signs and manifesting any or all FGS signs and symptoms, sometimes worse than evident symptoms, sometimes worse than evident hemizygoteshemizygotes

•• Migraines!Migraines!

•• Bipolar disorder and behavior/emotional Bipolar disorder and behavior/emotional disturbancesdisturbances

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CarriersCarriers

During pregnancy at risk for hypertension, During pregnancy at risk for hypertension,

toxemia, HELLP syndrome. toxemia, HELLP syndrome. PruriticPruritic

urticariaurticaria of pregnancy (PUP/PEP). Autoof pregnancy (PUP/PEP). Auto--

immune disease risk. Bianchi (maternalimmune disease risk. Bianchi (maternal--

fetal cell trafficking) phenomenon?fetal cell trafficking) phenomenon?

Bp

Bp

Bp

Bp

Bp

Bp

Bp

T

T T

TTTTTTTT

T

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FGS AND GENIUS?FGS AND GENIUS?

Extraordinary shapers of history in music,Extraordinary shapers of history in music,

religion, biology, physicsreligion, biology, physics……who were: who were: ·· MaleMale

·· Short Short ·· MegalencephalicMegalencephalic ·· Gifted Gifted ··““EccentricEccentric””

·· ConstipatedConstipated……

Religion: Dr. Martin Luther Religion: Dr. Martin Luther (Neumann, 1996, (Neumann, 1996, LuthersLuthers Leiden)Leiden)

Music: Beethoven, Bach?Music: Beethoven, Bach?


Biology: Karl Ernst von BaerBiology: Karl Ernst von Baer

……Physics: Physics: EisnsteinEisnstein

……for beginnersfor beginners


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Religion: Dr. Martin Luther Religion: Dr. Martin Luther (Neumann, 1996, (Neumann, 1996, LuthersLuthers Leiden)Leiden)

Music: Mozart, Beethoven?Music: Mozart, Beethoven?

Biology: Karl Ernst von BaerBiology: Karl Ernst von Baer

Physics: Physics: EisnsteinEisnstein……

……for beginnersfor beginners


FGS GENES: HETEROGENEITYFGS GENES: HETEROGENEITY

FGS1FGS1. OMIM 305450. . OMIM 305450. ““OpitzOpitz--KaveggiaKaveggia””

syndrome. syndrome. BriaultBriault et al., 1997; Graham et al., et al., 1997; Graham et al.,

1998. At Xq13: R961W mutations of 1998. At Xq13: R961W mutations of MED12 MED12

gene, gene, RishegRisheg et al., 2007, in 7% of FGS patients.et al., 2007, in 7% of FGS patients.

MED12MED12 mutation N1007S causes Lujanmutation N1007S causes Lujan--FrynsFryns

syndrome.syndrome.

FGS2FGS2. OMIM 300321. . OMIM 300321. BriaultBriault et al., 1999, 2000. et al., 1999, 2000.

At Xq28.2 near At Xq28.2 near protan/deutanprotan/deutan CB, Factor 8, CB, Factor 8,

FLNA FLNA genes (PVNH). Pro 1291 genes (PVNH). Pro 1291 LeuLeu at c.3872 at c.3872

((exonexon 23) of the 23) of the FLNAFLNA gene (Unger et al., 2007); gene (Unger et al., 2007);

HehrHehr et al. (2007): C1923T = FGS; et al. (2007): C1923T = FGS; GuerriniGuerrini et al. et al.

(2004), 4 families with PVNH(2004), 4 families with PVNH


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FGS3FGS3. OMIM 300406. . OMIM 300406. DessayDessay et al., 2001, at et al., 2001, at

Xp22.3 in a London and an LDS/SLC kindred. Xp22.3 in a London and an LDS/SLC kindred.

Candidate gene: Candidate gene: MID1MID1? Presumed to be near ? Presumed to be near

OCA1OCA1 gene because of ocular albinism in 3 FGS gene because of ocular albinism in 3 FGS

families (Opitz, unpublished).families (Opitz, unpublished).


FGS4FGS4. OMIM 300422. At Xp11.4. Missense . OMIM 300422. At Xp11.4. Missense

mutation in mutation in CASKCASK gene: 83G T(R28L), in a gene: 83G T(R28L), in a

single Italian family (single Italian family (PilusoPiluso et al., 2003, 2007).et al., 2003, 2007).


