COMPARISON OF CLOSURE TIMES FOR CRANIAL BASESYNCHONDROSES IN MESATICEPHALIC, BRACHYCEPHALIC,

AND CAVALIER KING CHARLES SPANIEL DOGS

MARTIN J. SCHMIDT, HOLGER VOLK, MELANIE KLINGLER, KLAUS FAILING, MARTIN KRAMER, NELE ONDREKA

Premature closure of cranial base synchondroses has been proposed as the mechanism for brachycephaly indogs and caudal occipital malformation syndrome (COMS) in Cavalier King Charles Spaniels. The purposeof this retrospective study was to compare times of closure for cranial base synchondroses in mesaticephalic,brachycephalic, and Cavalier King Charles Spaniel dogs. Cranial magnetic resonance imaging studies wereretrieved for client-owned dogs less than 18 months of age. Breed, age, skull conformation, and the open orclosed state of cranial base synchondroses were independently recorded by two observers. For dogs with aunanimous observer agreement, regression analysis was used to test effects of age and gender on the openor closed status of synchondroses and differences between groups. A total of 174 dogs were included in MRIinterpretations and 165 dogs were included in the regression analysis. Statistically significant differences inclosure time of the spheno-occipital synchondrosis were identified between brachycephalic and mesaticephalicdogs (P = 0.016), Cavalier King Charles Spaniels and mesaticephalic dogs (P < 0.0001), and Cavalier KingCharles Spaniels and brachycephalic dogs (P = 0.014). Findings from the current study supported the theorythat morphological changes leading to the skull phenotype of the Cavalier King Charles Spaniels could be dueto an earlier closure of the spheno-occipital synchondrosis. C© 2013 Veterinary Radiology & Ultrasound.

Key words: Chiari, craniosynostosis, dog, malformation.

Introduction

IT HAS BEEN proposed that the premature fusion of oneor more cranial sutures alters normal skull growth pat-

terns and lead to compensatory changes in the cranialvault of brachycephalic dogs.1 This growth disturbancemight also be involved in the pathogenesis of the caudaloccipital malformation syndrome that is frequently diag-nosed in brachycephalic dogs, especially in the CavalierKing Charles Spaniel.1 The neurocranium, which includesboth the cranial vault and the cranial base, expands rapidlyduring the postnatal period of dogs and other mammals.2

The main part of the longitudinal growth is dependent onthe extension of the cranial base. The basicranial bonesdevelop from a cartilaginous template (chondrocranium)that is replaced by bone through enchondral ossification.Whereas most of the cartilage is transformed into bone dur-ing prepartal life,3 some is preserved as boundaries whereendochondral ossification has ceased and growth of carti-

From the Department of Veterinary Clinical Science, Small AnimalClinic, Justus Liebig University, Gießen, Germany (Schmidt, Klinger,Kramer, and Ondreka), Unit for Biomathematics and Data ProcessingFaculty of Veterinary Medicine, (Failing), and Department of VeterinaryClinical Sciences, Royal Veterinary College, Hawkshead Lane, Hatfield,United Kingdom (Volk).

Address correspondence and reprint requests to Martin J. Schmidtat the above address. E-mail: Martin.J.Schmidt@vetmed.uni-giessen.de

Received August 6, 2012; accepted for publication March 6, 2013.doi: 10.1111/vru.12072

lage is ongoing (synchondrosis). The cranial base synchon-droses are analogous to the growth plates of long bones.They facilitate rapid growth in which the involved cartilagebecomes progressively thinner during skeletal maturationand ultimately converted into bone.2

Along the midline of the canine cranial base three syn-chondroses exist. They are the spheno-ethmoidal synchon-droses between the presphenoid and ethmoidal bones, theintersphenoid synchondrosis between pre- and basisphe-noid bone and the spheno-occipital synchondrosis betweenthe sphenoid and basioccipital bone.2, 4 The fusion of thesesynchondroses results in their transformation into a synos-tosis with a continuity of the bony trabeculae and marrowspaces of the adjacent cranial base bones.4

In dogs, information is currently lacking about the tem-poral relationship of skull base growth and closure ofthe synchondroses. A pathologically premature closure hasbeen suggested as the underlying cause for the morpholog-ical changes associated with brachycephaly in dogs.5 How-ever, to the authors’ knowledge, this assumption has not yetbeen tested. Whereas the epiphyseal closure of long bonesis well described,6 information about the cranial synchon-droses and sutures is scarce. The exact time of closure of thecranial base synchondroses has been reported to occur at 12months of age in the dog, however, no breed differences have

