CLINICAL ARTICLE

Achondroplasia Natural History Study (CLARITY):

60-year experience in cervicomedullary decompression in
achondroplasia from four skeletal dysplasia centers
Janet M. Legare, MD,1 Chengxin Liu, MPH,2 Richard M. Pauli, MD, PhD,1
Adekemi Yewande Alade, MD, MPH,3 S. Shahrukh Hashmi, MD, MPH, PhD,4
Jeffrey W. Campbell, MD, MS, MBA,5 Cory J. Smid, MS,1,6 Peggy Modaff, MS,1
Mary Ellen Little, BSN, RNC,5 David F. Rodriguez-Buritica, MD,4 Maria Elena Serna, BS,4
Jaqueline T. Hecht, PhD,4 Julie E. Hoover-Fong, MD, PhD,2 and Michael B. Bober, MD, PhD5
1
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin;​2Greenberg
Center for Skeletal Dysplasias, McKusick-Nathans Department of Genetic Medicine, and 3Department of Epidemiology, Johns
Hopkins University, Baltimore, Maryland;​4McGovern Medical School at University of Texas Health, Houston, Texas;​5A. I. duPont
Hospital for Children, Thomas Jefferson University, Wilmington, Delaware;​and 6Children’s Wisconsin, Medical College of Wis-
consin, Milwaukee, Wisconsin

OBJECTIVE The authors sought to determine the overall incidence of cervicomedullary decompression (CMD) in pa-
tients with achondroplasia and the characteristics associated with those surgeries across multiple institutions with expe-
rience caring for individuals with skeletal dysplasias.
METHODS Data from CLARITY (Achondroplasia Natural History Study) for 1374 patients with achondroplasia from four
skeletal dysplasia centers (A. I. duPont Hospital for Children, Johns Hopkins University, University of Texas Health, and
University of Wisconsin School of Medicine and Public Health) followed from 1957 to 2017 were recorded in a Research
Electronic Data Capture (REDCap) database. Data collected and analyzed included surgeries, indications, complica-
tions, ages at time of procedures, screening procedures, and medical diagnoses.
RESULTS There were 314 CMD procedures in 281 patients (20.5% of the entire cohort). The median age of first CMD
was 1.3 years in males and 1.1 years in females. Over time, there was a decrease in the median age of patients at first
CMD. All patients born before 1980 who underwent CMD had the procedure after 5 years of age, whereas 98% of pa-
tients born after 2010 underwent CMD before 5 years of age. In addition, a greater proportion of patients born in more
recent decades had documented neuroimaging and polysomnography (PSG) prior to CMD. Ventriculoperitoneal shunts
(VPSs) were placed more frequently in patients undergoing CMD (23%) than in the entire cohort (8%). Patients who re-
quired either CMD or VPS were 7 times more likely to require both surgeries than patients who required neither surgery
(OR 7.0, 95% CI 4.66–10.53;​p < 0.0001). Overall, 10.3% of patients who underwent CMD required a subsequent CMD.
CONCLUSIONS The prevalence of CMD in this large achondroplasia cohort was 20%, with more recently treated
patients undergoing first CMD at younger ages than earlier patients. The use of neuroimaging and PSG screening mo-
dalities increased over time, suggesting that increased and better surveillance contributed to earlier identification and
intervention in patients with cervicomedullary stenosis and its complications.
https://thejns.org/doi/abs/10.3171/2020.12.PEDS20715
KEYWORDS achondroplasia;​foramen magnum stenosis;​cervicomedullary decompression;​pediatrics;​database;​spine

A
chondroplasiais the most common short-stat-
ured skeletal dysplasia, with an estimated birth
prevalence of 1 per 20,000–30,000 live births.1
Achondroplasia is caused by a mutation in the fibroblast
growth factor receptor 3 gene (FGFR3),2 with one muta-
tion (G1138A) responsible for over 98% of all cases.3 This
mutation results in constitutive inhibition of endochondral
growth.1 The recognizable clinical characteristics include
disproportionate short stature with rhizomesomelia of the
limbs and macrocephaly with frontal bossing. In addition,

ABBREVIATIONS AIDHC = A. I. duPont Hospital for Children;​CLARITY = Achondroplasia Natural History Study;​CMD = cervicomedullary decompression;​JHU = Johns
Hopkins University;​PAC = Primary Achondroplasia Cohort;​PSG = polysomnography;​UTH = University of Texas Health;​UW = University of Wisconsin;​VPS = ventriculo-
peritoneal shunt.
SUBMITTED August 15, 2020. ACCEPTED December 21, 2020.
INCLUDE WHEN CITING Published online June 4, 2021;​DOI: 10.3171/2020.12.PEDS20715.

