Next Article in Journal
MOTH: Memory-Efficient On-the-Fly Tiling of Histological Image Annotations Using QuPath
Previous Article in Journal
Preclinical Implementation of matRadiomics: A Case Study for Early Malformation Prediction in Zebrafish Model
Previous Article in Special Issue
The Adversarial Robust and Generalizable Stereo Matching for Infrared Binocular Based on Deep Learning
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
J. Imaging
Volume 10
Issue 11
10.3390/jimaging10110291
jimaging-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Anatomical Characteristics of Cervicomedullary Compression on MRI Scans in Children with Achondroplasia

by
Isabella Trautwein
1,
Daniel Behme
2,
Philip Kunkel
3,
Jasper Gerdes
1 and
Klaus Mohnike
1,*
1
Children’s Hospital, Otto-von-Guericke-University, 39120 Magdeburg, Germany
2
Clinic for Neuroradiology, University Hospital, 39120 Magdeburg, Germany
3
Department of Pediatric Surgery, University Medical Centre Mannheim, 68167 Mannheim, Germany
*
Author to whom correspondence should be addressed.
J. Imaging 2024, 10(11), 291; https://doi.org/10.3390/jimaging10110291
Submission received: 1 October 2024 / Revised: 4 November 2024 / Accepted: 11 November 2024 / Published: 14 November 2024
(This article belongs to the Special Issue Deep Learning in Computer Vision)
Browse Figures
Review Reports Versions Notes

Abstract

:
This retrospective study assessed anatomical characteristics of cervicomedullary compression in children with achondroplasia. Twelve anatomical parameters were analyzed (foramen magnum diameter and area; myelon area; clivus length; tentorium and occipital angles; brainstem volume outside the posterior fossa; and posterior fossa, cerebellum, supratentorial ventricular system, intracranial cerebrospinal fluid, and fourth ventricle volumes) from sagittal and transversal T1- and T2-weighted magnetic resonance imaging (MRI) scans from 37 children with achondroplasia aged ≤ 4 years (median [range] 0.8 [0.1–3.6] years) and compared with scans from 37 children without achondroplasia (median age 1.5 [0–3.9] years). Mann–Whitney U testing was used for between-group comparisons. Foramen magnum diameter and area were significantly smaller in children with achondroplasia compared with the reference group (mean 10.0 vs. 16.1 mm [p < 0.001] and 109.0 vs. 160.8 mm2 [p = 0.005], respectively). The tentorial angle was also steeper in children with achondroplasia (mean 47.6 vs. 38.1 degrees; p < 0.001), while the clivus was significantly shorter (mean 23.5 vs. 30.3 mm; p < 0.001). Significant differences were also observed in myelon area, occipital angle, fourth ventricle, intracranial cerebrospinal fluid and supratentorial ventricular volumes, and the volume of brainstem protruding beyond the posterior fossa (all p < 0.05). MRI analysis of brain structures may provide a standardized value to indicate decompression surgery in children with achondroplasia.

1. Introduction

Achondroplasia is the most common form of non-lethal skeletal dysplasia, occurring in approximately 1 in 25,000–30,000 live births worldwide [1,2,3,4]. It is characterized by a disproportionate, short stature, a disproportionately large head (macrocephaly), midface and skull base hypoplasia, shortening of the proximal limbs (rhizomelia), and other skeletal abnormalities which can lead to medical, functional, and psychosocial problems throughout life [5]. Achondroplasia is an inherited genetic disorder caused by autosomal dominant gain-of-function pathogenic variants in the fibroblast growth factor receptor 3 gene (FGFR3) located on the short arm of chromosome 4 [6,7]. Overactivation of FGFR3 affects endochondral ossification and leads to reduced bone growth [8].
Foramen magnum stenosis (FMS) is one of the most common and serious complications of achondroplasia in infancy and early childhood [9]. The foramen magnum resides in the occipital bone, within the posterior cranial fossa, and is traversed by various structures including the medulla oblongata, radix spinalis of the nervus accessorius, and arteria vertebrales and spinales [10,11,12]. In babies with achondroplasia, the foramen magnum is smaller than average; restricted growth in the first 2 years of life and premature closure of the skull base synchondroses further impact foramen magnum size and shape [13,14]. A small and misshapen foramen magnum can result in compression of the brainstem and spinal cord, leading to frequent apnea episodes which greatly increase the risk of sudden infant death syndrome in infancy [15,16]. Possible signs of FMS include severe hypotonia, motor delays, feeding and sleep disturbances, and clinical features of myelopathy such as hyperreflexia [17,18]. Rates of mortality due to FMS in achondroplasia are 2–7.5% [19,20], which represents much higher rates of mortality than the general population [20,21,22]. In the absence of established guidelines, craniocervical decompression surgery rates in patients with achondroplasia vary significantly across centers, ranging from 6.3% to 40% [13,23,24]. In 2021, a simple scoring system for categorizing the severity of FMS on magnetic resonance imaging (MRI) was developed [25]. The objective of the Achondroplasia Foramen Magnum Score (AFMS) is to detect spinal cord compression in children with achondroplasia as early as possible through routine MRI screening. This helps to ensure timely intervention, thereby reducing morbidity and mortality as a consequence of FMS. In children with severe FMS, decompression surgery is the accepted treatment modality, with the aim of alleviating the impingement of the dural sac and spinal cord. In asymptomatic patients, there is no consistent approach to when surgery should or should not be performed [5].
In 1985, Cohen et al. [26] analyzed craniofacial morphology from lateral X-ray cephalograms of 51 achondroplastic individuals using 66 linear, angular, and area variables. In comparison with 951 average-stature adults, significant findings included shortened posterior cranial base length and acute cranial base angle. The authors interpreted the observed findings by earlier closure of the intersphenoidal synchondrosis [26]. Over the last few decades, MRI-based quantitative morphovolumetry has allowed a detailed approach to measure areas, volumes, and lengths of other parameters, including the clivus and supraocciput or tentorial angles [27].
These anatomical landmarks provide an informative dataset to be used for the development of deep learning (DL) systems. We therefore investigated MRI scans in children with achondroplasia compared with a healthy reference group. The children with achondroplasia were further subdivided into those who received decompression surgery for FMS and those who did not. The overall aim of the study was to build upon the AFMS to identify further anatomical characteristics in children with achondroplasia that may allow development of (1) a standard indication for decompression surgery and (2) a standardized evaluation of effect of medical treatment on critical intracranial structures.