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498 SCHMIDT ET AL. 2013

FIG. 1. Magnetic resonance images illustrating variations in morphology and signal intensity of the cranial base synchondroses during postnatal developmentin the dog. After birth (A) the synchondrosal cartilage appear hyperintense to the surrounding bone signal on sagittal T2-weighted magnetic resonance imagesof the skull base. The cartilage is flanked on each side by a thin hypointense rim, which represents the beginning of ossification. The bone of the adjacentcranial base bones increase in signal intensity over time (A–D) on T2-weighted magnetic resonance images. This is in contrast to the ossification zone of thesynchondrosis, which becomes hypointense. The cartilage is progressively thinning and the synchondrosis obliterates until both zones of ossification are incontact with each other (B, C). Bony bridges start to develop at the dorsal and ventral aspect of the synchondroses (D).

been specified.7–9 Thus, insights into the temporal courseof developmental changes of the synchondroses are neededin order to evaluate their role in pathological developmentof canine skull shapes.

Based on previous theories,5 the first hypothesis of thecurrent study was that closure of the skull base synchon-droses occurs earlier in brachycephalic dogs compared toclosure of the skull base in mesaticephalic dogs. The Cav-alier King Charles Spaniel has been recognized to be morebrachycephalic than other brachycephalic dog breeds.10

Therefore, the second hypothesis of the current study wasthat synchondroses in the Cavalier King Charles Spanielfuse earlier than other brachycephalic dogs.

Materials and Methods

The archive of magnetic resonance imaging (MRI) scansof the Justus Liebig University (JLU) in Germany wassearched for cranial studies of dogs ≤18 months of agethat included high-resolution images of cranial base growthplate morphology. Dogs at JLU were included if they hadbeen scanned between 2006 and 2010. In addition, MRIstudies of Cavalier King Charles Spaniels ≤18 months ofage were retrieved from the Department of Veterinary Clin-ical Sciences, Royal Veterinary College (RVC), London,United Kingdom.

Magnetic resonance images of the head were obtainedusing high field scanners at both institutions (JLU: Gy-roscan Intera, 1.0 T, Phillips, Hamburg, Germany) (RVC:Gyroscan NT Intera 1.5T. Phillips, Hamburg, Germany).The T2-weighted sagittal images of the head (T2-Turbospinecho, TE 110–120 ms, TR: 2900–3300 ms, slice thickness2.5–3.5 mm) were used for all image interpretations. An“open” synchondrosis was defined based on the presenceof a broad hyperintense signal zone (cartilage) with well-defined hypointense borders (endplates) running perpen-dicularly through the entire cranial base and with an irreg-ularly hyperintense adjacent medullary cavity (Fig. 1 A). A“closed” synchondrosis was defined based on the presenceof obliteration of the dorsal and ventral edges of the syn-chondrosis and replacement of cartilage by bone (from thedorsal and ventral aspect toward the center.15 The spheno-occipital synchondrosis was identified ventral to the rostralborder of the pons in mesaticephalic dogs and ventral tothe center of the pons in brachycephalic dogs and CavalierKing Charles Spaniels. The intersphenoid synchondrosiswas identified at the level of the caudal aspect of the opticchiasm. The ethmo-sphenoid synchondrosis was identifiedat the caudal end of the olfactory bulb. (Fig. 1 A–C). Twoobservers (MS and MK) independently reviewed all in-cluded scans and recorded their interpretation of open or

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closed status for each synchondrosis. Only dogs with syn-chondroses having a unanimous status decision were usedfor further statistical analysis.

Statistical Analysis

All statistical tests were selected and performed bya professional statistician (K.F.), using commerciallyavailable software (Graph Pad Prism 4.0, Graph PadSoftware Inc., San Diego, California). In the first step ofthe statistical analysis a multiple logistic regression wasperformed to test the global effect of age and sex on closureof the synchondroses within each group. In a second step,a multiple logistic regression was performed to comparedifferent groups of dogs, taking into account the effectof age and sex. In the last step, groups of the dogs werecompared pairwise by means of a Wald-test and using aChi-square statistic. For all tests, a (probability) P value of<0.05 was determined to be significant.

Results

Dogs

One hundred and thirty-four scans from JLU and 40scans from RVC met initial inclusion criteria (total 174).Group 1 included 68 mesaticephalic dogs, group 2 consistedof 39 brachycephalic dogs. Group 3 was represented by 27Cavalier King Charles Spaniels from JLU and 40 CavalierKing Charles Spaniels from RVC (total 67). The neonataldogs were obtained from the Department of Gynaecology,Andrology and Obstetrics (JLU) after their early postpartaldeath. All other Cavalier King Charles Spaniels includedin the study from JLU were scanned for breeding selectionagainst syringomyelia. Cavalier King Charles Spaniels fromthe RVC were presented for the workup of neurologicaldiseases.

