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Achondroplasia (ACh) is the most frequent bone dysplasia. The mode of inheritance is autosomal dominant. The incident of neurological complications ranges between 20% and 47%; frequently the symptoms are subtle but are due to such serious conditions as cervicomedullary compressive syndromes, syringomyelia or hydrocephalus; thus, the early identific...
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Twenty-six patients (4 months to 6 years old) with achondroplasia complicated by sleep apnea and/or other neurologic manifestations underwent plain computed tomography (CT) of the craniocervical junction; six also underwent CT myelography. For objectification, multiplanar reconstruction was used to complement axial plane measurements by providing c...
Citations
... The study by Hunter et al. showed an increase by age for neurological signs in the arms, neck and leg, which was most pronounced for the signs in the legs [17]. Ventriculomegaly was reported in only one study [29], whereas hydrocephalus was commonly reported from an early age and remained prevalent in later life stages [29,[31][32][33][34]. However, there were variable definitions and degrees of hydrocephalus based on a combination of MRI and clinical criteria, such as rapidly increasing head circumference or scalp vein engorgement. ...
... Infant, mean 7m (+-4m) (N=36) References: [28][29][30]33,69,71,75,76,80,82,84,86]; summary [25,27,91]. assessment of the medical history and an eye examination with subsequent recommendations [48]. ...
... Hunter 1998 References: [17,18,23,29,[31][32][33][34][35][36]38,69,71,76,78,83]. ...
Background:
Achondroplasia (ACH) is a rare, genetic condition and is the most common skeletal dysplasia resulting in disproportionate short stature and numerous multi-systemic comorbidities. As we enter an era of new treatment options which may impact comorbidities, it is important to understand the background rates of these events to aid evaluation of potential treatment effects. Thus, the aim of this literature review was to provide a comprehensive quantification of prevalence estimates of comorbidities in achondroplasia by age for use as a compiled reference to assist in quantifying the risk/benefit of new treatment options and informing timely management of ACH.
Methods:
PubMed and Embase databases were searched, complemented by manual bibliography searching, for peer-reviewed articles published between 1975 and 2021, guided by PRISMA principles. Number of patients and the prevalence of specific comorbidities by age were extracted. We calculated exact 95 %-confidence limits for the proportion of affected patients (prevalence) and data were presented visually using forest plots. An a priori decision was made not to utilise meta-analytic techniques to pool estimates as we intended to understand the variability in comorbidities by displaying each estimate separately.
Results:
The literature search identified 206 articles of which 73 were eligible for inclusion. The majority of studies (n = 34) had been conducted in the USA or in Europe (n = 20). Study designs were mostly retrospective chart reviews (n = 33) or small cohort studies (n = 19). The availability of literature on particular conditions varied but trended towards a focus on assessment and prevention of severe conditions, such as respiratory conditions in children (21 studies), neurological manifestations (16 studies) and upper spine compression (15 studies). There was substantial heterogeneity in study design, type of clinical setting, populations and use of definitions in reporting comorbidities which need to be considered when interpreting study results. Despite the variability of the studies, comorbidity patterns by age were recognizable. In infants, a high prevalence (>20 %) was found for kyphosis, a range of neurological manifestations and sleep apnea. There was also an excess mortality in infancy (4-7.8/100 person-years). Conditions identified in infancy continued to prevail in childhood. Genu varum was highly prevalent from the age children started to walk (9-75 %). Other conditions started to emerge in children; those with a high prevalence (>20 %) were hearing loss and pain. In adolescence, neurological manifestations in the arm, neck or leg were reported (~15 %), consistent with symptomatic spinal stenosis or spinal compression. Fewer studies were available in older populations, especially in adults; however limited data suggest that pain and cardiovascular conditions, particularly excess weight and obesity, became more prevalent into adulthood. Mortality rates increased again in older age-groups.
