ICCBH 22 Congress Review

ACHONDROPLASIA.EXPERT
CONGRESS REVIEWS
ICCBH 2022
Welcome to the ICCBH 2022 congress review.
The 10th International Conference on Children’s Bone Health
took place in Dublin from 2–5 July 2022. The meeting brought
together scientists, clinicians, and allied health professionals
from a variety of disciplines to gain a better understanding of
the growing skeleton in health and disease, with leading experts
delivering new insights into both molecular mechanisms and a
range of clinical aspects, from bone physiopathology to treatment.
As always, it is encouraging to see groups sharing posters
and oral communications on the natural history and treatment
of achondroplasia, which hopefully will translate into greater
awareness and understanding of the condition.
Tawfeg Ben-Omran, Senior Consultant and Division Chief
Genetics and Genomic Medicine, Sidra Medicine, Qatar
NATURAL HISTORY
Associations between
height, HRQoL and
functional independence
READ MORE ON PAGE 3
EMERGING THERAPIES
IN ACHONDROPLASIA
New clinical data
for vosoritide and
TransCon CNP
TURN TO PAGE 7
MORE
INSIDE
Bone development PAGE 2
Optimising care for bone diseases PAGE 11
Considering fracture risk PAGE 12
Expanding knowledge in skeletal dysplasia PAGE 14
Novel therapies in skeletal dysplasia PAGE 15
Meet the expert PAGE 17
SUPPORTING INDEPENDENCE
IN ACHONDROPLASIA
A look at how to support
independence in
school-age children, with a
particular focus on toileting
FIND OUT MORE ON PAGE 9
Oral communication abstracts, posters, and presentation can be found in full here
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Achondroplasia.expert Congress Reviews: ICCBH 2022
BONE DEVELOPMENT
Skeletal development and growth were covered in a selection of posters.
Here we summarise a study measuring skeletal robustness, and the
use of biomarkers to measure small increments of growth in children
with achondroplasia.
included correlation of biomarkers
with the annualised growth rate, AGV,
and within-participant CXM variability.
No significant association was found between
CXM concentrations and the annualized
change from baseline in height Z-score;
however, there were significant associations
between CXM concentrations and both
AGV for height and change from baseline
for sitting height. High within-participant
CXM variability was observed, comprising
approximately 57% of the total variability.
Significant associations were also detected
between CTX1 concentrations and the change
from baseline for sitting height, and between
PRO-C2 and the AGV for height. [P131]
Yingling et al. identified variation in skeletal
robustness as an important determinant of
bone strength in youth and young adults in
the Iowa Bone Development Study. Robusticity
reflects the relationship between periosteal
expansion relative to longitudinal growth,
and is a marker of bone strength. This may
be detrimental during training and with
ageing, but few studies have investigated the
impact of bone strength and functionality on
robustness during puberty and at maturity.
This study used pQCT measures of bone
strength of the tibial diaphysis for males and
females at age 11 and 25 from the Iowa Bone
Development Study. The results showed less
robust bones were weaker, and more robust
Change in quadrant from young to maturity
Percentage %
100
80
60
40
20
0
Same
Lower
Male
Improvement
Green–Same
Red–Same
bones were stronger. Furthermore, it was
shown that changes in robusticity and bone
strength can occur from puberty to maturity,
although the majority of individuals did
not move quadrants – instead tending
to stay weaker or stronger for their size.
The authors concluded that one factor
affecting these changes may be lifestyle
choices, such as exercise. [P3]
Ljungberg et al. assessed different circulating
biomarkers related to bone growth, including
collagen fragments as surrogate markers
for growth in 23 children. The biomarkers
analysed were CXM, N- terminal proCNP,
CTX1, P1NP, and PRO-C2. Endpoints
Percentage %
80
60
40
20
0
Same
Lower
Female
Improvement
Green–Same
Red–Same
Yingling et al. [P3]
ACHONDROPLASIA NATURAL HISTORY
With new treatments becoming available for achondroplasia, work continues
to understand the natural history – providing knowledge of complications,
manifestations, and the physical and mental burden across the lifespan.