2. Materials and Methods

2.1. Patient Population

Data collection for this retrospective study took place between October 2020 and April 2023 at Magdeburg University Hospital, Magdeburg, Germany. Children aged ≤ 4 years with confirmed achondroplasia who had received a skull base MRI scan were identified from the Germany-wide CrescNet Registry [28]. A reference population of children aged ≤ 4 years without achondroplasia who had received a skull base MRI scan were identified from Magdeburg University Hospital records. The reference population could have no evidence of cervicomedullary damage and no diseases that could have influenced associated anatomical structures.
MRI files were made available by the treating physicians, parents or guardians of the children for a second evaluation. The study was conducted in accordance with the Declaration of Helsinki and the opinion of the Ethics Committee of the Magdeburg University Hospital Medical Faculty, whereby an evaluation of stored data is permitted in accordance with the doctor–patient contract, the General Contractual Conditions (AVB) for the University Hospital Magdeburg, Institution under Public Law (A.ö.R) i. d. a. F., via § 16 (5). Patient consent was waived by the ethics committee due to the anonymized nature of the data.

2.2. Analysis of Anatomical Parameters

MRI images from the achondroplasia and reference groups were analyzed using Dornheim Segmenter Research software (v2019.1; Dornheim Medical Images GmbH, Magdeburg, Germany) [29]. To segment the region of interest (ROI), the investigator first annotated the image by drawing a bounding box. Thereafter, the software automatically calculated areas, volumes, lengths, and angles within the images. Only preoperative MRI scans were included in the study; if multiple scans were available, only the first MRI scan of each child was used.
The following 12 parameters were measured using T1- and T2-weighted images in sagittal and transversal planes: diameter of the foramen magnum (T1 sagittal); area of the foramen magnum; area of the myelon (T1 transversal); length of the clivus (from the dorsum sellae to the end of the clivus); tentorium angle (the angle between the highest point of the tentorium, the protuberantia occipitalis interna and the dorsum sellae in the mid-sagittal plane); occipital angle; volume of the posterior fossa; proportion of brainstem volume outside the posterior fossa; volume of the cerebellum (T2 sagittal); volume of the supratentorial ventricular system (including the third ventricle as well as the lateral ventricles); volume of the intracranial cerebrospinal fluid (CSF) system (T2 transversal); and volume of the fourth ventricle (T2 sagittal). These parameters were selected from previous observational studies [26,27] and based on personal experience of a board-certified neurosurgeon (PK) with sub-specialization in surgical treatment of conditions of the cranial cervical junction (CCJ).
Before each measurement, the selected structure and the quality of the MRI image were reviewed; images of insufficient quality and structures that were incomplete were excluded. The brightness and contrast of the image were optimized to better distinguish the structures to be measured and enable more accurate measurements to be taken by the software. Each measurement was conducted in duplicate per MRI scan to compensate for any measurement errors.

2.3. Calculation of AFMS

The AFMS was calculated according to the method described previously [25]. Briefly, sagittal and axial T2-weighted MRI images from the achondroplasia group were scored from 0 (no evidence of FMS) to 4 (severe FMS) based on the degree of foramen magnum narrowing and spinal cord changes.

2.4. Statistical Analysis

Anatomical parameters measured from MRI scans are presented as mean (standard deviation) and median (range). Parameters were compared between the achondroplasia and reference groups using a Mann–Whitney U test for independent samples based on a 0.05 significance level.

3. Results

MRI images from 37 patients (20 males and 17 females) with confirmed achondroplasia were analyzed and compared with MRI scans from 37 individuals (23 males and 14 females) without achondroplasia. Within the achondroplasia group, 13 patients (6 females and 7 males) had received decompression surgery of the foramen magnum.
The mean age of the children with achondroplasia at the time of MRI was 1.1 years (1.1 years in those who had received decompression surgery and 0.9 years in those who had not received decompression surgery), while the mean age of the reference group was 1.7 years (Table 1). The oldest patient at the time of MRI across both groups was 3.9 years.
Illustrative examples of key anatomical structures on MRI scans from children with achondroplasia are shown in Figure 1 and Figure 2. Of the 12 parameters measured and analyzed from the MRI scans, 10 showed significant differences between the achondroplasia and reference groups (Figure 3; Table S1). The diameter (mean 10.0 mm vs. 16.1 mm; p < 0.001) and area (mean 109.0 mm2 vs. 160.8 mm2; p = 0.005) of the foramen magnum were significantly smaller in children with achondroplasia compared with the reference group. Furthermore, the myelon area was significantly smaller (mean 40.6 mm2 vs. 47.7 mm2; p = 0.004) and the clivus significantly shorter (mean 23.5 mm vs. 30.3 mm; p < 0.001) in children with achondroplasia. The tentorium angle was significantly steeper in children with achondroplasia (mean 47.6 degrees vs. 38.1 degrees; p < 0.001) and was accompanied by a larger volume of “overhang” of the brainstem from the posterior cranial fossa (mean 4542.5 mm3 vs. 2614.4 mm3; p < 0.001). A significantly smaller volume of the fourth ventricle (mean 749.9 mm3 vs. 1056.2 mm3; p = 0.029) and corresponding significantly larger volume of the supratentorial ventricular system (mean 42,062.3 mm3 vs. 13,389.2 mm3; p < 0.001) was also observed in patients with achondroplasia. No significant differences between the achondroplasia and reference groups were observed in posterior fossa or cerebellum volume.
When comparing children with achondroplasia who had received decompression surgery with those who had not, the diameter of the foramen magnum showed a significant difference between groups (Table 2; p < 0.05).
AFMS could be retrospectively determined in 24 of the 37 children with achondroplasia (Figure 4). Of these, 9 children underwent decompression surgery, of whom 6 (66.7%) had an AFMS score of 3 or 4. Of the 15 children who did not undergo decompression surgery, 14 had an AFMS score of 1 or 2 (93.3%). Measurements of the diameter of the foramen magnum, the clivus length, the tentorial angle, the fourth ventricle volume, the supratentorial CSF system volume, and the area of “overhang” of the brainstem from the posterior cranial fossa were consistent with the AFMS (Table 3).

