Ehlers-Danlos Syndrome Rare Types - Cloud Object … · Ehlers-Danlos Syndrome Rare Types ......

Ehlers-Danlos Syndrome Rare Types

Clair A. Francomano, MD On behalf of Fransiska Malfait, MD and the

Rare Disease Committee

Defects in collagen primary structure and processing

EDS classical COL5A1/COL5A2 Type V collagen AD

EDS vascular COL3A1 Type III collagen AD

EDS cardiac-valvular COL1A2 Type I collagen (total absence of α2 chain) AR

EDS classical with vascular fragility

COL1A1 Type I collagen (R-to-Cys substitutions)

EDS arthrochalasis COL1A1/COL1A2 Type I collagen (N-propeptide processing) AD

EDS dermatosparaxis ADAMTS2 ADAMTS2 AR

Defects in collagen folding and crosslinking

EDS kyphoscoliosis PLOD1 Lysylhydroxylase 1 AR

EDS FKBP22 FKBP14 FKBP22 AR

Defects in structure and function of the myomatrix, the interface between muscle and ECM

EDS Tenascin-X TNXB Tenascin-X AR

EDS/Myopathy overlap COL12A1 Collagen XII AR/AD

Defects in glycosaminoglycan biosynthesis

Dermatan 4-sulfotransferase 1-deficient EDS

CHST14 Dermatan 4-sulfotransferase 1 AR

Dermatan sulfate epimerase 1-deficient EDS

DSE1 Dermatan sulfate epimerase 1 AR

β4GalT7 –deficient EDS B4GALT7 β4GalT7 (Galactosyltransferase I) AR

β3GalT6 –deficient EDS B3GALT6 β3GalT6 (Galactosyltransferase II) AR

Revised EDS Classification

•

Defects in intracellular processes

EDS spondylocheirodysplastic SLC39A13 ZIP13 AR

Brittle Cornea syndrome ZNF469 PRDM5

ZNF469 PRDM5

AR

Unresolved forms of EDS

Poly-articular EDS ? ? AD

Periodontal EDS ? ? AD

Defeccts in myomatrix, the interface between muscle and extracellular matrix

EDS Tenascin-X TNXB Tenascin-X AR

EDS/Myopathy overlap COL12A1 Collagen XII AR/AD

Conditions not included in EDS spectrum anymore

Occipital horn syndrome (EDS IX) ATP7 ATP7 X-L

Fibronectin-deficient (EDS X) - - AD

Familial articular hypermobility (EDS XI)

- - AD

X-linked EDS with muscle hematoma (EDS V)

- - X-L

Open for discussion

Filamin A related EDS FLNA Filamin A X-L

Revised EDS Classification (cont’d)

EDS Rarer subtypes Chair: Fransiska Malfait

EDS Kyphoscoliosis Angela Brady Neeti Ghali

Cecilia Giunta Marianne Rohrbach Tim Van Damme Anthony Vandersteen

FKBP22-deFicient EDS Mitzi Murray Tim Van Damme Marianne Rohrbach Cecilia Giunta Fransiska Malfait

EDS arthrochalasis Tomoki Kosho Marianne Rohrbach Cecilia Giunta Fransiska Malfait

EDS dermatosparaxis Tim van Damme Fransiska Malfait

SCD-EDS Cecilia Giunta Marianne Rohrbach

BCS Marianne Rohrbach Cecilia Giunta

EDS musculocontractural Tomoki Kosho Fransiska Malfait

B4GALT7/B3GALT6 deficient Fransiska Malfait Sylvie Fournel-Gigleux

Chair: Fransiska Malfait

Tenascin-X deficient EDS Nicol Voermans Eelco Dulfer Serwet Demirdas

EDS/Myopathy overlap Roberto Mendoza-Londono

EDS periodontal Anthony Vandersteen Ines Kapferer-Seebach Johannes Zschocke Cecilia Giunta Marianne Rohrbach Michael Pope,Mitzi Murray

Filamin A -associated Anthony Vandersteen Eyal Reinstein Steven Robertson

Tenascin X DeficiencyTotal absence of tenascin X, due to biallelic TNXB mutations

‣ Skin hyperextensibility ‣ Joint Hyperlaxity ‣ Easy bruising ‣ No atrophic scarring

Glycoprotein with multidomain structure Interacts with multiple other ECM molecules Involved in the regulation of collagen fibrillogenesis and of the elastin network