Conclusion:
This review provides a reference base of current knowledge of the type and frequency of comorbidities in ACH. This not only allows future contextualisation of new treatment options but supports clinical decision-making on the timely medical management and intervention of ACH. This review also reflects the current medical priorities in the management of ACH, indicating a focus on pediatric care and the complex needs of individuals with ACH involving many different disciplines. Further studies into the natural history of this rare disease using more consistent definitions of comorbidities, especially into adulthood, are needed to elucidate the multi-systemic nature of this condition.
... 15 Overall, the post-operative complications rate can reach up to 40%, while subsequent surgery can reach up to 50%. 13 ...
Background
This study aims to assess the quantity and quality of available literature on surgical treatment outcomes of spinal stenosis in adult and paediatric achondroplasia patients through a systematic review of literature and to investigate the suitability of conducting a meta-analysis on outcomes of surgical treatment.
Methods
Online databases were searched according to PRISMA guidelines. No restrictions regarding study design, sample size, previous treatment, or publication date were implemented. The following terms: “Spinal stenosis”, “Spinal Decompression”, “Spinal fusion”, each term separately combined with the term “Achondroplasia” were used. Quality of the included studies were assessed used the Modified Coleman method.
Results
Five adult and four paediatric single-sample non-comparative studies were identified for inclusion (176 adult and 102 paediatric patients). Meta-analyses assessed the proportion of patients achieving full resolution of symptoms to be 0.51 (95% CI 0.00 to 1.00); the proportion of patients achieving full or partial resolution of symptoms to be 0.90 (95% CI 0.84 to 0.97); the proportion of procedures requiring re-operation to be 0.42 (95% CI 0.34 to 0.50; and the proportion of procedures involving dural tears to be 0.20 (95% CI 0.02 to 0.39). Statistical heterogeneity was very high for full resolution of symptoms and requirement for dural repair; and very low for other outcomes.
Conclusions
The available literature on this population and condition is sparse, highly heterogenous, and is generally of low quality limiting the value of meta-analysis. Overall, outcomes of surgical decompression of symptomatic spinal stenosis in achondroplasia patients show consistent degree of resolution of symptoms. Duration of symptoms prior to surgical treatment appears to play an important role in the overall outcome of treatment. Therefore, a delay in diagnosis and treatment can potentially be detrimental in achieving a better outcome.
... A scarce number of ACH cases have been reported with neurologic and/or psychomotor delays. [10][11][12][13] However, to our knowledge, none of these have associated the FGFR3 gene c.1138G > A (p.G380R) pathogenic variation in the ACH patients with psychomotor delay. Thus, this is the first report to associate the detected mutation with the psychomotor deficits. ...
Achondroplasia (ACH) is a hereditary disorder of dwarfism that is caused by the aberrant proliferation and differentiation of chondrocyte growth plates. The common findings of macrocephaly and facial anomalies accompany dwarfism in these patients. Fibroblast growth factor receptor 3 (FGFR3) gene mutations are common causes of achondroplasia. The current study presents a case of 2-year-old male presenting with phenotypic characteristics of ACH. The interesting finding of the case is the presence of psychomotor delay that is not very common in these patients. Clinical exome sequencing analyzing 4.813 disease causing genes revealed a de novo c.1138G > A mutation within the FGFR3 gene. In conclusion, the mutation confirms the clinical diagnosis of ACH, and it seems to be causing the psychomotor delay in this patient.
... 18 Abnormal neurological manifestations of foramen magnum stenosis include hypotonia, motor delay, feeding, and sleep disorders, and clinical features of myelopathy such as hyper-reflexia and ankle clonus, which when present strongly predict the need for decompression surgery in the infant population. 9,19 Neurological sequelae, however, are a late manifestation of high cervical spinal cord compression and considerable experience of what is ''normal'' in achondroplasia is required to determine what constitutes clinically significant findings. Studies examining the predictive value of polysomnography or cardiorespiratory sleep study parameters in the identification of foramen magnum stenosis in children with achondroplasia suggest low screening sensitivity. ...