4. Discussion

Cervicomedullary compression and FMS are well recognized complications of achondroplasia, with infants and younger children at higher risk of these complications than adults and older children [5,25]. Certain measures, such as the AFMS, have been developed to aid identification of early spinal cord changes and grade severity of FMS. However, identifying candidates for decompression surgery remains an area of inconsistency [30,31,32,33]. In addition, a new medical treatment for achondroplasia, the recombinant C-type natriuretic peptide analogue vosoritide, has recently shown improved growth of facial volume, sinus volume, and foramen magnum area in achondroplastic infants [34]. Therefore, further proof of MRI changes induced by vosoritide or investigational products may help guide the decision to prescribe treatment.
The present study aimed to identify further anatomical characteristics in children with achondroplasia that may allow a standard indication for decompression surgery. Of 12 parameters defined and measured in MRI images from children with achondroplasia, 10 showed significant differences compared with the reference population. Some of the differences identified were consistent with previous studies in children with achondroplasia. The reduction in foramen magnum area and diameter observed in the present study has been well characterized previously in children with achondroplasia [14,25]. However, the postulated link between foramen magnum changes and a shorter posterior cranial fossa due to underdevelopment of the occipital and clivus bone components as a consequence of defective endochondral bone formation and premature fusion of posterior fossa synchondrose [35,36,37,38] was not confirmed in our study. This may have been related to a disparity in the number of children with complete imaging of the posterior fossa (n = 24 in the achondroplasia group vs. n = 37 in the reference group). Our study was also consistent with previous studies showing a shortening of the clivus in achondroplasia [35]. The underlying reason for clivus shortening might be the early fusion of the spheno-occipital synchondrosis [27]. A correlation between the length of the clivus and the supratentorial ventricular system, caused by either a CSF flow modeling effect during development or an early closure of spheno-occipital synchondrosis leading to the characteristic concave shape of the shortened clivus has been shown previously [27,36,39,40]. However, in contrast to previous results [27], our results also revealed changes in the fourth ventricle and the supratentorial ventricular system. While the fourth ventricle was smaller in children with achondroplasia, the volume of the supratentorial ventricular system was increased. Longer-term studies assessing the dynamics of cerebrospinal fluid could help elucidate the mechanisms underlying this observation. The alignment of the tentorial angle in children with achondroplasia has been characterized extensively in previous studies [27,35]. Accordingly, a significantly steeper angle in children with achondroplasia was observed in our study versus the reference group. It is noteworthy that the tentorial angle represented one of the borderlines in the measurement of the posterior fossa, the volume of which, in turn, determines the “overhang” of the brainstem beyond the posterior fossa. As a result, the increased volume of the overhang coincided with the steeper tentorial angle in children with achondroplasia versus the reference group. An increased tentorial angle caused by vertical orientation of the cerebellar tentorium supports the view that the tentorium is pushed forward and becomes steeper in children with achondroplasia to compensate for the undersized cranial base bone and abnormal growth of the neural structures of the posterior fossa [27]. A relative increase in volume of the brainstem may occur in achondroplasia, a disorder in which the skull base bone is primarily affected [41]. However, this could not be precisely demonstrated in our study as only the bony rim of the posterior fossa and the overload were measured, not the neural structures in the posterior fossa.
The AFMS was developed to categorize the severity of FMS on MRI, including measurements of the degree of narrowing of the foramen magnum, preservation of the CSF and evidence of spinal cord compression [25]. Eligibility for decompression surgery is based on evidence of spinal cord compression in the absence of spinal cord signal changes (AFMS3), or evidence of both spinal cord compression and spinal cord signal changes (AFMS4) [25]. Retrospectively applying AFMS criteria to our achondroplasia cohort indicated that the decision to conduct decompression surgery was made correctly in 66.3% of those operated upon, based on those who would have scored 3 or 4 on preoperative MRI scans; 93.3% of patients with an AFMS score of 1 or 2 did not receive surgery. In the present study, six of the 12 parameters measured on MRI scans aligned with AFMS when the latter scores were considered in their totality. This was not surprising, as these parameters overlapped with those that showed significant differences between children with achondroplasia and the reference population.
This study was initiated to assess anatomical differences in intracranial structures in patients with achondroplasia, to interpret advanced imaging modalities. Ten out of twelve parameters showed significant differences in patients with achondroplasia compared with the reference population. Therefore, MRI offers a great opportunity to develop a DL tool to assist in (1) the indication of decompression surgery and (2) to measure the outcome following vosoritide or other precision therapies.
The present study had some limitations. The sample size was small, with 37 patients in both the achondroplasia and reference groups, and only 14 and 23 patients, respectively, in the operated and non-operated subgroups. While the rarity of achondroplasia precluded enrollment of a larger cohort of infants of the same age with a preoperative MRI, a strength of our study was the inclusion of patients from across Germany via the CrescNet Registry. Future studies could perhaps be conducted in an international setting to include a larger number of patients and increase the validity of the data. Due to the retrospective study design, some MRI sequences were missing or the anatomical structure under investigation was not pictured fully; therefore, not every parameter could be measured in all children. In addition, the use of the Dornheim Segmenter software [29] was associated with some limitations during measurement. For example, poor focus in some MRI images may have prevented reliable identification of certain structures. Steps were taken to maximize inclusion of MRI images from our cohort, including optimization of image brightness and contrast to better distinguish the structures to be measured and enable more accurate measurement by the software. Each measurement was also conducted in duplicate to compensate for any measurement errors.