Group 1 (mesaticephalic dogs) included 44 males and22 females. Breeds represented were Golden Retriever,Hovawart, Bernese Mountain Dog, Irish Wolfhound,Entlebucher Mountain Dog, Doberman, Tervueren, Aus-tralian Shepherd, Rottweiler, Spitz, Dalmatian, JackRussel Terrier, German Shepherd Dog, English Setter,Dachshund, Rhodesian Ridgeback, Husky, Border Col-lie, Small Munsterlander, American Staffordshire Terrier,Vizsla, Weimaraner, and mixed-breed dogs. Ages rangedfrom neonatal to 18 months (mean age 10 months, me-dian 10.2 months). Group 2 (brachycephalic dogs) included13 male and 26 female dogs. Breeds represented were Pug,Chihuahua, French Bulldog, Pekingese, English Bulldog,Lhasa Apso, Shitzu, Yorkshire Terrier, Chihuahua. Agesranged from neonatal to 18 months (mean 8.9 months, me-dian 7.6 months). None of the dogs from Group 1 or 2 hadevidence of herniation of the cerebellum or syringomyeliain the upper cervical segments included in cranial scans.

TABLE 1. Number of Dogs in Each Age and Breed Group Sampled in theCurrent Study

Age Cavalier King(months) Brachycephalic Mesaticephalic Charles Spaniel

0–6 16 35 176–12 19 29 2412–18 9 21 20

Group 3 (Cavalier King Charles Spaniel dogs) included 32males and 35 females. The age ranged from neonatal to 18months (mean 10 months, median 10.2 months). Numberof dogs in each age and breed group are given in Table1. All Cavalier King Charles Spaniels had evidence of in-dentation of the occipital bone and deviation or herniationof the cerebellar vermis into the foramen magnum consis-tent with Chiari- like malformation. Fifty-two of the group3 dogs (78%) had syringomyelia of varying degrees of sever-ity in the cranial portion of the cervical spinal cord. Thecaudal cervical spinal cord and the thoracic and lumbarspinal cord segments were not evaluated. According to themedical records, none of the dogs from JLU had a history ofcervical hyperesthesia or head pruritus in their general andneurological examination findings. Cavalier King CharlesSpaniels from RVC had been diagnosed with epilepsy (n =13), meningoencephalomyelitis of unknown aetiology (n =4), infectious otitis media (n = 1), idiopathic vestibular dis-ease (n = 1), brainstem infarct (n = 1), oligoastrocytoma15

(n = 1), and atlanto-axial subluxation (n = 1). Eighteen ofthe Cavalier King Charles Spaniels from the RVC had signsof facial rubbing, phantom-scratching behavior, and/orhad cervical hyperesthesia, which were considered to besecondary to Chiari-like malformation and syringomyelia.

MRI Interpretation

The intersphenoid and spheno-ethmoidal synchondroseswere diagnosed as open in all 174 dogs by both observers.Therefore, no regression analyses were performed for clo-sure of the intersphenoid and spheno-ethmoidal synchon-droses. Both observers agreed that the open or closed statusof the spheno-occipital synchondrosis could be unequivo-cally determined in 165 dogs (94%) (Fig. 2). Only these165 dogs and this synchondrosis were used for subsequentstatistical analyses.

Statistical Analysis

Results of multiple regression analysis for the variable“closed” in the spheno-occipital synchondroses identifiedstatistically significant effects for group and age (group:P = 0.0013; age: P = 0.0002) but not for gender (P =0.657). A significant effect of the age was identified fortwo groups (mesaticephalic dogs: P = 0.0003; brachy-cephalic dogs: P = 0.11; Cavalier King Charles Spaniels

500 SCHMIDT ET AL. 2013

FIG. 2. Comparison of midsagittal T2-weighted magnetic resonance images of a mesaticaphalic dog (A, B) and a Cavalier King Charles Spaniel (C, D)showing the open and closed states of the sphenooccipital synchondrosis (arrows) as defined in this study. As long as the hypointense zones of ossificationcrossed the cranial base from the dorsal to the ventral margin, the synchondrosis was defined as open. Partial or total absence of hypointense signal comparedto the surrounding bone was defined as a closed synchondrosis.

P = 0.036). The effect of the variable age was positivelydirected (i.e., with increasing age the probability of closurealso increased). However the low P-value for the variablegroup (P = 0.013) indicated that there were differencesbetween the compared groups of dogs in closure when cor-rected for the effect of the age (global differences).

