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CONNECTIVE TISSUE ABNORMALITIES IN DIABETES
509 CONNECTIVE TISSUE ABNORMALITIES IN DIABETES
SIR,—Professor Soler and Dr Khardori (Jan 28, p 193) report that 12 out of 100 women with long-standing insulin-dependent diabetes had fibrous breast lumps, and they ask whether if breast lumps are another manifestation of connective tissue abnormalities found in diabetes, if autoimmunity is involved in the aetiology of these conncective tissue abnormalities, and if these patients represent a distinct subgroup of type I diabetics. Their report can pose these questions since it is simply an uncontrolled description of this subgroup of patients. Have Soler and Khardori examined a population of women in this age group without diabetes? One might background frequency of breast lumps to be equally expect
only
high.I the
The subgroup with lumps is examined for autoimmunity against the thyroid, for HLA phenotype, and for limited joint mobility without being compared with any of the three obvious control populations needed. With this non-design, their questions are thrown on the wind. They do not consider the possibility that 5 of 12 of their subjects with breast lumps having thyroid autoimmunity is not significantly different from the 3 or 4 out of 12 expected on the basis of the large series of Riley et a1.2 They also fail to note that the lack of an association between limited joint mobility and autoimmunity has been demonstrated in a genuine study of patients with and without limited joint mobility.3 Soler and Khardori group the stiff hands associated with pain, paraesthesias, and calcification of the small arteries of the hand4 with the asymptomatic limited joint mobility which does not have a neurological component or vascular changes and does not require 25 years of diabetes to manifest. We are not told how Soler and Khardori determined limited joint mobility, except that subjects had a "positive prayer sign". The reference given does not describe any such manoeuvre,5 although they may be referring to the illustration and description in a paper that appeared five years 6
later.
I do not understand how Goldstein and colleagues’ work on replication of cultured skin fibroblasts from persons with diabetes, generations removed from the host milieu, demonstrate "connective tissue abnormalities secondary to hyperglycaemia ...
in man". Soler and Khardori may have made an interesting clinical observation. However, these uncontrolled observations should not have seen the light of day. Division of Paediatric
Endocrinology,
College of Medicine, University of Florida, Gainesville, Florida 32610, USA
ARLAN L. ROSENBLOOM
SIR,—We read the paper by Professor Soler and Dr Khardori with interest. The concept of a clinical disorder of connective tissue involving several organs in long-standing diabetes is appealing, and is compatible with histological changes in various tissues. The significance of their reported associations is weakened, however, by a lack of control data, a paucity of statistical analysis, and ambiguity about the method of enrolment to the study, making an assessment of its importance difficult. Three claims are made: (1) Benign breast disease is more common in female patients with typeI diabetes; (2) there is an increased prevalence of thyroid microsomal antibody (TMA) in these patients; (3) patients with breast disease have a higher prevalence of limited joint mobility (LJM) than other diabetic women. SM, Gerlman RS, Silen W. Fibrocystic "disease" of the breast: a nondisease? N Engl J Med 1982; 307: 1010-14. 2. Riley WJ, Maclaren NK, Lezotte DC, Spillar RP, Rosenbloom AL. Thyroid autoimmunity in insulin dependent diabetes mellitus: The case for routine screening. J Pediatr 1981; 99: 350-54. 3 Rosenbloom AL, Silverstein JH, Lezotte DC, Riley WJ, Maclaren NK. Limited joint mobility in diabetes mellitus of childhood: Natural history and relationship to growth impairment. J Pediatr 1982; 101: 874-78. 4. Lundbeck K. Stiff hands in long-term diabetes. Acta Med Scand 1957; 158: 447-51. 5 Grgic A, Rosenbloom AL, Weber FT, Giordano B, Malone JI, Shuster JJ. Joint contractures-common manifestation of childhood diabetes mellitus. J Pediatr 1. Love
1976; 88: 584-88. AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited
6. Rosenbloom
joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981; 305: 191-94.
