"Hereditary Disorders of the Connective Tissues (HDCT).

A clinical study of 249 cases”

 

Explanation of the poster presented at the

ACR/ARHP 68th Annual Scientific Meeting,

16 - 21 October 2004, San Antonio, Texas,:

 

 

ABSTRACT

Published:  Arthritis &Rheumatism  Vol. 50, No 9(Suplemment), September 2004, pp S309

 

 

Introduction: Collagen fiber genetic alterations predispose to pain and instability of joints, with a tendency to early osteoarthritis, osteoporosis and fragility of other tissues. Joint Hypermobility Syndrome (JHS) is a forme fruste of the classical Hereditary Diseases of the Connective Tissuess (HDCT), such as Ehlers-Danlos (EDS), Marfan Syndrome (MFS) and Osteogenesis Imperfecta (OI).

 

Purpose: To demonstrate the high frequency, morbidity and mortality of JHS and Vascular EDS (VEDS), which usually go undiagnosed.

 

Material and methods:  Of 268 HDCT patients, 19 were excluded because of concomitant arthritis. All patients and controls were examined, applying the Brighton criteria (BC), by the same examiner. A total of 64 people, properly matched for age and sex, were evaluated as controls.

 

Results: In our rheumatological practice our early study showed a 34.6% HDCT frequency, which is now higher. Interestingly 39% of the controls had a positive BC. Of the 249 patients, 80.3 % were females. Range: 13 to 83 years. Median: 45 years. Of these, 230 (92.4 %) had JHS, 18 (7.2 %) had VEDS and 1 (0.4 %) had OI, no one had MFS, all of which fulfilled the appropriate diagnostic criteria.

 

A joint mobility comparison between JHS and VEDS, showed a low Beighton score of 3 or less, more frequently in the later group, as expected, 65.2% versus 83.3%.


 

The Brighton criteria showed:

 

 

JHS

%

VEDS

%

Controls

%

p

(1)

Skin abnormalities

93.9

100.0

95.3

 

Back problems

60.9

72.2

31.1

 

Arthralgias                  

56.5

50.0

26.6

 

Tendinitis

52.6

22.2

18.8

0.01 *

Varicose veins

20.4

33.3

17.2

 

Hernias                     

12.2

27.8

6.3

 

Subluxations                  

25.7

0.0

12.5

0.01 *

Marfanoids                    

14.4

11.1

4.7

 

Myopia                          

7.8

11.1

14.1

 

 

 

 

Of interest were also the following findings:

 

 

JHS

%

VEDS

%

p

(1)

Blue Sclera  (+,++,+++)

96.7

93.8

 

Flat foot

30.0

77.8

0.001*

Moderate osteopenia and osteoporosis

 

26.1

 

50.0

 

Dysautonomia

23.0

38.9

 

Dyslipidemia

12.2

33.3

0.01*

Scoliosis                                                                           

12.2

33.3

0.01*

Nasal cartilage abnormality

17.8

22.2

 

Early osteoarthritis

5.7

11.1

 

Raynaud´s phenomenon

2.3

12.5

0.03*

Complications in patients and  their relatives:

 

 

JHS

%

VEDS

%

p

(1)
Sudden death

1.3

27.8

0.001 *
Cerebral aneurysm

3.9

16.6

0.02   *
Spontaneous pneumothorax

1.3

11.0

0.004 *
Gravid uterus rupture                                                                

0.0

11.0

0.001 *

(1)  Chi Square Test: JHS vs VEDS

 

 

 


 

 


CRITERIA FOR THE JHS AND VASCULAR EHLER-DANLOS (VEDS) DIAGNOSIS

 

Currently the way to make the JHS diagnosis is using the Brighton Criteria.  Before, and for 30 years, the Beighton Score was used, which considers only certain joints, and does not include other tissues. The BC includes the BS, but also includes takes into account the involvement of non-musculoskeletal systems

 

 

Beighton score (BS) 1

 

 

 

 


 

 

 

 


1. Ref: Beighton PH, Solomon L, Soskolone CL.  Articular mobility in an African population.  Am. Rheum. Dis.1973; 32 : 413-18.

The Beighton score (BS) takes into account only a few joints and not the involvement of other collagen tissues, it is calculated as follows:

 

1.      Score one point for each elbow that will bend backwards.

2.      Score one point for each thumb that will bend backwards to touch the forearm *

3.      Score one point for each hand when you can bend the little finger back beyond 90°.

4.      Score one point for each knee that will bend backwards

5.      Score one point if you can bend and place your hands flat on the floor without bending you knees *.

*  At present or in the past.

 

The Beighton score is considered positive with 4 or more points, out of a total of 9. Maximum score is 9 out of 9.