... Patients randomized to receive vosoritide will be administered the dose determined to be appropriate for their current age as identified in the ongoing Phase 2 randomized, double-blind, placebo-controlled clinical trial to evaluate the safety 19. Have a condition or circumstance that, in the view of the Investigator, places the patient at high risk for poor treatment compliance or for not completing the study. ...
Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.
... Among the brainstem findings, absent gag reflex, vocal cord dysfunction, and facial sensory loss of pinprick were the most common findings, posited to result from deformation of the nucleus ambiguus and the trigeminal nucleus, respectively [32]. Respiratory and gastrointestinal disorders were highly represented in this series, as in others [2,13,14,25,39,42,51,63,65,66,96,111,122,123,131,133,143]. ...
... Platybasia is often associated with encephalomyelopathy from medullary kink [24,47,49,103,129,140] from degenerative conditions such as rheumatoid arthritis and other causes of hypertrophy of the odontoid [23,29,63,66] in inherited conditions such as Ehlers-Danlos syndrome [110], achondroplasia [59,79,133,151,163], osteogenesis imperfecta [88,144], Hurler's syndrome, and from acquired bone-softening conditions such as rickets, hyperparathyroidism, spondyloepiphyseal dysplasia, acro-osteolysis, osteomalacia, achondromalacia, renal osteodystrophy, and Paget's disease, in which abnormal bone remodeling causes bone weakening and subsequent platybasia and basilar invagination [19,20,69,70,104,112]. Platybasia may therefore signal the presence of a pathological CXA. ...
There is growing recognition of the kyphotic clivo-axial angle (CXA) as an index of risk of brainstem deformity and craniocervical instability. This review of literature and prospective pilot study is the first to address the potential correlation between correction of the pathological CXA and postoperative clinical outcome. The CXA is a useful sentinel to alert the radiologist and surgeon to the possibility of brainstem deformity or instability. Ten adult subjects with ventral brainstem compression, radiographically manifest as a kyphotic CXA, underwent correction of deformity (normalization of the CXA) prior to fusion and occipito-cervical stabilization. The subjects were assessed preoperatively and at one, three, six, and twelve months after surgery, using established clinical metrics: the visual analog pain scale (VAS), American Spinal InjuryAssociation Impairment Scale (ASIA), Oswestry Neck Disability Index, SF 36, and Karnofsky Index. Parametric and non-parametric statistical tests were performed to correlate clinical outcome with CXA. No major complications were observed. Two patients showed pedicle screws adjacent to but not deforming the vertebral artery on post-operative CT scan. All clinical metrics showed statistically significant improvement. Mean CXA was normalized from 135.8° to 163.7°. Correction of abnormal CXA correlated with statistically significant clinical improvement in this cohort of patients. The study supports the thesis that the CXA maybe an important metric for predicting the risk of brainstem and upper spinal cord deformation. Further study is feasible and warranted.
... Achondroplasia is an autosomal-dominant skeletal dysplasia resulting from a decreased endochondral ossification caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) [1][2][3][4][5]. Almost all patients with achondroplasia (98%) have a G380R substitution in the transmembrane domain of FGFR3 whereas other mutations in the same domain are rare [6]. ...
Purpose:
We propose an magnetic resonance imaging (MRI)-based quantitative morphovolumetric approach to the posterior cranial fossa (PCF) and craniocervical junction (CCJ) changes in achondroplastic patients investigating possible associations with ventriculomegaly and medullary compression.
Methods:
We analyzed MRI of 13 achondroplastic children not treated by surgery. 3D FSPGR T1-weighted images were used to analyze (1) PCF synchondroses; (2) PCF volume (PCFV), PCF brain volume (PCFBV), PCFV/PCFBV ratio, cerebellar volume, cerebrospinal fluid (CSF) spaces volume, and IV ventricle volume; (3) PCF (clivus, supraocciput, exocciput lengths, tentorial angle) and CCJ (AP and LL diameters of foramen magnum (FM)) morphometry; (4) measurements of FM and jugular foramina (JF) areas; and (5) supratentorial ventricular volume.