While the "incidence" of benign breast disease varies widely, about 20% of all women will require diagnostic procedures for such disease,and a large cohort study has shown a cumulative risk of9% at 30 years of age, and 31% at 50 years.2 Soler and Khardori report that 12 of 88 female diabetic patients (14%) had breast disease, which would correspond to this finding in a non-diabetic population. The prevalence of TMA in the diabetic population is well described, varying from 25% to 35% in white females with diabetes.3,4 Thus one would expect 4 patients with TMA in a series of 12 patients. The finding of five such patients hardly constitutes a significant difference from this and thus does not suggest an association between breast disease and TMA. in as much as 46% of diabetic patients LJM has been with type I disease. Diagnostic criteria being very subjective, an oversensitive appraisal will obviously result in a high prevalence. We have found the prevalence in our own clinic to be about 40% in the diabetic population as a whole. While 11 patients having LJM out of 12 seems impressive, we are not told the prevalence ofLJM in the diabetic control population, and thus cannot evaluate Soler and -
reported
Khardori’s observations statistically. From the data presented in this paper, it is difficult to prove that an association between benign breast disease, thyroid antibodies, and LJM, all of which are common in patients with diabetes, is more than fortuitous. Soler and Khardori state that "no association between diabetes mellitus and breast disease ... has been reported before"-this may be simply because it does not exist. Gartnavel General Hospital, 12 0YN
Glasgow G
J. G. LARKIN B. M. FRIER
ANTIBODIES TO PURKINJE CELLS AND PERIPHERAL NERVE IN OPOCLONIA
SIR,—Opoclonia (or opsoclonus), irregular jerky movements of the eyes, has long been postulated to have an immunological basis.6 The condition consistently improves if the patient is given corticotropin or corticosteroids;6. and increased CSF immunoglobulins7 and macrophage inhibition by neuroblastoma antigens8 have been reported. In a 10-month-old boy with opoclonia but no neuroblastoma we found serum IgG antibodies to neurofibrillary and membrane components of guineapig Purkinje cells with weak cytoplasmic staining and to axons of rat peripheral nerve. The boy walked at 8 months and ran at 9 months. A week after an otitis media infection, ataxia developed, followed within a day by bizarre eye movements. Immunofluorescence (IF) titres in his serum were 128 against fresh frozen sections of guineapig cerebellum and rat peripheral nerve. No significant reactions were found against human fetal thymus or guineapig adrenal medulla. He improved rapidly after intramuscular corticotropin. IF titres fell to 20, five weeks after therapy started. Before treatment the infant had had depressed cell-mediated immunity, as judged by skin tests. The time available before corticotropin therapy began did not permit evaluation of the anti-T-cell activity of his serum against his own or other T cells, but such an abnormality may have existed in view of the cross-antigenic relations between subsets ofT cells and Purkinje cells 9 and oligodendrocytes,1O and between natural killer cells and Humphrey LJ, Estes NC. Aspects of fibrocystic disease of the breast: Treatment with danazol. Postgrad Med J 1975; 55 (suppl 5): 48-51. 2. Hislop TG, Elwood JM. Risk factors for benign breast disease: a 30 year cohort study. Can Med Assoc J 1981; 124: 283-91. 3. Bright GM, Blizzard RM, Kaiser DL, Clark WL. Organ-specific autoantibodies in children with common endocrine diseases. J Pediatr 1982; 100: 8-14. 4. Riley WJ, Legotte DC, Rosenbloom AL. Thyroid autoimmunity in insulin-dependent diabetes mellitus: the case for routine screening. J Pediatr 1981; 99: 350-54. 5. Lawson PM, Maneschi F, Kohner EM. The relationship of hand abnormalities to diabetes and diabetic retinopathy Diabetes Care 1983; 6: 140-43. 6. Leder RM. The opsoclonus-myoclonus syndrome: a review of the literature. Bull Los Angeles Neurol Soc 1981; 46: 41-50. 7. Dyken P, Kolar O. Dancing eyes, dancing feet: Infantile polymyoclonia. Brain 1968; 1.
91: 305-20.
Graham-Pole J, Ogg L, Cochran AJ. Reactivity to neuroblastoma childhood cerebellar encephalopathy ("dancing eyes" syndrome). Lancet 1976; ii: 975-76. 9. Garson JA, Beverly PCL, Coakham HB, Harper EI. Monoclonal antibodies against human T lymphocytes label Purkinje neurones of many species. Nature 1982; 298: 375-77. 10. Oger J. A monoclonal antibody against human T suppressor lymphocytes binds specifically to the surface of cultured oligodendrocytes. Nature 1982; 295: 66-68. 8.
