Received: 26 December 2014 | Revised: 23 March 2015 | Accepted: 7 December 2015 | Published on: 0 Month 2016

DOI 10.1002/mc.99992

RESEARCH ARTICLES

Dysspondyloenchondromatosis (DSC) associatedwith COL2A1 mutation: clinical and radiologicaloverlap with spondyloepimetaphyseal dysplasia-Strudwick type (SEMD-S)1

Byung Suk Merrick1 | Myung Calder2 | Elliz Wakeling3 |

Bonna Benjamin1,4 | Golder N. Wilson2 | Vinson Diep1 |

Laurie H. Seaver2,3,5 | Haeyoung Kwon1 | Eunsook Ahn1 |

Seon-Young Kim1

1North West Thames Regional Genetics

Service, London North West Healthcare

NHS Trust, Harrow, UK

2Department of Radiology, Great Ormond

Street Hospital, London, UK

3University of Hawai’i John A. Burns School

of Medicine, Honolulu, Hawaii

4Department of Pediatrics, University of

Hawaii’, John A. Burns School of Medicine,

Honolulu, Hawaii

5 Kapiolani Medical Specialists, Honolulu,

Hawaii

Correspondence

Dr. Emma Wakeling, Consultant in Clinical

Genetics, North West Thames Regional

Genetics Service, London North West

Healthcare NHS Trust, Watford Rd,

Harrow, HA1 3UJ.

E-mail: e.wakeling@nhs.net

Funding Information

This work was supported by Norwegian

Cancer Society (EBBA-I study) 49 258 and

05087, and Foundation for the Norwegian

Health and Rehabilitation Organizations

59010-200/2001/2002.

AbstractObjectives: Dysspondyloenchondromatosis (DSC) is a rare skeletal

dysplasia characterised by enchondroma-like lesions and anisospon-

dyly.The former leads to discrepancies in limb length, and the latter, to

progressive kyphoscoliosis.

Methods: We report on a case with radiographic features of DSC

with overlap into the type II collagenopathy spondyloepimetaphy-

seal dysplasia, Strudwick type (SEMD, S), who was found to carry a

novel heterozygous mutation in the COL2A1 gene.

K E YWORD S

chalcogenide glasses, glass-ceramics, spark plasma sintering,

mechanisms of densification

JEL Classification: I12; I18; K42

1This paper is followed by discussions and a rejoinder.

Disclosures: The authors have no disclosures or other conflicts of interest to report.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and

reproduction in any medium, provided the original work is properly cited.

© 2015 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

Mol Carcinog 2016; 9999: 1–12 wileyonlinelibrary.com/mc | 1

Journal MSP No. Dispatch: January 19, 2016 CE:

MC 99992 No. of Pages: 12 PE:

1 | INTRODUCTION

Dysspondyloenchondromatosis (DSC) is a rare skeletal

dysplasia with enchondroma-like lesions predominantly

in the metaphyses (with potential extension into the

diaphyses) of long bones. These, in combination with

anisospondyly (abnormally increased variability of the

size of vertebral bodies secondary to abnormal ossifica-

tion), are characteristic of the condition. Mild facial

anomalies,visual abnormalities and developmental delay

have also been reported.1 First described by Mainzer,

Minagi, and Steinbach (1971), and classed as a distinct

entity in 1993 (Freisinger, Finidori, & Maroteaux, 1993;

Haga, Nakamura, Taniguchi, & Nakamura, 1998; Kenis

et al., 2013; Kozlowski, Brostrom, Kennedy, Lange, &

Morris, 1994), to our knowledge only 15 sporadic cases

have been reported in the literature to date.2

No, I mean you have to deal with security and the

hotel workers and make sure you get up to the room with the food; otherwise you won’t get your tip.

But the main thing is that you have to treat these khaleejiyeen [men from the Gulf] like they’re princes.You

have to know how to address them. . . . but I have known a lot of guys who have worked in service, and then

some guy liked their service and offered them a job right there, to go back to Saudi or wherever.

