584

April 1976 TheJournalofPEDIATRICS

Joint contracture--common manifestation of childhood diabetes mellitus Sixty-five of 229 seven to eighteen-year oM campers with diabetes' were found to have contractures of finger joints; in two thirds of affected children only the fifth finger was involved. Stiff resistance to passive finger manipulation and thickened adherent skin over the dorsa of the hands were additional .features. Short stature was associated with involvement of more than one.finger; the shortest youngsters also had contractures of large joints. Joint changes were independent of age, sex, age o f onset o f diabetes, and control of diabetes, but correlated with duration o f the' diabetes.

Ante Grgie, M.D., Arian L. Rosenbloom, M.D.,* F. Thomas Weber, M.D., Beverly Giordano, R.N., John I. Malone, M.D., and Jonathan J. Shuster, Ph.D., G a i n e s v i l l e , Fla.

WE RECENTLY noted multiple joint contractures, most apparent in the fingers, as well as thick, tight, waxy skin and short stature in three unrelated teen-age patients with long-standing diabetes. 1 Extensive reviews of complications of childhood diabetes ~, 3 have not included similar observations of joint and skin involvement, even in the presence of severe short stature. In screening the population of our diabetes camp for further instances of this constellation of findings, we noted that milder changes in finger mobility were common.

From the Division of Genetics, Endocrinology, and Metabolism, Department of Pediatrics, University of Florida College of Medicine, Department of Pediatrics, University of South Florida College o f Medicine, and Department o f Statisticss University o f Florida. Supported by N I H Grants 5 MO1 RRO0082 and 5 TO1 AM05680-04, and the Division of Children's Medical Serviees o f the Department of Health and Rehabilitative Services of the State of Florida. Presented in part to the Lawson Wilkins Pediatric Endocrine Society, April 16, 1975, Denver, Colo. Dr. Rosenbloom is the recipient of a Faculty Development Award from the University of Florida. *Reprint address: Department o5['Pediatrics, University of Florida College of Medicine, Gainesville, Fla. 32610.

Vol. 88, No. 4, part 1, pp. 584-588

METHODS Subjects were all of the 229 insulin-dependen t 7- to 18year-old patients attending the 1974 session of Florida's Camp for Children and Youth with Diabetes. On the day of admission to camp a detailed history was obtained with particular emphasis on hospitalization experience, school attendance, and episodes of hypoglycemia or ketosis. In addition, the record of urinary glucose and acetone concentrations for two weeks prior to camp was obtained. Physical examination was performed by a pediatric house officer. A single 24-hour urine specimen was obtained for protein estimation by reagent strip and for total glucose determination. Plasma glucose concentration was measured before breakfast and before supper on two separate days during camp. Both 24-hour urinary and plasma glucose determinations were done by an enzymatic method in a rapid automatic analyzer. A simple method for determining limitation of finger extension was devised which yielded consistent and reproducible findings by all four physician examiners. The child was asked to place his or her hands on a table top palm down with fingers fanned. The examiner determined contact of the fingers with the plane surface by viewing at table level. The entire palmar surface of the fingers normally makes contact. Patients were classified as Stage I if tt~ey were unable to make contact with some

Volume 88 Number 4, part 1

Joint contracture

50-

Table 1. Mean height percentiles and insulin dosages in campers with joint findings and in control campers and mean height percentiles in nondiabetic control subjects

Subjects Stage I Patients Camper control subjects Nondiabetic control subjects Stage H Patients Camper control subjects Nondiabetic control subjects

Daily insulin dose Height (units/kg body percentile weight) No. (mean +_ SEM) (mean +_ SEM) 47 47

45.9 + 4.4 50.4 +_ 4.2

0.94 _+ 0.05 0.85 _+ 0.05

25

2O

40r LU

49

I-LU U. g,.

55.4 _+ 3.9

18 18

25.2 _+ 5.8* 51.3 _+ 3.7

18

51.6 _+ 7.4

33

3076

I-z

8

Ill

20-

14

LU

47

a.