5. Conclusions

In conclusion, MRI analysis of anatomical structures such as the clivus, supratentorial ventricular system, tentorium angle, and brainstem protrusion, in combination with the AFMS, may provide a standard indication for decompression surgery. Further investigation is needed to improve understanding of the correlation between the anatomical structures and clinical presentation of children with achondroplasia. These specific MRI findings offer a great opportunity to develop a DL tool that will assist in (1) the indication of decompression surgery and (2) measuring the outcome following vosoritide or other precision therapies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jimaging10110291/s1, Table S1: Analysis of anatomical parameters on MRI scans in children with achondroplasia compared with the reference group.

Author Contributions

I.T., D.B., P.K., J.G. and K.M. contributed to the following: conceptualization, methodology, validation, formal analysis, investigation, resources, data curation, writing–original draft, writing–review and editing, visualization, supervision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding. Medical writing support for preparation of the manuscript was funded by BioMarin.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and the opinion (approval 27/22, date 28 February 2022) of the Ethics Committee of the Magdeburg University Hospital Medical Faculty, whereby an evaluation of stored data is permitted in accordance with the doctor–patient contract, the General Contractual Conditions (AVB) for the University Hospital Magdeburg, Institution under Public Law (A.ö.R) i. d. a. F., via § 16 (5).

Informed Consent Statement

Patient consent was waived.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, [KM], upon reasonable request.

Acknowledgments

The authors would like to thank all participating patients and their families. Medical writing support was provided by Ben Drever, AMICULUM Ltd., and was funded by BioMarin.

Conflicts of Interest

I.T., P.K. and J.G., have received medical writing support, funded by BioMarin. D.B. has received medical writing support, funded by BioMarin; consulting fees from Phenox, Balt, Acandis and Stryker; and honoraria for speaking engagements from Stryker and Acandis. K.M. has received medical writing support, funded by BioMarin; grants, consulting fees and participation on a Data Safety Monitoring Board or Advisory Board from BioMarin, QED Biobridge, Novo-Nordisk, and Ascendis; honoraria for speaking engagements from BioMarin, Novo-Nordisk and Merck; and support for meeting attendance from BioMarin and Merck. The authors declare no conflict of interest.

