a patient with arthrogryposis and...

A Patient With Arthrogryposis

And Hypotonia

• History

– Normal pregnancy – nuchal

– Chromosomes by CVS 46XX

– Normal fetal echocardiogram at 19 weeks

• Physical at birth

– camptodactyly

– arachnodactyly and long feet

– a midline facial nevus

– hypotonia

Arthrogryposis

And Hypotonia

nuchal lucency

Chromosomes by CVS 46XX

Normal fetal echocardiogram at 19 weeks

and long feet

a midline facial nevus flammeus

• Clinical Course

– failure to thrive – weight below 1

at 5th %

– delayed walking until 24 months

– normal cognitive development

• Physical at 18 months

– decreased bulk in the appendicular and axial

muscles, inverted nipples with diminished

subcutaneous fat, low tone and diminished reflexes

throughout

weight below 1st percentile, height

delayed walking until 24 months

normal cognitive development

decreased bulk in the appendicular and axial

muscles, inverted nipples with diminished

subcutaneous fat, low tone and diminished reflexes

Bifid UvulaBifid UvulaBifid UvulaBifid UvulaMetopic ridge Metopic ridge Metopic ridge Metopic ridge RetrognathiaRetrognathiaRetrognathiaRetrognathiaHypertelorismHypertelorismHypertelorismHypertelorismTubular noseTubular noseTubular noseTubular noseMalarMalarMalarMalar Hypoplasia Hypoplasia Hypoplasia Hypoplasia

Axial > Appendicular weaknessAxial > Appendicular weaknessAxial > Appendicular weaknessAxial > Appendicular weaknessMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatWeight below 1Weight below 1Weight below 1Weight below 1stststst PercentilePercentilePercentilePercentileMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatWeight below 1Weight below 1Weight below 1Weight below 1stststst PercentilePercentilePercentilePercentile

Normal aortic root dimensionsNormal aortic root dimensionsNormal aortic root dimensionsNormal aortic root dimensionsNormal skin Normal skin Normal skin Normal skin Normal wound healingNormal wound healingNormal wound healingNormal wound healingNormal palatal archNormal palatal archNormal palatal archNormal palatal archNormal cognitive functionNormal cognitive functionNormal cognitive functionNormal cognitive function

Hypoplasia Hypoplasia Hypoplasia Hypoplasia

Axial > Appendicular weaknessAxial > Appendicular weaknessAxial > Appendicular weaknessAxial > Appendicular weaknessMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fat

PercentilePercentilePercentilePercentileMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fatMinimal subcutaneous fat

PercentilePercentilePercentilePercentile

Normal aortic root dimensionsNormal aortic root dimensionsNormal aortic root dimensionsNormal aortic root dimensions

Normal wound healingNormal wound healingNormal wound healingNormal wound healingNormal palatal archNormal palatal archNormal palatal archNormal palatal archNormal cognitive functionNormal cognitive functionNormal cognitive functionNormal cognitive function

Working up a Sporadic

Candidate Genes: Candidate Genes: Candidate Genes: Candidate Genes: Related Syndromes

Candidate Genes: Candidate Genes: Candidate Genes: Candidate Genes: Implicated Pathways

Interactome

Site of PathologySite of Pathology

Transcriptome:Transcriptome:Transcriptome:Transcriptome: Expression + Sequence

Exome:Exome:Exome:Exome: Sequence


Related Syndromes

Implicated Pathways

Interactome

Site of PathologySite of Pathology

Expression + Sequence

Sequence

camptodactylycamptodactylycamptodactylycamptodactyly

arachnodactyly arachnodactyly arachnodactyly arachnodactyly

joint laxityjoint laxityjoint laxityjoint laxity

scoliosisscoliosisscoliosisscoliosis

MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia

dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia

pespespespes planusplanusplanusplanus

lens dislocationlens dislocationlens dislocationlens dislocation

MFS



joint laxityjoint laxityjoint laxityjoint laxityaortic aortic aortic aortic dilitationdilitationdilitationdilitation

pectuspectuspectuspectus deformitydeformitydeformitydeformity

planusplanusplanusplanus



arachnodactylyarachnodactylyarachnodactylyarachnodactyly



MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia




MFS


arachnodactylyarachnodactylyarachnodactylyarachnodactyly


scoliosisscoliosisscoliosisscoliosisaortic aortic aortic aortic dilitationdilitationdilitationdilitation




