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Charles I. Scott - One of the best experts on this subject based on the ideXlab platform.
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Health Supervision for People With Achondroplasia.
Pediatrics, 2020Co-Authors: Julie Hoover-fong, Charles I. Scott, Marilyn C. JonesAbstract:Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential medical complications associated with Achondroplasia include lower extremity long bone bowing, middle-ear dysfunction, obstructive sleep apnea, and, more rarely, cervicomedullary compression, hydrocephalus, thoracolumbar kyphosis, and central sleep apnea. This is the second revision to the original 1995 health supervision guidance from the American Academy of Pediatrics for caring for patients with Achondroplasia. Although many of the previously published recommendations remain appropriate for contemporary medical care, this document highlights interval advancements in the clinical methods available to monitor for complications associated with Achondroplasia. This document is intended to provide guidance for health care providers to help identify individual patients at high risk of developing serious sequelae and to enable intervention before complications develop.
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a height for age growth reference for children with Achondroplasia expanded applications and comparison with original reference data
American Journal of Medical Genetics Part A, 2017Co-Authors: Julie Hooverfong, J Mcgready, Kerry Schulze, Adekemi Yewande Alade, Charles I. ScottAbstract: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.
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age appropriate body mass index in children with Achondroplasia interpretation in relation to indexes of height
The American Journal of Clinical Nutrition, 2008Co-Authors: Julie Hooverfong, J Mcgready, Kerry Schulze, Hillary Barnes, Charles I. ScottAbstract:Background Achondroplasia is the most common short stature skeletal dysplasia, with an estimated worldwide prevalence of 250 000. Body mass index (BMI)-for-age references are required for weight management guidance for children with Achondroplasia, whose body proportions are unlike those of the average stature population. Objective This study used weight and height data in a clinical setting to derive smoothed BMI-for-age percentile curves for children with Achondroplasia and explored the relation of BMI with its components, weight and height. Design This was a longitudinal observational study of anthropometric measures of children with Achondroplasia from birth through 16 y of age. Results The analysis included 1807 BMI data points from 280 children (155 boys, 125 girls) with Achondroplasia. As compared with the BMI of peers of average stature, the BMI in children with Achondroplasia is higher at birth, lacks a steep increase in infancy and a later nadir between 1 and 2 y of age, and remains substantially higher through 16 y of age in both sexes. Patterns of change in height and weight in children with Achondroplasia are unique in that there is no overlap in the height distribution after 6 mo of age and no spike in height velocity during infancy or puberty-the 2 periods of greatest linear growth in individuals of average stature. Conclusions Sex- and age-specific BMI curves are available for children with Achondroplasia (birth to 16 y of age) for health surveillance and future research to determine associations with health outcomes (eg, cardiovascular disease, diabetes, and indication for and outcome of surgery).
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
Andrew R. Zinn - One of the best experts on this subject based on the ideXlab platform.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
Richard M Pauli - One of the best experts on this subject based on the ideXlab platform.
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Achondroplasia Natural History Study (CLARITY): a multicenter retrospective cohort study of Achondroplasia in the United States
Genetics in Medicine, 2021Co-Authors: Julie E. Hoover-fong, Jacqueline T. Hecht, Janet M Legare, Peggy Modaff, Mary Ellen Little, J Mcgready, Adekemi Y. Alade, S. Shahrukh Hashmi, Chengxin Liu, Richard M PauliAbstract: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.
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clarity co occurrences in Achondroplasia craniosynostosis seizures and decreased risk of diabetes mellitus
American Journal of Medical Genetics Part A, 2021Co-Authors: Janet M Legare, Richard M Pauli, Jacqueline T. Hecht, Michael B Bober, Cory J Smid, Peggy Modaff, Mary Ellen Little, David Rodriguezburitica, Maria Elena SernaAbstract: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.
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acanthosis nigricans in Achondroplasia
American Journal of Medical Genetics Part A, 2018Co-Authors: Cory J Smid, Janet M Legare, Peggy Modaff, Adekemi Yewande Alade, Richard M PauliAbstract: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.
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Double heterozygosity in bone growth disorders: four new observations and review.
American journal of medical genetics. Part A, 2003Co-Authors: Maureen A Flynn, Richard M PauliAbstract:Because matings between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. We summarize seven occurrences of four combinations of double heterozygosity (Achondroplasia/spondyloepiphyseal dysplasia congenita, Achondroplasia/pseudoAchondroplasia, Achondroplasia/osteogenesis imperfecta type I, Achondroplasia/hypochondroplasia (non-FGFR3)), and review additional reports from the literature. Each of the eight different examples of double heterozygosity for bone growth disorders now reported results in distinct phenotypic features, differing severity, and disparate expectations. We document the natural history of each. The genetic processes underlying these disorders also are examined to assess whether knowledge of molecular mechanisms can be used to predict clinical severity.