Irving et al. shared baseline characteristics
from ACHieve – a multicentre, longitudinal,
observational study in children with
achondroplasia from birth to age 8, at
enrolment, from North America, Europe,
and Oceania. The aim is to collect information
on complication onset and progression,
detailed anthropometry including longitudinal
height velocity, and changes in body
proportionality. As of December 2021,
154 children have been enrolled. The mean
age at enrolment was 4 years, with 26%
under 2 years. Anthropometrics are reported
by subgroups of age at enrolment, and the
mean height SDS in the various age groups
at baseline confirms progressive shortness
relative to peers without achondroplasia.
Likewise, the upper-to-lower body segment
ratios suggest that body proportions remain
disproportionate with age in children with
achondroplasia. ACHieve provides important
observational data which will serve as an
important reference for future intervention
trials targeting the underlying pathology,
and will continue to collect data on the
timing, frequency, and characteristics
of growth patterns, body proportionality,
and complications in children with
achondroplasia. [P147]
Irving et al. also reported associations
between height and HRQoL and functional
independence in an exploratory analysis in
121 children with achondroplasia enrolled in
the vosoritide Phase 3 trial. Height Z-scores
were assessed every 3 months, and HRQoL
assessed every 6 months using the PedsQL,
QoLISSY, and WeeFIM questionnaires. For
all instruments, mean scores were generally
lower in subjects with greater height deficit
(at least –6 SDS) compared to taller subjects
with height Z-score greater than −4 SDS.
Clear linear relationships between height
Z-scores and several domain scores were
observed, most notably in the PedsQL
Physical domain, the height-specific
QoLISSY Physical domain, and the WeeFIM
Self-care and Mobility domains. These data
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Achondroplasia.expert Congress Reviews: ICCBH 2022
WeeFIM and height Z-score
Mean (+/- SE) Score
60
55
50
45
40
35
30
0
N:
Self-care
102 190 82
187 102 82
confirm that height deficit in achondroplasia
impacts HRQoL and function, and suggest
that therapies with the potential to reduce
height deficit may also improve HRQoL and
functional independence. [P140]
Noori et al. conducted a systematic review
on the clinical burden of achondroplasia and
management of achondroplasia-associated
complications. The aim was to identify studies
published in English between 2011–2021
Mobility
Cognitive
WeeFIM Caregiver-reported
187 190
102 187 190 82
≤ -6 > -6 to ≤ -5 > -5 to ≤ -4 > -4
Clinical trials of compounds under investigation for achondroplasia
Irving et al. [P140]
reporting symptoms or complications
associated with achondroplasia, as well
as management options.
Of 4,337 records identified, 79 were selected.
Among children who underwent imaging
studies, cervicomedullary compression or
stenosis of the craniocervical junction was
prevalent in 24–94%. Hydrocephalus was
present in 3–41% of cases and thoracolumbar
spinal stenosis in 22–42%. High rates of
Investigational therapies Mechanism of action Trial status Study Number
Vosoritide*
TransCon CNP
Recifercept
lnfigratinib
*Approved by FDA and EMA in 2021
Analog of C-type
Natriuretic Peptide
Long-acting prodrug of
C-type Natriuretic Peptide
Soluble recombinant human fibroblast
growth factor receptor 3 decoy
Fibroblast growth factor receptor
1–3 typrosine kinase inhibitor
Phase 2 and phase 3 trials
completed; extension
studies ongoing
Phase 2 trials ongoing
Phase 2 trials ongoing
Phase 2 trial and its
extension study trial
NCT03989947;
NCT03424018
NCT04085523;
NCT05246033
NCT0463815;
NCT05116046
NCT04265651;
NCT05145010
Nooti et al. [P121]
sleep disordered breathing were reported,
including OSA in up to 80%. Ear infections
were a recurrent complication, with hearing
impairment evident in up to 75%. Between
19–63% underwent cervicomedullary
decompression, with neurologic improvement
in 50–100% of cases. Management of spinal
stenosis through decompressive surgery was
more commonly performed in adolescents
and adults, and was associated with a high
rate of intraoperative complications. Upper
airway surgery usually improved respiratory
indices, but few adolescents and adults
had complete resolution of symptoms.
