CURRENT UNDERSTANDING OF THE NATURAL HISTORY … Bailey.pdf · CURRENT UNDERSTANDING OF THE NATURAL...

CURRENT UNDERSTANDING OF

THE NATURAL HISTORY OF

EHLERS-DANLOS SYNDROME

TYPE IV

Sam Bailey MS, CGC

Collagen Diagnostic Laboratory

University of Washington, Dept. of Pathology

Collagen Diagnostic Laboratory

• Clinical diagnostic laboratory based at University of

Washington Dept. of Pathology

• Specialized in inherited connective tissue disorders

• Collagen-related disorders: osteogenesis imperfecta and EDS type

IV

Learning objectives

• Review previous EDS type IV natural history study,

general understanding of risk for complications

• Become aware of current understanding of EDS type IV

based on findings of recently-published natural history

study

• Understand type/nature of pregnancy related

complications, effect on overall survival

EDS type IV

• Diagnosis can be made on clinical basis, molecular and/or

biochemical testing to confirm

• Gene: COL3A1

• encodes the proα1(III) chains of type III collagen

• >95% of affected individuals have identifiable alteration

• Diagnostic criteria suggested by expert group (Beighton et

al., 1998)

• Diagnosis based on finding of two or more of the

following:

• Thin, translucent skin

• Arterial/intestinal/uterine rupture

• Easy bruising

• Characteristic facial appearance

EDS type IV: Natural History (2000)

• Purpose: Define lifetime risks for major health

complications

• Pepin et al., 2000: Reviewed clinical histories of 220 index

patients and 199 affected relatives

• Survival

• Age of complication onset

• Outcome of complications


• Pepin et al., 2000:

• Survival is shortened (mean lifespan: 48 yrs)

• 25% of index patients had major complication by age 20, >80% by

age 40

• avg age of 1st complication (index patients): 23.5 yrs

• Arterial dissection/rupture most common cause of death (79% of

deaths)


• Pepin et al., 2000: COL3A1 mutation identified in 135

index patients

• 41 had mutations resulting in exon skip

• 85 had mutations resulting in glycine substitution

• 9 had complex outcome

• No genotype-phenotype correlation with regards to major

complication type and frequency


• Pepin et al, 2014:

• 1231 total subjects

• 630 index subjects, 601 relatives

• Index subjects: identified by COL3A1 mutation (572) or abnormal

collagen protein analysis (58)

• Relatives: identified by COL3A1 mutation, abnormal protein study, or

retrospective family history analysis

• Similar focus: defining EDS IV clinical picture (how diagnosis is

reached, type and timing of complications, survival, genotype-

phenotype correlations)


• Pepin et al, 2014:

• 450 of 630 (70%) of index individuals ascertained due to major

complication

• 23% due to family history, 7% due to physical exam findings

• Mean age of ascertainment:

• 27.4 yrs for index patients

• 31.6 yrs for relatives

• Mean age of first complication: 30.6 yrs (all subjects)


• Mutations:

• 410 different mutations identified in 572 index subjects

• 356 had glycine substitutions

• 164 had splice site mutation

• donor site (144) or acceptor site (20)

• 52 had insertions, deletions, duplications, insertion/deletions


• Survival:

• Median survival for all subjects was 51 years

• males: 46 yrs

• females: 54 yrs

• Males: 30 deaths (18%) occurred before age 20 (compared with

7% for females)

• Higher death rate due to vascular rupture

• Survival curves for males and females parallel from age 20 on


• Survival affected by mutation type

• Hazard ratios (HR)

• Splice donor site mutations, glycine substitutions had highest HR

• HR for glycine substitutions varies by the substituted amino acid

• “Null” mutations lead to attentuated phenotype, delayed onset of

complications (Leistritz et al., 2011)

• Survival not affected by location of substitution in collagen

triple helix


• Vascular complications:

• 737 arterial complications in 638 individuals

• Greatest number occurred in abdominal (34%) and thoracic (33%)

vessels

• Aortic aneurysm/dissection/rupture was most common vascular

complications

• Mean age: 35.7 years

• Led to death in 68% of cases

• Males had aortic complications more often and at younger ages

• Aortic surgery resulted in death in 13/32 (39%) recorded instances


• Vascular complications:

• Coronary artery aneurysm/dissection/rupture occurred in 25

individuals (females > males)

• Also seen: carotid cavernous fistulae, intracranial aneurysms,

cervical artery dissections


• Gastrointestinal complications:

• 181 total bowel perforations

• Majority of surgical interventions were partial colectomy, creation of

colostomy, and reversal

• Congenital defects:

• clubfoot, congenital hip dislocation, limb deficiency, amniotic bands

• all occurred more frequently than estimated US prevalence

EDS type IV: Pregnancy

• Previous reports highlight increased risk for pregnancy-

related complications

• arterial dissection/rupture

• uterine rupture

• hemorrhage, premature rupture of membranes, lacerations, wound

dehiscence

• Published recommendations include discouraging

pregnancy, or encouraging early C-section

• Few empirical data to support these recommendations!


• Murray et al., 2014:

• Investigated maternal mortality and morbidity two

different ways:

• Semistructured interviews

• Retrospective pedigree analysis


• Murray et al., 2014: semistructured interview • interviewed 35 women with protein-altering mutation (nulls excluded),

representing 76 delivered pregnancies

• no complications occurred in 48% of pregnancies

• ~2/3 delivered vaginally

• Complications included arterial rupture (9.2%), uterine rupture (2.6%),

complications of C-section (2.6%)

• 5 pregnancy-related deaths

• 4 due to arterial rupture, 1 due to C-section complication

• nonfatal complications: arterial dissections, lacerations, pre-term

delivery, placenta previa, placental abruption


• Pedigree analysis: studied parous and nulliparous

females with EDS IV, ≥ 12 years of age

• 243 (46%) nulliparous, 283 (54%) had 1+ pregnancy

• 616 delivered pregnancies, 30 preg-related deaths

• death rate of 4.9% per delivery

• No difference in overall survival for nulliparous

women and women who had 1+ pregnancy

• Survival curves similar (see next slide)

• Mean age of death (53 years) is the same in both groups

Overall survival of 526 parous (n=283) and nulliparous (n=243) women of reproductive age with EDS type IV

Overall survival in parous (n=179) and nulliparous (n=86) affected female relatives with EDS

type IV

EDS type IV: Summary

• In most cases, affected individuals have shortened life

span

• Mutation type matters

• Arterial aneurysm/dissection/rupture most common cause

of death

• Increased risk for pregnancy-related complications

• Pregnancy does not appear to affect overall lifespan

Acknowledgements

• EDNF

• Collagen Diagnostic Laboratory

• Peter H. Byers, MD

• Mitzi L. Murray, MD

• Ulrike Schwarze, MD

• Melanie Pepin, MS, CGC

• Dru Leistritz, MS, CGC

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