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Oman Journal of Ophthalmology 2023Achondroplasia is an autosomal dominant congenital disorder of endochondral ossification, induced by abnormal activity of fibroblast growth factor receptor 3. Affected...
Achondroplasia is an autosomal dominant congenital disorder of endochondral ossification, induced by abnormal activity of fibroblast growth factor receptor 3. Affected individuals have short stature and often present with neurological and skeletal complications. Most have normal intelligence. Ocular association with achondroplasia include simple microphthalmos, congenital-onset glaucoma with presumed Axenfeld-Rieger anomaly, telecanthus, exotropia, inferior oblique overaction, angle anomalies, Duane retraction syndrome, cone-rod dystrophy, fundus albipunctatus, chorioretinal coloboma, macular coloboma, keratoconus, and developmental cataract. A 6-year-old achondroplasia boy with developmental delay had a high axial length (high myopia) in both eyes. This child had a left eye subluxated cataractous lens, while the other eye showed mild lens changes. All achondroplasia patients should be routinely screened in detail for lens and other ophthalmological anomalies so that they can undergo timely intervention and management.
PubMed: 38059098
DOI: 10.4103/ojo.ojo_42_23 -
Deutsches Arzteblatt International Feb 20243% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. (Review)
Review
BACKGROUND
3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders.
METHODS
This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience.
RESULTS
Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management.
CONCLUSION
There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.
Topics: Child; Adult; Humans; Adolescent; Insulin-Like Growth Factor I; Human Growth Hormone; Growth Disorders; Dwarfism, Pituitary; Physicians
PubMed: 38051162
DOI: 10.3238/arztebl.m2023.0247 -
Results and complications of bilateral limb lengthening in achondroplasia: a retrospective analysis.Frontiers in Pediatrics 2023Achondroplasia is one of the main causes of disharmonic dwarfism. Patients with achondroplasia might have physical and psychological limitations due to their...
BACKGROUND
Achondroplasia is one of the main causes of disharmonic dwarfism. Patients with achondroplasia might have physical and psychological limitations due to their disproportionate stature. Surgical limb lengthening is the only practical option available to achieve a stature comparable to normal population range. The purpose of this study is to analyze results and complications of our lengthening protocol.
METHODS
A retrospective analysis was performed on 33 patients with achondroplasia (21 females and 12 males) undergoing simultaneous bilateral tibia or femur lengthening in four surgical stages from 2017 to 2021 (46 lengthening procedures, with a total of 56 tibias and 36 femurs). For each patient, patients' characteristics and antero-posterior and lateral radiographs were obtained. The following parameters were analyzed: duration of lengthening with external fixator, amount of lengthening, complications or events that influenced outcomes and the healing index (HI).
RESULTS
The average tibial and femoral gain was 7.9 cm and 6.9 cm, respectively. The tibiae achieved better results than the femurs ( = 0.005). Nineteen complications were reported for 92 segments (20.7%), and the variables influencing complications were: step ( = 0.002) and fixation duration ( = 0.061).
CONCLUSIONS
Bilateral parallel lower limb lengthening in four surgical steps may be a viable technique in patients with achondroplasia.
PubMed: 38027309
DOI: 10.3389/fped.2023.1281099 -
Intractable & Rare Diseases Research Nov 2023Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not...
Dwarfism is a rare condition characterized by small stature. Achondroplasia is predominantly considered the leading cause of dwarfism. Although the condition is not life-threatening, it dramatically impacts the social life of the patient. The United States Food and Drug Administration (US FDA) first approved the drug Voxzogo (vosoritide) for achondroplasia. The drug also received approval from the European Medicines Agency (EMA) the centralized procedure. The drug is associated with a decrease in blood pressure, a severe adverse event. However, this adverse event/risk has been overcome by benefits, . fulfilling of unmet medical need. In the United States, the drug received accelerated approval as it satisfied the criteria of rare pediatric disease. This review includes a detailed orphan drug approval process with particular reference to vosoritide, which is considered a milestone for the treatment of achondroplasia.
PubMed: 38024582
DOI: 10.5582/irdr.2023.01055 -
Brain & Spine 2023Lumbar spinal stenosis (LSS) is the main problem for adult achondroplasia (Ach). Sagittal imbalance of the spine may play a role in LSS causing neurogenic claudication...