According to one multinational crosssectional
study, orthopaedic procedures
were among the most common surgeries
in people with achondroplasia, reported in
46%. The authors concluded that individuals
with achondroplasia require ongoing
medical surveillance and management
of complications that diminish functional
capacity, reduce quality of life, and can be
potentially life-threatening. [P121]
The same group presented a second poster
detailing a second set of findings from
their systematic literature review, focusing
on interventional and real-world studies
reporting efficacy or effectiveness, safety, or
quality of life outcomes for limb-lengthening
or pharmacologic treatment for patients
with achondroplasia. Smith et al. selected
4 interventional – 3 for vosoritide, and
1 examining the safety of meclizine. Phase 3
data show vosoritide significantly improves
mean AGV and height Z-scores compared
to placebo, but with no significant changes
in upper-to-lower body segment ratio or
mean standing height. An additional 29 realworld
studies examined limb-lengthening
and/or growth hormone treatment. Limblengthening
procedures effectively increased
limb length, with a mean gain of 7.1–10.2,
5.6–9.5, and 6–14.7 cm, for the femur, tibia,
and humerus, respectively. The procedures
also improved body proportionality, quality
of life, and daily functionality, but were
associated with a high complication rate
and required long recovery periods. Growth
hormone demonstrated inconsistent efficacy
in recent studies. These findings suggest that
patients with achondroplasia have limited
treatment options that increase height
and improve body proportionality, thereby
augmenting quality of life. [P120]
Watt et al. presented 2-year results of a
study offering annual hearing screening
in children with achondroplasia. A new
screening programme in Glasgow aims
to detect new otological problems, and to
estimate the prevalence of hearing loss, OSA,
and frequency of interventions in children
with achondroplasia in Scotland. To date,
9 children have participated; the mean age
was 10.6 years. First and second screening
appointments had a pick-up rate of new
problems of 0 and 11.1%, respectively.
Overall, 67% of the children were previously
known to the ENT or audiology departments.
Due to challenges of small sample size and
the impact of the COVID-19 pandemic, the
scope was expanded to a cross-sectional
review in a larger group of 26 children; here
the prevalence of hearing loss was 46.2%
with median age at detection of 3 years.
The prevalence of OSA was 34.6%, and 38.5%
and 34.6% of had undergone insertion of
grommets or tonsillectomy, respectively.
The authors concluded that the screening
programme did not detect new hearing
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Achondroplasia.expert Congress Reviews: ICCBH 2022
problems in children with achondroplasia
in its initial years but did confirm a high
prevalence of hearing loss and OSA compared
to the general paediatric population without
achondroplasia, however more data is
required for robust recommendations.
[P126]
Rhoda et al. shared the results of an
observational study of foetal foramen
magnum and foramen magnum stenosis
development in achondroplasia, looking for
early evidence of complications in utero.
Advances in novel therapies broaden the
scope for patents with achondroplasia, and
is theorised that earlier administration will
optimise outcomes. Foetal development
of the foramen magnum, thoracolumbar
spine, and hippocampus in achondroplasia
is not well understood. This study used MRI
to visualise these structures in 6 foetuses
with achondroplasia, and by generating 3D
reconstructed images to derive a measurable
dataset. A method was devised to orientate
images into standard sagittal, coronal, and
transverse planes, which helped to account
for foetal movement. Results suggested
the measurement system devised had an
average inter-observer variability of 7.2%.
Pre- and post-natal foramen magnum stenosis score
After birth, all babies had post-natal MRI
scans to detect foramen magnum stenosis;
this was confirmed in 4 children, 3 of
whom had been flagged by the radiologist
on the pre-natal scans, and who went on
to require decompression surgery. This
dataset demonstrates that complications
of achondroplasia initiate in the foetus, and
will form a foundation upon which to study
the early natural history. Further work using
motion-corrected MRI to gather normative
data in unaffected controls is needed, but
expanding on this knowledge will provide
tangible measures for the consideration of
early interventional therapy, perhaps even
in the pre-natal setting. [P2]
Brett et al. also presented a poster on
foramen magnum stenosis in infants with
achondroplasia, investigating the natural
history of cervicomedullary cord compression
without signal change. The AFMS was
developed to classify the severity of stenosis
and inform appropriate neurosurgical
management, and has been shown to
have good observer reliability. At baseline,
approximately half of infants demonstrate
AFMS3/4. All children with AFMS4 are
referred for neurosurgery, whilst well
Pt ID Prenatal FMS score Post-natal FMS score Post-natal FMS score Surgical Intervention
001 36 +6 AFMS0 4m AFMS1 17m AFMS1 N
002 32 +4 AFMS0 4m AFMS2 10m AFMS2 N
003 35 +2 AFMS1 5m 7m AFMS4 Y
004 34 +5 AFMS1 2m AFMS4 Y
005 34 +1 AFMS1 2m AFMS1 8m AFMS4 Y
006 34 +1 AFMS0
Rhoda et al. [P2]
children with AFMS3 undergo repeat MRI
after 12 months. As the natural history of
children with AFMS3 is currently unclear,
the objective of this study was to review
follow-up MRI assessments of 16 infants
initially classified as AFMS3 at two centres in
the UK to define the evolution of this degree of
stenosis. Follow-up MRI showed improvement
in 37.5% to either AFMS1 or AFMS2; there
was no change in 25%, and 37.5% progressed
to AFMS4. Given that more than one-third of
infant’s progress and require neurosurgical
referral, the authors recommend a refinement
of the screening approach to perform followup
MRI at 6 and 12 months, which will help
improve management in this at-risk cohort,
and inform family counselling. [P128]
EMERGING TREATMENT OPTIONS IN
ACHONDROPLASIA
Posters and Late Meeting presentations at the meeting shared data for both
vosoritide and TransCNP in children and adolescents with achondroplasia,
including early real-world experience from France and Germany.