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Double heterozygosity in bone growth disorders: Four new observations and review
American Journal of Medical Genetics Part A, 2003Co-Authors: Maureen A Flynn, Richard M PauliAbstract:Because matings between individuals of small stature is common, information regarding double heterozygosity for dominantly inherited bone growth disorders is of considerable importance. We summarize seven occurrences of four combinations of double heterozygosity (Achondroplasia/spondyloe-piphyseal dysplasia congenita, Achondroplasia/pseudoAchondroplasia, Achondroplasia/ osteogenesis imperfecta type I, Achondroplasia/hypochondroplasia (non-FGFR3)), and review additional reports from the literature. Each of the eight different examples of double heterozygosity for bone growth disorders now reported results in distinct phenotypic features, differing severity, and disparate expectations. We document the natural history of each. The genetic processes underlying these disorders also are examined to assess whether knowledge of molecular mechanisms can be used to predict clinical severity. 2003 Wiley-Liss, Inc.
Gary A. Bellus - One of the best experts on this subject based on the ideXlab platform.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American journal of medical genetics. Part A, 2003Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.
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Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and Achondroplasia or hypochondroplasia.
American Journal of Medical Genetics Part A, 2002Co-Authors: Judith L. Ross, Charles I. Scott, Giedre Grigelioniene, Gary A. Bellus, Jack Abboudi, Andrew R. ZinnAbstract:We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had Achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with Achondroplasia. The phenotypes of combined LWD and Achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development. © 2002 Wiley-Liss, Inc.
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mutations in fibroblast growth factor receptor 3 in sporadic cases of Achondroplasia occur exclusively on the paternally derived chromosome
American Journal of Human Genetics, 1998Co-Authors: Douglas J Wilkin, Gary A. Bellus, Shirley Henderson, Jinny Szabo, Rhoda Cameron, Michelle L Mack, Ilkka Kaitila, John LoughlinAbstract:More than 97% of Achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of Achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the Achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the Achondroplasia mutation site. Ninety-nine families, each with a sporadic case of Achondroplasia in a child, were analyzed in this study. In this population, the Achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of Achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations.
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localization of the Achondroplasia gene to the distal 2 5 mb of human chromosome 4p
Human Molecular Genetics, 1994Co-Authors: Clalr A Francomano, Gary A. Bellus, Deborah A. Meyers, Rosa Ortiz De Luna, Timothy W Hefferon, Caria E Turner, Eugene W Taylor, Susan H Blanton, Jeffrey C Murray, Lain MclntoshAbstract:: Achondroplasia has been mapped to 4p16.3 using 18 multigenerational families with Achondroplasia and 10 short tandem repeat polymorphic markers from this region. No evidence of genetic heterogeneity was found. Analysis of a recombinant family localizes the Achondroplasia locus to the 2.5 Mb region between D4S43 and the telomere. Multipoint linkage analysis favors placement telomeric of D4S412. The establishment of closely linked markers will facilitate positional cloning of the Achondroplasia gene and permit prenatal diagnosis of homozygous Achondroplasia for at risk couples.
Avner Yayon - One of the best experts on this subject based on the ideXlab platform.
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Effect of PPADS on achondroplasic chondrocytes: inhibition of FGF receptor type 3 over-activity.
European journal of pharmacology, 2008Co-Authors: Ana Guzman-aranguez, Almudena Crooke, Avner Yayon, Jesús PintorAbstract:Achondroplasia, results from a mutation in the FGF receptor type 3, leading to receptor hyperactivation and subsequent amplification of FGF receptor type 3 signals. We have tested the ability of pyridoxal-5'-phosphate-6-azophenyl-2', 4'-disulfonate (PPADS) to decrease the overactivation and signalling of FGF receptor type 3 in achondroplasic chondrocytes. PPADS reduced the tyrosine phosphorylation of FGF receptor type 3 triggered by fibroblast growth factor 9 (FGF9) (50% reduction), as well as the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway. As a consequence of this inhibitory effect on ERK1/2 activity the loss of extracellular matrix was also reversed by PPADS. The action of PPADS seems to be due to a mechanism independent of P2 receptor antagonism.