©AANS 2021, except where prohibited by US copyright law J Neurosurg Pediatr June 4, 2021 1

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Legare et al.
there are distinct, recognizable, but highly variable skel-
etal manifestations of achondroplasia, including cervico-
medullary compression.1 Because of premature closure
of cranial base synchondroses, the foramen magnum is
smaller in both the transverse and sagittal dimensions in
individuals with achondroplasia compared to those with
average stature.4
Stenosis of the foramen magnum and subsequent com-
pression of neurological tissues requiring cervicomed-
ullary decompression (CMD) is estimated to occur in
5%–41% of children with achondroplasia.5–8 The wide
variability reflects the various methods of ascertainment
used to obtain this information. Signs and symptoms of
compression include abnormal neurological examination
and long-track signs (e.g., clonus and hyperreflexia), gross
motor developmental delay, central apnea, signal changes
in the spinal cord as seen on MRI, and even sudden infant
death.5 Life-threatening respiratory difficulties and my-
elopathy can be cured by CMD.6,9–12 Increased awareness
and improved management of critical foramen magnum
stenosis began in the early 1980s.11,12 Untreated foramen
magnum stenosis and subsequent upper cervical and med-
ullary compression have been definitively related to the
increased rates of sudden unexpected death in infants with
achondroplasia.5,13–15
Infant mortality in achondroplasia has decreased in the
last few decades, and a recent study by Hashmi et al.,16
using the national death index to assess the vital status
of patients with achondroplasia seen in clinics since 1986,
identified only 1 infant death in 855 patients. It is gen-
erally considered that improved surveillance and inter-
vention for cervicomedullary compression help explain
this finding. Data on CMD were analyzed from a large
cohort of patients with achondroplasia over more than 4
decades cared for in four different skeletal dysplasia cen-
ters (CLARITY [Achondroplasia Natural History Study]).
Here, we present CLARITY data related to the rate of
CMD and characteristics associated with those surger-
ies across a multi-institutional cohort of individuals with
achondroplasia.
Methods
CLARITY was approved by the Institutional Review
Boards of Johns Hopkins University (JHU), A. I. du-
Pont Hospital for Children (AIDHC), McGovern Medi-
cal School at University of Texas Health (UTH), and
University of Wisconsin School of Medicine and Public
Health (UW). The CLARITY investigation and overall
study design were described previously and included both
a retrospective and prospective section.17 In this paper,
we focus on data collected during the retrospective por-
tion of CLARITY. In brief, all available medical records
pertaining to anthropometry, surgical burden, sleep dis-
ordered breathing, and radiographic imaging from 1374
patients with achondroplasia evaluated from 1957 through
2017 at the four institutions were entered into a Research
Electronic Data Capture (REDCap) database.17 The to-
tal achondroplasia cohort is referred to as the Primary
Achondroplasia Cohort (PAC). The analyses presented
herein focus on CMD, the date and patient age CMD was
2 J Neurosurg Pediatr June 4, 2021
performed, indications, and outcomes. For these analyses,
CMD was defined as surgical enlargement of the foramen
magnum alone or enlargement of the foramen magnum
plus C1 or C1 and C2 laminectomy.
Surgical indications were categorized as follows: acute
life-threatening event, central apnea by polysomnogra-
phy (PSG), abnormal MRI findings, persistent and severe
hypotonia, significant gross motor developmental delay,
hyperreflexia, asymmetrical reflexes, abnormal Babinski
response, and high cervical myelopathy (weakness/paraly-
sis, clonus, foramen magnum stenosis, cervical stenosis,
and abnormal neurological signs). MRI diagnostic find-
ings included T2-signal abnormality, syrinx, cord inden-
tation, and obliteration of subarachnoid fluid layer/fluid
flow. Outcomes were assessed and categorized as follows:
good outcome, no improvement, rehospitalization, repeat
procedure, anesthetic complication, bleeding, poor wound
healing, pseudarthrosis, paresthesia, dislocation, pulmo-
nary complication, infection, worsened medical condition,
unknown, and other. VPS procedures were noted in the
brain surgery category. There was no limitation as to num-
ber of responses within a category.
Descriptive statistics (SAS) were reported as frequen-
cies (percent) for categorical variables. Mean values (with
standard deviations [SDs]) were calculated for normally
distributed continuous variables, and median values (with
interquartile ranges [IQRs]) were reported for nonnor-
mally distributed continuous variables. Medians were
reported instead of means to decrease the effect of outli-
ers. PROC LIFTTEST, the nonparametric procedure, was
used to create the curves and calculate the probability of
being free from surgery at each time interval. The “fail-
ure” time or the time-to-event was calculated based on the
age at first CMD, and the “censor” time was calculated
based on the age at the last known medical contact for
people who did not have the surgery.
The odds ratio (OR) and 95% confidence interval (CI)
were calculated to determine the likelihood of spine and
lower-extremity surgery occurring after CMD and shunt-
ing, as well as other risk factors in this achondroplasia co-
hort. The OR and 95% CI were calculated for 2 × 2 contin-
gency tables. The Cochran-Mantel-Haenszel test was used
to compare the ORs of various 2 × 2 tables;​p < 0.05 was
considered significant.
Results
In CLARITY, the PAC consisted of 1374 patients, of
whom 281 (20.5%) underwent 314 CMD procedures. Of
the 281 patients who underwent CMD, 133 (47.3%) were
male and 148 (52.7%) were female, with 22% and 19%
of all female and male patients, respectively, undergoing
CMD. The median age at first CMD was 1.3 years in male
and 1.1 years in female patients. As shown in Table 1,
there was no statistically significant difference in the need
for decompression (p = 0.28) or in the mean or median
ages of first decompression in male versus female patients.
The percentages of patients undergoing CMD at each
study center were as follows: 83/299 (28%) at JHU, 73/384
(19%) at AIDHC, 39/218 (18%) at UTH, and 86/473 (18%)
at UW. Three centers had a similar median age for un-
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 Legare et al.