Irving et al. reported on growth velocity
and pubertal milestones with vosoritide for
achondroplasia, using data from the BMN
111-202 and BMN 111-301 studies, and their
ongoing extensions (111-205 and 111-302).
Subjects continuing into the extensions
had a median treatment exposure of 6.0
and 2.4 years, respectively. Standing
heights at each 6-month visit were used
to assess growth and calculate AGV. Overall,
82 subjects had data to assess onset of
Tanner stage 2–5, and 149 to assess AGV for
Tanner stage 1 or onset of Tanner stage 2–5.
AFMS at follow-up MRI in infants classified
as AFMS3 at baseline (n=16)
AFMS1/2 AFMS3 AFMS4
Brett et al. [P128]
As expected, peak growth velocity occurred
at Tanner 2 for females and Tanner 4 for
males. The peak growth velocity on vosoritide
was 5.81 and 6.36 cm/year for females and
males, respectively – compared to 6.65 and
7.66 cm/year in the general US population.
In conclusion, vosoritide preserved the
overall growth duration and the timing of
pubertal milestones while increasing growth
velocity. More data are required to determine
whether the timing of pubertal development
in children with achondroplasia treated with
vosoritide follows that of average stature
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Achondroplasia.expert Congress Reviews: ICCBH 2022
children, as well as to understand how the
timing compares to that of untreated children
with achondroplasia. Monitoring of these
subjects will continue until they reach their
final adult height in order to help better
understand the potential impact of pubertal
milestones in achondroplasia. [P139]
Cormier-Daire et al. shared the early
experience with vosoritide therapy in
clinical practice, with data from over
100 participants in France and Germany
treated with vosoritide in the first 3–4 months
of treatment availability. Children were
aged 2–15 years, and received treatment
for 0.5–4.0 months. Common practices
essential for successful therapy initiation
included establishing families and children’s
readiness for treatment, customised
information and training, readily available
support from healthcare professionals,
regular follow-up, a well-connected
multidisciplinary team, and seamless
logistics and storage arrangements for
pharmacies and families. Additional
support from nurses or other healthcare
personnel at patients’ homes in the early
days of home treatment was also useful.
Appropriate infrastructure was required for
prescription and treatment, as well as for
completing baseline assessments such as
anthropometrics, vital signs, radiographs,
bone-markers, blood tests, and Tannerstaging.
Common side effects for this group
of patients in real-world practice included
local reactions at the injection site, and
transient hypotension. Common concerns
from families and patients focused on
AGV over 6-month intervals by Tanner stage in children treated with vosoritide in studies 202/205 and 301/302
6-month interval
Annualised Growth Velocity (cm/yr)
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
I
Female
II III IV V
Tanner Stage
n 49 57 25 21 23 15 18 9 3 6
Whiskers indicate 2.5th and 97.5th percentiles. Of note, the peak growth velocity in the general US population
is 6.65 and 7.66 cm/year for females and males, respectively.
Male
Irving et al. [P139]
pain and the daily burden of injections, as
well as the duration of treatment needed,
long-term effects and safety, and potential
natural history changes after treatment.