Burch et al, 1997 Schalkwijk et al, 2001

http://content.nejm.org/content/vol345/issue16/images/large/05f2.jpeg

Lethias et al, 2006

Tenascin-X• The presence of joint hypermobility in heterozygote carriers of

TNXB null mutations suggested Tenascin X as a candidate for EDS hypermobility type

• 65% of female carriers presented joint hypermobility (Zweers et al, 2003) • However, wider screening identified mutations in TNXB in only

2.5% of persons with hypermobility (EDS) ! The role of TNXB in EDS hypermobility type remains currently unclear

Malfait et al, Hum Mut 2010

2 consanguineous families

Positional candidate gene sequencing

Homozygous mutations in CHST14

Musculocontractural EDS

Homozygosity Mapping

Malfait et al, Hum Mut, 2010

Adducted Thumb Clubfoot Syndrome (Dundar et al, 2009)

EDS Musculocontractural type (Malfait et al, 2010)

EDS, Kosho type (Kosho et al, 2010; Miyake et al, 2010)

CHST14

Mitzi Murray, Tim Van Damme, Fransiska Malfait

FKBP22-deficient Ehlers-Danlos Syndrome

Organ System Involvement

9 patients from 7 independent families reported to date

7 children and 2 adults

Musculoskeletal

Number of patients 9

Joint hypermobility 9

Dislocations 1

Muscle hypotonia/decreased muscle bulk 9

Kyphoscolisosis 8

Club feet 3

Pectus deformity (carinatum) 1

Coxa valga 1

Ocular involvementNumber of patients 9

Myopia 5

Retinal detachment 1

Dental/orofacial


Cleft palate 2

retrognathia 2

Cardiac involvementNumber of patients 9

Mitral valve prolapse 2

Tricuspid insufficiency 1

PDA 1

Vascular and visceral involvement


Aortic rupture 0

Multiple visceral arterial aneurysm/dissections 1

Arterial tortuosity 1

Bladder diverticulae 2

Skin and integumentNumber of patients 9

Hyperextensible 6

Soft, doughy 7

Hyperkeratosis follicularis 5

Easy bruising 3

Hernia (Inguinal/umbilical) 4

Excessive periumbilical skin 1

Number of patients

Sensorineural and conductive hearing loss 6

Hypotonia 9

Decreased endurance 9

Intellectual disability with white matter atrophy 1

Subdural hygroma 1

Nervous system

Clinical phenotype

Baumann et al, AJHG, 2012

Murray et al, AJMG, 2014

Allelic heterogeneity

Mutations

p.(Glu122Argfs*7) p.(Thr15*)c.197+5_197+8delGTAA

Gene: FKBP14 Gene locus: 7p14.3; 6 exons

Protein: FKBP22 Function: - ER-resident peptidyl-prolyl cis-trans isomerase (Prolyl isomerisation is rate-limiting step during triple helix formation of collagen) - Catalyzes folding of type III collagen - interacts with collagen III, VI and X, but not with collagen I and V (Ishikawa et al, 2014)

Inheritance pattern: Autosomal recessive

Diagnostic criteriaClinical criteria

Kyphoscoliosis

Joint hypermobility (large and small joints)

Muscle atrophy, hypotonia

Club feet

Osteopenia

Hearing loss

Myopia

Soft, hyperextensible skin

Bladder diverticulae

Differential Diagnosis

▪ Kyphoscoliotic Ehlers-Danlos syndrome ▪ D4ST1-deficient Ehlers-Danlos syndrome ▪ Ullrich congenital muscular dystrophy ▪ Bethlem myopathy ▪ Other neuromuscular disorders ▪ Arterial tortuosity syndrome, other arterial fragility syndromes

Confirmation of diagnosisMolecular diagnosis: sequencing of FKBP14 Methods:

• Sanger or NGS • Deletion/duplication analysis

No biochemical test; normal urinary pyridinolines

ManagementEvaluations following initial diagnosis

▪ Clinical evaluation for kyphoscoliosis ▪ Hearing evaluation ▪ Pulmonary function tests ▪ Developmental evaluation in children ▪ Functional assessment in adults ▪ Consider ophthalmologic exam ▪ Consider sleep study to assess for

nocturnal hypoxemia ▪ Consider bone mineral density

Treatment of Manifestations ▪ Management of kyphoscoliosis as indicated ▪ Therapy for motor development and functionality

as indicated ▪ Surgical management of hernias, bladder

diverticuli, kyphoscolisois etc, as indicated

Surveillance ▪ Hearing surveillance (annual?) ▪ Pulmonary function tests (optimal schedule

unknown) ▪ Sleep study (optimal schedule unknown) ▪ Consider vascular surveillance (optimal mode or

schedule unknown) ▪ Consider ophthalmologic surveillance

Tim Van Damme, MD PhD candidate Fransiska Malfait, MD PhD

Center for Medical Genetics Ghent University & Ghent University Hospital

Belgium

www.cmgg.be

Ehlers-Danlos Syndrome Dermatosparaxis type

History of dermatosparaxis

http://www3.unileon.es/personal/wwdmvjrl/dermatopatias/astenia_1.jpg

History of dermatosparaxis

Nusgens et al, Nat Gen. 1992 Malfait et al, AJMG. 2004

Cleavage by N-proteinase Cleavage by C-proteinase

pN-collagen

x

HIEROGLYPHS

pNα2(I)

pNα1(I)

α1(I)

α2(I)

C PT C

PROCOLLAGENS

Type I procollagen

ADAMTS2

Literature Review


Male 11

Female 4

Parental Consanguinity 3

Age at diagnosis Mean 62 months (range birth- 13 yrs)

Oldest patient 21 yrs

15 patients from 14 independent families reported to date

Craniofacial involvementNumber of patients 15

Blue sclerae 13

Epicanthic folds 12

Large fontanel 11

Edema eyelids/blepharochalasis 9

Downslanting palpebral fissuers 9

Excessive periorbital skin 8

Low-set ears 8

Telecanthus 7

Saggy cheeks 7

Large protruding eyes 3

Craniofacial involvement

Malfait et al, AJMG. 2004

Dental


Gingival Hyperplasia/hyperkeratosis 6

Tooth dysplasia 6

Gingival bleeding 4

Hypodontia/oligodontia 3

Tooth discoloration 3

Frontal open bite 3

Dental/orofacial

Malfait et al, AJMG. 2004


Severe skin fragility 14

Umbilical hernia 14

Skin tears 14

Soft, doughy 12

Excessive bruising 11

Sagging, redundant skin 11

Thin, translucent 6

Increased palmar wrinkling 6

Hypertrichosis 6

Hyperextensible skin 5

Atrophic scarring 5

C

D E

CA

B

Skin

MusculoskeletalNumber of patients 15

Postnatal growth retardation 13


Short limbs, hands and feet 11

Motor delay 8

Fractures 4

Congenital skull fractures 2

OtherNumber of patients 15

Bleeding complications (epistaxis, gum bleeding, (congenital) cerebral hemorrhage

7

Complications of visceral Fragility 5

Strabismus 5

Myopia 5

Astigmatism 3

Severe glaucoma at young age 1

Poor breast development 1

Visceral complications include: - Rupture of diaphragm (1) - Bladder diverticulae (2) with bladder rupture (1) - Rectal prolapse with profuse bleeding (2) - No vascular problems reported

Perinatal complicationsNumber of patients 15

PPROM 6

Gestational age 28-41 weeks Mean: 34 w 4 d

Friable umbilical cord 2

Multiple skull fractures and subgaleal hemorrhage (died) 1

Cerebral hemorrhage 2

Pneumothorax 1

Hydronephrosis 1

Hypoglycemia, hypocalcemia and hypothyroidism 1

Diagnostic criteriaMajor Diagnostic criteria

Characteristic craniofacial features

Extreme skin fragility

Soft and doughy skin

Redundant, almost lax skin with excessive skin folds around wrist, ankles

Increased palmar creases

Excessive bruising

Umbilical hernia

Postnatal growth retardation

Short limbs, hands and feet

Perinatal complications due to connective tissue fragility

Complications of visceral fragility (bladder diverticulae, rectal prolapse, …)

Diagnostic criteria

Minor Diagnostic criteria

skin hyperextensibility, atrophic scars

hypertrichosis

dental abnormalities

Joint hypermobility

delayed motor development

osteopenia

refractive errors (myopia, astigmatism)

strabismus


▪ Classical EDS ▪ Cutis laxa syndromes ▪ Achondroplasia ▪ Osteogenesis imperfecta

Inheritance PatternAutosomal recessive

Confirmation of diagnosisMolecular diagnosis: sequencing of ADAMTS2 gene Methods:


Confirmation of diagnosis• SDS-PAGE

abnormal processing of the N-propeptide of type I procollagen

pNα2(I)

pNα1(I)

α1(I)

α2(I)

C PT C

PROCOLLAGENS

• Transmission electron microscopy Hieroglyphic pattern of collagen fibrils

HIEROGLYPHS

Management• Skin

– Follow advice for classical EDS – Routine examination for umbilical/inguinal hernia

• Musculoskeletal – At diagnosis: whole body skeletal survey – Physical and occupational therapy, orthotic management – Avoid contact sports

• Cardiovascular screening • Ophthalmological screening • Pregnancy management: consider pregnancy as high risk

Research needed• Studies to determine the prevalence of EDS dermatosparaxis type

• Create a register of patients with prospective collection of detailed information regarding phenotype. This information should help address:

• genotype-phenotype correlations • clinical variability (inter- and intrafamilial) • age-dependent organ-system involvement • pregnancy outcome • The association of other signs and symptoms, eg pain, autonomic

dysfunction, fatigue, mast cell activation syndrome, psychological problems, neurological involvement etc

• Collection of tissue samples (Biobank) for future pathogenic and electron-microscopic studies

• Quality of Life studies

Research needed• In view of the role of ADAMTS in cancer: increased risk for cancer?

• Male ADAMTS2 knock-out mice show reduced spermatogenesis and sterility. Other animals with dermatosparaxis (cattle, dogs, cats, sheep), usually do not survive until the reproductive age, and so far human males with EDS dermatosparaxis type have not reached the reproductive age, so follow-up of these patients is needed to evaluate whether the sterility is also seen in human males.

• What is contribution of deficient processing of other ADAMTS2 substrates to pathogenesis the severity of the disorder, such as the extreme skin fragility and laxity (type V collagen) and the propensity for bruising and bleeding (type III collagen).

Li et al, 2001

http://www.biochemj.org/bj/355/0271/bj3550271f04.htm?resolution=HIGH

Tim Van Damme, MD PhD candidate Fransiska Malfait, MD PhD

Center for Medical Genetics Ghent University & Ghent University Hospital, Belgium

B4GALT7- and B3GALT6-associated Ehlers-Danlos Syndrome

Sylvie Fournel-Gigleux Research Director INSERM

UMR 7365 CNRS-Université de Lorraine, MolCelTEG Team

Vandœuvre-les-Nancy, France

History of Progeroid EDS• Hernandez et al (1979, 1981, 1986) reported 5 patients with EDS-features and

features of early aging • Wrinkled facies • Significant growth failure • Fine/curly hair • Peridontitis • Bilateral cryptorchidism • Apparent intellectual deficit • Classical features of EDS

No molecular diagnosis! • 4 additional patients showing resemblance to these 5 patients were further

identified (Kresse et al, 1987, Faiyaz-Ul-Haque et al, 2004, Guo et al, 2103)

• Defective glycosaminoglycan addition to several proteoglycan core proteins (Kresse et al, 1987)

• Shown to result from bi-allelic mutations in B4GALT7, encoding galactosyltransferase I (Quentin et al, 1990)

GAG synthesis

β4GALT7-deficient EDS

Organ System Involvement


Age at diagnosis 2 yrs-33 yrs

Oldest reported patient 33 yrs

6 independent EDS patients with bi-allelic B4GALT7 mutations reported to date

In addition: 22 patients reported with Larsen of Reunion Island Syndrome with bi-allelic B4GALT7 mutations

Craniofacial involvementNumber of patients 6

Triangular face 6

Wide forehead 3

Widely spaced eyes 5

Proptosis 5

Narrow mouth 4

Low-set ears 4

Sparse scalp hair 4

Abnormal dentition 4

Flat face 3

Blue sclerae 3

Cleft palate/Bifid uvula 2


Short stature (severe) 6

Muscle Hypotonia 6


Radio-Ulnar synostosis 6

Bowing of limbs 5

Osteopenia 4

Fractures (vertebral fractures) 1

Swedish key features of femur 1


Cognitive delay 5

Motor delay 5

Development


Hyperextensible skin 6

Delayed wound healing 3

Atrophic scarring 3

Hands and Feet


Syndactyly 2

Long fingers 4

Single Transverse Palmar crease 4

Pes planus 5

Salter et al, AJMG 2015

Clinical features

Flat face Blue sclerae Proptosis Smooth philtrum Scoliosis Joint hypermobility


Osteopenia with vertebral collapse Wrenched monkey prox femur Radio-ulnar synostosis


