Promising horizons in achondroplasia along with the development of new drugs.

Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.

Recommendations for neuroradiological examinations in children living with achondroplasia: a European Society of Pediatric Radiology and European Society of Neuroradiology opinion paper.

Children living with achondroplasia are at an increased risk of developing neurological complications, which may be associated with acute and life-altering events. To remediate this risk, the timely acquisition of effective neuroimaging that can help to guide clinical management is essential. We propose imaging protocols and follow-up strategies for evaluating the neuroanatomy of these children and to effectively identify potential neurological complications, including compression at the cervicomedullary junction secondary to foramen magnum stenosis, spinal deformity and spinal canal stenosis. When compiling these recommendations, emphasis has been placed on reducing scan times and avoiding unnecessary radiation exposure. Standardized imaging protocols are important to ensure that clinically useful neuroimaging is performed in children living with achondroplasia and to ensure reproducibility in future clinical trials. The members of the European Society of Pediatric Radiology (ESPR) Neuroradiology Taskforce and European Society of Neuroradiology pediatric subcommittee, together with clinicians and surgeons with specific expertise in achondroplasia, wrote this opinion paper. The research committee of the ESPR also endorsed the final draft. The rationale for these recommendations is based on currently available literature, supplemented by best practice opinion from radiologists and clinicians with subject-specific expertise.

Improvement in ventriculomegaly following cervicomedullary decompressive surgery in children with achondroplasia and foramen magnum stenosis.

The role of cervicomedullary decompression (CMD) in the care of hydrocephalic achondroplastic children who present with simultaneous foramen magnum stenosis is not well understood. We sought to determine the percentage of symptomatic achondroplastic children with foramen magnum stenosis who had stabilization or improvement in ventriculomegaly following CMD. The authors retrospectively reviewed the records of pediatric patients at Cedars-Sinai Medical Center with achondroplasia and signs of progressive ventriculomegaly who underwent CMD for symptomatic foramen magnum stenosis between the years 2000 and 2018. Clinical outcomes included changes in fontanelle characteristics, head circumference (HC) percentile, and incidence of ventriculoperitoneal (VP) shunting. Radiographic outcomes measured included changes in Evans ratio. We excluded individuals who were shunted before CMD from our study. Sixteen children presented with symptomatic foramen magnum stenosis and full anterior fontanelle or jump in the HC percentiles. Two children underwent placement of a VP shunt before decompressive surgery and were excluded from further analysis. Of the remaining 14 children who underwent CMD, 13 (93%) showed softening or flattening of their fontanelles post-operatively. Ten of these 14 children had both pre- and post-operative HC percentile records available, with 8 showing increasing HC percentiles before surgery. Seven of those eight children (88%) showed a deceleration or stabilization of HC growth velocity following decompression of the foramen magnum. Among 10 children with available pre- and post-operative brain imaging, ventricular size improved in 5 (50%), stabilized in 2 (20%), and slightly increased in 3 (30%) children after decompression. Two children (14%) required a shunt despite decompression of the foramen magnum. A significant proportion of children with concomitant signs of raised intracranial pressure or findings of progressive ventriculomegaly and foramen magnum stenosis may have improvement or stabilization of these findings following CMD. CMD may decrease the need for VP shunting and its associated complications in the select group of hydrocephalic children with achondroplasia presenting with symptomatic foramen magnum stenosis.

Cervical spinal cord compression in infants with achondroplasia: should neuroimaging be routine?

PURPOSE: To examine results of magnetic resonance imaging (MRI), polysomnograms (PSG), and patient outcomes in patients with achondroplasia in light of recent screening recommendations for infants with achondroplasia. METHODS: We reviewed medical records of 49 patients with achondroplasia followed at our institution between September 1997 and January 2017, including physical exams, MRIs, PSGs (when available), and surgical histories. Appropriate PSG data were available for 39 of these patients. RESULTS: Twenty-seven of 49 patients had cervical cord compression on MRI, and 20 of those patients required surgery. Central apnea was detected in 2/23 patients with cervical cord compression in whom PSG data was available. Physical exam revealed depressed deep-tendon reflexes in two patients with cord compression and one patient without cord compression. Besides hypotonia in some, the neurological exams of these patients were unremarkable. CONCLUSIONS: Cervical cord compression is a common occurrence in infants with achondroplasia and necessitates surgical intervention in some patients. Physical exam and PSG are poor predictors of the presence of cord compression or the need for surgery. All infants with achondroplasia should have MRIs of the craniocervical junction in the first 6 months of life.

Is there a correlation between sleep disordered breathing and foramen magnum stenosis in children with achondroplasia?