TABLE 1. Median and mean patient ages by sex, treatment

center, and birth decade of first CMD
Age, yrs
No. (%) of Total Pts
Pts w/ CMD Median Mean ± SD in PAC
Overall 281 (20.5%) 1.2 3.5 ± 6.5 1374
Male 133 (47.3%) 1.3 3.0 ± 5.5 704
Female 148 (52.7%) 1.1 4.0 ± 7.2 670
Treatment center
AIDHC 73 (19.0%) 1.5 2.4 ± 3.0 384
JHU 83 (27.8%) 1.1 3.5 ± 7.9 299
UTH 39 (17.9%) 4.1 6.9 ± 8.0 218
UW 86 (18.2%) 1.1 3.0 ± 6.0 473
Birth decade
2010s 55 (23.0%) 0.9 1.2 ± 1.1 239
2000s 80 (22.5%) 1.2 2.2 ± 2.7 356
1990s 79 (25.2%) 1.2 2.9 ± 4.2 314
1980s 47 (20.3%) 1.3 2.3 ± 2.9 231
<1980 20 (8.5%) 19.8 21.0 ± 12.1 234 FIG. 1. Percentage of patients undergoing CMD by age and birth dec-
ade. All patients born before 1980 had CMD surgery after 5 years of
AIDHC = A. I. duPont Hospital for Children;​JHU = Johns Hopkins University;​
age. Patients born in subsequent decades underwent CMD at younger
pts = patients;​UTH = University of Texas Health;​UW = University of Wisconsin.
ages.