Clinical features

Skeletal abnormalities


Squaring of vertebral bodies Proximal radio-ulnar synostosis Dislocation of right radial head

Guo et al, AJMG 2013


Gene: B4GALT7 Gene locus: 5q35.3; 6 exons

Protein: Galactosyltransferase I

Allelic condition: Larsen of Reunion Island syndrome

Large Joint Dislocation Ligamentous laxity/ Joint hypermobility Significant short stature (-6 SD) Radio-ulnar synostosis Swedish key appearance proximal femur Patella dislocation Characteristic facial appearance flat face wide forehead proptosis narrow mouth under-eye shadows Mutation: homozygous p.Arg270Cys

Cartault et al, EJHG, 2015

Approach to DiagnosisClinical Criteria

Radio-ulnar synostosis

Short Stature

Joint Hypermobility

Muscle Hypotonia

Hyperelastic Skin

Bowing of Limbs

Osteopenia

Hypermetropia

Craniofacial: Triangular face, proptosis, widely spaced eyes

Of note: No progressive premature aging features observed in molecularly confirmed patients!


▪ β3GALT6-deficient EDS ▪ Ehlers-Danlos syndrome kyphoscoliotic type ▪ Musculo-contractural EDS ▪ (FKBP22-deficient EDS) ▪ Skeletal dysplasias

Inheritance patternAutosomal recessive

Confirmation of diagnosisMolecular diagnosis: sequencing of B4GALT7 Methods:


β3GalT6-deficient EDS

β3GALT6-deficient EDS

Organ system involvement14 EDS patients from 11 families have been reported with bi-allelic B3GALT6 mutations Clinical data available from 10 patients from 8 families


Age at assessment 1 month-26 yrs

adults 3

Children 7

Oldest reported patient 26 yrs

In addition: patients with Spondyloepimethaphyseal Dysplasia with Joint Hyperlaxity type 1 (SEMD-JL) reported with bi-allelic B3GALT6 mutations (Nakajima et al, 2013, Vorster et al, 2015)

Craniofacial involvement14 EDS patients from 11 families have been reported with bi-allelic B3GALT6 mutations Clinical data available from 10 patients from 8 families


Flat face with wide forehead 11

Blue Sclerae 10

Sparse scalp hair 8

Abnormal dentition 6

Prognathism 2

Micrognathia 1

Cleft palate/Bifid uvula 1


Short stature 11

Muscle Hypotonia 11

Joint Hypermobility 11

Dislocations 4

Club feet/severe foot deformities 9

Kyphoscoliosis 8

Congenital bilateral hip dislocation 7

Pectus deformity 6

Osteopenia 6

Multiple low-impact fractures 5

Radio-ulnar synostosis 0

SkinNumber of patients 11

Hyperextensibility 10

Doughy skin 10

Thin, translucent skin 6

Atrophic scarring 2


Broad spatulate fingers 11

Increased palmar wrinkling 6

Finger contractures 7

Hands

Development


Cognitive delay 3

Motor Delay 7


Mitral valve Prolapse 2

Cerebral haemorhage 1

Retinal detachment 1

Myopia 2

Corneal clouding/sclerocornea 1

Clinical presentation• congenital muscle hypotonia

• mild delay in motor and cognitive development

• thin, hyperextensible and transparent skin

• generalized joint hypermobility

• repetitive shoulder dislocations

• broad, flat feet

• low bone mineral density (DEXA Z score -2.5)

Patient 2• 26-year old man

• congenital muscle hypotonia

• delayed motor development

• >15 atraumatic fractures

• generalized joint hyperlaxity

• progressive joint contractures

• kyphoscoliosis

• loose, thin and hyperextensible skin

• slow wound healing, atrophic scarring• easy bruising

• severe foot deformities

• mild intellectual disability

Clinical presentation

Patient 3, 9 yrs old• clubfeet,congenital bilateral hip dislocation

• congenital muscle hypotonia • progressive kyphoscoliosis, pectus excavatum

• multiple fractures after minor trauma

• mild dysmorphic features (prognathism, progeria)