Children with achondroplasia have midface hypoplasia, frontal bossing, spinal stenosis, rhizomelia, and a small foramen magnum. Central sleep apnea, with potential resultant sudden death, is thought to be related to compression of the spinal cord at the cervicomedullary junction in these patients. Screening polysomnography and/or cervical spine MRI are often performed for infants with achondroplasia. Decompressive suboccipital craniectomy has been performed in selected cases. We aim to better delineate the relationship between polysomnography, cervical spine MRI, and indications for surgical decompression in achondroplasia.We retrospectively review electronic medical records of all children with achondroplasia in our IRB-approved skeletal dysplasia registry who had received screening polysomnography and cervical spine MRI examination was performed. We explored correlations of polysomnography, MRI parameters, and need for decompressive surgery. Seventeen patients with both polysomnography and MRI of the cervical spine met inclusion criteria. The average age at time of the sleep study was 2.4 ± 3.6 years. An abnormal apnea-hypopnea index was found in all patients, with central sleep apnea found in 6/17. Five patients (29%) required foramen magnum decompression. We found no statistically significant correlation between central sleep apnea and abnormal MRI findings suggestive of foramen magnum stenosis. Screening polysomnography is an important tool but does not appear to correlate with MRI findings of foramen magnum stenosis. Cord compression, with either associated T2 cord signal abnormality or clinical findings of clonus, was most predictive of subsequent surgical decompression.

Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy.

Achondroplasia is the most common inherited disorder of bone growth (skeletal dysplasia). Despite this fact, consistent and evidence-based management approaches to recognized, life-threatening complications, such as foramen magnum stenosis, are lacking. This study aims to outline best practice, based on evidence and expert consensus, regarding the diagnosis, assessment, and management of foramen magnum stenosis in achondroplasia during infancy. A panel of 11 multidisciplinary international experts on skeletal dysplasia was invited to participate in a Delphi process. They were: 1) presented with a list of 26 indications and a thorough literature review, 2) given the opportunity to anonymously rate the indications and discuss in face to face discussion; 3) edit the list and rate it in a second round. Those indications with more than 80% agreement were considered as consensual. After two rounds of rating and a face-to-face meeting, consensus was reached to support 22 recommendations for the evaluation and treatment of foramen magnum stenosis in infants with achondroplasia. These recommendations include indications for surgical decompression, ventriculomegaly, and hydrocephalus, sleep-disordered breathing, physical exams and the use of polysomnography and imaging in this condition. We present a consensus-based best practice guidelines consisting of 22 recommendations. It is hoped that these guidelines will lead to more uniform and structured evaluation, standardizing care pathways, and improving mortality and morbidity outcomes for this cohort.

Sleep-Disordered Breathing in an Infant With Achondroplasia and Foramen Magnum Stenosis.

Sleep-disordered breathing (SDB) is a frequently recognized comorbidity in infants and children with achondroplasia due to alterations in craniofacial and upper airway anatomy. Foramen magnum stenosis and cervicomedullary compression can be associated with SDB in this population, requiring prompt evaluation by multidisciplinary teams. Untreated SDB is associated with adverse cardiovascular, metabolic, and behavioral effects in children, necessitating early screening and treatment of underlying causes. Cervicomedullary compression is also associated with increased mortality and sudden infant death in infants with achondroplasia. Management of SDB in children with achondroplasia may involve a combination of neurosurgical intervention, adenotonsillectomy, and/or continuous positive airway pressure (CPAP). We recognize a need for increased physician awareness of the recommended screening guidelines to optimize health outcomes for children with achondroplasia. In this report, we describe a case of a five-month-old infant with achondroplasia and severe SDB diagnosed by polysomnography and was found to have moderate-to-severe foramen magnum stenosis identified by MRI. Subsequently, this infant underwent foramen magnum decompression, which improved the severe SDB and was followed up for five years. Our case illustrates the importance of early screening in infants with achondroplasia for SDB to prevent further sequelae.

European Achondroplasia Forum guiding principles for the detection and management of foramen magnum stenosis.

Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death. There is a lack of clarity in the literature on the timing of regular monitoring for foramen magnum stenosis, which assessments should be carried out and when regular screening should be ceased. The European Achondroplasia Forum (EAF) is a group of clinicians and patient advocates, representative of the achondroplasia community. Members of the EAF Steering Committee were invited to submit suggestions for guiding principles for the detection and management of foramen magnum stenosis, which were collated and discussed at an open workshop. Each principle was scrutinised for content and wording, and anonymous voting held to pass the principle and vote on the level of agreement. A total of six guiding principles were developed which incorporate routine clinical monitoring of infants and young children, timing of routine MRI screening, referral of suspected foramen magnum stenosis to a neurosurgeon, the combination of assessments to inform the decision to decompress the foramen magnum, joint decision making to proceed with decompression, and management of older children in whom previously undetected foramen magnum stenosis is identified. All principles achieved the ≥ 75% majority needed to pass (range 89-100%), with high levels of agreement (range 7.6-8.9). By developing guiding principles for the detection and management of foramen magnum stenosis, the EAF aim to enable infants and young children to receive optimal monitoring for this potentially life-threatening complication.