dergoing first CMD—JHU (1.1 years), AIDHC (1.5 years), The overall first CMD rate ranged from 8.5% to 25.2%
and UW (1.1 years)—but the median age was considerably by birth decade (Table 1) and 17.9% to 27.8% by treatment
older at UTH (4.1 years). Examining the characteristics of center (Table 2). Analysis of CMD rate by center and birth
first CMD by birth decade revealed notable differences: decade yielded 20 unique treatment center–birth decade
the median age at the time of surgery was 19.8 years for cohorts with CMD rates of 0%–40%. The highest rates
patients born before 1980, whereas much earlier ages were were 40.0% in the 2000 birth decade at UT and 37.7% in
reported for patients born in later decades (1.3 years for the 1990 birth decade at JHU.
those born in the 1980s and 1990s, 1.2 years for those born
in the 2000s, and 0.9 years for those born in the 2010s).
All of the patients born before 1980 underwent initial
decompression after 5 years of age. For patients born in
the 1980s, 64% (30/47) who underwent CMD had the pro-
cedure by age 2 years and 91% (43/47) had the procedure
by age 5 years. In contrast, in the most recent birth cohort,
91% (50/55) of all first CMD surgeries were completed
by 2 years of age and 98% (54/55) by 5 years of age (Fig.
1). The greatest increase in proportion of a birth cohort
undergoing CMD was between patients born before 1980
and those born in the 1980s (9.0% vs 20.3%, an increase
of 11%). Over the subsequent 3 decades, there was little
change in the percentage of patients undergoing CMD
(24.8%, 22.5%, and 23% in the 1990s, 2000s, and 2010s,
respectively).
Kaplan-Meier survival analysis shows that the prob-
ability of having CMD increases rapidly to 14.5% during
the first 2 years of life, after which it gradually increases
before plateauing at 27% by age 40 years (Fig. 2). When FIG. 2. Kaplan-Meier curve showing the percentage of patients alive at
the analysis was performed with only patients born after each age who have not undergone CMD. The data demonstrate a rapid
1980, a similar increase to 14.4% was observed by age increase in the need for CMD over the first several years of life, followed
2 years, but the plateau was reached much earlier at age by a plateau. For the overall PAC and the most recent birth decades,
10 years, when 19.7% of the PAC born in 1980–2017 had 3.3% of patients had undergone CMD by 6 months of age, 8.4% by 1
year, 12.2% by 18 months, 14.2% by 2 years, and 16.0% by 3 years. The
undergone CMD. Interestingly, only 9 patients born after divergence in the curves becomes apparent by age 10 years, when the
1980 underwent initial CMD after 10 years of age, with rate is 20.2% in the PAC but 19.5% in younger patients. By age 20, the
the last CMD in this group of patients performed at age difference is 23%, compared to 21.3%. Only patients in the oldest cohort
16.6 years. had a CMD at older ages, with 27.8% at 40 years.

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Legare et al.

TABLE 2. Distribution of first CMD surgeries in PAC by birth decade and center

Birth AIDHC JHU UTH UW

Decade Pts w/ CMD All Pts % Pts w/ CMD All Pts % Pts w/ CMD All Pts % Pts w/ CMD All Pts %
2010s 16 98 16.3% 15 54 27.8% 0 7 0.0% 24 80 30.0%
2000s 23 128 18.0% 21 67 31.3% 4 10 40.0% 32 151 21.2%
1990s 22 89 24.7% 29 77 37.7% 8 42 19.0% 20 106 18.9%
1980s 12 55 21.8% 14 54 25.9% 15 55 27.3% 6 67 9.0%
<1980 0 14 0.0% 4 47 8.5% 12 104 11.5% 4 69 5.8%
Total 73 384 19.0% 83 299 27.8% 39 218 17.9% 86 473 18.2%