References

  1. Waller, D.; Correa, A.; Vo, T.M.; Wang, Y.; Hobbs, C.; Langlois, P.; Pearson, K.; Romitti, P.; Shaw, G.; Hecht, J. The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US. Am. J. Med. Genet. Part A 2008, 146, 2385–2389. [Google Scholar] [CrossRef] [PubMed]
  2. Moffitt, K.B.; Abiri, O.O.; Scheuerle, A.E.; Langlois, P.H. Descriptive epidemiology of selected heritable birth defects in Texas. Birth Defects Res. A Clin. Mol. Teratol. 2011, 91, 990–994. [Google Scholar] [CrossRef] [PubMed]
  3. Barbosa-Buck, C.O.; Orioli, I.M.; Dutra, M.d.G.; Lopez-Camelo, J.; Castilla, E.E.; Cavalcanti, D.P. Clinical epidemiology of skeletal dysplasias in South America. Am. J. Med. Genet. Part A 2012, 158, 1038–1045. [Google Scholar] [CrossRef] [PubMed]
  4. Stevenson, D.A.; Carey, J.C.; Byrne, J.L.; Srisukhumbowornchai, S.; Feldkamp, M.L. Analysis of skeletal dysplasias in the Utah population. Am. J. Med. Genet. Part A 2012, 158, 1046–1054. [Google Scholar] [CrossRef] [PubMed]
  5. Savarirayan, R.; Ireland, P.; Irving, M.; Thompson, D.; Alves, I.; Baratela, W.A.R.; Betts, J.; Bober, M.B.; Boero, S.; Briddell, J.; et al. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia. Nat. Rev. Endocrinol. 2022, 18, 173–189. [Google Scholar] [CrossRef] [PubMed]
  6. Bellus, G.A.; Hefferon, T.W.; Luna, R.I.O.D.; Hecht, J.T.; Horton, W.A.; Machado, M.; Kaitila, I.; McIntosh, I.; Francomano, C.A. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am. J. Hum. Genet. 1995, 56, 368–373. [Google Scholar]
  7. Rousseau, F.; Bonaventure, J.; Legeai-Mallet, L.; Pelet, A.; Rozet, J.-M.; Maroteaux, P.; Le Merrer, M.; Munnich, A. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994, 371, 252–254. [Google Scholar] [CrossRef]
  8. Di Rocco, F.; Duplan, M.B.; Heuzé, Y.; Kaci, N.; Komla-Ebri, D.; Munnich, A.; Mugniery, E.; Benoist-Lasselin, C.; Legeai-Mallet, L. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum. Mol. Genet. 2014, 23, 2914–2925. [Google Scholar] [CrossRef]
  9. Irving, M.; AlSayed, M.; Arundel, P.; Baujat, G.; Ben-Omran, T.; Boero, S.; Cormier-Daire, V.; Fredwall, S.; Guillen-Navarro, E.; Hoyer-Kuhn, H.; et al. European Achondroplasia Forum guiding principles for the detection and management of foramen magnum stenosis. Orphanet J. Rare Dis. 2023, 18, 219. [Google Scholar] [CrossRef]
  10. Ficke, J.; Varacallo, M. Anatomy, head and neck: Foramen Magnum. In StatPearls; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2024. [Google Scholar]
  11. White, K.K.; Savarirayan, R.; Goldberg, M.J.; MacKenzie, W.; Bompadre, V.; Bober, M.B.; Cho, T.J.; Hoover-Fong, J.; Parnell, S.E.; Raggio, C.; et al. Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy. Am. J. Med. Genet. Part A 2016, 170, 42–51. [Google Scholar] [CrossRef]
  12. Fornarino, S.; Rossi, D.P.; Severino, M.; Pistorio, A.; Allegri, A.E.M.; Martelli, S.; Lamba, L.D.; Lanteri, P. Early impairment of somatosensory evoked potentials in very young children with achondroplasia with foramen magnum stenosis. Dev. Med. Child Neurol. 2017, 59, 192–198. [Google Scholar] [CrossRef] [PubMed]
  13. Hoover-Fong, J.; Cheung, M.S.; Fano, V.; Hagenas, L.; Hecht, J.T.; Ireland, P.; Irving, M.; Mohnike, K.; Offiah, A.C.; Okenfuss, E.; et al. Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history. Bone 2021, 146, 115872. [Google Scholar] [CrossRef] [PubMed]
  14. Hecht, J.T.; Horton, W.A.; Reid, C.S.; Pyeritz, R.E.; Chakraborty, R. Growth of the foramen magnum in achondroplasia. Am. J. Med. Genet. 1989, 32, 528–535. [Google Scholar] [CrossRef] [PubMed]
  15. Pauli, R.M.; Scott, C.I.; Wassman, E.R.; Gilbert, E.F.; Leavitt, L.A.; Hoeve, J.V.; Hall, J.G.; Partington, M.W.; Jones, K.L.; Sommer, A.; et al. Apnea and sudden unexpected death in infants with achondroplasia. J. Pediatr. 1984, 104, 342–348. [Google Scholar] [CrossRef]
  16. Pauli, R.M. Achondroplasia: A comprehensive clinical review. Orphanet J. Rare Dis. 2019, 14, 1. [Google Scholar] [CrossRef]
  17. Pauli, R.M.; Horton, V.K.; Glinski, L.P.; Reiser, C.A. Prospective assessment of risks for cervicomedullary-junction compression in infants with achondroplasia. Am. J. Hum. Genet. 1995, 56, 732–744. [Google Scholar]
  18. Ruiz-Garcia, M.; Tovar-Baudin, A.; Del Castillo-Ruiz, V.; Rodriguez, H.P.; Collado, M.A.; Mora, T.M.A.; Rueda-Franco, F.; Gonzalez-Astiazaran, A. Early detection of neurological manifestations in achondroplasia. Childs Nerv. Syst. 1997, 13, 208–213. [Google Scholar] [CrossRef]
  19. Wright, M.J.; Irving, M.D. Clinical management of achondroplasia. Arch. Dis. Child. 2012, 97, 129–134. [Google Scholar] [CrossRef]
  20. Simmons, K.; Hashmi, S.S.; Scheuerle, A.; Canfield, M.; Hecht, J.T. Mortality in babies with achondroplasia: Revisited. Birth Defects Res. A Clin. Mol. Teratol. 2014, 100, 247–249. [Google Scholar] [CrossRef]
  21. Wynn, J.; King, T.M.; Gambello, M.J.; Waller, D.K.; Hecht, J.T. Mortality in achondroplasia study: A 42-year follow-up. Am. J. Med. Genet. Part A 2007, 143, 2502–2511. [Google Scholar] [CrossRef]