15 10-

5

~

25

1.11 +_ 0.11 0.87 _+ 0.07

*Differs from c a m p e r control m e a n at < 0.001 level and f r o m nondiabetic control subjects at the < 0.01 level.

portion of one finger, usually the proximal interphalangeal joint of the fifth. Stage II children could not make contact with two or more fingers, usually the proximal interphalangeal joints of the fourth and fifth. Contractures were confirmed by the examiners' attempt to passively extend the fingers. In no case was more than one examiner aware of details of the child's clinical history at the time of the examination. Height percentiles were estimated from the Iowa growth charts. The following variables were analyzed for correlation with the presence of joint contracture: chronologic age, height-age and height percentile, sex, race, Tanner classification of sexual maturation? age of onset and duration of diabetes, current insulin dosage and diabetes control measures of 24-hour glucosuria, plasma glucose levels, hospitalization history, and school atten, dance record? -8 The control group for stature and joint mobility was selected from Gainesville school children and matched for age, sex, and race with the campers. RESULTS Sixty-five of the patients (28.4%) had contractures of one or more fingers. Of these, 47 (20.5%) were Stage I and 18 (7.9%) were Stage II limitation. Two of the 210 control subjects, boys age 16 and'17 years, had Stage I involvement. The four most severely affected campers (described below) and some of the other youngsters with Stage II

585

0-

1~2

1-2 11/123-411/I2

DURATION

5-611/12 7-811/12

9+

OF D I A B E T E S (yrs.)

Fig. 1. Percentage of campers with joint limitation by duration of diabetes. The numbers above the bars indicate the total number of campers examined in the age group. The scored area represents the percentage of Stage II findings; and the numbers within the bars indicate the number of campers with Stage I (clear) and Stage II (scored area) findings.

changes were aware of finger limitation or stiffness. There was no muscle atrophy, altered sensation, or palmar fascial thickening. The relationship of joint limitation to duration of diabetes (Fig. 1) was highly significant (p < 0.0004). There were no statistically significant relationships between the occurrence of joint changes and chronologic age, age of onset of diabetes, sex, race, sex maturation stage, or height percentile for age. Mean height percentiles did not differ among affected and nonaffected campers (matched for age, sex, and duration of diabetes) and nondiabetic control subjects for the Stage I group. Affected Stage II campers had a mean height percentile one-half that for diabetic control subjects (Table I). Mean insulin doses for the campers with joint involvement were higher than those for their control groups, but the differences were not significant at the 0.05 level (Table I). Diabetic control variables (24-hour glucosuria, plasma glucose levels, history of hospitalization, and school attendance) did not differ between the most severely affected group (Stage II) and an age, sex, and duration of diabetes matched group of campers without joint findings. P~oteinuria was found in only one of the 229 campers, a boy with

586

Grgic et al.

The Journal of Pediatrics April 1976

and 2) were 25 and 17 cm shorter, respectively, than their fathers. Roentgenograms of all involved joints in Cases 1 to 4 were normal except for thickening of the periarticular tissues. Normal results were obtained for the following studies in Cases 1 to 4: sedimentation rate, antinuclear antibody titer, latex agglutination, and immunoglobulin electrophoresis. Cases 3 to 5 were found to have normal growth hormone responses to multiple stimuli and normal serum thyroxin levels. DISCUSSION

Fig. 2, Left upper, Maximal thumb and finger extension of left wrist and maximal extension of right wrist in patient five. Left lower, Maximal thumb and finger extension, maximal extension left wrist and flexion right wrist in patient one. Right upper, Maximal thumb and finger flexion and wrist extension in Case 3 (left) compared with flexions by a 40-year-old man without diabetes. Right lower, Maximal thumb, finger, and wrist extension in patient three.

Stage II changes who had diabetes for 16 years (Table II, Case 4). Four of the 18 campers who had Stage II findings were also well below the third percentile in height; no other control or affected campers were below the third percentile. The clinical data of these four campers are summarized in Table II, together with data of the three patients originally observed. 7 These seven patients noticed joint limitation from 7 1/2 to 13 years after onset of their diabetes. This invariably began as a stiffening in the fourth and fifth fingers with evolution to involve the interphalangeal joints of all the fingers over one to three years and stability thereafter (Fig. 2). The youngsters were generally unaware of the limitation of range of motion of joints other than that of their hands. Except for Case 4, who had difficulty with grasp, they were not functionally disabled. In addition to absolute limitation of motion in all planes by as much as 50% (Fig. 3), affected joints were stiffly resistant to passive movement. Joint changes were symmetrical. All seven of these patients had tight, thick, waxy skin which was most evident on the dorsal surface of the hands. Statural attainment was documented to be normal until three to seven years after onset of the diabetes in Cases 1 to 6. The two mature boys (Cases 1