This early experience is essential for practice
evaluation, and will help to develop standards
and guidelines for patient care. [P138]
TransCon CNP is an investigational prodrug
of CNP in development for children with
achondroplasia. McDonnell et al. reported
baseline characteristics for the Phase 2
ACcomplisH trial, which is evaluating
the safety and efficacy of once-weekly
TransCon CNP in 57 prepubertal children
with achondroplasia. The primary efficacy
endpoint evaluates AHV at 52 weeks, with
baseline AHV calculated based on either
medical history or a visit in the ACHieve
natural history study – taken around
12 months prior to randomisation. The
mean age at enrolment was 5.9 years, and
90% had been diagnosed prior to 6 months
of age. At ACcomplisH baseline, 54.4%
had sleep apnoea, 42.1% ear infections,
17.5% foramen magnum stenosis, 15.8%
kyphosis, and 15.8% reported nervous system
disorders – very similar to those reported
for the natural history in the published
literature. The baseline characteristics as
evaluated by different age groups show
expected differences in baseline variables
with expected variability in pre-treatment
AHV across age-groups. The high percentage
of early diagnoses indicates potential
opportunity for early intervention. [P148]
SUPPORTING INDEPENDENCE IN
ACHONDROPLASIA
Achondroplasia can affect an individual’s performance across a number of
activities of daily living, including independence in toileting. This can have a
knock-on effect on quality of life and self-esteem. Several posters presented
at the meeting looked at how to support independence for children and young
people with achondroplasia.
Massey et al. used PEDI-CAT to explore the
impact of achondroplasia on development
in areas including responsibility, social and
cognitive function, mobility, and daily activities.
PEDI-CAT assessments were conducted
with 25 parents through face-to-face and
virtual consultations at one specialist clinic
in the UK. Participant t-scores revealed
–1 SDS below the normative mean population
in the daily activities domain for young
children (3–7 years), and –1.5 in those aged
7–14 years. The mobility domain showed
–2 SDS in younger children, and –3 SDS in the
older group. Participants were within 0.5 SDS
for the social, cognitive, and responsibility
domains. Overall, the results showed a
greater impact on functional performance
relative to typical development for older versus
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Achondroplasia.expert Congress Reviews: ICCBH 2022
younger children. These results highlight
strengths of children and young people
with achondroplasia, as well as confirming
difficulties in mobility and daily activities.
In clinical practice, this may mean that
therapists see a decrease in functional ability
in the areas of daily activities and mobility,
but not necessarily in social, cognitive, and
responsibility domains. The authors note that
the disproportion and elbow contractures
associated with achondroplasia contribute
to the functional impact, and recommend
occupational therapy interventions that use
a strengths-based approach such as goaldirected
training to help maximise a child’s
performance across domains. Assessment of
Impact of achondroplasia on key domains
28%
Daily Activities t-scores
20%
16%
36%
the domains captured through the PEDI-CAT
will also have utility as a metric of response to
treatment with new and investigational drugs.
[P169]
A poster from Johnson et al. considered
whether children aged 7–12 years old with
achondroplasia have appropriate adaptations
required to support independence in toileting,
using data from a single retrospective
study in 24 children. Toileting is a complex
multistep task and there may be many
reasons for limitations in this area, such as
short stature, and loss of full extension at the
elbow and rhizomelia. The findings showed
that 58% had environmental adaptations
28%
Mobility t-scores
12%
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Achondroplasia.expert Congress Reviews: ICCBH 2022
advice/support and all found this to be helpful.
Patients and families suggested offering the
following services in the order of preference:
hydrotherapy, family days, information
sessions, a transition clinic, equipment advice,
information leaflets, and wheelchair advice.
In conclusion, multiple opinions from patients
and their families were positive, suggesting
the metabolic bone service is meeting current
needs. This feedback will be used to plan how
to develop the service further. [P152]
The European Registries for Rare Bone and
Mineral Conditions (EuRR-Bone), launched
in April 2020, started with prospective
data collection on the occurrence of rare
bone and mineral diseases by using an
electronic registry. To date, 40 centres from
18 countries have reported over 800 cases,
including 260 patients with bone and mineral
conditions. The Core Registry – the second
platform within EuRR-Bone – will gather a
little more information, and is collecting a
common dataset to support the goals of the
European Reference Network for Rare Bone
Diseases. In addition, four disease-specific
modules on achondroplasia, osteogenesis
imperfecta, rare hypophosphataemic
disorders and fibrous dysplasia have been
developed by expert working groups. The
modules make it possible to introduce more
detailed data, such as phenotype, genotype,
biochemistry, and clinical science – as well
as the opportunity to log follow-up data.