DSCwas formerly classified as a disorder of generalised enchondromatosis. Since then it has been re-classified as

a spondylometaphyseal dysplasia and the metaphyseal changes recognised to be regressive (Lerman-Sagie,

Grunebaum, &Mimouni, 1987;Mainzer et al., 1971; Nakane et al., 2011; Superti-Furga, Spranger, &Nishimura, 2012;

Superti-Furga & Unger, 2007; Terhal et al., 2012; Tran et al., 2014; Tysoe et al., 2003; Walter et al., 2007; Warman

et al., 2011) rather than proliferative in nature, as in TRPV4 and FGFR3-related dysplasias Box 1.3

1.1 | Glass powder synthesis

Nakane et al. noted the significant overlap in the phenotypes of DSC and type II collagenopathies, especially

spondyloepimetaphyseal dysplasia, Strudwick type (SEMD-S).They demonstrated a novel mutation (p.Gly753Asp) in

BOX 1. Categorization of reviews according to the strength of evidence.

Level 1. Systematic reviews, defined as an exhaustive summary of the high-quality literature on a

particular topic, typically involving an a priori comprehensive search strategy, with the goal of reducing

bias by identifying, appraising and synthesizing all relevant studies on a particular topic.

Level 2. Reviews with three core criteria; i.e. evidence of comprehensive search, clear selection

(inclusion/exclusion) criteria and process of quality assessment of papers reviewed.

Level 3. Reviews not meeting the criteria of level 2. This group is therefore weaker methodologically,

but was taken to represent ‘suggestive evidence’.

Key Points

� Antiepileptic drugs (AEDs) commonly given

to pregnant women alter the expression of

placental carriers in a human trophoblast

cell line.

� Affected carriers are involved in the trans-

placental transport of folate, thyroid hor-

mones, and medications.

� Some of the AEDs effects on carrier ex-

pression are concentration-dependent.

� If translated into the human placenta in

vivo, thesefindingsmay suggest a newmech-

anism for AEDs’ adverse effects on fetal

development.

2 | B. S. MERRICK ET AL.

the COL2A1 gene in a patient with DSC, indicating that the condition is part of the broad spectrum of type II collagen

disorders Table 1.4

1.2 | Spark plasma sintering (SPS)

However, a further case of DSC was subsequently reported in which no pathogenic mutation was identified, sug-

gesting that the condition is genetically heterogeneous.5

1.2.1 | Heating of the glass powder through SPS experiment

A week prior to this, mild polyhydramnios had been noted on ultrasound scan; the pregnancy was otherwise un-

remarkable. Birth weight (1.680 kg) and length (42 cm) fell on the 50th centile (Terhal et al., 2012; Tran et al., 2014;

Tysoe et al., 2003; Walter et al., 2007; Warman et al., 2011).

We report on a boy with characteristic skeletal features of DSC and clinical signs associated with type II

collagenopathy, in whom a novel COL2A1 mutation was identified.

2 | CLINICAL REPORT

The patient was born prematurely at 31 weeks gestation after spontaneous rupture of membranes to healthy, non-

consanguineous parents of Lithuanian origin (Table 2). A week prior to this, mild polyhydramnios had been noted on

ultrasound scan; the pregnancy was otherwise unremarkable. Birth weight (1.680kg) and length (42cm) fell on the

50th centile. Post-partum he required respiratory support and artificial feeding before he could be discharged home

at two months of age.

Dlil¼

Dhih

1þ Dbib

� �1− Dhi

h

� �−Dbib

1þ Dbib

ð1Þ

Whilst in hospital, concern was raised regarding the possibility of an epiphyseal dysplasia due to changes noted

on X-ray. However, at this stage no formal diagnosis or further testing was undertaken.

Si ¼ Dlil×105 I ¼ Dhi

h−Dbib

� �×105 I ð2Þ

TABLE 1 Genotypic transmission disequilibrium test(gTDT) of the 12 single nucleotide polymorphisms (SNP) in theDNA repair genes among 223 parent-proband trios of nonsyndromic cleft lip with or without cleft palate

