CLARITY - a Natural History Study of Achondroplasia in the US

Who carried out the study?
The CLARITY Natural History Study1 was conducted in the US by Dr. Julie Hoover-Fong (Professor of Genetic Medicine and Pediatrics and Director of the Greenberg Center for Skeletal Dysplasias at Johns Hopkins University).
How was this Study Conducted?
All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (or PSG, is a type of sleep study, a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine.), and imaging (e.g., X-ray, magnetic resonance imaging) from patients with achondroplasia (children and adults) evaluated by clinical geneticists at four skeletal dysplasia centers — Johns Hopkins University, A.I. duPont Hospital for Children (AIDHC), McGovern Medical School UTHealth, and University of Wisconsin — were gathered into a REDCap database (Research Electronic Data Capture — a software and workflow methodology for designing clinical and translational research databases) and included in the study to define the health risks and medical/surgical outcomes of patients with achondroplasia.
Natural history observations were presented in a statistics summary of surgical burden, growth curves comparing the achondroplasia patients with age-matched average stature peers, the prevalence of sleep disordered breathing, and general health characteristics over time to understand the chronology and interactions of health complications in achondroplasia.
What were the results?
Data from 1,374 patients (48.8% female) constitute the primary achondroplasia cohort (PAC). Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values in this registry, 1,631 PSGs and 10,727 imaging studies. Subjects were evaluated at least once between 1957 and 2017 by a clinical geneticist at one of the four academic skeletal dysplasia centers mentioned above, and of the 1,374 subjects, 496 continue to receive medical care from one of the 4 clinical sites. General characteristics of the PAC and active subjects are presented in Table 1:
Characteristic | PAC | Active | ||
---|---|---|---|---|
Total | Living | Deceased | Total | |
Participants, n | 1,374 | 1,354 | 20 | 496 |
Sex, n (%) | ||||
Male | 704 (51.2) | 696 (51.4) | 8 (40.0) | 256 (51.6) |
Female | 670 (48.8) | 658 (48.6) | 12 (60.0) | 240 (48.4) |
Age at last encounter, years | ||||
Mean ± SD | 15.4 ± 13.9 | 15.0 ± 13.3 | 39.7 ± 25.4 | 12.9 ± 12.2 |
Range | 0.0–79.7 | 0.0–71.7 | 0.3–79.7 | 0.0–71.7 |
Median (IQR) | 11.9 (5.6, 19.7) | 11.8 (5.5, 19.4) | 41.5 (18.1, 61.8) | 9.1 (4.3, 16.8) |
Clinical site, n (%) | ||||
Johns Hopkins | 299 (21.7) | 297 (21.9) | 2 (10.0) | 151 (30.4) |
AI DuPont | 384 (28.0) | 381 (28.1) | 3 (15.0) | 161 (32.5) |
Texas | 218 (15.9) | 210 (15.5) | 8 (40.0) | 27 (5.4) |
Wisconsin | 473 (34.4) | 466 (34.4) | 7 (35.0) | 157 (31.7) |
Inheritance, n (%) | ||||
De novo | 1,044 (76.0) | 1,029 (76.0) | 15 (75.0) | 392 (79.0) |
Inherited | 191 (13.9) | 190 (14.0) | 1 (5.0) | 73 (14.7) |
Unknown | 139 (10.1) | 135 (10.0) | 4 (20.0) | 31 (6.3) |
Adopted, n (%) | 86 (6.3) | 41 (8.3) | ||
Gestational, n (%) | ||||
Preterm | 174 (12.7) | 174 (12.9) | 0 | 71 (14.3) |
Term | 1,008 (73.5) | 997 (73.6) | 11 (55.0) | 379 (76.4) |
Post term | 15 (1.1) | 15 (1.1) | 0 | 1 (0.2) |
Unknown | 177 (12.8) | 168 (12.4) | 9 (45.0) | 45 (9.1) |
Limb lengthening, n (%) | 17 (1.2) | 17 (1.3) | 0 | 5 (1.0) |
GH deficiency, n (%) | 4a (0.3) | 4 (0.3) | 0 | 2 (0.4) |
GH treatment, n (%) | 2b (0.1) | 2 (01) | 0 | 0 |
Trial participants, n (%) | 12 (0.8) | 12 (0.8) | 0 | 12 (2.4) |
Table 2 shows the decade of birth of the population studied. There is limited information about the timing and precise clinical means (e.g., radiographs, family history, ultrasound) of diagnosis in the oldest patients due to missing records and/or loss to follow-up care, which reflectes in a higher proportion of “unknown” mode of diagnosis. However, all individuals included in the study had a clear diagnosis of achondroplasia as determined by a clinical geneticist.