 

COMPARISON OF THE JOINT MOBILITY

BETWEEN JHS, VEDS, AND CONTROLS

JHS

VEDS 

 

CONTROLS

 

 

n = 230

n = 18

 

n = 64

BEIGHTON SCORE

 

%

%

 

%

SB 1

Elbows

22,17

16,67

 

17,2

SB 2

Thumb – Forearm

6,96

5,56

 

12,5

SB 3

MCPs

59,57

55,56

 

40,6

SB 4

Genu-Recurvatum

22,17

11,11

 

14,1

SB 5

Hands flat on the floor

40,43

72,22

 

68,8

 

 

Brighton criteria (BC) 2

 

 

The BS was used for 30 years, now has been replaced by the BC for the diagnosis of JHS. The BS is now part of the BC, which has major and minor criteria.

 

Major Criteria

·               A Beighton score of 4/9 or greater (either currently or historically).

·               Arthralgia for longer than 3 months in 4 or more joints.

Minor Criteria

·               A Beighton score of 1, 2 or 3/9 (0, 1, 2 or 3 if aged 50+).

·               Arthralgia (> 3 months) in one to three joints or back pain (> 3 months), spondylosis, spondylolysis/spondylolisthesis.

·               Dislocation/subluxation in more than one joint, or in one joint on more than one occasion.

·               Soft tissue rheumatism. > 3 lesions (e.g. epicondylitis, tenosynovitis, bursitis).

·               Marfanoid habitus (tall, slim, span/height ratio >1.03, upper: lower segment ratio less than 0.89, arachnodactily [positive Steinberg/wrist signs].

·               Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring.

·               Eye signs: drooping eyelids or myopia or antimongoloid slant.

·               Varicose veins or hernia or uterine/rectal prolapse.

·               Mitral valve prolapse (by echocardiography).

 

 

 

2. Ref.  Grahame R.   Brighton Diagnosis Criteria for the Benign Joint Hypermobility Syndrome.    Br. J Rheumatol  2000 ; 27 :  1777-1779.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Same as table 6, but easier to follow:

 

 

JHS  %

VEDS  %

 

p

 

Skin abnormalities

93.9

100.0

 

Back problems

60.9

72.2

 

Arthralgias                  

56.5

50.0

 

Recurrent tendonitis

52.6

22.2

0.01 *

Subluxations                  

25.7

0.0

0.01 *

Varicose veins

20.4

33.3

 

Marfanoids                    

14.4

11.1

 

Hernias                     

12.2

27.8

 

Myopia                         

7.8

11.1

 

ONLY POSITIVE p VALUES ARE GIVEN

 

 

 

 

Note:

Back problems were more frequent in JHS than controls.

Subluxations and tendinitis were more frequent in JHS than in VEDS, with statistical significance.

Marfanoids were more frequent in JHS and VEDS than in controls

Skin abnormalities were seen in almost all patients and controls, some are unspecific, but others are typical: soft, lax, velvety skin and poor cicatrisation  (cheloids and papyraceous scars).

The finding of 14% myopia in controls is probably an error, since people gave this information and no ophthalmologic exam was done for this study.

Varicose veins and hernias, as expected, were more prevalent in VEDS, due to the fact that these patients have more fragile tissues.

The frequency of uterine/rectal prolapse and mitral valve prolapse (MVP) was low in JHS and VEDS (3-6%), but higher than in controls (0-2%).

Of interest were also the following findings:       

 

 Table 7

 

 

JHS %

VEDS %

 

p

Blue sclera (+, ++, +++)

96.7

93.8

 

Flat foot

30.0

77.8

0.0001 *

Moderate osteopenia and osteoporosis

26.1

50.0

 

Dysautonomia

23.0

38.9

 

Dyslipidemia

12.2

33.3

0.01 *

Scoliosis

12.2

33.3

0.01 *

Nasal cartilage abnormality

17.8

22.2

 

Early osteoarthritis

5.7

11.1

 

Raynaud´s phenomenon

2.3

12.5

0.03 *

 

Note:  Only positive p values are given.

 

Flat foot was much more prevalent in VEDS than JHS (statistically significant).

Flat foot, dyslipidemia and scoliosis were more frequent in VEDS than JHS (statistically significant).

Raynaud´s phenomenon was extremely rare in JHS.

 

 

Vascular type EDS (VEDS) criteria 3

 

 

Major Criteria

 

·        Thin, translucent skin.

·        Arterial/intestinal/uterine fragility or rupture.

·        Extensive bruising.

·        Characteristic facial appearance (See page 9).

 

Minor Criteria

 

·        Acrogeria  (old looking hands).

·        Hypermobility of small joints.

·        Tendon and muscle rupture.

·        Talipes equinovarus (clubfoot).