SNP Gene MAF T U OR 95% CI x2 p value

rs1136410 ADPRT 0.162 64 78 0.82 0.59-1.14 1.38 0.24

rs1052133 OGG1 0.238 73 88 0.83 0.60-1.13 1.39 0.23

rs1800734 MLH1 0.243 77 90 0.85 0.63-1.16 1.01 0.31

rs1130409 APEX1 0.439 104 109 0.95 0.72-1.24 0.11 0.73

rs861539 XRCC3 0.309 91 108 0.84 0.63-1.11 1.45 0.22

rs25487 XRCC1 0.248 77 88 0.87 0.64-1.18 0.73 0.39

rs25489 XRCC1 0.078 32 28 1.14 0.68-1.89 0.26 0.60

rs3213245 XRCC1 0.369 83 106 0.78 0.58-1.04 2.79 0.09

rs1799782 XRCC1 0.089 33 43 0.76 0.48-1.20 1.31 0.25

rs13181 ERCC2 0.287 101 85 1.18 0.89-1.58 1.37 0.24

rs1799793 ERCC2 0.260 96 92 1.04 0.78-1.38 0.08 0.77

MAF: minor allele frequency, T: the number of transmitted alleles, U: the number of untransmitted alleles.

B. S. MERRICK ET AL. | 3

He continued to have feeding difficulties for the first few months of life, with delayed motor milestones. He

first sat at one year and was able to walk by two years of age. He continues to have a waddling gait. There is no

concern regarding his cognitive development although this has not been formally assessed. He is currently in

mainstream school without additional support. He has a high myopia, corrected with glasses. A recent audiogram

was normal.

−Dszmin < Ds1max < Dsbmin

On examination at 5 years, his height was 88.5cm (-6.6 SD) and weight 17.7kg (-1 SD) x ¼ Bh. His midface was flat with

maxillary hypoplasia and a shortened neck. He has a normal palate but bifid uvula. Pes planus was noted bilaterally,

with leg length discrepancy; his right leg being longer than his left. There was widespread joint laxity with mild

enlargement of wrist, knee and elbow joints. Scoliosis was not demonstrable by clinical examination.

� Nem il excepta temquidust occum eruptatem doluptatest.

� Qui cuptatiis anis nate que sitaqui nus, te et aperis sitate id molorem desequo moles quiam, am, si aut ut officium.

� Ut doluptate veria nobis volores et verionsed et qui tate pla voloritibus.Rae. Olor remos ulparcillam ipsuntia

possinusande eum qui de velit alita vit ulparch illitate pla voloritibus.

A skeletal survey obtained at age 5 years and 5months is shown in Figure 1. Flexion and extension radiographs of

the cervical spine are shown in Figure 2. Overall, the radiographic appearances were felt to be highly suggestive of

DSC, with additional features (including odontoid hypoplasia, pelvic morphology and apparent flat face) in keeping

with a type II collagen disorder.

DNA was extracted from peripheral blood in the patient and his parents with informed consent. Unidirectional

fluorescent SangerDNA sequencing of theCOL2A1 genewas carried out. A heterozygous c. 1799G>Ap. (Gly600Asp)

sequence variant in exon 27 was detected and confirmed by bidirectional DNA sequencing in the patient. The

mutationwas not found in either parent. Aswith the only other described case ofDSCwith aCOL2A1mutation, this is

a missense mutation leading to the substitution of glycine for aspartic acid, and is predicted to be pathogenic.

1. Quaectur repel intionsequi corum reptusc ipidellorum fuga.

a. Nempore pudanimpos

b. estium reptur

c. omnis nonsequ aeperchit

TABLE 2 Analysis of variance for fitted quadratic polynomial model for biomass yield and BDO yield

Source Yx/sa Yxp/sb

Sum of squares F value Probe>F Sum of squares F value Probe>F

Model 0.000212 12.71 0.0001 0.000212 12.71 0.0001

X1-Acetic acid 0.000626 28.23 0.0002 0.000626 28.23 0.0002

X2-Furtural 0.000152 39.27 <0.0001 0.000152 39.27 <0.0001

X3-HMF 0.000212 41.00 <0.0002 0.000212 41.00 <0.0002

Residual 0.000626 0.37 0.5547 0.000626 0.37 0.5547

Lack of fit 0.000152 3.34 1.0000 0.000152 3.34 1.0000

Cor total 0.000152 1.78 0.2640 0.000152 1.78 0.2640

aAdjusted for age, BMI, smoking status, alcohol use, history of hormonal contraceptive use, and physical activity level. Amongthese covariates, BMI was the only significant predictor of estradiol, and no covariate significantly predicted progesteronelevels.bReference group: unmarried.

4 | B. S. MERRICK ET AL.