Table 2 Population characteristics by 10-year birth
Characteristic
|
Birth decade
| |||||
---|---|---|---|---|---|---|
Before 1980
|
1980s
|
1990s
|
2000s
|
After 2010
|
Total
| |
Population distribution, n
|
||||||
PAC
|
234
|
231
|
314
|
356
|
239
|
1,374
|
Active
|
29
|
25
|
66
|
177
|
199
|
496
|
Deceased
|
15
|
3
|
2
|
0
|
0
|
20
|
Age at last encounter, years
|
||||||
Mean
|
34.9
|
17.7
|
14.8
|
9.7
|
3.4
|
15.4
|
Range
|
0.3-79.7
|
0.5-36.9
|
0-27.3
|
0.4-17.3
|
0.0-7.4
|
0.0-79.7
|
Median (IQR)
|
36.6 (17.8, 50.0)
|
17.4 (9.9, 26.1)
|
16.5 (9.9, 20.1)
|
9.7 (7.1, 12.3)
|
3.2 (1.9, 4.9)
|
11.9 (5.6, 19.7)
|
Timing of diagnosis, n (%)
|
||||||
Prenatal
|
0 (0)
|
13 (5.6)
|
53 (16.9)
|
73 (20.5)
|
76 (31.8)
|
215 (15.6)
|
At birth
|
40 (17.1)
|
64 (27.7)
|
72 (22.9)
|
100 (28.1)
|
67 (28.0)
|
343 (25.0)
|
24 hours–1 month
|
16 (6.8)
|
42 (18.2)
|
51 (16.2)
|
74 (20.8)
|
39 (16.4)
|
222 (16.2)
|
>1 month
|
51 (21.8)
|
39 (16.9)
|
86 (27.4)
|
80 (22.5)
|
45 (18.8)
|
301 (21.9)
|
Unknown
|
127 (54.3)
|
73 (31.6)
|
52 (16.6)
|
29 (8.1)
|
12 (5.0)
|
293 (21.3)
|
Mode of diagnosis, n (%)
|
||||||
Molecular only
|
1 (0.4)
|
2 (0.9)
|
10 (3.2)
|
17 (4.8)
|
19 (7.9)
|
49 (3.6)
|
Clinical ± molecular
|
85 (36.3)
|
138 (59.7)
|
239 (76.1)
|
315 (88.5)
|
213 (89.1)
|
990 (72.1)
|
Unknown
|
148 (63.3)
|
91 (39.4)
|
65 (20.7)
|
24 (6.7)
|
7 (3.0)
|
335 (24.3)
|
Next, Table 3 indicates the number of anthropometric data points extracted from the medical records of the studied population, as well as the number of subjects who contributed those points in each age category. Across all age categories, 1,365 (99.3%) subjects contributed at least one anthropometric value to this database for a total of 37,016 anthropometry data points available for analysis:
Table 3 — Number of length/height, weight, and head circumference values by age group
Anthropometry
|
Age at last known contact
| |||
---|---|---|---|---|
<10 years
|
≥10 to 18 years
|
≥18 years
|
Total
| |
|
Points/subjects
|
Points/subjects
|
Points/subjects
|
Points/subjects
|
Length/height
|
4,725/565
|
4,466/369
|
3,553/384
|
12,744/1,318
|
Weight
|
5,582/555
|
5,160/361
|
4,217/376
|
14,959/1,292
|
Head circumference
|
3,610/558
|
3,269/366
|
2,434/315
|
9,313/1,239
|
Total
|
13,917/579
|
12,895/374
|
10,204/412
|
37,016/1,365
|
There were 1,094 (79.6%) subjects who had at least one surgical procedure in the five achondroplasia-related surgical categories of ENT (disorders of the ears, nose, and throat), brain, foramen magnum, spine, and extremities. 594 (54.3%) had one achondroplasia-related surgery, 359 (32.8%) had two, 103 (9.4%) had three, 29 (2.7%) had four, and 9 (0.8%) had at least one surgical procedure in all five categories. Of the remaining 280 subjects, 167 (12.2%) never had an achondroplasia-related surgery and the surgical history is unknown for the remaining 113 subjects (8.2%). The surgical burden of the 1,374 subjects with achondroplasia is shown in Table 4:
Table 4 Achondroplasia-related surgical categories
≥1 Achondroplasia-related surgery
|
Procedures
|
Subjects, n (%)
|
---|---|---|
Yes (ever)
|
4,552
|
1,094 (79.6)
|
No (never)
|
|
167 (12.2)
|
Unknown
|
|
113 (8.2)
|
Total
|
|
1,374
|
Surgical category
|
||
Ear, nose, and throat
|
2,803
|
893 (65.0)
|
Brain
|
326
|
137 (10.0)
|
Foramen magnum + C1/C2
|
314
|
281 (20.5)
|
Spine
|
425
|
175 (12.7)
|
Extremity
|
684
|
291 (21.2)
|
Regarding PSG, there is a trend in recent decades towards testing at a younger age, as Table 5 shows. This study was able to gather 1,631 polysomnograms of 677 subjects:
|
Before 1980
|
1980-90
|
1990–00
|
2000-–10
|
After 2010
|
Total
|
---|---|---|---|---|---|---|
Subjects born in decade, n
|
234
|
231
|
314
|
356