Ertl et al. outlined how patients can access
the platform, view their data and complete
patient-reported outcomes. The ability to
collect longitudinal patient- and clinicianreported
outcomes gives the platform the
functionality to study meaningful longterm
clinical outcomes in a wide range of
conditions across all ages. In addition, there
is a committee which will analyse data for
research purposes. [P158]
CONSIDERING FRACTURE RISK
Childhood cancer survivors are at risk of developing skeletal late effects,
and fracture is also a risk in children across a variety of skeletal disorders
treated with classic steroids, such as osteoporosis, Duchenne muscular
dystrophy, or rheumatic diseases.
Nicola Crabtree looked at promises and
pitfalls in interpretation of paediatric
vertebral fracture assessment. The
identification of vertebral fractures in
children is a critical component of the
assessment of bone health, and may be
common in children with osteoporosis due
to both their underlying condition or its
treatment, particularly with glucocorticoids.
Vertebral fracture assessment is performed
more often than plain lateral radio graphs.
Several studies have demonstrated this to
be at least as reliable as radiographs for
identifying moderate and severe vertebral
fractures. However, both techniques were
equally poor when identifying mild vertebral
fractures. Unfortunately, the lack of
agreement when identifying mild vertebral
fractures was also challenged when using
semi- or fully automated techniques,
where reader opinion is eliminated. The
main difficulty lies in reliably distinguishing
normal physiological or developmental
morphological variability from fracture,
which is further complicated by the lack of
normative vertebral morphological data.
However, despite these challenges, the
most recent paediatric position statement
from the International Society of Clinical
Densitometry (2019) has endorsed the use
of vertebral fracture assessment providing
the reader has experience of paediatric
vertebral fractures – and with the caveat that
further imaging is required in cases where
vertebral visualisation is limited, where a
single Genant Grade 1 fracture is identified
that would change management, or where
the radiographic findings are not typical for
an osteoporotic vertebral fracture. In such
cases, either plain lateral radiography or
whole-spine MRI is recommended. [IS10]
Stefan Jackowski’s oral focused on the
prevalence and severity of vertebral fracture
in children with various disorders treated
with classic or dissociative steroids. This
descriptive study of children enrolled in the
STOPP and VPB15 (vamorolone) research
programs showed average daily steroid
doses from highest to lowest (mg/kg/day in
prednisone equivalents) of 0.47, 0.44, 0.37,
and 0.30 for Duchenne muscular dystrophy,
nephrotic syndrome, rheumatic disorders,
and leukaemia, respectively. The proportion
of children with at least one vertebral fracture
was 13.6%, 10.3%, 8.3%, and 1.8% for
leukaemia, Duchenne muscular dystrophy,
rheumatic disorders, and nephrotic
syndrome, respectively. Despite the longest
average duration of vamorolone, and highest
average daily dose, boys with Duchenne
muscular dystrophy had the lowest average
Spine Deformity Index – a measure of overall
spine burden. Children with leukaemia had
the lowest classic glucocorticoid exposure,
yet the most severe osteoporotic phenotype –
highlighting disease-specific factors beyond
steroid exposure likely influenced
the vertebral fracture burden. [OC17]
Demi de Winter looked at risk and
determinants of reduced bone mineral
density and fractures in a Dutch cohort
of 2,003 childhood cancer survivors (the
DCCSS-LATER 2 study). BMD was measured
at the lumbar spine, total body, and total
hip, and fracture incidence compared with
Swedish normative data. The SIR of any
first fracture was 3.53 and 5.35 for male
and female survivors, respectively. Vertebral
fractures were prevalent in 13.3% of evaluable
survivors. In the models for low or very
low BMD, male sex, underweight, shorter
follow-up time, total body irradiation, cranial
irradiation, carboplatin dose ≥2,000 mg/m 2 ,
cyclophosphamide equivalent dose
≥8,000 g/m 2 , hypogonadism, growth
hormone deficiency, hyperthyroidism,
low physical activity, vitamin D or B12
deficiency, and folic acid deficiency were
statistically significant. Male sex, obesity,
previous or current smoking, and very
low lumbar spine BMD were significantly
associated with fractures. The authors
conclude that childhood cancer survivors are
at increased risk of any fracture, but identify
several modifiable risk factors for reduced
BMD and vertebral fractures. [OC18]
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Achondroplasia.expert Congress Reviews: ICCBH 2022
EXPANDING KNOWLEDGE IN
SKELETAL DYSPLASIA
Groups from around the world shared new information on genetic mutations
contributing to the development of various skeletal dysplasias. Some of these
may provide targets for future novel therapies.