2. Nempore pudanimpos estium reptur, omnis nonsequ aeperchit remost officab orerum sunt que sus,volorepre audi

bla eictota ssimus, et lam fuga. Itatur mossimetust.

3. Quat accum hicias evellac cuscidunt aut aut harumdolenist, cus voloreptat post laccuptaque sim ipsunt reperia iur.

3 | DISCUSSION

Mutations in COL2A1 result in a group of skeletal dysplasias known as type II collagenopathies. These include

conditions with a wide range of severity, ranging from lethal to milder phenotypes (such as avascular necrosis of the

femoral heads), predominantly affecting the spine and epiphyses. Metaphyseal changes are also seen in a number of

type II collagenopathies, including the Strudwick variant of SEMD (SEMD-S).

3.1 | Dual representation

There is significant overlap between the phenotype described in SEMD-S and DSC. At the more severe end of the

SEMD-S spectrum, metaphyseal involvement can lead to disruption of the growth plate and subsequent limb length

discrepancy. Conversely, there is variability in the severity of vertebral changes seen in patients with DSC. The

majority of patients described have severe scoliosis, even within the first few years of life.

3.1.1 | Time consistency

However, others, like our patient, have milder vertebral anomalies, despite otherwise typical radiological findings of

DSC. It could be argued that patients with radiological findings previously associatedwithDSC andCOL2A1mutation

should be considered as having SEMD-S, albeit at the more severe end of the spectrum.

Cpp conditionals tree models the nesting of Cpp conditionals in a file. Each node of this tree is a Cpp

conditional descriptor, which stores the condition plus the start and end positions of each branch. The

conditional completion algorithm uses this information to complete Cpp conditionals and the pretty printer

FIGURE 1 Standing leg lengths radiograph with magnification view of left knee. There is asymmetric metaphysealirregularity, with more severe changes on the left, particularly around the knee. These metaphyses show longitudinalstriations and irregular calcific density, suggestive of ‘chondromatous’ change (arrows). The left tibia is shortened

B. S. MERRICK ET AL. | 5

uses it to reverse pseudo-preprocessing. During refactorings that involve code movement, this tree is queried

to check that the selected code includes complete Cpp conditional constructs (i.e., all branches). Moreover, the

conditions stored in Cpp conditional descriptors are first-class objects that can be composed, analyzed and

compared, for example, to check for compatibility of conditions during code movement.

Guarding condition.While tokenizing the code, P-Cpp labels each token with the current condition in terms of

the nesting of Cpp conditionals that surround it. Note that the current condition is the conjunction among the

condition in the current node of the Cpp conditionals tree and its ancestors. The nodes in the AST inherit the

‘guarding condition’ from their tokens.

Multiple definitions for a symbol table entry. Because a program elementmay have more than one applicable

definition, the symbol table in CRefactory was enhanced to support multiple definitions for a given symbol,

each one labeled with the guarding condition under which the definition applies. The lookup operation on this

FIGURE 2 AP radiograph of right upper limb. There is metaphyseal irregularity most pronounced in the upperhumerus with mild chondromatous change (arrow). The hand appearances, other than showing a delay in boneage, are normal

6 | B. S. MERRICK ET AL.

enhanced symbol table takes two arguments: a name and a condition. The name selects an entry in the table,

and the condition selects among the possible definitions for the symbol. Moreover, given a symbol S with

multiple definitions: D1, D2, . . ., Dn, the semantic analyzer binds a use of S under condition Q to all definitions

Di under condition Ci for which Ci is compatible with Q.With this representation, the symbol table can easily

be queried to find out if a refactoring is applicable to a single or multiple definitions of a symbol.

Themajority of type II collagenopathies are associatedwith heterozygousmutationswithin different parts of the

triple helical domain of COL2A1. The triple helical domain is characterised by repeating Gly-X-Y triplets. Missense

mutations resulting in substitution of the glycine residue within this triplet with a bulkier amino acid, such as arginine

or aspartic acid, are known to be pathogenic.Typically, suchmutations give rise to a clinical phenotype consistentwith

spondyloepiphyseal dysplasia congenital (SEDC) or SEMD-S (Table 3).