BEALSBEALSBEALSBEALS

large jointlarge jointlarge jointlarge joint

contracturescontracturescontracturescontractures

ear deformityear deformityear deformityear deformity

PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD



scoliosisscoliosisscoliosisscoliosisMVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia



lens dislocationlens dislocationlens dislocationlens dislocationMFSMFSMFSMFS




aortic aortic aortic aortic dilitationdilitationdilitationdilitation











arachnodactlyarachnodactlyarachnodactlyarachnodactly

scoliosisscoliosisscoliosisscoliosisMVPMVPMVPMVP












A New Aortic Aneurysm SyndromeLike Marfan syndrome:

- Curvature of spine

- Chest wall deformity

- Long fingers

- Aortic root aneurysm

Unique:Unique:- widely-spaced eyes

- cleft palate/bifid uvula

- premature skull fusion

- club foot deformity

- congenital heart disease

(PDA, BAV, ASD)

Loeys-Dietz syndrome (LDS)

(> 200 families)

A New Aortic Aneurysm SyndromeLike Marfan syndrome:

Curvature of spine

Chest wall deformity

Long fingers

Aortic root aneurysm

spaced eyes - arterial tortuosity

cleft palate/bifid uvula - diffuse aneurysms

premature skull fusion - rupture w/ small

club foot deformity dimensions

congenital heart disease - death @ 26 y.o.

(PDA, BAV, ASD)

Dietz syndrome (LDS)










MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia





LDSLDSLDSLDS

blue blue blue blue scleraescleraescleraesclerae

vascular tortuosityvascular tortuosityvascular tortuosityvascular tortuosity

hypertelorismhypertelorismhypertelorismhypertelorism

bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactyly






Vascular

Ehlers-

Danlos 4

Arterial

Tortuosity

Tetraology

of Fallot

GLUT10

AR

LOF

CO L3A1

AD

Dom Neg

Aortic

Aneurysm

TGFb

Marfan

with

Aneurysm FLNA

XD

FBN1

Haploinsufficiency

Loeys-

Dietz

Arterial

Tortuosity

TGFBR1/2

Gain of

GLUT10

AR

LOF

Aortic

Aneurysm

TGFb

Recessive

Cuta Laxa

FBLN4

AR,

LOF

Gain of

Function










MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia





LDSLDSLDSLDS



















MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia aortic aortic aortic aortic scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia


MFSMFSMFSMFS



aortic aortic aortic aortic

pectuspectuspectuspectus


LDSLDSLDSLDS










CESCESCESCES

muscle weaknessmuscle weaknessmuscle weaknessmuscle weakness

reduced fatreduced fatreduced fatreduced fat

hearing losshearing losshearing losshearing loss

hyperostosishyperostosishyperostosishyperostosis

Key Observations

in Bea’s Syndrome

• Hypomyoplasia with Weakness

• Bifid Uvula and Craniofacial Changes

• Overlap with Autosomal Dominant Syndromes

• Wild-type: FBN1 & FBN2• Wild-type: FBN1 & FBN2

• Normal Connective Tissue: skin, great vessels

….at risk for vascular disease?

Key Observations

s Syndrome

Hypomyoplasia with Weakness

Bifid Uvula and Craniofacial Changes

Overlap with Autosomal Dominant Syndromes

FBN2 and TGFBRI & IIFBN2 and TGFBRI & II

Normal Connective Tissue: skin, great vessels

at risk for vascular disease?

A Working Hypothesis

• Autosomal Dominant

– New mutation

• Affects regulatory or signaling pathways involving

TGFβ or family member

• Genetic Model?• Genetic Model?