  22. Hashmi, S.S.; Gamble, C.; Hoover-Fong, J.; Alade, A.Y.; Pauli, R.M.; Modaff, P.; Carney, M.; Brown, C.; Bober, M.B.; Hecht, J.T. Multicenter study of mortality in achondroplasia. Am. J. Med. Genet. Part A 2018, 176, 2359–2364. [Google Scholar] [CrossRef]
  23. Nadel, J.L.; Wilkinson, D.A.; Garton, H.J.L.; Muraszko, K.M.; Maher, C.O. Screening and surgery for foramen magnum stenosis in children with achondroplasia: A large, national database analysis. J. Neurosurg. Pediatr. 2018, 23, 374–380. [Google Scholar] [CrossRef] [PubMed]
  24. Okenfuss, E.; Moghaddam, B.; Avins, A.L. Natural history of achondroplasia: A retrospective review of longitudinal clinical data. Am. J. Med. Genet. Part A 2020, 182, 2540–2551. [Google Scholar] [CrossRef] [PubMed]
  25. Cheung, M.S.; Irving, M.; Cocca, A.; Santos, R.; Shaunak, M.; Dougherty, H.; Siddiqui, A.; Gringras, P.; Thompson, D. Achondroplasia Foramen Magnum Score: Screening infants for stenosis. Arch. Dis. Child. 2021, 106, 180–184. [Google Scholar] [CrossRef] [PubMed]
  26. Cohen, M.M., Jr.; Walker, G.F.; Phillips, C. A morphometric analysis of the craniofacial configuration in achondroplasia. J. Craniofac. Genet. Dev. Biol. Suppl. 1985, 1, 139–165. [Google Scholar] [PubMed]
  27. Calandrelli, R.; Panfili, M.; D’apolito, G.; Zampino, G.; Pedicelli, A.; Pilato, F.; Colosimo, C. Quantitative approach to the posterior cranial fossa and craniocervical junction in asymptomatic children with achondroplasia. Neuroradiology 2017, 59, 1031–1041. [Google Scholar] [CrossRef] [PubMed]
  28. Kunkel, P.; Al Halak, M.; Pozza, S.B.-D.; Grasemann, C.; Keller, A.; Muschol, N.; Nader, S.; Palm, K.; Poetzsch, S.; Rohrer, T.; et al. Multidisciplinary approach in achondroplasia–real world experience after drug approval of vosoritide. In Proceedings of the European Society for Paediatric Endocrinology (ESPE) Annual Conference, Hague, The Netherlands, 21–23 September 2023. [Google Scholar]
  29. Dornheim Medical Images GmbH. Dornheim Segmenter. Available online: https://dornheim.tech/en/segmenter (accessed on 24 September 2024).
  30. Craven, C.; Jankovic, I.; Dyson, E.; Boyd, S.G.; D’Arco, F.; Cheung, M.S.-M.; Thompson, D. Association of the Achondroplasia Foramen Magnum Score and intraoperative neuromonitoring. Arch. Dis. Child. 2024, 109, 755–758. [Google Scholar] [CrossRef]
  31. Sandvik, U.; Ringvall, E.; Klangemo, K.; Hallgrimsdottir, S.; Gkourogianni, A.; Ottosson, L.; Svoboda, J.; Nilsson, O. Management and outcomes of foramen magnum stenosis in children with achondroplasia at a single center over 15 years. J. Neurosurg. Pediatr. 2024, 34, 470–478. [Google Scholar] [CrossRef]
  32. Cheung, M.S.-M.; Cocca, A.; Harvey, C.H.; Brett, C.S.S.; Offiah, A.C.; Borg, S.; Jenko, N.; D’arco, F.; Thompson, D. Natural history of spinal cord compression stage AFMS3 in infants with achondroplasia: Retrospective cohort study. Arch. Dis. Child. 2024. online ahead of print. [Google Scholar] [CrossRef]
  33. Akinnusotu, O.; Isaacs, A.M.; Stone, M.; Bonfield, C.M. Neurosurgical management of cervicomedullary compression, spinal stenosis, and hydrocephalus in pediatric achondroplasia: A systematic review. J. Neurosurg. Pediatr. 2023, 32, 597–606. [Google Scholar] [CrossRef]
  34. Savarirayan, R.; Wilcox, W.R.; Harmatz, P.; Phillips, J., 3rd; Polgreen, L.E.; Tofts, L.; Ozono, K.; Arundel, P.; Irving, M.; Bacino, C.A.; et al. Vosoritide therapy in children with achondroplasia aged 3–59 months: A multinational, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Child Adolesc. Health 2023, 8, 40–50. [Google Scholar] [CrossRef] [PubMed]
  35. Bianchi, F.; Benato, A.; Frassanito, P.; Tamburrini, G.; Massimi, L. Functional and morphological changes in hypoplasic posterior fossa. Child’s Nerv. Syst. 2021, 37, 3093–3104. [Google Scholar] [CrossRef] [PubMed]
  36. DiMario, F.J.; Ramsby, G.R.; Burleson, J.A.; Greensheilds, I.R. Brain Morphometric Analysis in Achondroplasia. Neurology 1995, 45, 519–524. [Google Scholar] [CrossRef] [PubMed]
  37. Marin-Padilla, M.; Marin-Padilla, T.M. Developmental abnormalities of the occipital bone in human chondrodystrophies (achondroplasia and thanatophoric dwarfism). Birth Defects Orig. Artic. Ser. 1977, 13, 7–23. [Google Scholar] [PubMed]
  38. Brühl, K.; Stoeter, P.; Wietek, B.; Schwarz, M.; Humpl, T.; Schumacher, R.; Spranger, J. Cerebral spinal fluid flow, venous drainage and spinal cord compression in achondroplastic children: Impact of magnetic resonance findings for decompressive surgery at the cranio-cervical junction. Eur. J. Pediatr. 2001, 160, 10–20. [Google Scholar] [CrossRef]
  39. Steinbok, P.; Hall, J.; Flodmark, O. Hydrocephalus in achondroplasia: The possible role of intracranial venous hypertension. J. Neurosurg. 1989, 71, 42–48. [Google Scholar] [CrossRef]
  40. Jha, R.M.; Klimo, P.; Smith, E.R. Foramen magnum stenosis from overgrowth of the opisthion in a child with achondroplasia. J. Neurosurg. Pediatr. 2008, 2, 136–138. [Google Scholar] [CrossRef]
