Syndrome
Rooij, A.M. de
Citation
Rooij, A. M. de. (2010, April 27). Genetic and epidemiological aspect of Complex Regional Pain Syndrome. Retrieved from https://hdl.handle.net/1887/15335
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/15335
3 Familial occurrence
of Complex Regional Pain Syndrome
Annetje M. de Rooij a Marissa de Mos b Miriam C.J.M. Sturkenboom b
Johan Marinus a Arn M.J.M. van den Maagdenberg a,c Jacobus J. van Hilten a
a Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
b Departments of Medical Informatics and Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands
c Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
European Journal of Pain. 2009 Feb;13(2):171-177
Abstract
Genetic factors are suggested to play a role in Complex Regional Pain Syndrome (CRPS), but familial occurrence has not been extensively studied. In the present study we evaluated familial occurrence in Dutch patients with CRPS.
Families were recruited through the Dutch Association of CRPS patients and through referral by clinicians. The number of affected members per family, the phenotypic expression and inheritance were assessed. Demographic and clinical characteristics of familial CRPS (fCRPS) patients were compared with those of sporadic CRPS (sCRPS) patients from a Dutch population-based study and with a group of sCRPS patients that was proportionally matched for referral center of the fCRPS probandi to control for referral bias.
Thirty-one CRPS families with two or more affected relatives were identified, including two families with five, four with four, eight with three and seventeen with two affected relatives. In comparison with sCRPS patients, fCRPS patients had a younger age at onset and more often had multiple affected extremities and dystonia.
We conclude that CRPS may occur in a familial form, but did not find a clear inheritance pattern. Patients with fCRPS develop the disease at a younger age and have a more severe phenotype than sporadic cases, suggesting a genetic predisposition to develop CRPS.
Introduction
Complex Regional Pain Syndrome (CRPS) is characterized by pain in association with different combinations of edema, changes in sensory perception, color, temperature, transpiration and abnormal hair and nail growth in the affected limb.1 The reported incidence of CRPS ranges from 5.5 to 26.2 per 100,000 person-years.2,3 CRPS predominantly affects women (~75%) and may occur at all ages although the highest incidence is found between 50 and 70 years.3
The etiology of CRPS is still largely unclear, but a trauma, which can be minor in severity, often precedes the onset in a majority of the patients. A spontaneous onset has been described in 3-11% of cases 4,5,6,7,8,9 indicating that factors other than trauma may contribute to the etiology of the disease. There are indications that genetic factors may play a role. Compared to patients in whom CRPS remits or stabilizes, patients with a more severe phenotype have a considerable younger age at onset,9,10 which may suggest an increased genetic susceptibility to develop the disease.11,12 An increased susceptibility to develop CRPS is also apparent from genetic associations that were found with different human leukocyte antigen (HLA) factors.13,14,15,16
Familial occurrence of a disease is another indication that genetic factors may be involved.17 Although CRPS families with two or three patients have occasionally been reported,8,18,19,20,21,22 familial occurrence of CRPS has not systematically been evaluated. Here we studied familial occurrence of CRPS, evaluated CRPS families and compared the clinical characteristics of familial CRPS (fCRPS) patients with those of sporadic CRPS (sCRPS) patients.
Material and methods
Patient database
This study was performed within the national Trauma RElated Neuronal Dysfunction (TREND) Consortium (http://www.trendconsortium.nl/), which integrates Dutch research on CRPS. In TREND, the acquisition of data concerning the clinical diagnosis and other phenotype characteristics is performed in a standardized manner, after which this information is stored in a central internet-based database.
Recruitment of families with CRPS
During the period from April 2005 to August 2007, two strategies were followed to collect Dutch families with two or more CRPS patients. First, an announcement was placed on our TREND Consortium website and in newsletters of the Dutch
Association of CRPS patients, in which patients were asked to respond if they had at least one affected relative with CRPS. Second, clinicians that participated in TREND, clinicians working in large regional pain clinics and clinicians with an interest in CRPS were asked to send in patients who indicated they had affected relatives.
Ascertainment of CRPS families
Patients who agreed to participate were asked to provide detailed family information.
