ACHONDROPLASIA NATURAL HISTORY:

A MULTICENTER COHORT STUDY

Julie Hoover-Fong, MD, PhD

Director, Greenberg Center for Skeletal Dysplasias

McKusick-Nathans Institute of Genetic Medicine

Johns Hopkins University

Baltimore, Maryland

DISCLOSURES

Funding for this achondroplasia natural history study was provided by BioMarin, Inc. through an Independent Research Grant. Dr. Hoover-Fong is a paid consultant to BioMarin.

These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

All images from Google Images unless otherwise noted.

TOPICS FOR TODAY

• Discuss design of achondroplasia natural history study

• Results from primary achondroplasia cohort (n = 1377)

• Demographics, anthropometry, surgical burden, sleep disordered breathing, radiographic catalogue

• Next steps in analysis

• Next steps in study expansion

STUDY TEAM

Johns Hopkins University

Baltimore, Maryland

PI: Julie Hoover-Fong, MD, PhD

Biostatistician: Chengxin Liu, MS

Study Administrator: Colleen Gioffreda, BA

Former co-ordinator: Yewande Alade, MPH

AI duPont Hospital for Children

Wilmington, Delaware

Co-PI: Michael Bober, MD, PhD

Study Coordinator: Mary Ellen Little, BSN, RN

University of Texas

Houston, Texas

Co-PI: Jacqueline Hecht, PhD

Co-Investigator: Syed Hashmi, MD, MPH

Consultant: David Rodriguez-Buritica, MD

Study Coordinator: Elena Serna

University of Wisconsin

Madison, Wisconsin

Co-PI: Janet Legare, MD

Consultant: Richard Pauli, MD, PhD

Study co-ordinators: Cory Smid, BS, Peggy Modaff, MS, CGC

Key Johns Hopkins members: John McGready, PhD and Kerry Schulze, PhD

PROBLEM & PURPOSE:

• Problem: Increased risk of adverse health outcomes related to cardiovascular disease, pain, compromised physical function and obstructive and central sleep apnea in ACHONDROPLASIA.

Natural history and interactions of risk factors poorly understood.

• Purpose: To understand natural history of achondroplasia and the health outcomes of past,current and future pharmacologic, medical and surgical interventions.

ACHONDROPLASIA

• Most common skeletal dysplasia

• 1:20,000-1:30,000

• Dwarfism in ancient Egypt, Greece, Rome, ~3,000 to ~30 BCE

• Revered by rulers, general population

Per-ni-ankh

Discovered in limestone tomb in 1989Western field of great pyramid Khufu

ACHONDROPLASIA• Cervicomedullary compression

• Spinal stenosis

• Central sleep apnea

• Obstructive sleep apnea

• Chronic otitis media, fluid with speech delay and hearing deficit

• Genu varus, tibial bowing

• Long track signs

• Rhizomelia

• Thoracolumbar kyphosis

• Fibroblast growth factor receptor 3 FGFR3• 99% with same Gly380Arg substitution; <1% with Gly375Cys • Autosomal dominant• 100% penetrant• 80-90% spontaneous mutation • 1-2% risk gonadal mosaicism • Advance paternal age

OVERVIEW: ACHONDROPLASIA NATURAL HISTORY STUDY

• All available medical records

• Achondroplasia (molecular or clinical)

• Saw clinical geneticist, 1957-2017

• 2 year, multi-center, retrospective and cross-sectional data collection

with prospective functionality

• Research Electronic Data Capture (REDCap) system

Web-based database, hosted at Johns Hopkins Biostatistics Center

(JHBC) on servers at Data Info Services Core (DISC)

4 primary study domains

1. Anthropometry

2. Surgical burden

3. Sleep disordered breathing

4. Image catalogue

Lots of data…

Long road between ‘data in

hand’ and results…

Tempting…

STUDY DESIGN

Phase 1:

Retrospective and cross-

sectional data collection

REALIGN DATA FROM BIRTH

TIME

Birth 10 yrs 20 yrs 30 yrs 40 yrs 50 yrs

Example:

5 subjects

4 at least 10 years old

2 had lower extremity osteotomies

Compare osteotomy versus not:

• Why surgery?

• Degrees varus?

• Pain?

• Weight?

• Physical function now?

Birth 5 yrs 10 yrs 15 yrs 20 yrs 25 yrs

TIME

duPont

Hopkins

Texas

Wisconsin

REALIGN DATA FROM BIRTH

TO COMPARE SITES

1970s 1980s 1990s 2000s 2010s

EXAMINE BY BIRTH COHORT/DECADE,

2 of 16 had MRIs 6 of 7 had MRIs

How often were

MRIs of the

foramen magnum

done in the 1980s

versus 2000s?

TO ASSESS SECULAR TRENDS

STUDY DESIGN

Phase 1:

Retrospective and cross-

sectional data collection

1,377 SUBJECTS

PRIMARY

ACHONDROPLASIA

COHORT

And identify patients from

natural history study for

Phase 2 prospective study

IDENTIFIED ~ 500

‘ACTIVE’ SUBJECTS

FOR PROSPECTIVE

STUDY

STUDY DESIGN

Phase 2:

~ 500 subjects from Primary

Achondroplasia Cohort will be

studied prospectively

Lost to followup

Opts out of prospective studies

1. Craniofacial structure

2. Metabolism

3. Neurocognition

4. Pain & physical

function related to

osteotomies & spine

surgery

NOW THE FUN STUFF! DATA!