Of the 281 patients who underwent CMD, 257 (91%)
had at least one indication for CMD documented in the
medical record, of whom 217 had imaging indications
documented, 90 had clinical motor indications document-
ed, and 59 had respiratory indications documented (Table
3). Although many patients had indications in multiple do-
mains, the largest indication category was imaging abnor-
malities (Fig. 3). In contrast, in the birth cohort born before
1980, motor indications (n = 10) were the predominant in-
dication for the 20 patients with a documented indication,
followed by imaging (n = 9) and respiratory concerns (n =
2). When different combinations of two indication catego-
ries were examined, motor and imaging findings were the
most common combination of indications in cohorts born
before 1980 and after 1980.
The median (range) follow-up time for patients with
a CMD was 10.7 years (range 1.2–64.6 years). The me-
dian follow-up time for patients without a CMD was 11.7
years (range 0.03–70.2 years), with person-years measured
as the age at the last known contact. Most patients (78%)
had positive and uncomplicated outcomes;​11 (3.9%) did
not improve, 3 (1.0%) had worsened medical status, and
13 (4.6%) had no outcome recorded. Eight patients (2.8%)
required readmission within 1 month, and 4 (1.4%) re-
quired a repeat procedure within 1 year. Eighteen percent
of patients had at least one complication, with 4 patients
(1.4%) developing an infection, 3 (1.0%) bleeding, 3 (1.0%)
paresthesia, 2 (0.7%) poor wound healing, and 2 patients
(0.7%) developing pulmonary complication. There were
no CMD-related deaths.
Overall, 10.3% (29/281) of patients undergoing CMD
required a subsequent CMD, most commonly due to per-
sistent stenosis demonstrated by imaging or recurrence
of motor symptoms. Two patients (1.1%) had three CMDs
and 1 patient (0.4%) had four CMDs. Of repeat CMD
procedures, 41% (12/29) occurred in patients born in the
1990s (Table 4). The median time between repeat proce-
dures ranged from 2.2 to 3.0 years, and the median (range)
patient age for the second CMD was 6.1 years (range 0.8–
37.7 years) (Table 4). No correlation was found between
patient age at first CMD and the need for a second CMD
(the median age for first CMD in those requiring subse-
quent CMD was 1.2 years, with a range of 0.7-36.7 years).
JHU had the highest prevalence of subsequent CMD, with
14/83 (17%) patients requiring this procedure, followed
by AIDHC (7/73;​9.5%), UW (7/86;​8%), and UTH (1/39;​
2.6%).
Screening procedures to detect critical cervicomedul-
lary compression included PSG and imaging of the cra-
niocervical junction with MRI or CT scan. Over the entire
study period, 63.6% of patients undergoing CMD had ei-
ther PSG or MRI/CT within 4 months prior to undergoing
CMD, with 27.8% having both PSG and imaging screen-
ing (Table 5). Prior to the year 2000, 50% of patients had
one of the two screening tests, compared with 70% and
92.8% of patients in the 2000 and 2010 birth cohorts, re-
spectively.

TABLE 3. Indication categories for CMD

Neurological/Motor Respiratory Imaging
Indications Indications Indications
Excessive hypotonia Central apnea Syrinx
Excessively delayed Severe obstructive Cord indentation or oblit-
gross motor develop- apnea eration of subarach-
ment noid fluid later
Signs of myelopathy Apparent life- T2-signal abnormality in
such as abnormal threatening upper cervical cord FIG. 3. Venn diagram of indications for all first CMDs. Imaging (n = 217)
reflexes or clonus event near foramen magnum was the most common single indication, and neurological/motor and
imaging findings (n = 195) were the most common combined indications.