Patients and potentially affected family members were visited at home to verify the diagnosis of CRPS by medical history and physical examination. Information about signs (observed by examiner) and symptoms (reported by patients) were collected using a standard assessment form on which information on pain, sensory impairments, autonomic impairments, trophic changes and motor impairments was recorded. The disease status of family members reported by the probandi as unaffected was also confirmed.
CRPS was considered to be present if the IASP criteria were fulfilled (Table 1).
Patients not fulfilling the criteria at examination were considered to have been affected in the past if information on symptoms and signs retrieved from the general physician or consulting specialist supported the diagnosis of CRPS.
Table 1: Criteria for Complex Regional Pain Syndrome type I
a) CRPS is a syndrome that develops after an initiating noxious event.
b) Spontaneous pain, allodynia or hyperalgesia occurs, is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event.
c) There is or has been evidence of oedema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event.
d) This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.
For the diagnosis of CRPS-1, criteria b-d must be fulfilled.1
Ascertainment of sporadic CRPS patients
The characteristics of probandi with fCRPS were compared with two control groups.
The first control group consisted of CRPS patients from a Dutch population-based study 3 and was chosen to evaluate whether differences between sCRPS and fCRPS patients existed while ignoring the referral pattern, since, as in several other diseases, patients from affected families may experience a more severe disease course and therefore expected to be referred differently. This retrospective cohort study was
conducted in the Integrated Primary Care Information (IPCI) project, which is a longitudinal observational database including electronic patients’ records of more than 600,000 patients from more than 150 general practitioners in The Netherlands. The IPCI population is representative of the Dutch population regarding age and sex.23 Potential CRPS patients that were present in this database in the period between 1996 and 2005, were identified using synonyms and abbreviations of CRPS.3 Identified cases were validated using the patient’s electronic records supplemented with specialist letters and by reconfirmation of the diagnosis by their general practitioners.
Subsequently, the selected cases of the IPCI project were asked to participate in a case-control study. If patients agreed to participate (sCRPS-IPCI), their diagnosis was additionally verified during a home visit, using the same standardized assessment form as used in the present study.
A second control group was used to evaluate whether differences in phenotype between fCRPS patients and IPCI control patients would still exist if the potential effect of referral bias of the fCRPS patients was eliminated. Referral bias could be of relevance, since the fCRPS patients were collected in a different manner than the sCRPS-IPCI patients.
This second control group comprised sCRPS patients from the TREND database.
sCRPS patients are patients who had indicated in a questionnaire that they had no relatives with CRPS. To control for referral bias of the fCRPS patients, the distribution of sCRPS patients across the various clinical centers was chosen proportionally equal to that of the fCRPS probandi. Because of this distribution criterion, not all sCRPS patients in the database were used and a random sample was taken from each referral center. Information about the signs and symptoms of these patients (sCRPS-TREND) was collected using the same standard form as was used for the fCRPS patients.
Statistical analysis
Continuous variables were compared with a t-test for independent samples.
Proportions of categorical data were compared with the chi-square test, using the Newcombe’s method to calculate 95% confidence intervals (CI). If the 95% CI for the between-group differences did not contain the value 0, differences were considered significant. Statistical analyses were performed with SPSS (version 14) and Confidence Interval Analysis (version 2.0.0).
The study was approved by the Medical Ethical Committee of the Leiden University Medical Center. All patients gave written informed consent before participation.
Results
Familial CRPS patients
Thirty-one families with two or more affected family members who fulfilled the eligibility criteria were collected (Tables 2 and 3).
Twenty-two families were referred by clinicians that participated in TREND, the remaining nine families responded to website or newsletter announcements of this study. Of the nine probandi of these latter families, seven were treated by a specialist and two were only seen by a general practitioner.
The 31 probandi had 53 family members with CRPS, thus 84 fCRPS patients were included in this study. Seventy-four patients (88 %) fulfilled the IASP criteria at the time of the visit. The remaining patients had fulfilled the criteria in the past, as confirmed by the medical information retrieved from their physician or consulting specialist.
Of these 31 families, seventeen had two, eight had three, four had four and two families had five affected family members. Seventy patients (83%) were female. The mean (standard deviation [SD]) age at onset was 36.7 (14.5) with a range of 11 to 71 years. The most frequent noxious events for the first affected extremity were fractures (27%), surgery (20%), and soft tissue injury (20%). In 23% of the patients no causative event could be identified. The upper extremity was affected first in 49%, the lower extremity in 44%, whereas in 7% upper and lower extremities were simultaneously affected. Thirty-eight patients (45%) had two or more affected extremities. Twenty- one patients (25%) had dystonia on examination, whereas an additional 35 patients (42%) reported intermittent dystonia.
