a patient with arthrogryposis and...
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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
Working up a Sporadic
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
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactyly arachnodactyly arachnodactyly arachnodactyly
joint laxityjoint laxityjoint laxityjoint laxityaortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocation
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactylyarachnodactylyarachnodactylyarachnodactyly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosisscoliosisscoliosisscoliosis
MVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocation
MFS
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactylyarachnodactylyarachnodactylyarachnodactyly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosisscoliosisscoliosisscoliosisaortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocation
BEALSBEALSBEALSBEALS
large jointlarge jointlarge jointlarge joint
contracturescontracturescontracturescontractures
ear deformityear deformityear deformityear deformity
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactyly arachnodactyly arachnodactyly arachnodactyly
scoliosisscoliosisscoliosisscoliosisMVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocationMFSMFSMFSMFS
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactyly arachnodactyly arachnodactyly arachnodactyly
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
joint laxityjoint laxityjoint laxityjoint laxity
BEALSBEALSBEALSBEALS
large jointlarge jointlarge jointlarge joint
contracturescontracturescontracturescontractures
ear deformityear deformityear deformityear deformity
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
scoliosisscoliosisscoliosisscoliosisMVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocationMFSMFSMFSMFS
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
joint laxityjoint laxityjoint laxityjoint laxity
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)
BEALSBEALSBEALSBEALS
large jointlarge jointlarge jointlarge joint
contracturescontracturescontracturescontractures
ear deformityear deformityear deformityear deformity
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosisscoliosisscoliosisscoliosis
MVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocationMFSMFSMFSMFS
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
LDSLDSLDSLDS
blue blue blue blue scleraescleraescleraesclerae
vascular tortuosityvascular tortuosityvascular tortuosityvascular tortuosity
hypertelorismhypertelorismhypertelorismhypertelorism
bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
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
BEALSBEALSBEALSBEALS
large jointlarge jointlarge jointlarge joint
contracturescontracturescontracturescontractures
ear deformityear deformityear deformityear deformity
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosisscoliosisscoliosisscoliosis
MVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocationMFSMFSMFSMFS
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
LDSLDSLDSLDS
blue blue blue blue scleraescleraescleraesclerae
vascular tortuosityvascular tortuosityvascular tortuosityvascular tortuosity
hypertelorismhypertelorismhypertelorismhypertelorism
bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
BEALSBEALSBEALSBEALS
large jointlarge jointlarge jointlarge joint
contracturescontracturescontracturescontractures
ear deformityear deformityear deformityear deformity
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosisscoliosisscoliosisscoliosis
MVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia aortic aortic aortic aortic scoliosisscoliosisscoliosisscoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomeliadolichostenomeliadolichostenomeliadolichostenomelia
MFSMFSMFSMFS
pespespespes planusplanusplanusplanus
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic
pectuspectuspectuspectus
PDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASDPDA, VSD, ASD
LDSLDSLDSLDS
blue blue blue blue scleraescleraescleraesclerae
vascular tortuosityvascular tortuosityvascular tortuosityvascular tortuosity
hypertelorismhypertelorismhypertelorismhypertelorism
bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
lens dislocationlens dislocationlens dislocationlens dislocation
aortic aortic aortic aortic dilitationdilitationdilitationdilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
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:
Working up a Sporadic
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
Working up a Sporadic
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
BEALSBEALSBEALSBEALS
large joint
contractures
ear deformity
PDA, VSD, ASD
camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
joint laxityjoint laxityjoint laxityjoint laxity
scoliosis
MVPMVPMVPMVP
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia aortic scoliosishypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
dolichostenomelia
pespespespes planusplanusplanusplanus
lens dislocation
aortic
pectuspectuspectuspectus
MFSMFSMFSMFS
PDA, VSD, ASD
LDSLDSLDSLDS
blue blue blue blue scleraescleraescleraesclerae
vascular tortuosity
hypertelorismhypertelorismhypertelorismhypertelorism
bifid uvula bifid uvula bifid uvula bifid uvula camptodactylycamptodactylycamptodactylycamptodactyly
arachnodactlyarachnodactlyarachnodactlyarachnodactly
aortic dilitation
lens dislocation
aortic dilitation
pectuspectuspectuspectus deformitydeformitydeformitydeformity
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
hypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasiahypomyoplasia
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
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