Results:
All patients showed synostosis of spheno-occipital synchondroses, eight showed synostosis of intra-occipital synchondroses, nine showed CCJ impingement on the cervical cord but only three had cervical myelopathy. Compared to controls, clivus and exocciput lengths, LL and AP diameters of FM, FM area and JF area were significantly reduced, supraocciput length, tentorial angle, PCFV, PCFBV, cerebellar volume, supratentorial ventricular system volume were significantly increased. A correlation was found between clivus length and supratentorial ventricular volume, premature closure of intra-occipital synchondroses and FM area while a trend was found between FM area and supraocciput length.
Conclusion:
Our analysis demonstrates a relationship between the shortening of the clivus and the ventriculomegaly. On the other hand the premature closure of PCF synchondroses, the shape, and the growth direction of supraocciput bone contribute to reduce the FM area, causing in some patients medullary compression.
... The variation of practice in our study may be due to the fact that there is some controversy about when children with ACH should be fully evaluated including an MRI scan to identify possible stenosis in the spinal canal. Multiple authors recommend full investigation in the first six months of life or when first referred and neuroimaging should be repeated at a predetermined interval afterwards 17,19,[22][23][24] . Another author argues against these criteria as it was found that the MRI scans showed that most of the affected children have some degree of cord compression and most of them gain normal motor development and neurological function suddenly within the first two to three years of age as the cord compression disappears 25 . ...
... The neurological symptoms registered in ACH patients in this study correspond to the symptoms recently described 10 . The percentage of sleep apnoea in our study was high but within the range seen in other studies 15,24,32,33 . The high rate of sleep apnoea could be due to frequent upper airway infections combined with the midfacial hypoplasia in patients with ACH and HCH. ...
... The number of patients with pain in back or neck resemble results in another study although their cumulative rate exceeds ours for patients above age 30 years but the prevalence of bladder dysfunction in our studies is very similar even though our data is limited and therefore not conclusive (4,2% vs. 3,1%) 15 . The occurrence of hypotonia was lower in our study compared to another (39,6% vs. 58,9%) and the rate of paraesthesia was higher in our study (10,4% vs. 2,6%) 24 . The rate of conductive hearing loss in our study was comparable with other results (31,3% vs. 38%) but the rate of tonsillectomy was low in our study (18,8% vs. 40%) 15 . ...
Aim: To investigate the prevalence of neurological symptoms and the types of complications in a cohort of Danish patients with mutation verified achondroplasia and hypochondroplasia and compare the results with previously reported findings. Methods: Retrospective descriptive study by chart review of patients followed in three outpatients clinics in the period 1997-2014. Forty-eight patients with achondroplasia and a median age of 9,5 years old and 20 patients with hypochondroplasia and a median age of 12 years old were enrolled. Neurological manifestations, epidemiological variables and clinical data were collected. Results: Data on neurological symptoms and surgical interventions were extracted and compared with existing knowledge. Description of phenotypes revealed frequent headaches, pain in back, neck and lower limbs, sleep apnoea and conductive hearing loss. No sub-phenotype was predictive for referral to an MRI scan or neurosurgery. Conclusion: Through investigation of phenotypes and genotypes in patients with achondroplasia and hypochondroplasia we report the frequencies of neurological symptoms, foramen magnum stenosis, spinal cord compression and neurosurgery in Danish patients. Variation in the evaluation of patients among the three clinics is found and discussed. To further standardise the management of patients, national guidelines for follow-up on children with ACH and HCH are recommended. Keynotes • Achondroplasia and hypochondroplasia patients can suffer from a small foramen magnum and a narrow spinal canal. Untreated this may lead to serious impediments.
... Achondroplasia is a congenital short-limbed dwarfing condition, caused by a G380R mutation in fibroblast growth factor receptor 3. 1,2 In these patients, neurological complications have incidence ranging between 20% and 47%. 3 The foramen magnum, already small at birth, does not present a normal growth pattern during the first 18 months of life, 4 and might result in early stenosis of the cranio-cervical junction with possible lower brainstem/upper cervical spinal cord compression and consequent neurological impairment. 1,5 Sudden death caused by lesion of the respiratory control network may occur, especially in the first 4 years of age. ...