Juliana Marulanda presented insights into the
dysregulation of the osteocyte transcriptome
in a mouse model of Duchenne muscular
dystrophy by the assessment of dysregulation
of bone gene expression by comparing the
transcriptome of the tibia diaphysis in growing
mdx and wild-type mice. RNA sequencing
revealed 13,231 actively expressed genes
across both genotypes. Of these, 438 genes
were differentially expressed in mdx mice
(77 upregulated, 361 downregulated). Of
the downregulated genes, 259 were part
of the osteocyte transcriptome signature,
and were predominantly expressed by
mature osteocytes. In an overrepresentation
analysis of the differentially expressed
genes that were not part of the osteocyte
transcriptome signature (77 upregulated,
102 downregulated), 56 of the upregulated
genes were found to play a role in immune
function and haematopoiesis, whereas
extracellular matrix organisation genes
were highly enriched among downregulated
genes. Dmd was not actively expressed in
the tibia of either wild-type or mdx mice,
suggesting dysregulation of the cortical bone
transcriptome in mdx mice is unlikely to be
directly caused by the Dmd defect. [OC22]
Dominyka Batkovskyte presented the case
of a patient with a syndromic short stature,
skeletal abnormalities and developmental
delay and a homozygous missense variant in
TOMM7 (c.73T>C, p.W25R). The boy was born
to healthy non-consanguineous parents, but
presented with failure to thrive, severe short
stature, and muscular hypotonia. Skeletal
survey revealed mild platyspondyly with
ovoid vertebral bodies, slender long tubular
bones with relatively large epiphyses, coxa
valga, slender metacarpals and proximal
phalanges, and relatively large neurocranium.
The patient died before the age of 3. Previous
evidence from functional studies suggests
the TOMM7 variant is hypomorphic and leads
to abnormal growth and severe lipoatrophy.
In this study, variant-specific and knock-out
mouse models were used to validate the
functional consequences. Tomm7 R/R mice had
normal early growth but developed rapidly
progressing emaciation at 9–10 weeks of age
and died, whereas Tomm7 del/del mice showed
severe growth failure in early postnatal
stages. In addition, mutant mice showed
slight shortening of vertebral bodies and
the tibial growth plate, with reduced cellular
density and proliferation. Tomm7 mutant mice
also showed severe lipoatrophy and unique
alteration in mitochondrial function. This
study identifies TOMM7 as a new candidate
gene for human disease with syndromic short
stature and developmental delay. [LM3]
NOVEL THERAPIES IN SKELETAL DYSPLASIA
New therapies are in development for many different skeletal dysplasias.
This round-up gives a selection across several conditions, including
hypochondroplasia, hypophosphatasia, and other genetic bone disorders.
As part of the Allied Health Professionals Orals
Session, Raja Padidela presented an interim
analysis from a UK cohort of 20 children with
hypophosphatasia treated with asfotase alfa.
Visits occurred at enrolment, 3 and 6 months,
and every 6 months thereafter. Height Z-score
at first assessment was −2.67, and changed
by −0.09, while weight Z-score was −2.15 and
changed by 0.11. BAMF scores for lower and
upper extremities were 6 and 7.5, respectively,
and were significantly improved. Parent- and
child-reported PedsQoL scores were 52.50
and 64.13, respectively, and changed by 4.35
and 14.67. Starting Bleck scores were relatively
high and remained stable throughout followup.
Serious adverse events were infrequent
(n=5, 10 events), with only one event (injectionsite
atrophy) related to asfotase alfa.