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TABLE 4. Description of 281 patients undergoing CMD
1st to 2nd 2nd to 3rd 3rd to 4th
CMD CMD CMD
Overall no. of pts 29 3 1
Time between repeat CMDs, yrs
Median 3.4 2.2 3.0
Mean ± SD 4.3 ± 4.1 6.1 ± 6.7 3.0
Birth decade
2010s 0 0 0 1990s
2000s 9 0 0 1980s
1990s 12 3 1
1980s 4 0 0
<1980 4 0 0
A substantial number of patients who underwent CMD
also underwent ventriculoperitoneal shunt (VPS) place-
ment, with an almost equal number having VPS before
and after the CMD. Of the 281 patients who underwent
CMD, 65 (23%;​34 males, 31 females) had VPS placement,
with 26 patients having VPS placement before CMD, 25
after CMD, and 14 concurrently with CMD. Of the 1374
PAC patients, 110 patients (64 males, 46 females) had a
total of 141 VPS surgeries. While 8% (110/1374) of the
entire cohort required VPS, 23% of patients who required
CMD also underwent VPS. The overall OR of a patient re-
quiring both a CMD and VPS after needing either surgery
was 7.0 (95% CI 4.66–10.53;​p < 0.0001). VPS placement
was less common in the 2010–2017 cohort and peaked in
the 1990s’ cohort when some surgeons placed a VPS in
conjunction with the CMD procedure to prevent a postop-
erative CSF fistula.10 Interestingly, patients who had CMD
were 1.9 times (95% CI 1.30–2.63) more likely to have
distal spine surgery later in their lives than patients who
did not undergo CMD.
Discussion
CLARITY, the large, multicenter, historical cohort
study spanning more than 60 years, showed that 20.5% of
the PAC underwent CMD. This rate falls well within pub-
lished CMD rates of 5%–41% in achondroplasia cohorts
and is similar to the 18% CMD rate reported in a recent
15-year review of achondroplasia outcomes in France.18
The similarity of the results of these studies provides im-
portant guidance information for healthcare providers and
families.
In the oldest birth cohort (those born before 1980), the
overall CMD rate (9%) was lower and CMDs were per-
formed at a much older patient age (median age 19.9 years)
than later cohorts with a median age at first CMD of 1.3
years. This outcome is not surprising, as foramen mag-
num compression and sudden death were not recognized
and reported until the 1980s.6,15,19,20 Increased surveillance
following these reports led to better recognition of this se-
vere and life-threatening problem and more CMDs, as re-
flected at these four skeletal dysplasia centers.6,14,15,19,21 The
reasons for higher rates of CMD in certain birth cohorts
Legare et al.
TABLE 5. Distribution of evaluations within 4 months of first CMD
Evaluations for CMD, %
PSG MRI/CT PSG & MRI/ PSG or
Only Only CT MRI/CT
Overall 5.7 30.1 27.8 63.6
Birth decade
2010s 5.5 30.9 56.4 92.8
2000s 5.0 38.8 26.3 70.1
5.1 27.8 15.2 48.1
8.5 21.3 23.4 53.2
<1980 5.0 35.0 15.0 55.0
at certain centers are not clear, and factors such as smaller
sample size, selection bias, and surgeon-specific indica-
tions may play a role.
Screening for cervical compression has increased over
the years and is correlated with a continuous decrease in
the median age of patients undergoing CMD (Tables 1 and
5). This is unlikely to be only a result of increased aware-
ness, since each of the study centers had played a pivotal
role in recognizing the issues related to the craniocervical
junction in achondroplasia. It is possible that earlier refer-
rals spurred by earlier (prenatal and neonatal) diagnosis
trends and better evaluation tools led to this phenomenon.
Indications for CMD dramatically changed over the
more than 40 years for which there is information in the
PAC. For patients evaluated after the year 2000, more
than 88% had an imaging finding indication for CMD,
and only one-third had neurological signs reported in the
medical record. In contrast, 50% of patients in the oldest
cohort had neurological signs/symptoms as an indication
for CMD. This change is likely related to increased rec-
ognition of foramen magnum compression and interven-
tion prior to neurological damage. Similarly, indications
for CMD related to respiratory issues have increased as
PSG screening has increased and also likely reflect better
assessment and documentation.
The outcomes from initial CMD were positive overall.
Serious complications were infrequent and, remarkably,
there were no deaths attributed to CMD surgery. These
findings complement the study results of Ho et al.,22 who
found that quality of life was not diminished in patients
who underwent CMD compared with individuals with