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short communication effect of ppads on achondroplasic chondrocytes inhibition of fgf receptor type 3 over activity
2008Co-Authors: Ana Guzmanaranguez, Almudena Crooke, Avner Yayon, Jesús PintorAbstract:AbstractAchondroplasia, results from a mutation in the FGF receptor type 3, leading to receptor hyperactivation and subsequent amplification of FGFreceptor type 3 signals. W e have tested the ability of pyridoxal-5'-phosphate-6-azophenyl-2', 4'-disulfonate (PP ADS) to decrease theoveractivation and signalling of FGF receptor type 3 in achondroplasic chondrocytes. PP ADS reduced the tyrosine phosphorylation of FGFreceptor type 3 triggered by fibroblast growth factor 9 (FGF9) (50% reduction), as well as the activation of extracellular signal-regulated kinases 1and 2 (ERK1/2) pathway . A s a consequence of this inhibitory effect on ERK1/2 activity the loss of extracellular matrix was also reversed byPP ADS. The action of PP ADS seems to be due to a mechanism independent of P2 receptor antagonism.© 2008 Elsevier B.V . All rights reserved. Keywor ds: Achondroplasia ; Chondroc ytes; FGF receptor type 3; ERK1/2; PP ADS 1. IntroductionAchondropl asia is one of the most repres entative types ofcongeni tal skele tal dysplasias . In this pathol ogy the mut antrecept or (FGF receptor type 3
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P2Y receptors activated by diadenosine polyphosphates reestablish Ca2+ transients in achondroplasic chondrocytes
Bone, 2007Co-Authors: Ana Guzman-aranguez, Avner Yayon, Marta Irazu, Jesús PintorAbstract:Achondroplasia is the most common type of dwarfism, characterised by a mutation in the gene that encodes the fibroblast growth factor receptor 3 (FGFR3). Achondroplasia mainly affects the chondrocytes and therefore bones do not grow properly since intracellular pathways are altered. In this sense, defective calcium signaling by mutant FGFR3 has been previously described. The purpose of this study was to investigate the presence of purinergic P2Y receptors and how the activation of these receptors can have influence on defective calcium signaling observed in achondroplasic chondrocytes. The presence of P2Y receptors was determined by immunocytochemical and western blot techniques. Calcium mobilization after stimulation with nucleotides, dinucleotides, or, FGF9 application, was measured using the ratiometric dye fura-2/AM and fluorescence imaging. Our results demonstrate the expression of P2Y1, P2Y2, P2Y6 and P2Y11 receptors in achondroplasic chondrocytes, as well as the activation of these receptors after nucleotides and dinucleotides exposure. The altered calcium signaling of achondroplasic chondrocytes was confirmed, since FGF9 treatment fails to induce calcium mobilization. However, achondroplasic chondrocytes pre-treated with Ap4A are able to respond with increases in intracellular calcium after FGF9 stimulation. These findings show the rescue effect of diadenosine tetraphosphate (Ap4A), acting by means of P2Y receptors, on defective calcium response triggered by achondroplasic FGFR3.
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fibroblast growth factor receptor 3 as a therapeutic target for Achondroplasia genetic short limbed dwarfism
Current Drug Targets, 2003Co-Authors: David Aviezer, Myriam Golembo, Avner YayonAbstract:Achondroplasia, the most common form of human dwarfism is a sporadic autosomal dominant condition that occurs in approximately 1:20,000 births. The major clinical outcome of Achondroplasia is attenuated growth, rhizomelic shortening of the long bones and craniofacial abnormalities. As of today there is no pharmacological treatment for Achondroplasia. Some improvement in the patients well being and daily function can be achieved by a surgical limb lengthening procedure. Growth hormone treatment seems to have only modest short term success and to lack long term benefits. Achondroplasia results from a single point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, there is a Glycine to Arginine substitution at position 380 within the FGFR-3 transmembrane domain leading to receptor overactivation. This FGF receptor tyrosine kinase is expressed by chondrocytes in the growth plate of developing long bones and plays a crucial role in bone growth. Genetic disruption of the FGFR-3 gene in mice leads to a remarkable increase in the length of the vertebral column and long bones. This suggests that overaction of FGFR3 signaling may specifically impair chondrocyte function within the epiphyseal growth plates and cause Achondroplasia. Reconstituted normal bone growth may therefore be achieved by attenuation of FGFR3 signaling in the appropriate cells within the growth plate. It is highly conceivable that drug development strategies aimed either towards blocking extracellular ligand binding or towards intracellular checkpoints along the FGF signal transduction cascade, may prove successful in the treatment of Achondroplasia. This review focuses on the possible approaches for developing a drug for Achondroplasia and related skeletal disorders, using chemical, biochemical and molecular strategies.