Acceptance set

Only one previous patient with DCS has been reported to have a COL2A1mutation: a novel, heterozygous missense

mutation, c.2258 G>A (p.Gly753Asp) in exon 34. This mutation lies within the triple-helical domain, as found in our

patient (p.Gly600Asp) and others reported in patients with SEMD-S.

Properties There is considerable variability in phenotype in patients with missense mutations spanning the triple-

helical domain. Substitution of glycine to arginine may confer an increased likelihood of metaphyseal changes.

However, there are also examples of glycine to arginine mutations that do not result in metaphyseal involvement. In

addition,Tysoe et al. reported a glycine to aspartic acid substitution (p.Gly262Asp), close to that found in our patient,

in a family with SEMD-S with metaphyseal and vertebral changes similar to those seen in DSC. This variability may

arise due to molecular microenvironments within the triple helical domain, or complex interaction with other genes/

gene products.

TABLE 3 OXTR genotype distribution among ADHD group and control group

ADHD Group (n=99) Control Group (n=99)

rs2268493 Gene Polymorphism

T/T genotype 51(51.50) 65(65.70)

T/C genotype 40(40.40) 31(31.30)

C/C genotype 8(8.10) 3(3)

T Allele 142(71.72%) 161(81.31%)

C Allele 56(28.28%) 37(18.69%)

rs53576 Gene Polymorphism

G/G genotype 46(46.50) 40(40.40)

G/A genotype 46(46.50) 46(46.50)

A/A genotype 7(7.10) 13(13.10)

G Allele 138(69.70%) 126(63.64%)

A Allele 60(30.30%) 72(36.36%)

rs13316193 Gene Polymorphism

T/T genotype 42(42.40) 53(53.30)

T/C genotype 46(46.50) 41(41.40)

C/C genotype 11(11.10) 5(5.10)

T Allele 130(65.66%) 147(74.24%)

C Allele 68(34.34%) 51(25.76%)

B. S. MERRICK ET AL. | 7

Lemma 1. Let G be a connected plane graph which satisfies the following.

i. V(G) = S T, where S = {s1, s2, . . ., sm} and T= {x1, x2, . . ., xk} T {y1, y2, . . ., yk} with m ≥ 5 and k ≥ 1.

ii. xiyi E(G) and |N({xi, yi}) S| ≥ 2 for every i. Moreover, G[S] F and all the vertices in T are contained in O(G[S]).

iii. If N(s j) {xi, yi}= for some i and j, then N(s j) {xi, yi}= for every i= i.

The patient reported by Nakane et al. had typical radiological features of DSC but was also noted to have flat

midface and cleft palate. These features are not mentioned in other reports of patients with DSC, including the case

described byMau-Them et al, whose COL2A1mutation analysis was normal. Furthermore, the radiographs presented

in this COL2A1 negative case did not demonstrate COL2A1 features, such as pubic bone hypoplasia, hypoplasia of

lower lumbar vertebrae, and also showed brachydactyly, which is unusual in COL2A1 disorders. We suggest that

patients without clinical and radiological features known to be associated with type II collagenopathies have a

separate condition and that absence of these features should cast doubt on the diagnosis of DSC.

Proposition 1. If the conditional preference functional Ut : smax < Dsmin is upper semicontinuous with respect to

theweak*-topology (L, L1), then the conditional indifference price has the following dual representation,

Dt : Amax > Amin

Identification of COL2A1 mutation may have important clinical implications. Our patient was found to have odontoid

hypoplasia on skeletal survey (Figure 3), with some mild atlanto-axial instability demonstrated on flexion and extension views

of the cervical spine (Figure 3) in common with some patients with type II collagenopathy. Neither he nor the patient reported

by Nakane et al, has any problems with hearing or vision, aside from refractory error. However, in view of the association of

high myopia, retinal detachment and hearing loss in other patients with COL2A1-related skeletal dysplasias, ophthalmology

and audiology follow up has been recommended.

Our patient’s birth length fell on the mean, unusual for DSC, as unlike all but one of the cases previously reporte,

birth length is normallywell below 0.4th C. In our patient, hismarked prematuritymay in part be an explanation for his

FIGURE 3 AP radiograph of the pelvis. The pubic bones are hypoplastic with separate ossicles for the pubicbody (arrowhead) and superior ramus (arrow), and absent inferior ramus ossification. There is bilateral severecoxa vara. The right femoral capital epiphysis is small and fragmented, the left capital femoral epiphysis is absent.There is irregular metaphyseal ossification in both upper femora

8 | B. S. MERRICK ET AL.

normal birth length, with length discrepancy in DSC not becoming apparent until the latter part of fetal development.