achondroplasia who did not require CMD surgery. How-
ever, 10% of patients undergoing CMD required a second
CMD, indicating that at least in this large cohort, 1/50
(2%) individuals with achondroplasia require more than
one CMD surgery.
A substantially larger proportion of individuals un-
dergoing CMD also had a VPS (23% compared to 8% in
the PAC). This large percentage may reflect surgical care
in earlier decades when some surgeons elected to place
a VPS concurrent with CMD surgery.9,10 Alternatively,
since individuals with severe foramen magnum constric-
tion usually have severe narrowing of the jugular foramina
(due to the same biological phenomenon), there may be
an increased occurrence of hydrocephalus secondary to
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Legare et al.
intracranial venous hypertension requiring VPS.1 Further
study is needed in this area.
There are limitations to this study. Medical records
were up to 63 years old and varied in their accessibility and
completeness such that details regarding surgery indica-
tions and outcomes may have been missing. Differences in
outcomes by birth cohort are likely influenced by changes
in training and surgical methods as well as advances in
diagnostic technologies over the long study period. MRI
and CT scan data could not be separated. We acknowl-
edge the lack of data regarding MRI indications for CMD.
We plan to analyze the MRI scans we have cataloged and
present these findings in a future paper. The CMD proce-
dure itself has changed, which may affect CMD and VPS
data. Only prospective investigations will allow for more
detailed analyses to address the questions raised in this
retrospective study.
Conclusions
In summary, CLARITY provides a rich resource for
expanding and validating the natural history of achondro-
plasia. While cervical medullary compression is a well-
documented complication in achondroplasia, our study
results demonstrate that only 20% of individuals required
CMD. This rate was consistent across study centers, virtu-
ally constant during the more recent birth decades, and
similar to the findings of a recent study in France.18 The
present study also indicates that CMD is relatively safe
and resolves neurological and life-threatening complica-
tions. Future prospective studies will focus on collecting
more details regarding the signs, symptoms, indications,
and optimal timing of surgical intervention to better im-
prove quality of life in achondroplasia.
Acknowledgments
We are indebted to all patients included in this large historical
cohort.
References
1. Pauli RM. Achondroplasia:​a comprehensive clinical review.
Orphanet J Rare Dis. 2019;​14(1):​1.
2. Sanders VR, Sheldon SH, Charrow J. Cervical spinal cord
compression in infants with achondroplasia:​should neuroim-
aging be routine? Genet Med. 2019;​21(2):​459–463.
3. Bellus GA, Hefferon TW, Ortiz de Luna RI, et al. Achondro-
plasia is defined by recurrent G380R mutations of FGFR3.
Am J Hum Genet. 1995;​56(2):​368–373.
4. Matsushita T, Wilcox WR, Chan YY, et al. FGFR3 promotes
synchondrosis closure and fusion of ossification centers
through the MAPK pathway. Hum Mol Genet. 2009;​18(2):​
227–240.
5. Pauli RM, Horton VK, Glinski LP, Reiser CA. Prospective
assessment of risks for cervicomedullary-junction compres-
sion in infants with achondroplasia. Am J Hum Genet. 1995;​
56(3):​732–744.
6. Reid CS, Pyeritz RE, Kopits SE, et al. Cervicomedullary
compression in young patients with achondroplasia:​value of
comprehensive neurologic and respiratory evaluation. J Pedi-
atr. 1987;​110(4):​522–530.
7. Rimoin DL. Cervicomedullary junction compression in in-
fants with achondroplasia:​when to perform neurosurgical
decompression. Am J Hum Genet. 1995;​56(4):​824–827.
6 J Neurosurg Pediatr June 4, 2021
8. Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the
transmembrane domain of FGFR3 cause the most common
genetic form of dwarfism, achondroplasia. Cell. 1994;​78(2):​
335–342.
9. Aryanpur J, Hurko O, Francomano C, et al. Craniocervical
decompression for cervicomedullary compression in pedi-
atric patients with achondroplasia. J Neurosurg. 1990;​73(3):​
375–382.
10. Bagley CA, Pindrik JA, Bookland MJ, et al. Cervicomedul-
lary decompression for foramen magnum stenosis in achon-
droplasia. J Neurosurg. 2006;​104(3)(suppl):​166–172.
11. Carson B, Winfield J, Wang H, et al. Surgical management of
cervicomedullary compression in achondroplastic patients.
Basic Life Sci. 1988;​48:​207–214.
12. Yamada H, Nakamura S, Tajima M, Kageyama N. Neurologi-