Results of the pairwise comparisons for spheno-occipitalclosure are summarized in Fig. 3. All pairwise groupcomparisons identified statistically significant differences(brachycephalic dogs vs. mesaticephalic dogs: P = 0.016;Cavalier King Charles Spaniels vs. mesaticephalic dogs:P < 0.0001; Cavalier King Charles Spaniels vs. brachy-cephalic dogs: P = 0.014. The probability of finding a closedspheno-occipital synchondrosis at a given time was higherin brachycephalic dogs and Cavalier King Charles Spanielscompared to mesaticephalic dogs and higher in CavalierKing Charles Spaniels compared to brachycephalic dogs.Due to the bidirectionally censored data, a 100% proba-bility for closure of the synchondroses could not be deter-mined. The time shift where 80% of the dogs in the groupshad a closed synchondrosis was approximately 4 months.Cavalier King Charles Spaniel dogs had an 80% probabil-ity for a closed spheno-occipital synchondrosis at 8 months,brachycephalic dogs at 12 months and mesaticephalic dogsat approximately 16 months.

FIG. 3. Plot of logistic regression curves for the probability of spheno-occipital synchondrosis closure and effect of age for the different dog groups,assuming a logistic model without interaction between age and group. Thegray lines highlight the time shift points where different groups have a prob-ability of synchondrosis closure of 80%.

Discussion

The spheno-occipital synchondrosis in brachycephalicdogs and Cavalier King Charles Spaniels had a higherprobability to be closed at an earlier time point than in

VOL. 54, NO. 5 CRANIAL BASE GROWTH IN CAVALIER KING CHARLES SPANIELS 501

mesaticephalic dogs. Furthermore, we detected a signifi-cant difference in the probability of closure of the spheno-occipital synchondrosis between brachycephalic dogs andCavalier King Charles Spaniels. This synchondrosis there-fore seems to ossify at an earlier time point in the CavalierKing Charles Spaniels. The intersphenoid and spheno-ethmoidal synchondroses were open in all of the dogs ex-amined in the current study, precluding further analyses ofage and breed effects for these synchondroses. This was anunexpected finding, as closure times for all synchondrosesin all breeds have been previously reported to occur withinthe first 18 months of life.6–8 It is possible that this dis-crepancy occurred because MRI techniques in the currentstudy were more sensitive for detecting open physes thantechniques used in previous reports. Future studies may beneeded to redefine physeal closure times using MRI and asample population of dogs older than 18 months.

Observer disagreement on the open or closed state ofthe spheno-occipital synchondrosis was exclusively foundin brachycephalic dogs and Cavalier King Charles Spaniels.It is likely that this occurred because the determination ofthe closed state is highly dependent on visualization of ahyperintense signal from the medullary cavity adjacent tothe synchondroses. If the basioccipital bone is thin, theremay be little or no hyperintense signal from the medullarycavity. The differentiation between the entirely hypointensebasioccipital bone and the hypointense endplates of thesynchondroses would therefore be difficult in these cases.

In spite of this limitation, results of this study supportedour first hypothesis that the closure of some synchondrosesoccurs earlier in brachycephalic dogs and Cavalier KingCharles Spaniels in comparison to mesaticephalic dogs.The association of the brachycephalic skull morphologyand developmental defects of the cranial base has been re-ported in other species.16–20 Specifically, the early fusion ofthe spheno-occipital synchondrosis has been reported to beresponsible for morphological variation in brachycephalicskull types because this synchondrosis primarily accountsfor the longitudinal expansion of the skull base.21 In brachy-cephalic cattle, a premature closure of the spheno-occipitalsynchondrosis was found to lead to the “short-headed”variant of the Hereford and Aberdeen Angus cattle. Syn-chondrosis closure in some calves was detectable at birth. Inall animals that were examined at 5.5 months or older, fu-sion of the synchondrosis was complete.22 The length of thebasicranium was also reduced due to the premature closureof the spheno-occipital synchondrosis in achondroplasticmice and rabbits in comparison with that of normal ani-mals of similar size.23–25 The same finding has been reportedin humans with achondroplasia and brachycephaly.26