There is also some evidence that effect on growth in patients with substitution of asparagine for glycine tends to be

less pronounced than with substitution of alternative amino acids.

In summary, this case provides supporting evidence that there is overlap of DSCwith the broad-spectrum of type

II collagenopathies. We believe that DSC is best described as a disorder of in which endochondromatosis occurs as

a secondary phenomenon. These characteristic lesions are seen in a range of skeletal dysplasias, including TRPV4

dysplasias, achondroplasia and severe osteogenesis imperfecta. Increased understanding of the disruption in mole-

cular pathways which lead to formation of these enchondroma-like lesions will help to identify additional genetic

causes in cases with radiological features of DSC in which no COL2A1 mutation is identified.

ACKNOWLEDGMENTS

Authors would like to thank the MRCT-CNRS (Mission Ressources et Compétences Technologiques) for its financial

support and B. Soulestin (SPCTS, Limoges) for TEM observations.

NOMENCLATURE

VAM vinyl acetate monomer

XRD X-ray diffraction

XPS X-ray photoelectron spectroscopy

TEM transmission electron microscopy

TPO temperature-programmed oxidation

TPD temperature-programmed desorption

a,a activity

X degree of reaction conversion

F flow rate of feed (mol�min−1)

W catalyst mass (g)

SUBSCRIPT

C concentration (mol�L−1)Ea activation energy (kJ�mol−1)

Ed deactivation energy (kJ�mol−1)

K rate constant

K0 pre-exponential constant or frequency factor in the Arrhenius equation

R universal gas constant (kJ �mol−1 �K−1)

APPENDIX

ASyncRE Software Framework, Modular Design, and Implementations on Different Computer Resources

As discussed above, the reliance on a static pool of computational resources and zero fault tolerance prevents the

SyncRE approach from being a feasible solution for new application areas that demand multidimensional RE algo-

rithms using hundreds to thousands of replicas. To address these challenges, we have developed a novel Python

package named ASyncRE for distributed replicaexchange applications (https://github.com/ComputationalBiophy-

sicsCollaborative/AsyncRE). An upcoming publicationwill focus on the design of the software. Briefly, as illustrated in

Figure 3, the idea behindASyncRE is the implementation of replicas as independent executions of theMDengine for a

predetermined amount of simulation time. Each replica lives in a separate subdirectory of a local coordination server

where the ASyncRE application runs. MD engine input files are prepared for each replica according to the RE scheme

under consideration. As resources become available, a randomly chosen subset of the replicas are submitted to a Job

Manager, which launches them on remote resources using a direct ssh link or through a BOINC infrastructure,

B. S. MERRICK ET AL. | 9

and enter a running state. When a replica completes a cycle remotely (e.g., on XSEDE compute nodes or a BOINC

client), the output data is transferred back to the server and the replica enters a waiting state, making it eligible for

exchange with other replicas as well as the initiation of a new cycle. Periodically, exchanges of thermodynamic

parameters are attempted between replicas in a waiting state using the MIS algorithm described above restricted to

only the pool of replicas in the waiting state. Exchanges are conducted based on the appropriate reduced energies as

specified in user-defined modules. This usually entails, see below, extracting energetic and structural information

from the MD engine output files. Exchanges result in a new set of MD engine input files ready to begin a new

execution cycle.

1. Modules to interfaceMD engines.Thesemodules facilitate the interaction with the specifiedMD engine (IMPACT

in this case), such as providing routines to compose input control files and to read output files for collecting MD

simulation results.

2. Modules to perform common tasks such as job staging through job manager and coordinating exchanges of

parameters among replicas. Independence sampling algorithms are implemented in the core module, which

often calls specialized routines defined in user-provided modules implementing specific RE schemes with a given

Figure 3. Schematic diagram of the AsyncRE algorithm implemented in the ASyncRE software. The file system

resides on a coordination server, each cell represent a replica which can be either in a waiting (W) state or running

(R) state. Replicas in the waiting state can exchange thermodynamic parameters as illustrated by the curved

arrows at the bottom of the diagram. Replica in the running state is submitted to the jobmanager for execution on

remote compute resources. WWW.C-CHEM.ORG FULL PAPER Journal of Computational Chemistry 2015, 36,

1772–1785 1783MD engine (temperature, Hamiltonian, etc., including multidimensional combinations of these).