|
239
|
1,374
|
Obstructive sleep apnea diagnosis, n
|
||||||
Confirmed by PSG
|
26
|
31
|
72
|
164
|
138
|
429 (31.2)
|
Denied by PSG
|
10
|
31
|
44
|
63
|
46
|
195 (14.2)
|
Inconclusive PSG
|
7
|
32
|
13
|
8
|
5
|
38 (2.8)
|
Suspected by medical history
|
13
|
22
|
53
|
32
|
11
|
131 (9.5)
|
Unknown
|
178
|
141
|
132
|
89
|
41
|
581 (42.3)
|
Age first PSG, years, mean ± SD
|
31.1 ± 16.9
|
5.6 ± 7.9
|
3.0 ± 4.2
|
2.2 ± 3.1
|
0.8 ± 0.9
|
3.8 ± 8.4
|
≥1 PSG, n (%)
|
35 (15.0)
|
79 (34.2)
|
127 (40.4)
|
242 (68.0)
|
194 (81.2)
|
677 (49.3)
|
Subjects with moderate or severe OSA
|
||||||
≥1 PSG, n (%)
|
16 (45.7)
|
16 (20.3)
|
38 (30.0)
|
99 (40.9)
|
91 (46.9)
|
260 (38.4)
|
Conclusions
This is the largest multicentre natural history study of achondroplasia, providing a registry spanning over 40 years of follow-up data with a wide range of medical information for use in the care of these patients. This well phenotyped cohort is a reference population with which future medical and surgical interventions can be studied and compared in order to improve anticipatory guidance and patient care.
The natural history of this cohort may be utilized as a baseline comparison for future studies of novel pharmacologic, medical, and surgical interventions.
Anthropometric data indicates that linear growth deviates from mean stature by 6 months of age, although weight is the same of age-matched peers of mean stature. Further study of these trends in adulthood is needed to determine whether excess weight is connected with negative health outcomes (such as hypertension or coronary heart disease) in achondroplasia as in middle stature. Identification in childhood of those at risk of adult obesity would be extremely useful for early intervention.2
Another important conclusion to be drawn is that, as surgical data show, there is a heavy surgical burden in achondroplasia. Almost 80% of patients had at least one surgery. Regarding sleep disordered breathing there are more polysomnograms available in recent decades as awareness of this achondroplasia-related problem increased. In average stature the prevalence is 5% in children,3 and 22% and 17% in adult men and women,4 respectively, while 38.4% of the PAC have moderate to severe OSA.
The main strengths of this study:
- The size of this natural history cohort
- The follow-up of more than four decades
- The uniform collection of data by medical providers with extensive experience in achondroplasia care.
The CLARITY Natural History Study has shown the feasibility of collecting clinical data across multiple institutions in a uniform manner. As said by the authors, "to explore these data with multivariate analysis and (...) expand this study to compare global differences in healthcare resources and practices (...) the knowledge gained will be invaluable for patients, their families and healthcare providers everywhere to better prepare for complications and improve clinical outcomes".
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References
1. Hoover-Fong, J.E., Alade, A.Y., Hashmi, S.S. et al. Achondroplasia Natural History Study (CLARITY): a multicenter retrospective cohort study of achondroplasia in the United States. Genet Med 23, 1498–1505 (2021). https://doi.org/10.1038/s41436-021-01165-2
2. Hoover-Fong, J. et al. Blood pressure in adults with short stature dysplasias. Am. J. Med. Genet. A. 182, 150–161 (2020).
3. Marcus, C. L. et al. for American Academy of Pediatrics. Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 130, e714–e755 (2012).
4. Franklin, K. A. & Eva Lindberg, E. Obstructive sleep apnea is a common disorder in the population—a review on the epidemiology of sleep apnea. J. Thorac. Dis. 7, 1311–1322 (2015).