Cavalier King Charles Spaniel dogs differ from otherbrachycephalic dogs in their extremely short but wide skullshape (high cranial index).10 Our finding of an earlier clo-sure time of the spheno-occipital synchondroses in the Cav-

alier King Charles Spaniels versus other brachycephalicdogs supported previous theories that premature cranialsynchondrosis closure might be responsible for the extremestocky skull phenotype and perhaps for the developmentthe morphologic changes associated with Chiari-like mal-formation, too. However, we acknowledge that this find-ing should be critically assessed before making a definitiveconclusion. When comparing the data of both groups, weidentified great variation in the time of synchondrosis clo-sure (between 2–9 months of age). Due to this large timerange, a significant difference in ossification and interindi-vidual variation can only be partially discriminated. Thereis also a lack of published data concerning gender differ-ences of synchondroses closure in dogs. Radiographic27 andhistological28 studies have reported sexual dimorphism infusion age in children. One study determined the onset ofthe spheno-occipital synchondroses fusion in females to oc-cur between 11 and 16 years of age and in males betweenthe ages of 12 and 18 years,29 depending on the onset ofpuberty. Closure time variation between dogs of oppositesex could also mask significant differences in closure age.However, there was no influence of gender on the vari-able closure of the synchondrosis in our analysis in neithergroup. We, therefore, considered the effect of sexual hor-mones on the open or closed state of the growth centers tobe excluded.

One limitation of the study was that the open or closedstate of cranial base growth plates were defined based onMR imaging interpretation only and that no pathologicreference standard was available. An open synchondrosisin MRI studies does not necessarily indicate that growthis continuing until the time of synchondrosis closure. Adefinitive assessment of the functional integrity of chon-drocytes in the synchondroses would require histologicalinvestigation.

A differentiation between Cavalier King Charles Spanielswith and without syringomyelia was considered for the cur-rent study. However, syringomyelia can be a late onset dis-ease and the odds of the presence of syringomyelia wereconsidered to be low for a Cavalier King Charles Spanielunder 18 months of age.11–13 Authors concluded that ana-lysis based on this differentiation would have introduceda bias, because a Cavalier King Charles Spaniel withoutsyringomyelia at 18 months of age could have the potentialto develop the disease later in life.13–15

In addition to premature cranial base synchondrosisclosure, brachycephaly could also be caused by othergrowth defects. Achondroplasia may lead to dispropor-tional dwarfism, as presented in the Pug or the FrenchBulldog. More proportionate skeletal formation distur-bances may be caused by a reduced level of growth hor-mones, such as those seen in the Chihuahua or the York-shire Terrier. This form of dwarfism has been referred to asateliotic dwarfism.9 It is well described in human medicine

502 SCHMIDT ET AL. 2013

that growth hormone deficiency results in an immature fa-cial appearance and a skull maintaining a child-like con-vexity. Affected children show an overall general reductionin cranial base length.30, 31 There is a lack of histologicaland molecular studies describing the precise mechanismsresponsible for the impaired cartilage growth leading tobrachycephaly in different dog breeds.30, 31 In the absenceof clear biochemical and physiologic data the canine skulltypes can only be defined in morphologic terms. Given theextreme heterogeneity of the canine breeds sharing brachy-cephalic features in group 2 of the current study, it is there-fore possible that the comparison of Cavalier King CharlesSpaniels with this group could be unsound.

In the literature, Chiari-like malformation has only beenreported in brachycephalic dogs with a high prevalence inthe Cavalier King Charles Spaniel.32 If the higher cranial in-dex in the Cavalier King Charles Spaniel is one feature thatdistinguishes this group from other dogs, it is conceivablethat the degree of brachycephaly may be involved in thepathogenesis of Chiari-like malformation in this breed.10

The shortening of the cranial base seems to play a keyrole in animals and humans with Chiari malformation type1.33–38 In humans a reduced length of the clivus, reducedlength of the basisphenoid and a reduced length of thebasiocciput have been found in children and adults with

Chiari malformation type 1 in comparison to unaffectedindividuals.39–41

The growth impairment of the spheno-occipital synchon-drosis in the Cavalier King Charles Spaniel may not be dueto a primary defect of the cranial base growth center, butcould also represent a secondary effect of a growth distur-bance of the calvarial sutures (craniosynostosis). Closure ofcalvarias sutures in Crouzons- and Apert-Syndrome havean influence on the growth of the cranial base synchon-droses, leading to foreshortening of skull base, cerebellarherniation and alterations in venous outflow tracts in thecranial base causing intravenous and intraventricular hy-pertension and hydrocephalus.42

In conclusion, findings from the current study supporttheories that premature closure of the spheno-occipital syn-chondrosis may be a contributing factor for brachycephalicskull conformation in dogs, and caudal occipital malforma-tion syndrome in Cavalier King Charles Spaniels. Furtherstudies are needed to identify specific causes leading to thealteration in skull phenotype for the Cavalier King CharlesSpaniel.

ACKNOWLEDGMENTS

We would like to thank Marion Sparenberg for the construction of allgraphs in this study.

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