DEMOGRAPHICS

POPULATION

INHERITANCE & DIAGNOSIS

* Prenatal diagnosis began in the 1980s

** ~70% of unknown age at diagnosis was from archive records before 1990

4 PRIMARY STUDY DOMAINS

1. ANTHROPOMETRY

2. SURGICAL BURDEN

3. SLEEP DISORDERED BREATHING

4. RADIOLOGY CATALOGUE

ANTHROPOMETRY

Height velocity decreases earlier in females than males.

This is reflected subtly in the height-for-age curves above.

Data from this cohort indicates minimal linear growth continues

in females until 21.7 years; 19.3 years in males.

ACHONDROPLASIA HEIGHT

He

igh

t ve

loc

ity (

cm

/yr)

EARLIER ACHONDROPLASIA COHORT (N= 202) AJCN, 2008

No height velocity ‘bump’ with puberty.

Average height velocity was steady at ~4 cm/yr from ~2 years of age on

in males and females.

HEIGHT VELOCITY

Average stature males:

Median peak height velocity

9.3 cm/yr at 13.5 years.

Average stature females:

Median peak height velocity

8.3 cm/yr at 12 years.

Until 10 years,

average stature

5th %ile velocity

=

Achondroplasia

mean velocity

SURGICAL BURDEN

SURGICAL BURDEN 5 categories:

ENT: tonsillectomy,

adenoidectomy, tubes,

tympanoplasty

Brain: VP shunt, VPS revision,

ventriculostomy

Foramen: cervicomedullary

decompression, cervical

decompression, C-spine

fusion

Spine: C/T/L laminectomy,

fusion, kyphosis

Extremity: Osteotomies

SURGICAL BURDEN

Average stature Achondroplasia

CERVICOMEDULLARY DECOMPRESSION

FOR CERVICOMEDULLARY COMPRESSION

OSTEOTOMTIES FOR LOWER

EXTREMITY MALALIGNMENT

PROXIMAL TIBIAL OSTEOTOMIES

DISTAL TIBIAL OSTEOTOMIES & GROWTH MODULATION

Films from Dr. Will Mackenzie and Dr. Michael Bober

DISTAL TIBIAL AND FIBULAR OSTETOTOMIES, EXTERNAL FIXATION

DIFFERENT WAY TO EXAMINE OSTEOTOMIES OVER TIME

PERSON YEARS

Survival analysis (free of surgery) reveals probability of lower extremity osteotomy at 10 years of age is 12.0%; at 20 years it is 25.3%

Subjects w/ PE tubes,N (% of total)

Subjects with T&A, N (% of total)

duPont 240 (62.3) 215 (55.8)

JHU 130 (43.2) 112 (37.2)

Texas 67 (30.7) 59 (27.1)

Wisc 334 (70.6) 349 (73.8)

Total 771 (56.0) 735 (55.3)

TYPMANOSTOMY TUBES AND

TONSILLECTOMY / ADENOIDECTOMY

SLEEP DISORDERED BREATHING

RADIOGRAPHIC CATALOGUE

SUMMARY OF PROGRESS

• 1st multi-center natural history study of achondroplasia

• Novel observations about growth velocity, final adult height, surgical burden and sleep disordered breathing

• Now examining interactions among study domains

• This cohort may serve as controls against subjects treated with novel pharmacologic, medical and surgical interventions

• Active subjects can participate in prospective studies pertaining to craniofacial structure, neurocognition, metabolism, foramen magnum

NEXT STEPS

• Complete descriptive analysis of retrospective data from 1377 subjects in Primary Achondroplasia Cohort

• 9 manuscripts, multiple presentations

• Begin prospective study of Active subcohort

• Craniofacial structure, metabolism, neurocognition, pain & physical function related to osteotomies, spine surgery

• Secure funding for phase 3 (RDN?)

• Biorepository (i.e. WES, biomarker identification)

• More study sites

• More dysplasias

ADDITIONAL COMMENTS ABOUT THE DATA ‘IN HAND’

1. Combine data across domains to learn clues about cause and effect for prospective studies

COMBINING DATA ACROSS DOMAINS

• Pre- and post-operative studies

• 239 subjects had CMD

• 130 had > 1 sleep study

• 190 had MRI

• Can examine sleep study for central apnea and MRI for size FM before and after CMD.

• 753 adenotonsillectomies in 598 subjects

• 388 had sleep studies.

• Can examine effect of surgery at different ages, severity of OSA.

• Co-morbidities prompting surgery (e.g. weight, pain); when is best timing for X procedure?

ADDITIONAL COMMENTS ABOUT THE DATA ‘IN HAND’

1. Combine data across domains to learn clues about cause and effect for prospective studies

2. Can we formulate recommendations for better treatment?

RECOMMENDATIONS FOR BETTER TREATMENT

• Is patient better or worse after surgery?

• How bad should lower extremity malalignment be before operating?

• Should surgery be performed before the patient is in severe pain? (i.e. prophylactically)

• Can we predict who will need X surgery (who won’t)?

• Which is more of a burden: 2 lower extremity surgeries or 1 back surgery? Difficult to compare

ADDITIONAL COMMENTS ABOUT THE DATA ‘IN HAND’

1. Combine data across domains to learn clues about cause and effect for prospective studies

2. Can we formulate recommendations for better treatment?

3. Recognize huge phenotypic variability among subjects, yet all have same mutation

**Golden opportunity to study genetic and environmental modifiers of the phenotype

BACKUP

86 individuals had an adult height percentile and height data between 8 and 20 years.

The mean difference in adult height percentile and average height percentile between 8 and 20 years of

age is 0.012 with 95% CI (-0.04, 0.0712).

On average there is no difference in the final adult height percentile and that before 20 years of age.

Your eyes are very good!

9 of the 86 have a diff > .25 in absolute values!

John

Mean of height percentiles for 8-20 years

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