– Haplo-insufficiency Loss of Function

– Dominant Negative

– Gain of New Function

A Working Hypothesis

Affects regulatory or signaling pathways involving

insufficiency Loss of Function

Gain of New Function

Parents: The Filter

for New Variants in the Child

~3M

Variants/g

91-238

New Variations/g/gen

or 0-3/ exome

Genetics 2000:156, 297-304 Curr. Biol. 2009:19, 1

Parents: The Filter

for New Variants in the Child

304 Curr. Biol. 2009:19, 1-5 Nature 2010:


Candidate Genes: Candidate Genes: Candidate Genes: Candidate Genes: Related SyndromesRelated SyndromesRelated SyndromesRelated Syndromes

Candidate Genes: Candidate Genes: Candidate Genes: Candidate Genes: Implicated PathwaysImplicated PathwaysImplicated PathwaysImplicated Pathways

InteractomeInteractomeInteractomeInteractomeInteractomeInteractomeInteractomeInteractome

Site of PathologySite of PathologySite of PathologySite of Pathology

Transcriptome: Transcriptome: Transcriptome: Transcriptome: Expression + SequenceExpression + SequenceExpression + SequenceExpression + Sequence

Exome:Exome:Exome:Exome: SequenceSequenceSequenceSequence


Related SyndromesRelated SyndromesRelated SyndromesRelated Syndromes

Implicated PathwaysImplicated PathwaysImplicated PathwaysImplicated Pathways

InteractomeInteractomeInteractomeInteractomeInteractomeInteractomeInteractomeInteractome

Site of PathologySite of PathologySite of PathologySite of Pathology

Expression + SequenceExpression + SequenceExpression + SequenceExpression + Sequence

SequenceSequenceSequenceSequence

Homozygous Recessives in Child

(Parents are heterozygous)

• 932 dHom932 dHom932 dHom932 dHom----pHetpHetpHetpHet

– 56 novel nucleotide variants

– 876 known variants including rare alleles

• LocationLocationLocationLocation• LocationLocationLocationLocation

– 5’ UTR 101

– Coding

• 184 synonymous

• 81 non-synonymous

– Intronic 66

– 3’ UTR 398

Homozygous Recessives in Child

(Parents are heterozygous)

56 novel nucleotide variants

876 known variants including rare alleles


large joint

contractures

ear deformity

PDA, VSD, ASD




scoliosis

MVPMVPMVPMVP

hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia aortic scoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia

dolichostenomelia


lens dislocation

aortic

pectuspectuspectuspectus

MFSMFSMFSMFS

PDA, VSD, ASD

LDSLDSLDSLDS


vascular tortuosity




aortic dilitation

lens dislocation

aortic dilitation


CESCESCESCES

muscle weaknessmuscle weaknessmuscle weaknessmuscle weakness

reduced fatreduced fatreduced fatreduced fat

hearing loss

hyperostosis

camptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactyly

joint laxityjoint laxityjoint laxityjoint laxityjoint laxityjoint laxityjoint laxityjoint laxityhypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia

BEA’S BEA’S BEA’S BEA’S BEA’S BEA’S BEA’S BEA’S

SYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROME


pespespespespespespespes planusplanusplanusplanusplanusplanusplanusplanus

pectuspectuspectuspectuspectuspectuspectuspectus

blue blue blue blue blue blue blue blue scleraescleraescleraescleraescleraescleraescleraesclerae

hypertelorismhypertelorismhypertelorismhypertelorismhypertelorismhypertelorismhypertelorismhypertelorism

bifid uvula bifid uvula bifid uvula bifid uvula bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactylycamptodactyly

SYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROMESYNDROME

pectuspectuspectuspectuspectuspectuspectuspectus deformitydeformitydeformitydeformitydeformitydeformitydeformitydeformity

muscle weaknessmuscle weaknessmuscle weaknessmuscle weaknessmuscle weaknessmuscle weaknessmuscle weaknessmuscle weakness

reduced fatreduced fatreduced fatreduced fatreduced fatreduced fatreduced fatreduced fat

The Distribution of Nearly NormalThe Distribution of Nearly Normal

Translational Research:

Potential Flaws in the Strategy? • Favor Specialist over Generalists?

• Neglect Basic Science? We need details.

• Corporatize labs even more?

• Drugs as probes not products?• Drugs as probes not products?

• Hand off to who?

Translational Research:

Potential Flaws in the Strategy? Favor Specialist over Generalists?

Neglect Basic Science? We need details.

Corporatize labs even more?

Drugs as probes not products?Drugs as probes not products?

Managing Beatrice

Monitor her vasculature

Continue ARAs (ibersartan)?

Further the investigation

Find other BeatricesFind other Beatrices

Managing Beatrice

Monitor her vasculature

Continue ARAs (ibersartan)?

Further the investigation

Find other BeatricesFind other Beatrices

The Ultimate Charmer The Ultimate Charmer

a patient with arthrogryposis and...

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