FGS5FGS5. OMIM 300581. A 4 or #. OMIM 300581. A 4 or # MbMb

duplication (including duplication (including MID2MID2) at Xq22.3 in) at Xq22.3 in

a single Brazilian family (a single Brazilian family (JeheeJehee et al., 2005).et al., 2005).


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““FGS6FGS6””. OMIM 300298. Schwartz et al., . OMIM 300298. Schwartz et al.,

2007, 2007, TarpeyTarpey et al., 2007: Truncating mutations et al., 2007: Truncating mutations

of the of the UPF3BUPF3B gene at Xq25 gene at Xq25 –– 26 may give rise 26 may give rise

to FGS or Lujanto FGS or Lujan--FrynsFryns syndrome.syndrome.


““FGS7FGS7””(?): (?): BRWD3BRWD3 gene at Xq21.1 (OMIM gene at Xq21.1 (OMIM 300553). In two 300553). In two ““nonnon--syndromicsyndromic”” XLMR XLMR families, affected males manifesting mildfamilies, affected males manifesting mild--moderate DD, early speech delay; and high, moderate DD, early speech delay; and high, broad forehead (family 336, Field et al., 2007).broad forehead (family 336, Field et al., 2007).


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FGS2 (near Factor 8, deutan/protancolor-blindness, Filamin A-FLNA-PVNH?)

FGS1 (MED12)

FGS4 (MKRN4; DDX3)

FGS3 (MID1?)

FGS5 (M4 duplication, Xq22.3 including MID2 gene)

“FGS6” (UPF3B)

CHALLENGES: GENETICCHALLENGES: GENETIC

•• Clone Clone FGS3 !FGS3 !

•• Determine relative prevalence of Determine relative prevalence of FGS1, 2, 3, FGS1, 2, 3, 6, 7 6, 7 in the overall FGS populationin the overall FGS population

•• Determine Determine FGS1, 2, 3, 6, 7 FGS1, 2, 3, 6, 7 in in specialspecialpopulations with many FGS casespopulations with many FGS cases

FGS special populations (most urgent):FGS special populations (most urgent):•• Pediatric NDD/LD/hypotonia groupsPediatric NDD/LD/hypotonia groups

•• Constipation Constipation –– pediatric GI clinicspediatric GI clinics

•• Pediatric psychiatry clinics for Pediatric psychiatry clinics for ““autismautism””, , Asperger, PDDAsperger, PDD--NOS, OCD, ODD, bipolarNOS, OCD, ODD, bipolar

•• SyndromalSyndromal hypospadiashypospadias populations with populations with FGS manifestationsFGS manifestations


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J Urol 178:656-659, 2007

•• Genotype/phenotype correlations, (omitting Genotype/phenotype correlations, (omitting propositipropositi), FGS1 now has emerged as a ), FGS1 now has emerged as a clearly recognizable phenotypeclearly recognizable phenotype

•• Genotype/XGenotype/X--inactivation correlationsinactivation correlations

•• Genotype (male) correlation with carrier Genotype (male) correlation with carrier manifestationsmanifestations


Transmission ratio distortion (TRD)Transmission ratio distortion (TRD)

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•• Disprove null hypothesis that there is Disprove null hypothesis that there is nonosegregation distortion (TRD) in FGSsegregation distortion (TRD) in FGS

•• If there If there isis TRD in FGS, test TRD in FGS, test ““SapienzaSapienza””hypothesis of correlation between TRD hypothesis of correlation between TRD and Xand X--inactivation ratioinactivation ratio


•• Investigate genotype in those apparent FGS Investigate genotype in those apparent FGS cases indistinguishable from GBBBcases indistinguishable from GBBB

•• Ratio of new mutations to segregating cases?Ratio of new mutations to segregating cases?

•• Create animal Create animal ““modelsmodels””


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Relationship to VATER?Relationship to VATER?