  41. Pascoe, H.M.; Yang, J.Y.; Chen, J.; Fink, A.M.; Kumbla, S. Macrocerebellum in achondroplasia: A further CNS manifestation of FGFR3 mutations? AJNR Am. J. Neuroradiol. 2020, 41, 338–342. [Google Scholar] [CrossRef]
Jimaging 10 00291 g001
Figure 1. Illustrative examples of selected anatomical structures measured from magnetic resonance imaging scans from a child with achondroplasia. Shown are images used to calculate the following parameters: (a) foramen magnum diameter, (b) foramen magnum area, (c) myelon area, (d) clivus length, (e) tentorium angle, and (f) occipital angle.
Figure 1. Illustrative examples of selected anatomical structures measured from magnetic resonance imaging scans from a child with achondroplasia. Shown are images used to calculate the following parameters: (a) foramen magnum diameter, (b) foramen magnum area, (c) myelon area, (d) clivus length, (e) tentorium angle, and (f) occipital angle.
Jimaging 10 00291 g001
Jimaging 10 00291 g002
Figure 2. Illustrative examples of selected anatomical structures measured from magnetic resonance imaging scans from a child with achondroplasia, including screenshots of the data segmentation process using Dornheim Segmenter Research software (v2019.1; Dornheim Medical Images GmbH, Magdeburg, Germany). 3-D reconstructions of the following segmented structures are shown: (a) posterior fossa volume, (b) proportion of brainstem volume outside the posterior fossa, (c) cerebellum volume, (d) supratentorial ventricular system volume, (e) intracranial cerebrospinal fluid system volume, and (f) fourth ventricle volume.
Figure 2. Illustrative examples of selected anatomical structures measured from magnetic resonance imaging scans from a child with achondroplasia, including screenshots of the data segmentation process using Dornheim Segmenter Research software (v2019.1; Dornheim Medical Images GmbH, Magdeburg, Germany). 3-D reconstructions of the following segmented structures are shown: (a) posterior fossa volume, (b) proportion of brainstem volume outside the posterior fossa, (c) cerebellum volume, (d) supratentorial ventricular system volume, (e) intracranial cerebrospinal fluid system volume, and (f) fourth ventricle volume.
Jimaging 10 00291 g002
Jimaging 10 00291 g003
Figure 3. Analysis of the following anatomical parameters on magnetic resonance imaging scans in children with achondroplasia compared with the reference group: (a) foramen magnum diameter, (b) foramen magnum area, (c) myelon area, (d) clivus length, (e) tentorium angle, (f) occipital angle, (g) posterior fossa volume, (h) proportion of brainstem volume outside the posterior fossa, (i) cerebellum volume, (j) supratentorial ventricular system volume, (k) intracranial cerebrospinal fluid (CSF) system volume, and (l) fourth ventricle volume. Mean (standard deviation [SD]) data are shown. p-values are from Mann–Whitney U tests for independent samples.
Figure 3. Analysis of the following anatomical parameters on magnetic resonance imaging scans in children with achondroplasia compared with the reference group: (a) foramen magnum diameter, (b) foramen magnum area, (c) myelon area, (d) clivus length, (e) tentorium angle, (f) occipital angle, (g) posterior fossa volume, (h) proportion of brainstem volume outside the posterior fossa, (i) cerebellum volume, (j) supratentorial ventricular system volume, (k) intracranial cerebrospinal fluid (CSF) system volume, and (l) fourth ventricle volume. Mean (standard deviation [SD]) data are shown. p-values are from Mann–Whitney U tests for independent samples.
Jimaging 10 00291 g003
Jimaging 10 00291 g004
Figure 4. Proportion of patients who did/did not receive decompression surgery who were retrospectively graded as candidates for decompression surgery based on application of the Achondroplasia Foramen Magnum Score (AFMS) to magnetic resonance imaging scans.
Figure 4. Proportion of patients who did/did not receive decompression surgery who were retrospectively graded as candidates for decompression surgery based on application of the Achondroplasia Foramen Magnum Score (AFMS) to magnetic resonance imaging scans.
Jimaging 10 00291 g004
Table 1. Baseline characteristics.
Table 1. Baseline characteristics.
CharacteristicAchondroplasia (N = 37)Reference (N = 37)
Sex, n (%)
Male20 (54.1)23 (62.2)
Female17 (45.9)14 (37.8)
Age, years a
Mean (SD)1.1 (0.9)1.7 (1.3)
Median (range)0.8 (0.1–3.6)1.5 (0–3.9)
Decompression surgery, n (%)
Yes13 (35.1)0
No23 (62.2)37 (100)
a At time of magnetic resonance imaging.
Table 2. Analysis of anatomical parameters on magnetic resonance imaging scans in children with achondroplasia who received decompression surgery compared with those who did not receive surgery.
Table 2. Analysis of anatomical parameters on magnetic resonance imaging scans in children with achondroplasia who received decompression surgery compared with those who did not receive surgery.
ParameterReceived SurgeryDid Not Receive Surgeryp-Value *
Foramen magnum
