Ehlers-Danlos Syndrome Rare Types. Clair A. Francomano, MD On behalf of Fransiska Malfait, MD and the Rare Disease Committee

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2 Ehlers-Danlos Syndrome Rare Types Clair A. Francomano, MD On behalf of Fransiska Malfait, MD and the Rare Disease Committee

3 Revised EDS Classification 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 Dermatan sulfate epimerase 1- deficient EDS CHST14 Dermatan 4-sulfotransferase 1 AR DSE1 Dermatan sulfate epimerase 1 AR β4galt7 deficient EDS B4GALT7 β4galt7 (Galactosyltransferase I) AR β3galt6 deficient EDS B3GALT6 β3galt6 (Galactosyltransferase II) AR

4 Defects in intracellular processes EDS spondylocheirodysplastic SLC39A13 ZIP13 AR Brittle Cornea syndrome Unresolved forms of EDS Revised EDS Classification (cont d) ZNF469 PRDM5 ZNF469 PRDM5 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 AR Familial articular hypermobility (EDS XI) X-linked EDS with muscle hematoma (EDS V) - - AD - - X-L Open for discussion Filamin A related EDS FLNA Filamin A X-L

5 EDS Rarer subtypes EDS Kyphoscoliosis Chair: Fransiska Malfait 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

6 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 Deficiency Total absence of tenascin X, due to

Hyperlaxity Easy bruising No atrophic scarring Glycoprotein

molecules Involved in the regulation of collagen

7 Tenascin X Deficiency Total 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

8 Lethias et al, 2006

9 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

10 2 consanguineous families Homozygosity Mapping Positional candidate gene sequencing Homozygous mutations in CHST14 Musculocontractural EDS Malfait et al, Hum Mut 2010

11 Malfait et al, Hum Mut, 2010

12 EDS, Kosho type (Kosho et al, 2010; Miyake et al, 2010) EDS Musculocontractural type (Malfait et al, 2010) CHST14 Adducted Thumb Clubfoot Syndrome (Dundar et al, 2009)

13 FKBP22-deficient Ehlers-Danlos Syndrome Mitzi Murray, Tim Van Damme, Fransiska Malfait

14 Organ System Involvement 9 patients from 7 independent families reported to date 7 children and 2 adults

15 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

16 Number of patients Ocular involvement 9 Myopia 5 Retinal detachment 1 Dental/orofacial Number of patients 9 Cleft palate 2 retrognathia 2

17 Cardiac involvement Number of patients 9 Mitral valve prolapse 2 Tricuspid insufficiency 1 PDA 1 Vascular and visceral involvement Number of patients 9 Aortic rupture 0 Multiple visceral arterial aneurysm/dissections 1 Arterial tortuosity 1 Bladder diverticulae 2

18 Number of patients 9 Skin and integument Hyperextensible 6 Soft, doughy 7 Hyperkeratosis follicularis 5 Easy bruising 3 Hernia (Inguinal/umbilical) 4 Excessive periumbilical skin 1 Nervous system Number of patients Sensorineural and conductive hearing loss 6 Hypotonia 9 Decreased endurance 9 Intellectual disability with white matter atrophy 1 Subdural hygroma 1

19 Clinical phenotype Baumann et al, AJHG, 2012

20 Murray et al, AJMG, 2014

21 Murray et al, AJMG, 2014

22 Allelic heterogeneity 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 with collagen I and V - interacts with collagen III, VI and X, but not (Ishikawa et al, 2014) Mutations p.(glu122argfs*7) p.(thr15*) c.197+5_197+8delgtaa Inheritance pattern: Autosomal recessive

23 Diagnostic criteria Clinical criteria Kyphoscoliosis Joint hypermobility (large and small joints) Muscle atrophy, hypotonia Club feet Osteopenia Hearing loss Myopia Soft, hyperextensible skin Bladder diverticulae

24 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

25 Confirmation of diagnosis Molecular diagnosis: sequencing of FKBP14 Methods: Sanger or NGS Deletion/duplication analysis No biochemical test; normal urinary pyridinolines

26 Management Evaluations 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

27 Ehlers-Danlos Syndrome Dermatosparaxis type Tim Van Damme, MD PhD candidate Fransiska Malfait, MD PhD Center for Medical Genetics Ghent University & Ghent University Hospital Belgium

28 History of dermatosparaxis

29 History of dermatosparaxis Nusgens et al, Nat Gen Malfait et al, AJMG. 2004

30 C PT C HIEROGLYPHS Type I procollagen pnα1(i) α1(i) pnα2(i) x ADAMTS2 Cleavage by N-proteinase Cleavage by C-proteinase α2(i) PROCOLLAGENS pn-collagen

31 Literature Review 15 patients from 14 independent families reported to date Number of patients 15 Male 11 Female 4 Parental Consanguinity 3 Age at diagnosis Mean 62 months (range birth- 13 yrs) Oldest patient 21 yrs

32 Number Craniofacial patients involvement 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

33 Craniofacial involvement Malfait et al, AJMG. 2004

35 Dental Number of patients 15 Gingival Hyperplasia/hyperkeratosis 6 Tooth dysplasia 6 Gingival bleeding 4 Hypodontia/oligodontia 3 Tooth discoloration 3 Frontal open bite 3

36 Dental/orofacial Malfait et al, AJMG. 2004

37 Skin and integument Number of patients 15 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

38 Skin

39 Skin

40 Skin A C C B D E

41 Skin

42 Musculoskeletal Number of patients 15 Postnatal growth retardation 13 Joint hypermobility 11 Short limbs, hands and feet 11 Motor delay 8 Fractures 4 Congenital skull fractures 2

43 Other Number of patients 15 Bleeding complications (epistaxis, gum bleeding, (congenital) cerebral hemorrhage 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 7

44 Perinatal complications Number of patients 15 PPROM 6 Gestational age Friable umbilical cord 2 Multiple skull fractures and subgaleal hemorrhage (died) 1 Cerebral hemorrhage 2 Pneumothorax 1 Hydronephrosis 1 Hypoglycemia, hypocalcemia and hypothyroidism weeks Mean: 34 w 4 d

45 Diagnostic criteria Major 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, )

46 Diagnostic criteria Minor Diagnostic criteria skin hyperextensibility, atrophic scars hypertrichosis dental abnormalities Joint hypermobility delayed motor development osteopenia refractive errors (myopia, astigmatism) strabismus

47 Differential Diagnosis Classical EDS Cutis laxa syndromes Achondroplasia Osteogenesis imperfecta Inheritance Pattern Autosomal recessive

48 Confirmation of diagnosis Molecular diagnosis: sequencing of ADAMTS2 gene Methods: Sanger or NGS Deletion/duplication analysis

49 Confirmation of diagnosis SDS-PAGE abnormal processing of the N-propeptide of type I procollagen C PT C Transmission electron microscopy Hieroglyphic pattern of collagen fibrils pnα1(i) α1(i) pnα2(i) α2(i) HIEROGLYPHS PROCOLLAGENS

50 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

51 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 electronmicroscopic studies Quality of Life studies

52 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. Li et al, 2001 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).

53 B4GALT7- and B3GALT6-associated Ehlers-Danlos Syndrome Tim Van Damme, MD PhD candidate Fransiska Malfait, MD PhD Center for Medical Genetics Ghent University & Ghent University Hospital, Belgium Sylvie Fournel-Gigleux Research Director INSERM UMR 7365 CNRS-Université de Lorraine, MolCelTEG Team Vandœuvre-les-Nancy, France

54 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)

55 GAG synthesis β4galt7-deficient EDS

56 Organ System Involvement 6 independent EDS patients with bi-allelic B4GALT7 mutations reported to date Number of patients 6 Age at diagnosis Oldest reported patient 2 yrs-33 yrs 33 yrs In addition: 22 patients reported with Larsen of Reunion Island Syndrome with bi-allelic B4GALT7 mutations

57 Craniofacial involvement Number 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

58 Musculoskeletal Number of patients 6 Short stature (severe) 6 Muscle Hypotonia 6 Joint hypermobility 6 Radio-Ulnar synostosis 6 Bowing of limbs 5 Osteopenia 4 Fractures (vertebral fractures) 1 Swedish key features of femur 1 Development Number of patients 6 Cognitive delay 5 Motor delay 5

59 Skin and integument Number of patients 6 Hyperextensible skin 6 Delayed wound healing 3 Atrophic scarring 3 Hands and Feet Number of patients 6 Syndactyly 2 Long fingers 4 Single Transverse Palmar crease 4 Pes planus 5

60 Clinical features Flat face Blue sclerae Proptosis Smooth philtrum Scoliosis Joint hypermobility Salter et al, AJMG 2015

61 Osteopenia with vertebral collapse Wrenched monkey prox femur Radio-ulnar synostosis Salter et al, AJMG 2015

62 Clinical features Salter et al, AJMG 2015

63 Skeletal abnormalities Squaring of vertebral bodies Proximal radio-ulnar synostosis Dislocation of right radial head Salter et al, AJMG 2015

64 Guo et al, AJMG 2013

65 Allelic heterogeneity Gene: B4GALT7 Gene locus: 5q35.3; 6 exons Protein: Galactosyltransferase I

66 Allelic condition: Larsen of Reunion Island syndrome Mutation: homozygous p.arg270cys 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 Cartault et al, EJHG, 2015