·        Early-onset varicose veins.

·        Arteriovenous, carotid-cavernous sinus fistula.

·        Pneumothorax/pneumohemothorax.

·        Gingival recession.

·        Positive family history, sudden death in (a) close relative (s).

 

The presence of any two or more of the major criteria is highly indicative of the diagnosis, and laboratory testing is strongly recommended.

 

 

3 Ref. Beighton P,  DePaepe A,  Steinmann B,  Tsipouras P  and  Wenstrup RJ.  Ehlers-Danlos Syndromes: Revised Nosology,  Villefranche, 1977.  Am J Med Gen 1998; 77: 31-37

 

 

 

Blue Sclera in JHS patients

 

 

 

Mild  (+)

 

 

Moderate  (+ +)

 

 

Severe  (+ + +)

 

 

Normal Sclera

 

 

 

BLUE SCLERA IN JHS

 

BLUE SCLERA

MALES

FEMALES

 

TOTALS ( M  +  F )

 

 

n

%

%

n

 

 

 

 

 

 

 

 

 

 

NEGATIVE

 

5

10,87%

1,20%

2

 

7 NEGATIVES           3.29%

 

 

 

 

 

 

 

 

POSITIVE

+ (MILD)

27

58,70%

25,75%

43

 

 POSITIVE MALES

 

++ (MODERATE)

13

28,26%

61,08%

102

 

    41  /  46                    89.13%

 

+++ (MARKED)

0

0,00%

8,98%

15

 

POSITIVE FEMALES

 

POSITIVE UNDEFINED

1

2,17%

2,99%

5

 

  165  /   167                 98.80%

 

 

 

 

 

 

 

M + F POSITIVES

206  /  213                96.71%

NOT RECORDED

2

 

 

 

 

 

 

 

 

 

 

 

 

TOTAL PATIENTS STUDIED

46

100.00%

100.00%

167

 

 

TOTAL

 

48

 

 

182

 

 

 

 

 

 

 

 

 

 

 

 

BLUE SCLERA IN VEDS

 

BLUE SCLERA

MALES

FEMALES

 

TOTALS ( M  +  F )

 

 

n

%

%

n

 

 

 

 

 

 

 

 

 

 

NEGATIVE

 

0

0,00%

6,67%

1

 

    1  NEGATIVE         6,67%

 

 

 

 

 

 

 

 

POSITIVE

+ (MILD)

1

100,00%

26,67%

4

 

POSITIVE   MALES

 

++(MODERATE)

0

0,00%

60,00%

9

 

   1  /  1                      100.00%

 

+++ (MARKED)

0

0,00%

6,67%

1

 

POSITIVE FEMALES

 

POSITIVE UNDEFINED

0

0,00%

0,00%

0

 

   14 / 15                     93.33%

 

 

 

 

 

 

 

M+F POSITIVES

   15  /  16                   93.75%

NOT RECORDED

0

 

 

 

 

 

 

 

 

 

 

 

 

TOTAL PATIENTS STUDIED

1

100.00%

100.00%

15

 

 

TOTAL

 

1

 

 

17

 

 

 

Moderate intensity Blue sclera (++) is seen more frequently in women than in men:  in JHS, 61.08% in women vs. 28.26% in men and in VEDS, 60.00% vs. 0.00%. Most JHS males had mild blue sclera (58.70%) and none had marked blue sclera.

 

TOTAL POSITIVE BLUE SCLERA IN

RELATION TO SEX

 

 

 

 

TOTAL

STUDIED

POSITIVES

%

MALE

47

42 

89.36%

 

 

 

 

FEMALE

182

179

98.35%

 

 

 

 

TOTAL

229

221

96.51%

Note:  8 NEGATIVES OUT OF 229 STUDIED ( 5 M AND  3 F )          3.49%

 

 

 

Complications in patients and relatives:

 

Table 9.

 

 

JHS %

VEDS %

 

p

Sudden death

1.3

27.8

0.001 *

Cerebral aneurysm

3.9

16.6

0.02 *

Spontaneous pneumothorax

1.3

11.0

0.004 *

Gravid uterus rupture                                                                 

0.0

11.0

0.001 *

 

 

Table 10.

COMPARISON USING THE BRIGHTON CRITERIA

BETWEEN JHS, VEDS AND CONTROLS *

 

CASES GROUPED ACCORDING TO CRITERIA

 

 

JHS

 

VEDS

 

CONTROLS

 

 

 

n = 230

 p ( JHS

n = 18

p ( VEDS

n = 64

p ( Cont.

 

 

 

 

vs

 

 

vs

 

 

vs

 

 

 

 

 

 

 VEDS)

 

 

Cont.)

 

 

JHS)

 

MAJOR

MINOR

 

FREQ.