diameter, mm		No. patients1221<0.1
Mean (SD)8.6 (1.9)10.7 (2.2)
Median (range)8.5 (5.5–12.5)10.5 (7.5–16.6)
Foramen magnum
area, mm2		No. patients12210.922
Mean (SD)108.3 (31.5)109.4 (32.2)
Median (range)118.8 (49.6–155.4)111.8 (54.9–163.8)
Myelon area, mm2No. patients12210.228
Mean (SD)36.0 (14.2)43.3 (16.8)
Median (range)33.9 (16.5–66.9)39.3 (25.2–102.3)
Clivus length, mmNo. patients14220.602
Mean (SD)23.2 (3.2)23.7 (3.1)
Median (range)22.6 (19.5–32.5)23.3 (16.0–30.0)
Tentorium angle,
degrees		No. patients1421<0.001
Mean (SD)49.0 (4.4)46.6 (6.0)
Median (range)49.0 (43.5–57.0)47.0 (31.5–58.0)
Occipital angle,
degrees		No. patients14210.513
Mean (SD)79.1 (5.8)77.0 (7.1)
Median (range)79.5 (70.0–89.5)78.5 (64.0–88.0)
Posterior fossa
volume, mm3		No. patients7170.120
Mean (SD)110,595.6 (20,307.3)132,456.8 (32,772.2)
Median (range)106,081.3 (84,624.6–140,277.7)134,941.4 (48,439.7–177,870.0)
Proportion of brainstem volume outside the posterior fossa, mm3No. patients717<0.001
Mean (SD)4698.3 (1034.4)4478.3 (1136.4)
Median (range)4532.0 (3233.8–6301.0)4428.4 (2778.6–7021.3)
Cerebellum volume, mm3No. patients7170.782
Mean (SD)90,139.4 (16,998.3)68,607.0 (51,701.3)
Median (range)86,698.1 (68,759.5–113,405.8)84,353.8 (98.7–141,281.0)
Supratentorial
ventricular system
volume, mm3		No. patients1220<0.001
Mean (SD)43,054.2 (28,955.2)41,467.1 (21,845.7)
Median (range)33,671.7 (16,830.3–115,394.5)35,651.9 (10,782.3–108,493.8)
Intracranial CSF
system volume, mm3		No. patients1219<0.001
Mean (SD)221,020.3 (86,479.5)228,826.5 (71,079.6)
Median (range)189,483.0 (124,900.2–376,599.0)236,400.2 (118,999.2–337,691.4)
Fourth ventricle
volume, mm3		No. patients14210.797
Mean (SD)716.1 (318.5)772.5 (383.8)
Median (range)732.0 (292.0–1279.2)660.3 (319.6–1607.8)
* Mann–Whitney U test for independent samples.
Table 3. Analysis of anatomical parameters on magnetic resonance imaging scans in children with achondroplasia by Achondroplasia Foramen Magnum Score (AFMS).
Table 3. Analysis of anatomical parameters on magnetic resonance imaging scans in children with achondroplasia by Achondroplasia Foramen Magnum Score (AFMS).
ParameterAFMS 1 or 2AFMS 3 or 4
Foramen magnum
diameter, mm		No. patients147
Mean (SD)10.2 (1.6)8.5 (1.5)
Median (range)10.0 (7.5–13.0)8.5 (7.0–11.1)
Foramen magnum area, mm2No. patients147
Mean (SD)119.4 (35.3)97.2 (32.5)
Median (range)120.8 (64.4–163.8)113.4 (49.6–129.9)
Myelon area, mm2No. patients147
Mean (SD)43.9 (19.4)32.5 (12.0)
Median (range)38.4 (26.7–102.3)31.4 (16.5–47.0)
Clivus length, mmNo. patients167
Mean (SD)24.4 (3.2)22.3 (2.2)
Median (range)24.3 (20.0–32.5)22.0 (19.5–25.5)
Tentorium angle, degreesNo. patients167
Mean (SD)47.7 (3.9)46.9 (3.9)
Median (range)47.3 (38.0–56.5)45.0 (43.5–54.0)
Occipital angle, degreesNo. patients167
Mean (SD)78.7 (4.8)76.4 (5.8)
Median (range)79.8 (70.5–85.0)75.0 (70.0–85.0)
Posterior fossa volume, mm3No. patients103
Mean (SD)121,354.9 (33,762.1)119,011.8 (34,362.1)
Median (range)127,663.5 (48,439.7–174,505.8)106,081.3 (92,990.8–157,963.2)
Proportion of brainstem
volume outside the posterior fossa, mm3		No. patients103
Mean (SD)4227.0 (693.0)4823.3 (1633.2)
Median (range)4448.4 (2778.6–5169.0)4739.1 (3233.8–6497.0)
Cerebellum volume, mm3No. patients103
Mean (SD)95,285.9 (30,564.1)93,927.2 (28,891.0)
Median (range)100,206.7 (29,592.2–141,281.0)81,541.8 (73,293.8–126,946.0)
Supratentorial ventricular
system volume, mm3		No. patients147
Mean (SD)39,401.9 (24,497.0)41,211.5 (15,093.3)
Median (range)33,539.9 (10,782.3–115,394.5)37,651.3 (25,549.6–62,386.6)
Intracranial CSF
system volume, mm3		No. patients137
Mean (SD)229,855.0 (88,536.2)201,651.5 (71,421.0)
Median (range)198,043.8 (118,999.2–376,599.0)189,151.4 (124,900.2–337,691.4)
Fourth ventricle
volume, mm3		No. patients167
Mean (SD)831.5 (422.4)651.5 (254.4)
Median (range)729.6 (338.3–1607.8)635.7 (356.5–982.6)
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Trautwein, I.; Behme, D.; Kunkel, P.; Gerdes, J.; Mohnike, K. Anatomical Characteristics of Cervicomedullary Compression on MRI Scans in Children with Achondroplasia. J. Imaging 2024, 10, 291. https://doi.org/10.3390/jimaging10110291

AMA Style

Trautwein I, Behme D, Kunkel P, Gerdes J, Mohnike K. Anatomical Characteristics of Cervicomedullary Compression on MRI Scans in Children with Achondroplasia. Journal of Imaging. 2024; 10(11):291. https://doi.org/10.3390/jimaging10110291

Chicago/Turabian Style

Trautwein, Isabella, Daniel Behme, Philip Kunkel, Jasper Gerdes, and Klaus Mohnike. 2024. "Anatomical Characteristics of Cervicomedullary Compression on MRI Scans in Children with Achondroplasia" Journal of Imaging 10, no. 11: 291. https://doi.org/10.3390/jimaging10110291

APA Style

Trautwein, I., Behme, D., Kunkel, P., Gerdes, J., & Mohnike, K. (2024). Anatomical Characteristics of Cervicomedullary Compression on MRI Scans in Children with Achondroplasia. Journal of Imaging, 10(11), 291. https://doi.org/10.3390/jimaging10110291

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop