Achondroplasia Natural History Study (CLARITY): 60-Year Experience in Orthopedic Surgery from Four Skeletal Dysplasia Centers

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery

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

Achondroplasia Natural History Study (CLARITY): 60-Year Experience in Orthopedic Surgery from Four Skeletal Dysplasia Centers

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery

Achondroplasia natural history study (CLARITY): 60-year experience in orthopedic surgery from four skeletal dysplasia centers

BACKGROUND: The purpose of this study was to describe the frequency and risk factors for orthopedic surgery in patients with achondroplasia. CLARITY (The Achondroplasia Natural History Study) includes clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the United States from 1957 to 2018. Data were entered and stored in a Research Electronic Data Capture (REDCap) database. RESULTS: Information from one thousand three hundred and seventy-four patients with achondroplasia were included in this study. Four hundred and eight (29.7%) patients had at least one orthopedic surgery during their lifetime and 299 (21.8%) patients underwent multiple procedures. 12.7% (n = 175) of patients underwent spine surgery at a mean age at first surgery of 22.4 ± 15.3 years old. The median age was 16.7 years old (0.1-67.4). 21.2% (n = 291) of patients underwent lower extremity surgery at a mean age at first surgery of 9.9 ± 8.3 years old with a median age of 8.2 years (0.2-57.8). The most common spinal procedure was decompression (152 patients underwent 271 laminectomy procedures), while the most common lower extremity procedure was osteotomy (200 patients underwent 434 procedures). Fifty-eight (4.2%) patients had both a spine and lower extremity surgery. Specific risk factors increasing the likelihood of orthopedic surgery included: patients with hydrocephalus requiring shunt placement having higher odds of undergoing spine surgery (OR 1.97, 95% CI 1.14-3.26); patients having a cervicomedullary decompression also had higher odds of undergoing spine surgery (OR 1.85, 95% CI 1.30-2.63); and having lower extremity surgery increased the odds of spine surgery (OR 2.05, 95% CI 1.45-2.90). CONCLUSIONS: Orthopedic surgery was a common occurrence in achondroplasia with 29.7% of patients undergoing at least one orthopedic procedure. Spine surgery (12.7%) was less common and occurred at a later age than lower extremity surgery (21.2%). Cervicomedullary decompression and hydrocephalus with shunt placement were associated with an increased risk for spine surgery. The results from CLARITY, the largest natural history study of achondroplasia, should aid clinicians in counseling patients and families about orthopedic surgery

Apparently benign craniocervical signs in achondroplasia: “neurologic leftovers” identified through a retrospective dataset

AbstractBackgroundAchondroplasia is the most common dwarfing disorder. It can result in a variety of sequelae, including neurologic complications, among which high cervical myelopathy is one of particular concern. However, some individuals with achondroplasia appear to have persistent signs by physical examination that, while they might suggest the presence of high cervical myelopathy, remain isolated, non-progressive and apparently benign. To document and quantify these apparently benign craniocervical signs (ABCS) a cohort of 477 individuals with achondroplasia was retrospectively analyzed and information regarding persistent neurologic features suggestive of high cervical myelopathy was recorded in a REDCap database.ResultsWithin this cohort, 151 individuals (31.7%) had neurologic examinations that were in some manner concerning. Of these, 46 (30.5% of the subpopulation) required cervicomedullary decompressive surgery. The remaining 105 had concerning signs by examination but no apparent evidence for clinically significant cervical myelopathy. Of those 105 individuals, 88 (83.8%; 18.4% of the entire population) remained neurologically intact throughout their follow-up, and without clinical sequelae.ConclusionsIt appears that many individuals with achondroplasia, if carefully examined, may demonstrate isolated, initially concerning signs suggestive of cervical myelopathy, but in the vast majority these are benign and do not indicate need for aggressive neurosurgical intervention. Further investigations may help to identify ways to differentiate these benign features from the less common but more problematic true myelopathic ones. We postulate that the “neurologic leftovers” may arise from temporally remote, subtle damage to the spinal cord at the craniocervical junction, which damage otherwise does not reach clinical relevance.</jats:sec

Pelger-huet anomaly and a mild skeletal phenotype secondary to mutations in LBR

The Lamin B receptor (LBR) gene has been described to encode a bifunctional protein. Mutations in the LBR gene can affect neutrophil segmentation and sterol reductase activity and have been associated with two different recognized clinical conditions, Pelger-Huet anomaly (PHA) and Greenberg skeletal dysplasia. PHA is a benign autosomal co-dominant laminopathy resulting in bilobed neutrophil nuclei in heterozygotes, and unsegmented (ovoid) neutrophil nuclei in homozygotes. Some putative PHA homozygotes have been reported with minor skeletal malformations. Greenberg skeletal dysplasia is a severe autosomal recessive, perinatal lethal dwarfing disorder in which heterozygous carriers are usually without clinical manifestations. We here report a girl who has bilobed neutrophil nuclei and a mild skeletal dysplasia. Mutation analysis showed two novel mutations in the LBR gene: c.651_653 delinsTGATGAGAAA (p.Ile218Aspfs*19) and c.1757G > A (p.Arg586His). These mutations were found to be in trans, and, thus, she is a compound heterozygote. Sterol analysis found trace amounts of cholesta-8,14-dien-3beta-ol, which is normally undetected in healthy individuals. This and previously reported cases suggest that mutations in LBR can result in a continuum of phenotypic manifestation

Real-world effectiveness of burosumab in children with X-linked hypophosphatemic rickets

Background: X-linked hypophosphatemic rickets (XLH) is the most common cause of inherited rickets. Historically, XLH was treated with oral phosphate and calcitriol (conventional treatment). Burosumab, a fibroblast growth factor 23 (FGF-23) monoclonal antibody, was approved by the United States Food and Drug Administration (FDA) in 2018 for XLH treatment. Nevertheless, conventional treatment of XLH continues to be recommended by some specialists due to lack of published experience with burosumab in the clinical setting. We compared laboratory and radiographic changes observed following transition from conventional therapy to burosumab in pediatric XLH patients as part of routine care. Methods: This retrospective single-center study identified and retroactively studied twelve patients aged 1-18 years old with XLH previously treated with conventional therapy and transitioned to burosumab. Laboratory studies and radiographs were obtained routinely as standard of care during two treatment periods: (1) conventional therapy and (2) burosumab treatment. Laboratory values and radiologic rickets severity scores were compared between periods. Results: All laboratory values demonstrated improvement following 1 month of burosumab treatment, findings which were sustained over the 2-year study period. Rickets severity scores and height z-scores also improved with burosumab. There were no serious adverse events with burosumab, and adverse events overall were very infrequent and mild. One patient developed an asymptomatic mild elevation of serum phosphate while taking burosumab resulting in a temporary pause in therapy. Conclusions: Safety and effectiveness of burosumab in treatment of XLH were demonstrated as burosumab yielded statistically significant improvement in laboratory and radiographic markers of rickets and height compared to conventional therapy. A higher resolution version of the Graphical abstract is available as Supplementary information

Typical achondroplasia secondary to a unique insertional variant of FGFR3 with in vitro demonstration of its effect on FGFR3 function

We describe an individual in whom clinical and radiographic features are typical for achondroplasia, but in whom the common variants of FGFR3 that result in achondroplasia are absent. Whole exome sequencing demonstrated a novel, de novo 6 base pair tandem duplication in FGFR3 that results in the insertion of Ser-Phe after position Leu324. in vitro studies showed that this variant results in aberrant dimerization, excessive spontaneous phosphorylation of FGFR3 dimers and excessive, ligand-independent tyrosine kinase activity. Together, these data suggest that this variant leads to constitutive disulfide bond-mediated dimerization, and that this, surprisingly, occurs to an extent similar to the neonatal lethal thanatophoric dysplasia type I Ser249Cys variant