The authors concluded that asfotase alfa
helps children with hypophosphatasia
maintain stable outcomes. [P129]
Carl Dambkowski shared an oral
communication on low-dose infigratinib –
an oral selective fibroblast growth factor
receptor TKI – which has demonstrated
activity in a preclinical model of
hypochondroplasia. FGFR3 mutations
play a crucial role in achondroplasia,
but also in thanatophoric dysplasia
and hypochondroplasia – a condition
characterised by disproportionate short
stature and a growth deficit affecting both
endochondral and intramembranous
ossification. There are currently no approved
therapies for hypochondroplasia, but the
group tested the hypothesis that infigratinib
could improve the hypochondroplasia
phenotype and improve ossification in
a preclinical mouse model. Fgfr3 N534K/+
mice treated with 1 mg/kg infigratinib
every 3 days did not show obvious and
significant modification of the dwarf
phenotype. In contrast, Fgfr3 N534K/+ mice
treated with 1 mg/kg infigratinib daily for
21 days showed a statistically significant
increase in appendicular and axial skeletal
measures. Long bone length was statistically
significantly increased in Fgfr3 N534K/+ mice vs
Fgfr3 +/+ mice, and treatment also modified
skull shape and mandible length, with
an increase in foramen magnum length
(+3.72%). Infigratinib also modified cartilage
growth plate organisation, in particular the
hypertrophic chondrocyte area. These results
provide a rationale for targeting FGFR3 with a
specific TKI for the treatment of children with
hypochondroplasia. [OC1]
Alison Boyce presented results from a
Phase 2, open-label trial in 9 subjects
who were administered with denosumab
for fibrous dysplasia. Denosumab was
administered for 6-months at 120 mg/dose
monthly, with loading doses on Weeks 2 and 3.
14 15

Achondroplasia.expert Congress Reviews: ICCBH 2022
Treatment was followed by a 14-month
observation period with intensive monitoring.
Bone formation marker procollagen-1
propeptide decreased by 92% from baseline,
and resorption marker C-telopeptide by
81%. Scans showed decreased measures of
lesion activity, and lesion biopsies confirmed
decreased cellularity in both fibrous and
osseous tissue, and decreased osteocyte
lacunae size. Five serious adverse events
occurred in two subjects, all unrelated to
treatment. Six subjects had treatmentrelated
adverse events, but all were mineral
abnormalities of mild-to-moderate severity.
Post-denosumab discontinuation data was
available in five subjects: two experienced
bone turnover rebound above pre-treatment
levels after 3 and 8 months. In one
subject with panostotic disease, rebound
resulted in severe hypercalcemia requiring
hospitalisation. The authors conclude that
denosumab has the potential to provide
clinical benefit by reducing lesion activity
in adults with fibrous dysplasia, although
post-discontinuation rebound may
be associated with life-threatening
hypercalcemia, particularly in individuals
with severe disease. [OC2]
Leanne Ward shared skeletal health data
for boys with Duchenne muscular dystrophy
treated with vamorolone, a first-in-class
dissociative steroid. In total 48 treatmentnaïve
ambulatory boys 4–7 years of age
initiated vamorolone at one of four doses
for 6 months, followed by permitted dose
escalations/de-escalations for 2 years.
Serum bone turnover marker Z-scores were
assessed from baseline to 6 and 30 months
(adjusted for age and height percentile at
each visit). Significant increases in serum
osteocalcin and CTX z-scores were observed
from baseline to 6 and 30 months; P1NP
Z-scores were similar from baseline to
6 and 30 months. The average bone
age to chronological age difference was
–1.1 years (P

LIST OF ABBREVIATIONS
AFMS – Achondroplasia Foramen
Magnum Score
AGV – annualised growth velocity
AHV – annualised height velocity
BAMF – Brief Assessment of Motor Function
BMD – bone mineral density
CTX1 – C-terminal telopeptide of
type 1 collagen
CXM – collagen X fragment
DXA – dual-energy x-ray absorptiometry
ENT – ear, nose, and throat
hr-pQCT – High-resolution peripheral
quantitative computed tomography
HRQoL – Health-related quality of life
iPSC – induced pluripotent stem cells
MRI – magnetic resonance imaging
N-terminal proCNP – C-type natriuretic
peptide propeptide
OSA – obstructive sleep apnoea
P1NP – N-terminal propeptide of
type 1 collagen
PEDI-CAT – Pediatric Evaluation of Disability
Inventory – Computer Adaptive Test
pQCT – Peripheral Quantitative Computed
Tomography
PedsQoL – Pediatric Quality of Life Inventory
PRO-C2 – N-terminal propeptide of
type 2 collagen
QoLISSY – Quality of Life in Short
Stature Youth
SDS – standard deviation score
Siglec15 – sialic acid-binding
immunoglobulin-like lectin 15
SIR – standardised incidence ratio
TKI – tyrosine kinase inhibitor
WeeFIM – Functional Independence
Measures in Children