Table 2: Characteristics of familial CRPS patients
Number of patients 84
Percentage (N) of females 82% (70)
Mean (SD) age at onset of CRPS -years 36.7 (14.5) Percentage (N) patients with > 1 affected extremity 45% (38) Percentage (N) patients with observed dystonia 24% (20) Preceding trauma – Percentage (N)
Trauma 77% (65)
Fracture 27% (23)
Surgery 20% (17)
Soft tissue 20% (17)
Other 9% (8)
Non-Trauma 23% (19)
First affected extremity– N (%)
Arm 49% (41)
Leg 44% (37)
Both 7% (6)
N= Number; SD = Standard deviation
Table 3: Signs and symptoms of 84 familial CRPS patients.
fCRPS
Reported % (N) Observed %
(N)
Spontaneous pain 97% (82) Na
Hyperesthesia 67% (57) 49% (42)
Hyperalgesia 76% (65) 54% (46)
Allodynia 76% (65) 33% (28)
Temperature asymmetry 95% (81) 55% (47)
Colour asymmetry 91% (77) 49% (42)
Edema 87% (74) 42% (36)
Sweating disturbances 69% (59) 37% (32)
Trophic disturbances 88% (75) 72% (61)
Limited range of motion 85% (72) 67% (57)
Dystonia 69% (58) 25% (21)
Tremor 52% (44) 18% (15)
Myoclonus 45% (38) 11% (9)
fCRPS= CRPS families; N= Number; Na= not applicable
The three largest CRPS families and their detailed clinical characteristics are presented in Figure 1 and Table 4.
Family 1
This family consisted of five affected members in two successive generations (Fig. 1).
The proband (II-5) developed CRPS at the age of 39. Symptoms occurred in her right leg after surgical treatment of a lumbar herniated disc. Five years later, again after surgical treatment of a lumbar herniated disc, she developed symptoms in her left leg.
The symptoms in her left and right arm developed spontaneously ten and twelve years later. Her sister (II-7) developed CRPS following a fracture of her left arm when she was 58 years old. The daughter (III-12) of sister II-7 developed CRPS after an operation of her right hand when she was 21 years old. Her uncle (II-8), the brother of the two sisters, developed his symptoms without a causative event at the age of 51.
His daughter (III-13) developed CRPS of both legs spontaneously at the age of 14 years. At the age of 19 symptoms in her arms developed spontaneously.
Family 2
In this family three siblings (two sisters and a brother) were affected as well as a daughter of one of the affected sisters (Fig. 1). The proband (III-10) developed CRPS in her left leg after a fracture at the age of 24 years. Two years later she spontaneously developed symptoms in her right leg. Her mother (II-7) developed symptoms of CRPS in her left leg after a sprain of her ankle at the age of 45 years. Five years later CRPS developed spontaneously in her right leg and again three years later in her left arm. Her sister (II-3) developed symptoms in her right arm after surgical treatment of a tendovaginitis at the age of 70 years. Their brother (II-5) developed CRPS after a fracture of his left leg when he was 65 years old.
Family 3
In this four-generation family two sisters, a cousin and two cousins of the father of the two sisters were affected (Fig. 1). The proband (IV-25) developed CRPS at the age of 17 years after a contusion of her right arm. Three years later she developed symptoms in her left leg after an insect bite and at the age of 23 symptoms started after overuse of her right leg. Her sister (IV-26) developed CRPS in her left arm after an accident at work when she was 21 years old. Their cousin (IV-21) developed symptoms in his left arm after a traffic accident at the age of 17. The first cousin of the father of the two sisters (III-13) developed CRPS after a fracture of his left
metatarsal bone when he was 40 years old. The symptoms of the second cousin of the father of the two sisters (III-12) started after a sprain of her left hand at the age of 29.