• severe generalized joint hyperlaxity

• loose, hyperextensible and thin skin

• spatular fingers with broad distal phalanges, palmar wrinkling

• retinal detachment

• traumatic cerebral hemorrhage

• intellectual disability


• congenital bilateral hip dislocation

• clubfeet

• spontaneous bilateral fractures

• low muscle mass and hypotonia

• mild dysmorphic and progeric features

• joint hyperlaxity

• severe pectus excavatum

• soft and doughy skin

• spatular fingers, broad distal phalanges, increased palmar wrinkling


• hypoplastic iliac bodies, poorly formed acetabulae

• osteoporotic aspect of femur and tibia

• broad metaphyses with abnormal trabecular patterning, diaphyseal narrowing, epiphyseal changes

• ovoid vertebrae, severe kyphocoliosis

• mild bowing of long bones

Patient 5, X-rays at 24 months


Congenital contractures Club feet Congenital scoliosios Cervical kyphosis with basilar invagination and stenosis of foramen magnum Radio-ulnar synostosis Hip dislocation Multiple low-impact fractures Hypermobilty + contractures

Mild ascending aortic aneurysm Mitral valve prolapse Dextrocardia Tracheomalacia and pulmonar hypoplasia with diaphragmatic hernia Marked hypotonia Motor delay

Hydrocephalus Plagocephaly

Hyperextensible, fragile skin Spontaneous hemorrhages


Van Damme et al, in prep


Gene: B3GALT6 Gene locus: 1p36.33; single-exon Protein: Galactosyltransferase II

p.(Arg6Trp)

p.(Ser65Gly)

p.(Pro67Leu)

p.(Ile76Thrfs*202)

p.(Ala108Glyfs*163)

p.(Asp118Alafs*160)

p.(Met139Ala141del)

p.(Asp156Asn)

p.(Ser159Tyr)

p.(Arg197Alafs*81)

p.(Asp207His)

p.(Gly217Ser)

p.(Arg232Cys)

p.(Arg256Trp)

p.(Glu265Asp)

p.(Cys300Ser)

p.(Ser309Thr)

Approach to DiagnosisClinical Criteria

Short Stature

Joint Hypermobility with joint contractures

Muscle Hypotonia

Congenital hip dislocation

Club feet

Kyphoscoliosis

Hyperelastic Skin

Doughy skin

Osteopenia

Multiple low-impact fractures

Broad spatulate fingers

Increased palmar wrinkling

Craniofacial: Flat face with prominent forehead, blue sclerae

Spondylo-epimetaphyseal dysplasia

Spondylo-epimetaphyseal dysplasia with joint laxity due to B3GALT6 mutations

Nakajima et al, AJHG, 2013

GAG linkeropathies

Larsen-like syndrome with congenital heart defects

SEMD-JL1 β3GalT6 deficient EDS

EDS progeroid subtype

LRS

Spondylo-ocular syndrome


▪ Other “Linkeropathies” ▪ Osteogenesis imperfecta ▪ Larsen syndrome ▪ Ehlers-Danlos syndrome kyphoscoliotic type ▪ Musculo-contractural EDS ▪ (FKBP22-deficient EDS) ▪ Skeletal dysplasias

Inheritance patternAutosomal recessive

Confirmation of diagnosisMolecular diagnosis: sequencing of B3GALT6 Methods:


Management• Musculoskeletal

– At diagnosis: • Whole body skeletal survey • Bone densitometry

– Physical and occupational therapy, orthotic management – Avoid contact sports – Consider bisphosphonate therapy

• Cardiovascular work-up • Neurological work up • Dental examination • Ophtalmological work-up • Skin

– Cfr advice for classical EDS – Routine examination for umbilical/inguinal hernia

Research needed• Studies to determine the prevalence of these EDS types • Create a register of patients with prospective collection of detailed

information regarding phenotype. This information should help address: • genotype-phenotype correlations • clinical variability (inter- and intrafamilial) • age-dependent organ-system involvement • pregnancy outcome • The association of other signs and symptoms, eg pain, autonomic

dysfunction, fatigue, mast cell activation syndrome, psychological problems, neurological involvement etc

• Quality of Life studies • Collection of tissue samples (Biobank) for future pathogenic and electron-

microscopic studies • Development of animal models for study of pathogenetic basis and

preclinical studies

Thanks

• Fransiska Malfait and the Entire Rare Disorders Committee

• EDS and EDS-UK • Lara Bloom and Shane Robinson

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