Mary (Proposita)Mary (Proposita)•• SUASUA•• Congenital hypotoniaCongenital hypotonia•• Small inferior Small inferior limballimbal dermoiddermoid OSOS•• ½½ vertebra C2, abs. anterior & posterior vertebra C2, abs. anterior & posterior

elements C1elements C1•• Cervical ribs; fused ribs 1 & 2 rightCervical ribs; fused ribs 1 & 2 right•• Bilateral cleft hard & soft palateBilateral cleft hard & soft palate•• Imperforate anus with RV fistulaImperforate anus with RV fistula•• GER, severe OTA, GGER, severe OTA, G--tube, tube, NissenNissen

Mary (contMary (cont’’d)d)•• CHD: VSD, ASD, right aortic arch, small PFO; CHD: VSD, ASD, right aortic arch, small PFO;

PDA PDA –– coil closurecoil closure•• Bilateral renal duplication, function only Rt. Bilateral renal duplication, function only Rt.

lower pole, borderline renal failure, lower pole, borderline renal failure, ureteroceleureterocele•• No vertebrae below S3 (No vertebrae below S3 (““caudal regressioncaudal regression””))•• Fatty Fatty filumfilum, mild , mild hydromyeliahydromyelia, sacral dimple , sacral dimple

with patch of hair (T.C.?)with patch of hair (T.C.?)•• OtitisOtitis x n, x n, PETsPETs

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•• Severe defect LUL; deficiency distal Severe defect LUL; deficiency distal humerus, agenesis radius, curved ulna, humerus, agenesis radius, curved ulna, absence digits 1 & 2absence digits 1 & 2

Mary (contMary (cont’’d)d)

•• SUA (Rt.)SUA (Rt.)

•• Enlarged MCDKEnlarged MCDK

•• Thoracic cleft vertebra / scoliosis, Thoracic cleft vertebra / scoliosis, lumbar lumbar ½½ vertebra with 15vertebra with 15°° curve, curve, Sacral dimple with Sacral dimple with ½½ vertebravertebra

•• CHD: CHD: perimembranousperimembranous VSD, repaired;VSD, repaired;PFO: suture closure; LSVCPFO: suture closure; LSVC coronary sinuscoronary sinus

LarryLarry

Larry (contLarry (cont’’d)d)•• Height, weight < 3%, OFC 50%Height, weight < 3%, OFC 50%•• Single Single palmarpalmar crease L.crease L.•• SS--hair whorl, HBF, anterior & posterior hair whorl, HBF, anterior & posterior

cowlickscowlicks•• Curved toenails Curved toenails •• Hypotonia, SD, mechanical fascinations; Hypotonia, SD, mechanical fascinations;

cars: 1cars: 1--22--33--44

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FGS FGS –– SUMMARYSUMMARY

FGS may be the most common and most FGS may be the most common and most

important DD/neurobehavioral/mental important DD/neurobehavioral/mental

health condition in the population; MR health condition in the population; MR notnot

an obligatory manifestation.an obligatory manifestation.

•• FGS: Huge impact on pediatric FGS: Huge impact on pediatric neurobehaviorneurobehavior/psychiatric, (re)/psychiatric, (re)--habilitationhabilitation(ST, OT, PT(ST, OT, PT……), pedagogical (special ), pedagogical (special education) professionseducation) professions

•• The medical/developmental/family history is The medical/developmental/family history is as, if not as, if not moremore important in evaluating FGS important in evaluating FGS than the physical findingsthan the physical findings


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FGS: To what extent are behaviors (OCD, FGS: To what extent are behaviors (OCD,

ODDODD……) ) ““hard wiredhard wired””, i.e. genetically, , i.e. genetically,

developmentally, physiologically determined, developmentally, physiologically determined,

treatable, environmentally modifiable?treatable, environmentally modifiable?


FGS: It is impossible to underestimate the FGS: It is impossible to underestimate the

role of the FGS families/Support Groups in role of the FGS families/Support Groups in

contributing to the development of ourcontributing to the development of our

knowledge of these and related conditions!knowledge of these and related conditions!


FGS: To what extent have FGS genes, FGS: To what extent have FGS genes,

phenotypes contributed to the phenotypes contributed to the

development of (western) civilization?development of (western) civilization?


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FGS FGS -- ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

–– The FG Family and all FGS FamiliesThe FG Family and all FGS Families

–– Feliz MartinezFeliz Martinez

–– All collaborating colleagues over the All collaborating colleagues over the decades decades –– lastly, James F. Smith, UU and lastly, James F. Smith, UU and UCSF, Gary UCSF, Gary HedlundHedlund (Radiology, PCMC), (Radiology, PCMC), Lucia Santoro (Lucia Santoro (AnconaAncona, UU), UU)

FG Syndrome (FGS) 40 –Year Retrospective · 3 FGS: DEFINITION The FGS syndromes constitute a:...

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Transcript of FG Syndrome (FGS) 40 –Year Retrospective · 3 FGS: DEFINITION The FGS syndromes constitute a:...