Patient characteristics of CRPS probandi and comparisons with other CRPS patient groups
Clinical characteristics of the probandi of the CRPS families as well the two sCRPS control groups are described in Tables 5 and 6. Of the 31 probandi, 29 (94%) fulfilled the IASP criteria at time of the examination; the remaining two (6%) patients had fulfilled the criteria in the past. Twenty-seven patients (87%) were female. The mean (SD) age at onset was 33.9 (11.9) with a range of 11 to 57 years. Time between onset of CRPS and examination varied between 1 and 35 years (median 10.7 years). The most frequent noxious events for the first affected extremity were soft tissue injuries (26%), fractures (23%), and surgery (19%). In 26% of the patients no causative event could be identified. The upper extremity was affected first in 45%, the lower extremity in 45%, whereas 10% had a simultaneous onset in upper and lower extremities.
Twenty-one patients (68%) had two or more affected extremities. Fifteen patients (48%) had dystonia on examination. No significant differences in age at onset, proportion of patients with spontaneous onset, number of affected extremities and proportion of patients with dystonia were found between the 22 probands who were referred by clinicians and the 9 who referred themselves.
Figure 1: Pedigrees of three largest CRPS families
Figure represents the pedigrees of the three largest CRPS families. Circles indicate females; squares indicate males; crossed-out symbols: deceased individuals;
number in symbol indicates number of extra siblings. Black symbols indicate individuals with CRPS. Arrows indicate the probands of the families.
3 I-1 I-2
II-6
III-14 III-13
II-5 II-8
3 II-7 II-3 II-4
III-11 III-12 Family 3
III-17 III-18
IV-22
II-9 II-10
III-20 III-21
IV-25 IV-26
IV-21 IV-23 IV-24 IV-28
III-16
III-15 III-19
IV-27
3 3
I-1 I-2
II-7 II-8 II-9 II-10
III-12 III-13 III-11
II-6 II-5 II-4 II-3
III-14 Family 1
I-1 I-2
II-6 II-7 II-8
III-9 II-5 II-3
III-11 Family 2
II-4
III-10
?
fCRPS - sCRPS-IPCI comparisons
Two hundred and thirty-eight CRPS patients were identified in the IPCI database. Of these, 216 could be contacted, of which 134 (56% of the total group) cases agreed to participate in the follow-up study. Twenty-four cases were subsequently excluded from the analysis, since a detailed history and examination revealed no present or past fulfillment of the IASP criteria, despite the fact that these patients had previously been diagnosed as having CRPS by their GP (n=11) or specialist (n=13). Additionally, eight were excluded because the symptoms of CRPS started before the study period of the IPCI study and this study focused on incident cases. Of the remaining 102 cases, 87 (85%) were treated by a specialist; the other 15 patients (15%) by their general practitioners. Sixty-five patients (64%) fulfilled the IASP criteria at the time of the visit; the other 37 patients had fulfilled the criteria in the past. Eighty-one patients (79%) were female. The mean (SD) age at onset was 50.8 (15.6) with a range of 12 to 86 years. The most common noxious event for the first extremity in which symptoms of CRPS occurred was a fracture in 54% of the patients, followed by soft tissue injury (27%) and a surgery (12%). Three patients (3%) developed symptoms without a clear causative event. The upper extremity was affected first in 55% of the patients, the lower extremity in 45%. Nine patients (9%) also developed symptoms in other extremities in a later stage. Nine patients (9%) had dystonia on examination, whereas an additional 24 patients (24%) reported intermittent dystonia. Compared to the sCRPS-IPCI patients, patients with fCRPS were on an average 17 years younger at disease onset (33.9 versus 50.7; 95% confidence interval of the difference [95% CI]:
-22.8 to -10.8), more often had multiple affected extremities (68% versus 9%;
difference 59%, 95% CI: 40% to 73%), and more often had dystonia (48% versus 9%;
difference 40%, 95% CI: 22% to 57%). No clear causative event before the development of CRPS was found in 26% of the fCRPS patients and only in 3% of the sCRPS-IPCI patients (difference 23%, 95% CI: 10% to 40%) No differences were found in the distribution by gender between both groups (table 5).
fCRPS - sCRPS-TREND comparisons
Of the 187 sCRPS-TREND patients, 181 (97%) fulfilled the IASP criteria at the time of the examination; the other 6 patients had fulfilled the criteria in the past. One- hundred-fifty-one patients (81%) were female. The mean (SD) age at onset was 41.9 (14.2) with a range of 8 to 80 years. Time between onset of CRPS and examination varied between 0.8 and 32 years (median 1.8 years). The most common noxious event for the first extremity in which symptoms of CRPS occurred was an operation in 29%
of the patients, followed by fracture (25%) and soft tissue injury (18%); 16% of the
patients developed symptoms without a clear causative event. The upper extremity was affected first in 55% of the patients, the lower extremity in 43%, whereas in 2%
of the patients upper and lower extremities were affected simultaneously. Fifty-nine patients (32%) had two or more affected extremities. Fifty-seven patients (31%) had dystonia on examination.