INTRODUCTION
Lumbar spinal stenosis (LSS) is the main problem for adult achondroplasia (Ach). Sagittal imbalance of the spine may play a role in LSS causing neurogenic claudication in Ach patients.
RESEARCH QUESTION
The purpose of this study is to describe the sagittal balance parameters in Ach patients.
METHODS
A single-centre retrospective study of Ach patients that visited the Neurosurgery outpatient clinic of the Leiden University Medical Centre (LUMC) between 2019 and 2022 was performed. We defined sagittal imbalance by a C7 sagittal vertical axis (SVA) of more than 10 mm.
RESULTS
There were 13 patients with a spinal sagittal imbalance and 15 patients with a balanced spine. In both groups, the sacral slope (SS) was comparable (45.0° and 49.0°, p = 0.305), but exceeding the mean SS in non achondroplasts (38.0°). Lumbar lordosis (LL) was more pronounced in the balanced group (55.5° versus 41.7°, p = 0.019), and positively correlated to SS in contrast to the absence of a correlation in the imbalanced group. Thoracolumbar kyphosis (TLK) was increased comparably in both groups (19.6° and 24.6°), and far exceeding the TLK in non achondroplasts (circa 0°), and in both groups negatively correlated with the LL, although not enough to compensate for the smaller LL in the imbalanced group.
CONCLUSION
Only if the LL compensates for both a larger SS and TLK, the Ach spine can maintain sagittal balance. An explanation for the current data can be the failure of the lumbar spine to give sufficient lordosis due to degenerative processes.
PubMed: 38021024
DOI: 10.1016/j.bas.2023.102670 -
Pediatric Radiology Jan 2024Skeletal dysplasias collectively affect a large number of patients worldwide. Most of these disorders cause growth anomalies. Hence, evaluating skeletal maturity via the...
BACKGROUND
Skeletal dysplasias collectively affect a large number of patients worldwide. Most of these disorders cause growth anomalies. Hence, evaluating skeletal maturity via the determination of bone age (BA) is a useful tool. Moreover, consecutive BA measurements are crucial for monitoring the growth of patients with such disorders, especially for timing hormonal treatment or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra- and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automate BA assessment have been proposed, few are validated for BA assessment on children with skeletal dysplasias.
OBJECTIVE
We present Deeplasia, an open-source prior-free deep-learning approach designed for BA assessment specifically validated on patients with skeletal dysplasias.
MATERIALS AND METHODS
We trained multiple convolutional neural network models under various conditions and selected three to build a precise model ensemble. We utilized the public BA dataset from the Radiological Society of North America (RSNA) consisting of training, validation, and test subsets containing 12,611, 1,425, and 200 hand and wrist radiographs, respectively. For testing the performance of our model ensemble on dysplastic hands, we retrospectively collected 568 radiographs from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders including achondroplasia and hypochondroplasia. A subset of the dysplastic cohort (149 images) was used to estimate the test-retest precision of our model ensemble on longitudinal data.
RESULTS
The mean absolute difference of Deeplasia for the RSNA test set (based on the average of six different reference ratings) and dysplastic set (based on the average of two different reference ratings) were 3.87 and 5.84 months, respectively. The test-retest precision of Deeplasia on longitudinal data (2.74 months) is estimated to be similar to a human expert.
CONCLUSION
We demonstrated that Deeplasia is competent in assessing the age and monitoring the development of both normal and dysplastic bones.
Topics: Child; Humans; Deep Learning; Retrospective Studies; Radiography; Age Determination by Skeleton; Osteochondrodysplasias; Achondroplasia
PubMed: 37953411
DOI: 10.1007/s00247-023-05789-1 -
Advances in Therapy Jan 2024Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across...
INTRODUCTION
Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide.
METHODS
Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations.
RESULTS
A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged.
CONCLUSION
The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.
