Table 1 Clinical phenotype and investigation results of 18 individuals with glutamic acid to lysine substitutions in COL3A1

Proband V.3

F1

Age 44; vascular and classical EDS—Villefranche classification

c.2044G>A

p.Glu682Lys

Exon 31

Irregularity of collagen diameter; collagen fibers with irregular outline

Normal

M

50

Y

Easy bruising,

smooth, doughy skin,

hyperextensible skin,

atrophic scarring from surgery,

mild thin skin with visible veins,

subcutaneous hematomas

Shoulder subluxations

Pectus excavatum

Hypermobility

Hiatus hernia

Varicose veins

Focal aneurysm of celiac artery Mildly dilated aortic root

and mildly dilated left ventricle

43 years—esophageal rupture secondary to vomiting

43 years—L pneumothorax

50 years—rectal sheath hematoma secondary to cough

IV.1

F1

Age 8 (1952)

EDS—not specified

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

M

73

Y

Easy bruising,

hyperextensible skin,

skin fragility,

delayed wound healing,

one scar on knee from major injury (slightly widened, not atrophic)

Hypermobility

Mild varicose veins in later life

17 years—large muscular hematoma in leg from injury whilst in army

22 years—abdominal hematoma from minor insult

IV.4

F1

n/a (familial variant known at assessment)

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

65

Y

Easy bruising,

hematomas,

hyperextensible skin,

no significant scarring

Hypermobility

Pes planus

Nil

Severe hematoma as child (fell off bike and required hospitalization)

III.1

F1

Unknown age

EDS—not specified

n/c but obligate carrier

n/p

n/p

M

Deceased age 74

Y

Easy bruising, hyperextensible skin,

hematoma,

atrophic scarring

Acrogeria of feet

None known

Died from sigmoid colon perforation age 74

VI.1

F1

n/a (familial variant known at assessment)

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

M

3

Y

Easy bruising,

soft doughy skin,

hyperextensible skin,

multiple subcutaneous hematomas

Minor pectus excavatum

 Nil

Nil

V.6

F1

Age 29; classical EDS—Villefranche classification

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

35

Y

Hyperextensible skin,

aged appearance to hands,

no scarring

No hypermobility

 Nil

Two intramuscular hematomas secondary to RTA and leg injury (resolved spontaneously)

Grade 2 perineal tear with childbirth

V.8

F1

Age 36; classical EDS—Villefranche classification

c.2044G>A

p.Glu682Lys

Exon 31

n/p

Normal

M

44

Y

Easy bruising, hyperextensible skin,

soft doughy skin,

multiple subcutaneous hematomas

Hypermobility

Elbow dislocation (age 17—fall)

Shoulder dislocation (early 30s—hockey injury)

Meniscus repair in knee

 Nil

Pectoral muscle hematoma from watersports injury age 18 requiring hospitalization and drainage. More than 5 further hematomas from minor injuries requiring drainage

VI.5

F1

n/a (familial variant known at assessment)

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

8

Y

Easy bruising,

soft skin,

hyperextensible skin,

multiple subcutaneous hematomas

Hypermobility

 Nil

 Nil

VI.6

F1

n/a (familial variant known at assessment)

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

5

Y

Easy bruising,

soft skin,

hyperextensible skin,

multiple subcutaneous hematomas

Hypermobility

Minor pectus excavatum

 Nil

Unexplained global developmental delay

Proband

II.6

F2

Age 49; classical EDS—Villefranche classification

c.3511G>A

p.Glu1171Lys

Exon 48

Florid collagen flowers

Normal

F

53

N

Easy bruising,

scarring,

hyperextensible skin,

subcutaneous hematoma

Hypermobility

Patella dislocation

Varicose veins

Tissue friability noted at surgery

Severe hematoma formation

III.1

F2

Age 23; classical EDS—Villefranche classification

c.3511G>A

p.Glu1171Lys

Exon 48

Rare collagen flowers; collagen fibers with irregular outline

Normal

M

27

Y

Hyperextensible skin,

thin skin with visible veins,

widened atrophic scarring from surgery,

subcutaneous hematoma,

striae rubrae,

piezogenic papules

Age 22—shoulder dislocation

Age 17—inguinal hernia

Nil

Age 24—small bowel perforation from minor insult

II.1

F3

Age 8; classical EDS type I gravis—Berlin classification

c.721G>A

p.Glu241Lys

Exon 10

No collagen flowers

No variability in fiber diameter

n/p

F

33

N

Easy bruising,

hematoma formation,

extensive atrophic scarring,

hyperextensible skin,

thin skin with visible veins

Shoulder and elbow dislocations

Piezogenic papules

Easy fatiguability

Joint pain

Pes planus

Age 29—brachial artery rupture following blood gas sampling

Mild ectatic dilatation of hepatic artery

Proband

II.1

F4

Age 30; vascular EDS—Villefranche criteria

c.2044G>A

p.Glu682Lys

Exon 31

Reduced collagen in reticular dermis; focal variation in diameter of fibers

Normal

M

37

N

Soft skin,

hyperextensible skin

atrophic scarring from surgery,

piezogenic papules,

hematoma formation after venesection

Hypermobility including distal hypermobility

Few dislocations

High arched palate

Generalized joint pain and fatigue

Parastomal hernia

Pes planus

 Nil

Age 29—pneumothorax

Age 30—bowel rupture

Proband V.1

F5

Age 22; classical EDS—2017 nosology

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

22

Y

Easy bruising,

doughy and hyperextensible

skin thinning,

1 small atrophic scar (from cellulitis secondary to hematoma)

Flat feet

Hypermobility (Beighton 9/9)

Distal hypermobility

 Nil

One large hematoma age 18 complicated by cellulitis

V.3

F5

n/a (familial variant known at assessment)

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

F

14

Y

Easy bruising,

hyperextensible skin,

doughy skin,

thinning of skin

Hypermobility (Beighton 9/9) Inguinal herniae

Shoulder and patellae subluxation

Flat feet

Piezogenic papules

 Nil

Nil

IV.1

F5

Age childhood;classical EDS—Villefranche criteria

c.2044G>A

p.Glu682Lys

Exon 31

n/p

n/p

M

50

Y

Easy bruising,

hyperextensible skin,

significant scarring, (widened but not atrophic)

Shoulder subluxations

Bilateral inguinal herniae

Distal joint hypermobility (Beighton 4/9)

Flat feet

Piezogenic papules

Dilation of subclavian vein (conservatively managed)

Minor varicose veins

Large jugular venous aneurysm (surgery age 48)

Large hematomas secondary to trauma

Proband

II.1

F6

Age 22; vascular EDS but with features of classical EDS—Villefranche criteria

c.3511G>A

p.Glu1171Lys

Exon 48

n/p

n/p

M

33

N

Easy bruising,

hyperextensible skin,

soft doughy skin,

thin translucent fragile skin,

atrophic scarring,

delayed wound healing

Hypermobility including distal hypermobility

 Nil

3 major intramuscular hematomas (first age 21);

Slightly floppy mitral valve;

Characteristic facial features of vEDS

Proband

II.1

F7

Age 53; classical EDS—Villefranche criteria

c.721G>A

p.Glu241Lys

Exon 10

n/p

n/p

M

Deceased age 54

n/c

Easy bruising (but not extensive),

hyperextensible skin,

fragile skin since childhood,

doughy skin, premature aging, multiple scars

Joint hypermobility

(Beighton score 8/9)

Inguinal hernia

 Nil

Rectal perforation secondary to hemorrhoid surgery. Reperforation after catheter removal for peritoneal dialysis (age 54)