%

 

FREQ.

%

 

FREQ.

%

 

NEGATIVES

0

2

 

0

0.00

 

0

0.00

 0.006 *

20

31.25

0.0001 *

60.94%

0

3

 

0

0.00

 

0

0.00

 0.008 *

19

29.69

60.94%

0

4

 

105

45.89

59.74%

 

10

55.56

77.78%

 

7

10.94

0.0001 *

 

 

0

5

 

32

13.85

4

22.22

2

3.13

14.06%

 

0

6

 

1

0.43

 

0

0.00

0.0001 *

0

0.00

0.0001 *

POSITIVES

0

7

 

0

0.00

 

0

0.00

0.006 *

0

0.00

0.02 *

39.06%

0

8

 

0

0.00

 

0

0.00

 

0

0.00

 

 

0

9

 

0

0.00

60.17%

0

0.00

77.78%

0

0.00

14.06%

 

1

2

 

31

13.42

 

2

11.11

 

4

6.25

 

 

1

3

 

33

14.29

 

1

5.56

 

7

10.94

 

POSITIVES WITH MAYOR CRITERIAS

1

4

 

20

8.66

 

0

0.00

 

2

3.13

 

1

5

 

4

1.73

 

1

5.56

 

0

0.00

 

1

6

 

1

0.43

38.53%

0

0.00

22.22%

1

1.56

21.88%

2

1

 

0

0.00

 

0

0.00

 

1

1.56

 

25.00%

2

2

 

1

0.43

 

0

0.00

 

0

0.00

 

 

2

3

 

2

0.87

 

0

0.00

 

1

1.56

 

 

2

4

 

0

0.00

 

0

0.00

 

0

0.00

 

 

2

5

 

0

0.00

1.30%

0

0.00

0.00%

0

0.00

3.13%

 

 

*   VEDS IS AN EXCLUSION OF THE BRIGHTON CRITERIA, USED HERE FOR COMPARATIVE AND NOT FOR DIAGNOSTIC PURPOSES 

 

*   ONLY POSITIVE p VALUES ARE GIVEN

 

 

 

 

 

SYMPTOMS AND SIGNS OF HDCT PATIENTS

 

 

 

 

 

 

 

 

 

 

 

 

JHS

 

VEDS

 

OI

 

 

 

n

%

 

n

%

 

n

%

 

 

 

 

 

 

 

 

 

 

 

EARLY  OSTEOARTHRITIS  

 

14

6,08

 

1

5,55

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

EARLY OSTEOPENIA AND  OSTEOPOROSIS

 

13

5,65

 

2

11,11

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OSTEOPENIA AND OSTEOPOROSIS

 

60

26,10

 

9

50,00

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DYSAUTONOMIA

 

53

23,04

 

7

38,88

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

DYSLIPIDEMIA

 

44

19,13

 

3

16,66

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

SCOLIOSIS

 

28

12,17

 

6

33,33

 

0

0,00

 

 

 

 

 

 

 

 

 

 

 

FLAT FEET

 

69

30,00

 

14

77,77

 

1

100,00

 

 

 

 

 

 

 

 

 

 

 

NASAL CARTILAGE ALTERATION

 

41

17,82

 

4

22,22

 

0

0,00

 

 

 

 

 

 

 

 

 

 

 

 

 

 

EAR ALTERATIONS

 

24

10,43

 

2

11,11

 

0

0,00

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Some of our patients showing the typical VEDS facial appearance as described in the literature:

 


 

 


An example of a typical JHS patient:

 


 

 

 


An additional important finding in the diagnosis of JHS has been Dr. Bravos’ description of the typical JHS facial appearance. 

The following pictures show this typical JHS facial appearance:

 

 

 

 

 

 

 

 


Conclusions:

 

 

 

Classical Hereditary Diseases of the Connective Tissues (HDCT) are rare, but the emergent forme fruste, the Joint Hypermobility Syndrome (JHS) is very frequent, but usually not diagnosed.

 

Fragility of tissues, including osteoporosis and sudden death are prevalent in VEDS patients and their relatives.

 

A high index of suspicion is necessary to make the diagnosis of JHS. We suggest to look for blue sclerae, atypical ears and nose, marfanoid habitus and the use of the Brighton criteria.

 

The Beighton score alone was confirmed to be inadequate for the diagnosis of JHS.

 

Raynaud´s phenomenon is barely seen in JHS (2.3%).

 

Dysautonomia, dyslipidemia, early osteoarthritis and early osteoporosis, even in males, should be looked for.

 

We recommend that the Brighton criteria be routinely used in the evaluation of rheumatological patients.

 

Similar studies in other countries, using the Brighton criteria, are needed to determine if this high prevalence is particular of Chile.