Achondroplasia Natural History Study (CLARITY): a multicenter retrospective cohort study of achondroplasia in the United States.

PURPOSE: Achondroplasia is the most common short stature skeletal dysplasia (1:20,000-30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. METHODS: Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. RESULTS: Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. 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, 1,631 PSGs and 10,727 imaging studies. CONCLUSION: This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared.

CLARITY: Co-occurrences in achondroplasia-craniosynostosis, seizures, and decreased risk of diabetes mellitus.

Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.

Blood pressure in adults with short stature skeletal dysplasias.

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.

Acanthosis nigricans in achondroplasia.

Acanthosis nigricans (AN) in those with achondroplasia has been reported occasionally in the literature previously. Other disorders arising from constitutive activation of FGFR3 also manifest AN at various frequencies. We assessed the prevalence of AN in a sequential series of 477 individuals with achondroplasia. Using a REDCap database, we collected and analyzed what other features or medical issues may co-occur with AN in those with achondroplasia. AN arises in approximately 10% of individuals with achondroplasia. It usually first appears in preadolescence or adolescence, is more likely in the non-White population and in those who are obese. It is not severe and generally will need no treatment. It is not associated with any evident risk for neither hyperinsulinemic states nor malignancy, and therefore, no special investigations are warranted when it is recognized. Thus, clinicians should not be surprised or concerned upon discovering this finding in those with achondroplasia. In addition, the mechanisms and genetic causes of AN are detailed.

Multicenter study of mortality in achondroplasia.

Sudden death and higher mortality are recognized in achondroplasia, with acute brainstem compression, a common cause of mortality in children <4 years and cardiovascular deaths being more prevalent in adults. Although, changes in clinical management have improved survival, mortality is still higher than in the general population. The aim of this multicenter clinic-based study was to assess the rate and causes of mortality in patients seen in clinic since 1986. Information was ascertained for achondroplasia patients clinically assessed in four skeletal dysplasia clinics. Data was sent to the National Death Index to identify vital status and cause of death. Standardized mortality rates (SMR) were calculated based on U.S. populations from 1975, 1995, and 2000. Eight hundred fifty-five patients were identified, contributing 12,117 person-years and a total of 12 deaths. One case died in infancy. In the 1-4 year age group, which had the highest age-adjusted SMR, three out of five deaths were because of cerebrovascular/cardiovascular events. Half the deaths in ages 5 through 24 were because of accidental events, including motor vehicle accidents. Decreased mortality in children with achondroplasia was noted, particularly in younger age groups. This improvement in childhood survival is outpaced by improved survival in the general population. Causes of death in these patients have shifted over the last 30 years, with fewer sudden death and deaths because of pneumonia or hydrocephalus countered by more cardiovascular or cerebrovascular and accidental deaths. Clinicians should be aware of the apparent increased risk of vehicular accidents and counsel patients accordingly.

A height-for-age growth reference for children with achondroplasia: Expanded applications and comparison with original reference data.

The height-for-age (HA) reference currently used for children with achondroplasia is not adaptable for electronic records or calculation of HA Z-scores. We report new HA curves and tables of mean and standard deviation (SD) HA, for calculating Z-scores, from birth-16 years in achondroplasia. Mixed longitudinal data were abstracted from medical records of achondroplasia patients from a single clinical practice (CIS, 1967-2004). Gender-specific height percentiles (5, 25, 50, 75, 95th) were estimated across the age continuum, using a 2 month window per time point smoothed by a quadratic smoothing algorithm. HA curves were constructed for 0-36 months and 2-16 years to optimize resolution for younger children. Mean monthly height (SD) was tabulated. These novel HA curves were compared to reference data currently in use for children with achondroplasia. 293 subjects (162 male/131 female) contributed 1,005 and 932 height measures, with greater data paucity with age. Mean HA tracked with original achondroplasia norms, particularly through mid-childhood (2-9 years), but with no evidence of a pubertal growth spurt. Standard deviation of height at each month interval increased from birth through 16 years. Birth length was lower in achondroplasia than average stature and, as expected, height deficits increased with age. A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z-score calculations. This is an important contribution to clinical care and research endeavors for the achondroplasia population.

Achondroplasia Natural History Study (CLARITY): 60-year experience in cervicomedullary decompression in achondroplasia from four skeletal dysplasia centers.

OBJECTIVE: The authors sought to determine the overall incidence of cervicomedullary decompression (CMD) in patients with achondroplasia and the characteristics associated with those surgeries across multiple institutions with experience 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, complications, 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 patients 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 required 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 modalities increased over time, suggesting that increased and better surveillance contributed to earlier identification and intervention in patients with cervicomedullary stenosis and its complications.

Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study-a multi-center retrospective cohort study of achondroplasia in the US.

BACKGROUND: Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface retrusion, macrocephaly and a generalized spondylometaphyseal dysplasia which manifest as spinal cord compression, sleep disordered breathing, delayed motor skill acquisition and genu varus with musculoskeletal pain. To better understand the interactions and health outcomes of these potential complications, we embarked on a multi-center, natural history study entitled CLARITY (achondroplasia natural history study). One of the CLARITY objectives was to develop growth curves (length/height, weight, head circumference, weight-for-height) and corresponding reference tables of mean and standard deviations at 1 month increments from birth through 18 years for clinical use and research for achondroplasia patients. METHODS: All available retrospective anthropometry data including length/height, weight and head circumference from achondroplasia patients were collected at 4 US skeletal dysplasia centers (Johns Hopkins University, AI DuPont Hospital for Children, McGovern Medical School University of Texas Health, University of Wisconsin School of Medicine and Public Health). Weight-for-age values beyond 3 SD above the mean were excluded from the weight-for-height and weight-for-age curves to create a stricter tool for weight assessment in this population. RESULTS: Over 37,000 length/height, weight and head circumference measures from 1374 patients with achondroplasia from birth through 75 years of age were compiled in a REDCap database. Stature and weight data from birth through 18 years of age and head circumference from birth through 5 years of age were utilized to construct new length/height-for-age, weight-for-age, head circumference-for-age and weight-for-height curves. CONCLUSION: Achondroplasia-specific growth curves are essential for clinical care of growing infants and children with this condition. In an effort to provide prescriptive, rather than purely descriptive, references for weight in this population, extreme weight values were omitted from the weight-for-age and weight-for-height curves. This well-phenotyped cohort may be studied with other global achondroplasia populations (e.g. Europe, Argentina, Australia, Japan) to gain further insight into environmental or ethnic influences on growth.