... 9 However, few data on somatosensory evoked potentials in patients with achondroplasia have been reported in the literature. 3,[10][11][12] Two studies 11,12 showed that SEPs after median nerve stimulation (MN-SEPs), especially the peaks generated near the cranio-cervical junction (N13b-P13), are both sensitive and specific in detecting cervical spinal cord compression and myelomalacia in children with achondroplasia. ...
Aim:
To evaluate the contribution of somatosensory evoked potentials after median nerve (MN-SEPs) and posterior tibial nerve (PTN-SEPs) stimulation in functional assessment of cervical and lumbar spinal stenosis in children with achondroplasia.
Method:
We reviewed MN-SEPs, PTN-SEPs, and spinal magnetic resonance imaging (MRI) examinations performed in 58 patients with achondroplasia (25 males, 33 females; age range 21d-16y 10mo; mean age 4y 3mo [SD 4y 1mo]). Patients were subdivided into four age categories: <2 years, between 2 to 4 years, between 4 to 8 years, and ≥8 years. The peak latency of P37 for PTN-SEPs, the peak latencies of N11, N13, P14, and N20, and the N13-N20 interpeak latency (IPL) for MN-SEPs were collected; the diagnostic accuracy measures of these parameters (analysis of receiver operating characteristic [ROC] curves) with respect to the presence of foramen magnum or lumbar spinal stenosis were analysed in each age category.
Results:
The ROC curve analysis showed that the most sensitive parameter in detecting the presence of foramen magnum stenosis was P37 latency in the first two age categories (<2y and ≥2-4y; sensitivity 0.63, specificity 1.00, and sensitivity 1.00, specificity 0.75 respectively). In the third age category (≥4-8y), the most sensitive parameter in detecting the presence of foramen magnum stenosis was IPLs N13-N20 (sensitivity 0.73, specificity 0.87), whereas in the last age category (≥8y), the most important parameter was N20 latency (sensitivity 0.75, specificity 0.77).
Interpretation:
In children with achondroplasia, the cortical component of PTN-SEPs is more sensitive than the cortical component and central conduction time of MN-SEPs in detection of cervical spinal cord compression at early ages.
... Akondroplazik çocuklarda en sık görülen solunumsal bozukluk obstrüktif uyku apnesidir (2). İlk kez akondroplazide OUAS 1983´te tanımlanmıştır (2,3,8,9). Akondroplazi ile birlikte göğüs deformiteleri, üst solunum yolu obstrüktif uyku ile ilişkili solunum bozuklukları, kronik pulmoner hastalıklar ve nörolojik komplikasyonlar görülmektedir. Klinik olarak olgular üç gruba ayrılmaktadır. ...
... The effects of achondroplasia on the developing calvarium can produce signs and symptoms similar to those seen in CM Ⅱ. In addition to the characteristic macrocephalic changes commonly seen, changes in the shape and size of the foramen magnum, cervical stenosis, cervicomedullary compression and upward herniation of the brainstem are common [8,11] . ...
... Given our patients' concurrent conditions, the concern for hydrocephalus was high. Brainstem herniation as a result of hydrocephalus in both CM Ⅱ and achondroplasia can be acutely progressive, and greatly increases the risk of apneic spells and acute respiratory failure [1,11,27] . At the time of presentation we believed the degree of cervicomedullary constriction present did not warrant surgical Chiari decompression, as a result the patient underwent myelomeningocele repair with acute follow-up. ...
We report the first case of a neonate with concurrent Chiari II malformation and achondroplasia. Although rare, both these conditions contribute to several deleterious anatomical changes at the cervicomedullary junction and thus predispose to acute hydrocephalus. Although our patient was initially asymptomatic, hydrocephalus ensued several weeks after birth and required cerebral spinal fluid diversion. We discuss the potential links between the two conditions, the pathophysiology, and the important clinical implications for the management of the increased risk of hydrocephalus.