Neurosurgical Evaluation and Management of Adults with Achondroplasia.

Much of the current medical discussion for within centers for skeletal dysplasia and specifically patients with achondroplasia focuses on infancy and early childhood. Most neurosurgical concerns arise due to a defect in the endochondral ossification, resulting on early fusion of the synchondrosis. As patients age, the neurosurgical focus shifts from primarily cranial to spinal concerns. Often pediatric neurosurgeons may continue to follow their patients with skeletal dysplasia. However, general adult neurosurgeons and orthopedic surgeons may see these graduated adults in their practice. This article provides a review of the common neurosurgical concerns for patients with achondroplasia.

Neurosurgical Evaluation and Management of Children with Achondroplasia.

Achondroplasia is the most common of skeletal dysplasias and is caused by a defect in endochondral bone formation. In addition to skeletal deformities, patients with achondroplasia possess significant abnormalities of the axial skeleton, including small skull base with a narrowed foramen magnum and small vertebral bodies with shortened pedicles. Consequently, patients with achondroplasia are at risk of several severe neurologic conditions, such as cervicomedullary compression, spinal stenosis, and hydrocephalus, which frequently require the attention of a neurosurgeon. This article provides an updated review on the neurosurgical evaluation and care of children with Achondroplasia.

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.

Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history.

Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology, and interrelationships of achondroplasia-related comorbidities across the lifespan. When possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.

Meeting report from the achondroplasia foramen magnum workshop, Salzburg, Austria 22nd June 2019.

A pre-meeting workshop on foramen magnum stenosis in children with achondroplasia was held in Salzburg, Austria at the 9th International Conference on Children's Bone Health (ICCBH) 22-25 June 2019. The screening, monitoring and surgical approach to foramen magnum stenosis still remains controversial with conflicting guidance in the literature. The structure of the workshop consisted of lectures, a debate, expert and delegate discussion and concluded with a research proposal and further next steps. In total, representation by 40 institutions from 22 different countries that care for approximately 1375 children with achondroplasia, were in attendance.

Screening and surgery for foramen magnum stenosis in children with achondroplasia: a large, national database analysis.

OBJECTIVE The goal of this study was to determine the rates of screening and surgery for foramen magnum stenosis in children with achondroplasia in a large, privately insured healthcare network. METHODS Rates of screening and surgery for foramen magnum stenosis in children with achondroplasia were determined using de-identified insurance claims data from a large, privately insured healthcare network of over 58 million beneficiaries across the United States between 2001 and 2014. Cases of achondroplasia and screening and surgery claims were identified using a combination of International Classification of Diseases diagnosis codes and Current Procedural Terminology codes. American Academy of Pediatrics (AAP) practice guidelines were used to determine screening trends. RESULTS The search yielded 3577 children age 19 years or younger with achondroplasia. Of them, 236 met criteria for inclusion in the screening analysis. Among the screening cohort, 41.9% received some form of screening for foramen magnum stenosis, whereas 13.9% of patients were fully and appropriately screened according to the 2005 guidelines from the AAP. The screening rate significantly increased after the issuance of the AAP guidelines. Among all children in the cohort, 25 underwent cervicomedullary decompression for foramen magnum stenosis. The incidence rate of undergoing cervicomedullary decompression was highest in infancy (28 per 1000 patient-years) and decreased with age (5 per 1000 patient-years for all other ages combined). CONCLUSIONS Children with achondroplasia continue to be underscreened for foramen magnum stenosis, although screening rates have improved since the release of the 2005 AAP surveillance guidelines. The incidence of surgery was highest in infants and decreased with age.

Maternal administration of meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.

OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony bridges were scored on PD 4.5. In wild-type mice, tissue concentrations of meclozine in ED 17.5 fetuses and PD 6.5 pups were investigated. RESULTS The area of the foramen magnum was significantly smaller in 17-day-old Fgfr3ach mice than in wild-type mice (p < 0.005). There were no bony bridges in the spheno-occipital and anterior intraoccipital synchondroses in wild-type mice, while some of the synchondroses prematurely closed in untreated Fgfr3ach mice at PD 4.5. The average bony bridge score in the cranial base was 7.053 ± 1.393 in untreated Fgfr3ach mice and 6.125 ± 2.029 in meclozine-treated Fgfr3ach mice. The scores were not statistically significant between mice with and those without meclozine treatment (p = 0.12). The average tissue concentration of meclozine was significantly higher (508.88 ± 205.16 ng/g) in PD 6.5 mice than in ED 17.5 mice (56.91 ± 20.05 ng/g) (p < 0.005). CONCLUSIONS Maternal administration of meclozine postponed premature closure of synchondroses in some Fgfr3ach mice, but the effect on preventing bony bridge formation was not significant, probably due to low placental transmission of the drug. Meclozine is likely to exhibit a marginal effect on premature closure of synchondroses at the cranial base in ACH.