Compared to the sCRPS-TREND patients, patients with fCRPS were on an average 8 years younger at disease onset (33.9 versus 41.9; 95% CI: -13.3 to -2.7), more often had multiple affected extremities (68% versus 32%; difference 36%, 95% CI: 17% to 51%), and more often had dystonia (48% versus 31%; difference 18%, 95% CI: 0.1%
to 36%). No causative event before the development of CRPS was reported in 26% of the fCRPS patients and 16% of the sCRPS-TREND patients (difference 10%, 95%
CI: -28% to 3%) Additionally, no group differences were found for the distribution by gender.
Significant difference in signs and symptoms were found between the probandi of the fCRPS patients and sCRPS-TREND patients in reported hyperesthesia, observed hyperesthesia, reported hyperalgesia, reported allodynia, observed temperature difference, observed color asymmetry, observed sweating disturbances, observed trophic disturbances and reported limited range of motion (table 6).
Table 4: Signs and symptoms of the patients from the three described families
Criteria family person extrem. age onset trauma pain allodynia hyperesth. hyperalg. color temp. edema sweat trophic dystonia tremor IASP
1 II-6 RL 39 + + ob. ob. ob. ob. ob. ob. ob. ob. ob. - +
LL 44 + + ob. ob. ob. ob. ob. re. ob. ob. ob. re. +
RA 54 - + ob. ob. ob. re. ob. - ob. ob. ob. ob. +
LA 56 - + ob. ob. ob. re. ob. re. ob. ob. ob. re. +
II-11 LA 58 + + ob. ob. ob. ob. ob. ob. ob. ob. ob. re. +
II-12 RA 51 - + - ob. ob. - re. - - - - - +
LA 51 - + - ob. ob. - re. - - - - - +
RL 51 - + - ob. ob. - ob. - - - - - +
LL 51 - + - ob. ob. - re. - - - - - +
III-16 LA 21 + + re. - re. ob. ob. ob. ob. ob. - - +
III-17 RL 14 - + - ob. ob. - - - ob. - - - +
LL 14 - + - ob. ob. - - - ob. - - - +
RA 19 - + ob. ob. ob. - - - ob. ob. - re. +
LA 19 - + ob. ob. ob. - - - ob. ob. - re. +
2 III-10 LA 29 + + ob. - re. ob. ob. ob. - ob. - - +
III-11 LL 40 + + - - re. re. re. re. re. re. - re. Past
IV-20 LA 17 + + re. re. re. re. re. re. - re. re. - past
IV-24 RA 17 + + ob. ob. ob. re. re. re. re. re. ob. ob. +
LL 20 + + ob. ob. ob. re. ob. ob. re. ob. ob. ob. +
RL 23 - + ob. ob. ob. re. re. re. - re. ob. ob. +
IV-25 LA 21 + + re. ob. ob. re. re. ob. ob. ob. +
3 II-3 RA 70 + + ob. - ob. re. ob. ob. ob. ob. re. - +
II-5 LB 65 + + - - - ob. ob. ob. ob. ob. - - +
II-7 LB 45 + + ob. re. ob. ob. ob. re. ob. ob. re. re. +
RB 50 - + re. ob. ob. ob. ob. ob. ob. ob. ob. re. +
LA 54 - + ob. ob. ob. ob. ob. ob. ob. ob. - - +
III-10 RB 24 - + re. ob. - ob. ob. - ob. ob. - re. +
LB 26 + + re. ob. - ob. ob. ob. ob. ob. ob. re. +
Sensory Vasomotor Sudomotor Motor/Trophic
RA=Right arm; LA=Left arm; RL=Left leg; LL=Left leg; + = present; - = absent; ob. =observed; re. = reported; extrem.= extremity;
hyperesth.=hyperesthesia;. hyperalg.= hyperalgesia; temp.=temperature.