Topics: Child; Humans; Natriuretic Peptide, C-Type; Delivery of Health Care; Pain Management; Achondroplasia
PubMed: 37882884
DOI: 10.1007/s12325-023-02705-9 -
European Journal of Pediatrics Mar 2024Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or... (Review)
Review
Noonan syndrome belongs to the family of RASopathies, a group of multiple congenital anomaly disorders caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Collectively, all these pathogenic variants lead to increased RAS/MAPK activation. The better understanding of the molecular mechanisms underlying the different manifestations of NS and RASopathies has led to the identification of molecular targets for specific pharmacological interventions. Many specific agents (e.g. SHP2 and MEK inhibitors) have already been developed for the treatment of RAS/MAPK-driven malignancies. In addition, other molecules with the property of modulating RAS/MAPK activation are indicated in non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolemia). Conclusion: Drug repositioning of these molecules represents a challenging approach to treat or prevent medical complications associated with RASopathies. What is Known: • Noonan syndrome and related disorders are caused by pathogenic variants in genes encoding components or regulators of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway, resulting in increased activation of this pathway. • This group of disorders is now known as RASopathies and represents one of the largest groups of multiple congenital anomaly diseases known. What is New: • The identification of pathophysiological mechanisms provides new insights into the development of specific therapeutic strategies, in particular treatment aimed at reducing RAS/MAPK hyperactivation. • Drug repositioning of specific agents already developed for the treatment of malignant (e.g. SHP2 and MEK inhibitors) or non-malignant diseases (e.g. C-type natriuretic peptide analogues in achondroplasia or statins in hypercholesterolaemia) represents a challenging approach to the treatment of RASopathies.
Topics: Humans; Noonan Syndrome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Natriuretic Peptide, C-Type; Mitogen-Activated Protein Kinases; Abnormalities, Multiple; Achondroplasia; Mitogen-Activated Protein Kinase Kinases
PubMed: 37863846
DOI: 10.1007/s00431-023-05263-y -
Cureus Sep 2023We report the case of an achondroplastic female who presented with acute neurologic decline following epidural anesthesia for an elective cesarean section....
We report the case of an achondroplastic female who presented with acute neurologic decline following epidural anesthesia for an elective cesarean section. Achondroplasia presents unique anatomical challenges to anesthesiologists in perioperative management, and cesarean sections are standard for achondroplastic pregnancies. High rates of spinal stenosis and lumbar radiculopathy in this patient population make administration of epidural analgesia technically challenging and may increase the risk of neurologic injury. Ultrasound is an effective means of administering epidural anesthesia for most patients; however, its utility is user-dependent and more challenging for those with obesity and abnormal spinal anatomy, both of which are common in achondroplasia. Cephalic and thoracic anatomical features in achondroplasia can also make general anesthesia challenging. Therefore, preoperative imaging may help guide preoperative planning based on patient anatomy and individual risk factors to reduce the risks of complications in this patient population. This report includes details from the patient's prenatal care, cesarean section, and 18 months of follow-up.
PubMed: 37842487
DOI: 10.7759/cureus.45170 -
JCI Insight Nov 2023Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including...
Overactive fibroblast growth factor receptor 3 (FGFR3) signaling drives pathogenesis in a variety of cancers and a spectrum of short-limbed bone dysplasias, including the most common form of human dwarfism, achondroplasia (ACH). Targeting FGFR3 activity holds great promise as a therapeutic approach for treatment of these diseases. Here, we established a receptor/adaptor translocation assay system that can specifically monitor FGFR3 activation, and we applied it to identify FGFR3 modulators from complex natural mixtures. An FGFR3-suppressing plant extract of Amaranthus viridis was identified from the screen, and 2 bioactive porphyrins, pheophorbide a (Pa) and pyropheophorbide a, were sequentially isolated from the extract and functionally characterized. Further analysis showed that Pa reduced excessive FGFR3 signaling by decreasing its half-life in FGFR3-overactivated multiple myeloma cells and chondrocytes. In an ex vivo culture system, Pa alleviated defective long bone growth in humanized ACH mice (FGFR3ACH mice). Overall, our study presents an approach to discovery and validation of plant extracts or drug candidates that target FGFR3 activation. The compounds identified by this approach may have applications as therapeutics for FGFR3-associated cancers and skeletal dysplasias.
Topics: Mice; Humans; Animals; Receptor, Fibroblast Growth Factor, Type 3; Porphyrins; Achondroplasia; Signal Transduction; Neoplasms
PubMed: 37824212
DOI: 10.1172/jci.insight.171257