Currently, modules formultidimensional RE andBEDAMk-RE alchemical binding free energy calculationswith the

IMPACT MD engine are provided. One key function of modules implementing RE schemes is the computation of

the reduced potential energy matrix in eq.

How to cite this article:Merrick BS,CalderM,Wakeling E, Benjamin B,WilsonGN,DiepV, Seaver LH, KwonH,

Ahn E, Kim S-Y. 2015. Dysspondyloenchondromatosis (DSC) associated with COL2A1 mutation: clinical

and radiological overlap with spondyloepimetaphyseal dysplasia-Strudwick type (SEMD-S). Molecular

Carcinogenesis 9999:000–000.

ENDNOTES1 More specifically, by neoliberal subjectivity, we mean the ongoing process of becoming a “responsible” and “self-help”

economic actor who shoulders the blame for his socioeconomic position (Pine 2008:12–17); it is the unfinished acquisition

of a rationality that “makes sense” of the inequalities that take shape in everyday practice, but without challenging such

inequalities. Central to this neoliberal worldview is an emphasis on the 318 Antipode© 2014 The Author. Antipode© 2014

Antipode Foundation Ltd. behavior of the atomized individual, as opposed to the role of national or local community or

circumstance, as the determinant of socio-economic destiny.2 Neoliberal economic policy assumes that individuals have a consistent preference ordering and respond to material

incentives (DeMartino 2000: 39). This assumption leaves no room to explore how preferences change over time or across

different cultural and structural contexts. Furthermore, there is no room for true altruism or transformative social process

in this atomized model.3 It is worth noting that Tilly (1984) famously studied large social orders with encompassing comparison, not decisions, but

this method nevertheless proves useful for our purpose.4 We conducted this fieldwork independently between 2006 and 2013 for our doctoral dissertations, under the supervision

of IRB at our respective institutions. Our methods included semi-structured interviews, participant observation and

volunteer work at migrant shelters located along the route.We both worked as shelter volunteers for over a year where we

met and interviewed hundreds of migrants. Ethnographic fieldwork was also conducted with student veterans returning

from Iraq and Afghanistan as part of a larger project between 2007 and 2008.

10 | B. S. MERRICK ET AL.

5 Official Salvadoran government statistics report a dramatic decrease in homicides since the FMLN and Catholic Church

brokered gang truce between the MS 13 and M18 gangs. However, some analysts have questioned the validity of body

counts and the sustainability of the truce (Robbins 2013).

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Kozlowski, K., Brostrom, K., Kennedy, J., Lange, H., & Morris, L. (1994). Dysspondyloenchondromatosis in the newborn.

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SUPPORTING INFORMATION

Additional supporting information may be found in the online version of this article at the publisher’s web-site.

AUTHORS ’ BIOGRAPHIES

B. Merrick is currently a research fellow at the National Centre for Computer Animation,

BournemouthUniversity, UK, and an associate professor at Computer Centre, Communication

University of China. He received his bachelor and master’s degree in Computer Science from

China University of Mining and Technology and PhD degree from Communication University

of China. His current research interests include computer animation, intelligent data manage-

ment and software engineering.

B. S. MERRICK ET AL. | 11

A. Calder is a senior lecturer in theNational Centre for Computer Animation,TheMedia School,

Bournemouth University, UK. He received his bachelor (1993) and master’s degree (1996) in

Computer Science from ZJU (China) and PhD (2000) in computing mechanics from Dalian

University of Technology (China). He worked as a postdoc (2000-2002) in the Department of

Computer Science and Technology of Tsinghua University for 2 years and a research assistant

(2001-2002) at the ‘Virtual Reality, Visualization and Imaging Research Centre’ of Chinese

Unversity of Hong Kong. His research interests include 3D modelling, animation, real-time

rendering, virtual reality, virtual surgery simulation and computer-aided design.

12 | B. S. MERRICK ET AL.