Discussion
Here we assessed the familial occurrence of CRPS in the Netherlands and showed that, although rare, reasonable-size CRPS families do exist. Although several studies reported small pedigrees with two to three affected members with CRPS,19,20,21,22 we here describe the largest set of familial CRPS patients to date: thirty-one families were identified with two to five affected relatives.
To evaluate whether there were differences between the familial CRPS and sporadic forms of the syndrome, the clinical characteristics of CRPS probandi were first compared with those of sCRPS patients from a Dutch population-based study.3 These patients may be considered representative of the more common type of CRPS since they were identified independent of referral. Compared to the sCRPS-IPCI patient group, patients with fCRPS had a younger age at onset and more often experienced a spontaneous development of CRPS. Additionally, fCRPS patients more frequently had multiple affected extremities and dystonia. Referral bias limits comparison between fCRPS from tertiary centers and sCRPS patients from a population-based study. We therefore compared fCRPS patients with sCRPS patients who were randomly sampled in proportionally equal distributions from the same or similar referral centers as the fCRPS probandi. Again we found that patients with fCRPS had a lower age at onset and more often exhibited multiple affected extremities and dystonia compared to sCRPS-TREND patients. fCRPS patients also showed a trend towards a higher percentage of spontaneous onset. Thus, even after controlling for the effects of referral patterns, most of the differences between fCRPS patients and sCRPS remained significant.
The fact that we found similar differences with both control groups lends more credit to the value of the findings and makes bias resulting from the selection of control groups less likely. The question then arises whether differences could be explained by the way the fCRPS patients were recruited. One cannot rule out that especially families with more severely affected members responded, which may have led to an overestimation of the established differences. This would, however, only hold for families that referred themselves, since clinicians were asked to send in families with 2 or more potentially affected members, irrespective of the severity of their complaints.
Since the majority of patients were referred by clinicians (22 out of 31), we expect that this effect will be small. Additionally, no significant differences in the aforementioned characteristics were found between probands who were referred and those who referred themselves.
Table 5: Characteristics compared between sCRPS IPCI patients, sCRPS-TREND patients and probandi of familial CRPS patients.
Control group 1 Control group 2
fCRPS probandi
sCRPS-IPCI Diff (95% CI) sCRPS- TREND
Diff (95% CI)
Number of patients 31 102 187
Percentage (N) of females 87% (27) 79% (81) -8% (-20 to 10%) 81% (151) 6% (-16 to 10%) Percentage (N) of present IASP fulfilled 94% (29) 4% (65) 30% (13 to 41%) a 97% (181)
Mean (SD) age at onset of CRPS -years 33.9 (11.9) 50.7 (15.6) 17 (22.8 to 10.8) a 41.9 (14.2) 8 (-13.3 to -2.7) a Percentage (N) with > 1 affected
extremity
68% (21) 9% (9) 59% (50 to 73%) a 32% (59) 36% (17 to 51%) a
Percentage (N) with observed dystonia 48% (15) 9% (9) 40% (22 to 57%) a 31% (57) 18%(0.1 to 36%) a Preceding trauma – Percentage (N)
Trauma 74% (23) 97% (99) -23% (-40 to -10
%) a
84% (158) -10% (-28 to 3 %)
Fracture 23% (7) 54% (55) -31% (-46 to -12%) a
25% (46) -2% (-15 to 16%)
Surgery 19% (6) 12% (12) 8% (-5 to 25%) 29% (55) -10% (-22 to 8%) Soft tissue 26% (8) 27% (27) -1% (-16 to 18%) 18% (33) 5% (-7 to 22%)
Other 7% (2) 5% (5) 2% (-6 to 16%) 13% (24) -6% (-14 to 9%)
Non-Trauma 26% (8) 3% (3) 23% (10 to 40%) a 16 (29) 10% (-3 to 28%)
First affected extremity– Percentage (N)
Arm 45% (14) 55% (56) -10% (-28 to 10%) 55% (103) -10% (-27 to 9%)
Leg 45% (14) 45% (46) 0% (-19 to 20%) 43% (80) 2% (-15 to 21%)
Both 10% (3) (0) 10% (2 to 25%) a 2% (4) 8% (0.4 to 23%) a a = Significant result; N= Number; SD = Standard deviation
Compared to sCRPS-TREND patients, fCRPS probandi more often had observed temperature asymmetry, color asymmetry, as well as sweating and trophic disturbances. The median time between onset of CRPS and examination was much larger for fCRPS probandi; this suggests that fCRPS patients have a more severe phenotype than sCRPS-TREND patients. All this may point at an increased genetic susceptibility to develop CRPS.