cal manifestations of pediatric achondroplasia. J Neurosurg.
1981;​54(1):​49–57.
13. Bland JD, Emery JL. Unexpected death of children with
achondroplasia after the perinatal period. Dev Med Child
Neurol. 1982;​24(4):​489–492.
14. Fremion AS, Garg BP, Kalsbeck J. Apnea as the sole mani-
festation of cord compression in achondroplasia. J Pediatr.
1984;​104(3):​398–401.
15. Pauli RM, Scott CI, Wassman ER Jr, et al. Apnea and sudden
unexpected death in infants with achondroplasia. J Pediatr.
1984;​104(3):​342–348.
16. Hashmi SS, Gamble C, Hoover-Fong J. Multicenter study of
mortality in achondroplasia. Am J Med Gent A. 2018;​176(11):​
2359–2364.
17. Hoover-Fong JE, Alade AY, Hashmi SS, et al. Achondropla-
sia Natural History Study (CLARITY): a multicenter retro-
spective cohort study of achondroplasia in the United States.
Genet Med. Published online May 18, 2021. doi:10.1038/
s41436-021-01165-2
18. Baujat G, Michot C, Fauroux B. Achondroplasia, a 15-year
retrospective review of outcomes in 110 French pediatric pa-
tients. Poster presented at:​14th International Skeletal Dyspla-
sia Society Meeting. September 11–14, 2019;​Oslo, Norway.
19. Hecht JT, Francomano CA, Horton WA, Annegers JF.
Mortality in achondroplasia. Am J Hum Genet. 1987;​41(3):​
454–464.
20. Hecht JT, Nelson FW, Butler IJ, et al. Computerized to-
mography of the foramen magnum:​achondroplastic values
compared to normal standards. Am J Med Genet. 1985;​20(2):​
355–360.
21. Hecht JT, Horton WA, Reid CS, et al. Growth of the foramen
magnum in achondroplasia. Am J Med Genet. 1989;​32(4):​
528–535.
22. Ho NC, Guarnieri M, Brant LJ, et al. Living with achondro-
plasia:​quality of life evaluation following cervico-medullary
decompression. Am J Med Genet A. 2004;​131(2):​163–167.
Disclosures
This research was funded through a grant from BioMarin Phar-
maceutical Inc., project ID AAB2897, contract ID 68873 v5, and
The Greenberg Center for Skeletal Dysplasias in the McKusick-
Nathans Institute of the Department of Genetic Medicine at
Johns Hopkins University (agency reference no. 2002941785,
MSN 188299). The BioMarin Pharmaceutical Inc. grant was to
Dr. Hoover-Fong with subcontracts to participating institutions.
The authors maintain ownership of the data unless further agree-
ment is pursued. Dr. Hoover-Fong, Dr. Bober, Dr. Hecht, and
Dr. Legare have participated in advisory boards sponsored by
BioMarin pertaining to achondroplasia. Dr. Hoover-Fong and Dr.
Bober have been consulted by BioMarin, Alexion, and Therachon
for clinical issues related to achondroplasia and other genetic
skeletal conditions. Dr. Bober also reports consulting for Pfizer
and Ascendis and receiving support of non–study-related clinical
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or research effort overseen by the author from BioMarin, Pfizer,
Ascendis, and QED. Dr. Hoover-Fong also reports receiving clini-
cal or research support for the study described (includes equip-
ment or material) from Pfizer. Dr. Legare has provided education
for BioMarin internal teaching conferences and been consulted
by QED Therapeutics for clinical issues related to achondroplasia.
All activities were reviewed and approved by the authors’ respec-
tive institutions. The data presented in this paper do not pertain
to the investigational pharmaceutical agent under development by
BioMarin.
Author Contributions
Conception and design: Pauli, Alade, Hecht, Hoover-Fong, Bober.
Acquisition of data: Legare, Pauli, Alade, Hashmi, Smid, Modaff,
Little, Rodriguez-Buritica, Serna. Analysis and interpretation
of data: Legare, Hashmi, Campbell, Rodriguez-Buritica,
Hecht, Hoover-Fong, Bober. Drafting the article: Legare,
Bober. Critically revising the article: Legare, Pauli, Campbell,
Rodriguez-Buritica, Hecht, Hoover-Fong, Bober. Reviewed
Legare et al.
submitted version of manuscript: all authors. Approved the
final version of the manuscript on behalf of all authors: Legare.
Statistical analysis: Legare, Liu. Administrative/technical/material
support: Modaff. Study supervision: Legare, Pauli, Alade, Hecht,
Hoover-Fong, Bober.
Supplemental Information
Previous Presentations
Some of these data were presented as a platform presentation at
the International Skeletal Dysplasia Society meeting in Oslo, Nor-
way, September 11, 2019.
Correspondence
Janet M. Legare: University of Wisconsin School of Medicine and
Public Health, Madison, WI. jmlegare@pediatrics.wisc.edu.
J Neurosurg Pediatr June 4, 2021 7
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