67 Approach to Diagnosis Clinical 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!

68 Differential Diagnosis β3galt6-deficient EDS Ehlers-Danlos syndrome kyphoscoliotic type Musculo-contractural EDS (FKBP22-deficient EDS) Skeletal dysplasias Inheritance pattern Autosomal recessive

69 Confirmation of diagnosis Molecular diagnosis: sequencing of B4GALT7 Methods: Sanger or NGS Deletion/duplication analysis

70 β3galt6-deficient EDS β3galt6-deficient EDS

71 Organ system involvement 14 EDS patients from 11 families have been reported with bi-allelic B3GALT6 mutations Clinical data available from 10 patients from 8 families Number of patients 10 Age at assessment adults 3 Children 7 Oldest reported patient 1 month-26 yrs 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)

72 Craniofacial involvement 14 EDS patients from 11 families have been reported with bi-allelic B3GALT6 mutations Clinical data available from 10 patients from 8 families Number of patients 11 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

73 Musculoskeletal Number of patients 11 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

74 Skin Number of patients 11 Hyperextensibility 10 Doughy skin 10 Thin, translucent skin 6 Atrophic scarring 2 Hands Number of patients 11 Broad spatulate fingers 11 Increased palmar wrinkling 6 Finger contractures 7

75 Development Number of patients 11 Cognitive delay 3 Motor Delay 7 Number of patients 10 Mitral valve Prolapse 2 Cerebral haemorhage 1 Retinal detachment 1 Myopia 2 Corneal clouding/sclerocornea 1

76 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)

$Clinical presentation Patient 2 26-year old man congenital muscle hypotonia delayed motor development >15 atraumatic fractures generalized joint hyperlaxity progressive$

77 Clinical presentation 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

$Clinical presentation Patient 3, 9 yrs old clubfeet,congenital bilateral hip dislocation congenital muscle hypotonia progressive kyphoscoliosis, pectus excavatum multiple fractures after minor trauma$

79 Clinical presentation Patient 3, 9 yrs old clubfeet,congenital bilateral hip dislocation congenital muscle hypotonia progressive kyphoscoliosis, pectus excavatum multiple fractures after minor trauma severe generalized joint hyperlaxity spatular fingers with broad distal phalanges, palmar wrinkling loose, hyperextensible and thin skin mild dysmorphic features (prognathism, progeria) retinal detachment traumatic cerebral hemorrhage intellectual disability

$Clinical presentation congenital bilateral hip dislocation clubfeet spontaneous bilateral fractures low muscle mass and hypotonia mild dysmorphic and$

80 Clinical presentation 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

Clinical presentation Patient 5, X-rays at 24 months hypoplastic iliac bodies, poorly formed acetabulae osteoporotic aspect of femur and tibia broad

81 Clinical presentation Patient 5, X-rays at 24 months 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

$Multiple low-impact fractures Hypermobilty + contractures Mild ascending aortic aneurysm Mitral valve prolapse Dextrocardia Tracheomalacia and pulmonar hypoplasia with diaphragmatic hernia Marked$

82 Clinical presentation 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 Van Damme et al, in prep Hyperextensible, fragile skin Spontaneous hemorrhages

83 Allelic heterogeneity 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)

84 Approach to Diagnosis Clinical 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

85 Spondylo-epimetaphyseal dysplasia with joint laxity due to B3GALT6 mutations Nakajima et al, AJHG, 2013

86 GAG linkeropathies Spondylo-ocular syndrome EDS progeroid subtype Larsen-like syndrome with congenital heart defects SEMD-JL1 β3galt6 deficient EDS LRS

87 Differential Diagnosis Other Linkeropathies Osteogenesis imperfecta Larsen syndrome Ehlers-Danlos syndrome kyphoscoliotic type Musculo-contractural EDS (FKBP22-deficient EDS) Skeletal dysplasias Inheritance pattern Autosomal recessive

88 Confirmation of diagnosis Molecular diagnosis: sequencing of B3GALT6 Methods: Sanger or NGS Deletion/duplication analysis

89 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

90 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 electronmicroscopic studies Development of animal models for study of pathogenetic basis and preclinical studies

91 Thanks Fransiska Malfait and the Entire Rare Disorders Committee EDS and EDS-UK Lara Bloom and Shane Robinson

EHLERS DANLOS SYNDROME. Fransiska Malfait, MD PhD Centre for Medical Genetics Ghent University Hospital Ghent, Belgium

EHLERS DANLOS SYNDROME. Fransiska Malfait, MD PhD Centre for Medical Genetics Ghent University Hospital Ghent, Belgium EHLERS DANLOS SYNDROME Fransiska Malfait, MD PhD Centre for Medical Genetics Ghent University Hospital Ghent, Belgium EDS is a heritable collagen disorder Heterogeneous group of diseases with: - Multi-systemic