Familial clustering may also occur because of a shared exposure to environmental factors, but this is unlikely as CRPS was not limited to first-degree family members who share a more similar environment, but also occurred in more distant relatives.
Unless environmental factors are associated with extreme relative risks and demonstrate extreme patterns of familial clustering, such a risk factor would not account for familial aggregation of CRPS 24. Familial aggregation may also have occurred by chance. However, in view of the low incidence of CRPS, chances that three out of five siblings (family 2) get affected by the disease are extremely low.
The limitations of this study include the possibility of underestimating the number of affected family members per family since we did not contact all members of every family. Consequently, we cannot exclude that more relatives were affected within these families. Additionally, families with milder forms of CRPS may go undiagnosed, which would also result in an underestimation of the occurrence of fCRPS.
Reliable inferences regarding the mode of inheritance cannot be made based on our findings because of the limited number of affected subjects within families and the variable pattern between families. In 77% of the patients with fCRPS the syndrome was preceded by a trauma. Therefore, we cannot exclude that CRPS would have developed in other family members if they had been exposed to a trauma of sufficient severity to trigger the syndrome. Against this background, it is difficult to disentangle the influence of reduced penetrance.
In conclusion, CRPS may occur in a familial form. Compared to sCPRS patients, fCRPS probandi have a more severe phenotype of the disease. These findings may point towards a genetic predisposition to develop CRPS.
More studies are needed to elucidate the contribution of genetic factors in CRPS. The ultimate goal is to identify genetic factors for CRPS. Undoubtedly, this will be a very challenging endeavor. One logical approach is the identification of endophenotypes that will result in more homogenous traits for genetic studies. In this respect, it is important that clinical research and basic research (aimed at identifying biomarkers for diagnosis) are integrated to obtain more reliable diagnoses for genetic studies. In modern day genetics, testing hundreds of thousands of genetic markers in hundreds
Table 6 Signs and symptoms of probandi and sporadic CRPS-TREND patients (sCRPS-TREND)
Probandi (N=31) sCRPS-TREND (N=187) Significant differences
Reported
%(N)
Observed
%(N)
Reported
%(N)
Observed
%(N)
Difference (95% CI)
Spontaneous pain 97% (30) Na 96% (179) Na Ns
Hyperesthesia 81% (25) a 65% (20) a 37% (67) 31% (58) 45% (27-57%) 34% (15-49%)
Hyperalgesia 81% (25) a 61% (19) 57% (107) 51% (95) 23% (5-36%) Ns
Allodynia 84% (26) a 42% (13) 57% (108) 28% (53) 26% (8-38%) Ns
Temperature asymmetry 97% (30) 61% (19) a 87% (162) 37% (69) Ns 24% (6-41%)
Color asymmetry 100%(31) 58% (18) a 90% (169) 38% (71) Ns 20% (1-37%)
Edema 90% (28) 32% (10) 87% (162) 33% (62) Ns Ns
Sweating disturbances 74% (23) 39% (12) a 62% (116) 17% (31) Ns 22% (6-40%)
Trophic disturbances 87% (27) 71% (22) a 72% (134) 42% (79) Ns 29% (10-43%)
Limited range of motion 94% (29) a 84% (26) 75% (140) 67% (125) 19% (3-27%) Ns
Motoric disturbances 87% (27) 45% (14)) 74% (137) 34% (64) Ns Ns
Na= not applicable Ns= Non significant difference
a = significant difference between Probandi and sCRPS-TREND patients
(to even thousands) of well characterized patients seems the most attractive approach to identify genetic factors. Such hypothesis-free genetic association studies have yielded gene variants for a wide range of complex diseases,25 but are not without problems.26 With the collection of large numbers of CRPS patients and families, preferably in an International collaborative effort, such studies will become more and more feasible.
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