It is apparent that joint contracture is a common and readily noted manifestation of diabetes mellitus in children and adolescents. Following our initial report of multiple joint limitation, short stature, and thick, tight, waxy skin in three teen-agers with long-standing diabetes, 1we were informed of a number of other diabetic children from various centers in whom attempts had been made to verify diagnoses of rheumatoid arthritis or scleroderma. The skin changes in these youngsters are quite distinct from those of scleroderma, which is characterized by thinning of the skin and does not have the attendant joint manifestations. The clinical, laboratory, and roentgenographic findings are not those of rheumatoid arthritis. We were unable to quantitate the stiff resistance to passive movement of finger joints that was present in all affected youngsters. Many patients also had thickened adherent skin most readily discernible as an inability of the examiner to grasp a fold over the dorsal surface of the proximal phalanges of the hand. Methods for quantitation of these features are under study. Wentworth 9has examined 100 youngsters with diabetes and found a similar prevalence of joint changes. We are not aware of any other observations of common joint manifestations in childhood diabetes. With the frequency of 50% after 9 years' duration of diabetes that we have noted, further progression should have been described in a large number of adults. In older patients with diabetes, finger joint limitation is frequently associated with Dupuytren contracture. 1~Joint changes in these patients may also occur in the absence of palmar fascial thickening, in which case there is invariably evidence of vascular insufficiency11 or neuropathy. 12 No vascular calcifications were seen on roentgenograms of the hands of our most severely affected patients, and paresthesias, intrinsic hand muscle atrophy, and palmar fascial thickening were not found. The common periarticular and dermal thickening and rigidity relaffvely early in the course of childhood diabetes

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Fig. 3. Maximal lateral flexion of cervical and thoracolumbar spine in (left to right) Case 3 (limited), Case 2 (normal), and Case 1 (limited). Table II. Clinical features of seven ~atients with short stature, joint changes, and long-standing diabetes mellitus

Patient/Sex Clinicalfeatures Age onset of diabetes Age short stature onset Age onset joint limitation Age last evaluation Height age Sex maturation stage 4 Osseous maturation Retinopathy Proteinuria Joints involved~" Wrist Elbow Spine Knees Ankles Toes

I/M*

I

1 2/12 4 14 18 8/12 14 3/12 5 18 X

X X X X

2/M* 3 8 15 19 13 5 18 X X X X X X X

t

3/F* 7 10 14 6/12 16 7/12 11 3 13 6/12 X X X X

I

4/M

5/F

6/F

[

7/F

2 6 16 18 12 6/12 4 13 6/12 X X

6 8 13 14 2/12 10 3/12 2 11

1 8 12 15 3/12 10 8/12 3 11 6/12 X

2 13 15 15 8/12 11 8/12 3 NA

X

X X

X X

X

X

X

X

X X

*Previously reported. tAll have interphalangeal and metacarpophalangeal limitation. may represent increased cross-linking o f ground substance (e.g., collagen) thought to account for the decreased elasticity and toughening of connective tissue and skin that occurs with age. 13 Our findings in diabetes may also be related to conhective tissue changes occurring prematurely in the blood vessels of persons with this disorder. The hallmark of these changes, muscle capillary basement membrane thickening, has been found to corre-

late with chronologic age but not with duration of diabetes in youngsters and to be present in one third o f newly diagnosed children, indicating independence from the metabolic abnormafity. TM Despite the statistical correlation o f j o i n t changes with duration of diabetes, it is our impression that the findings we report are also independent expressions of diabetes. Nearly 10% of campers with diabetes for less than a year

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Grgic et al.

had joint limitation and by three years' duration one fourth were affected. One of our campers had Stage II changes after just over one year of diabetes; we have recently observed a 12-year-old girl with newly diagnosed diabetes who also had Stage II contracture. We have further noted Stage I changes in a 17-year-old boy with stable, mild chemical diabetes of six years' duration; his brother, insulin dependent for 20 years, has Stage II changes and short stature at age 23. Finally, those with Stage II changes, as a group, are significantly shorter than an age, sex, and duration of diabetes matched control group which in turn does not differ from a nondiabetic 'control population in stature. The influence of duration of diabetes on the appearance of joint changes and the delay in onset of growth failure, however, implies the requirement of a period of metabolic derangement. We were not able to ascertain any difference in degree of metabolic disturbance between affected and unaffected campers, using available and quantifiable criteria of school attendance, hospitalization history, and plasma and urinary glucose concentrations during camp. A checklist review of the two-week urine record prior to camp and of the intake histories for other evidence of instability of the diabetes also failed to reveal differences between affected and unaffected campers. The inability to implicate the metabolic disturbance for these connective tissue findings or to fully reject such a contribution extends the familiar debate about the vascular complications of diabetes? 4, ,5 The most apparent resolution of this debate is that both primary (genetic) and secondary (metabolic control) factors are involved in the expression of the findings we have described. As with the vascular complications, complete escape from joint involvement might be more a reflection of the kind of diabetes than the level of metabolic control? 6 This point of view is emphasized at the one extreme by our single patient with mild chemical diabetes and contractures and at the other extreme by those campers who have poorly managed diabetes for 10 to 15 years without contracture. Determination of the relationship of the joint, skin, and growth abnormalities we have described to microvascular

The Journal of Pediatrics April 1976

changes also seen early in diabetes TM and whether these findings occur in a distinct subpopulation of patients will require further study. We have recently taken retinal photographs and have done fluorescein angiographic studies on 180 campers. The results will be analyzed for correlation with joint findings in these same campers. A preliminary report of these observations has been published as a letter to the editor? ~ REFERENCES

1. Rosenbloom AL, and Frias JL: Diabetes, short stature and joint stiffness-a new syndrome, Clin Res 22:92A, 1974. 2. White P: Childhood diabetes, Diabetes 9:345, 1960. 3. Wagner R, White P, and Bogan I: Diabetic dwarfism, Am J Dis Child 63:667, 1942. 4. Tanner JM: Growth at adolescence, ed 2, Oxford, 1962, Blackwell ScientificPublications, pp 28-39. 5. WalkerSH, and Duncan DB: Estimation of the probability of an event as a function of several independent variables, Biometrika 54:167, 1967. 6. Beyer WH: Handbook of probability and statistics, ed 2, Cleveland, Ohio, 1968, Chemical Rubber Company. 7. Anderson TW: An introduction to multivariate statistical analysis, New York, i958, John Wiley & Sons, Inc, p 85. 8. Burr, IW: Applied statistical methods, New York, 1974, Academic Press, Inc, p 239. 9. WentworthSM: Personal communication. 10. PodolskyS: Dupuytreu's contracture, in Marble A, White P, Bradley R, and Krall L, editors: Joslin's diabetes mellitus, ed 11, Philadelphia, 1971, Lea & Febiger, Publishers, pp 740-742. 1i. Jung Y, Hohmann T, Gerneth J, Novak J, Wasserman R, D'Andrea B, Newton R, and Danowski T: Diabetic hand syndrome, Metabolism 20:1008, 1971. 12. Lundbaek K: Stiff hands in long-term diabetes, Acta Med Scand 158:445, 1957. 13. Grant ME, and Prockop J: The biosynthesis of collagen, N Engl J Med 286:291, 1972. 14. Raskin P, Marks JF, Burns M Jr, Plumer ME, and Siperstein MD: Capillary basement membrane width in diabetic children, Am J Med 58:365, 1975. 15. Vracko R, and Benditt EP: Manifestations of diabetes mellitus-their possible relationships to an underlying cell defect, Am J Pathol 75:204, 1974. 16. Knowles H: Long term juvenile diabetes treated with unmeasured diet, Trans Assoc Am Physicians 85:95, 1971. 17. Grgic A, Rosenbloom AL, Weber FT, Giordano B, and Malone JI: Joint contracture in childhood diabetes, N Engl J Med 292:372, 1975.

Joint contracture--common manifestation of childhood diabetes mellitus.

Sixty-five of 229 seven to eighteen-year-old campers with diabetes were found to have contractures of finger joints; in two thirds of affected childre...
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