Stephenson JBP, extracts in
,
SIR,—Professor Soler and Dr Khardori (Jan 28, p 193) report that 12 out of 100 women with long-standing insulin-dependent diabetes had fibrous breast lumps, and they ask whether if breast lumps are another manifestation of connective tissue abnormalities found in diabetes, if autoimmunity is involved in the aetiology of these conncective tissue abnormalities, and if these patients represent a distinct subgroup of type I diabetics. Their report can pose these questions since it is simply an uncontrolled description of this subgroup of patients. Have Soler and Khardori examined a population of women in this age group without diabetes? One might background frequency of breast lumps to be equally expect
only
high.I the
The subgroup with lumps is examined for autoimmunity against the thyroid, for HLA phenotype, and for limited joint mobility without being compared with any of the three obvious control populations needed. With this non-design, their questions are thrown on the wind. They do not consider the possibility that 5 of 12 of their subjects with breast lumps having thyroid autoimmunity is not significantly different from the 3 or 4 out of 12 expected on the basis of the large series of Riley et a1.2 They also fail to note that the lack of an association between limited joint mobility and autoimmunity has been demonstrated in a genuine study of patients with and without limited joint mobility.3 Soler and Khardori group the stiff hands associated with pain, paraesthesias, and calcification of the small arteries of the hand4 with the asymptomatic limited joint mobility which does not have a neurological component or vascular changes and does not require 25 years of diabetes to manifest. We are not told how Soler and Khardori determined limited joint mobility, except that subjects had a "positive prayer sign". The reference given does not describe any such manoeuvre,5 although they may be referring to the illustration and description in a paper that appeared five years 6
later.
I do not understand how Goldstein and colleagues’ work on replication of cultured skin fibroblasts from persons with diabetes, generations removed from the host milieu, demonstrate "connective tissue abnormalities secondary to hyperglycaemia ...
in man". Soler and Khardori may have made an interesting clinical observation. However, these uncontrolled observations should not have seen the light of day. Division of Paediatric
Endocrinology,
College of Medicine, University of Florida, Gainesville, Florida 32610, USA
ARLAN L. ROSENBLOOM
SIR,—We read the paper by Professor Soler and Dr Khardori with interest. The concept of a clinical disorder of connective tissue involving several organs in long-standing diabetes is appealing, and is compatible with histological changes in various tissues. The significance of their reported associations is weakened, however, by a lack of control data, a paucity of statistical analysis, and ambiguity about the method of enrolment to the study, making an assessment of its importance difficult. Three claims are made: (1) Benign breast disease is more common in female patients with typeI diabetes; (2) there is an increased prevalence of thyroid microsomal antibody (TMA) in these patients; (3) patients with breast disease have a higher prevalence of limited joint mobility (LJM) than other diabetic women. SM, Gerlman RS, Silen W. Fibrocystic "disease" of the breast: a nondisease? N Engl J Med 1982; 307: 1010-14. 2. Riley WJ, Maclaren NK, Lezotte DC, Spillar RP, Rosenbloom AL. Thyroid autoimmunity in insulin dependent diabetes mellitus: The case for routine screening. J Pediatr 1981; 99: 350-54. 3 Rosenbloom AL, Silverstein JH, Lezotte DC, Riley WJ, Maclaren NK. Limited joint mobility in diabetes mellitus of childhood: Natural history and relationship to growth impairment. J Pediatr 1982; 101: 874-78. 4. Lundbeck K. Stiff hands in long-term diabetes. Acta Med Scand 1957; 158: 447-51. 5 Grgic A, Rosenbloom AL, Weber FT, Giordano B, Malone JI, Shuster JJ. Joint contractures-common manifestation of childhood diabetes mellitus. J Pediatr 1. Love
1976; 88: 584-88. AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M. Limited
6. Rosenbloom
joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med 1981; 305: 191-94.
While the "incidence" of benign breast disease varies widely, about 20% of all women will require diagnostic procedures for such disease,and a large cohort study has shown a cumulative risk of9% at 30 years of age, and 31% at 50 years.2 Soler and Khardori report that 12 of 88 female diabetic patients (14%) had breast disease, which would correspond to this finding in a non-diabetic population. The prevalence of TMA in the diabetic population is well described, varying from 25% to 35% in white females with diabetes.3,4 Thus one would expect 4 patients with TMA in a series of 12 patients. The finding of five such patients hardly constitutes a significant difference from this and thus does not suggest an association between breast disease and TMA. in as much as 46% of diabetic patients LJM has been with type I disease. Diagnostic criteria being very subjective, an oversensitive appraisal will obviously result in a high prevalence. We have found the prevalence in our own clinic to be about 40% in the diabetic population as a whole. While 11 patients having LJM out of 12 seems impressive, we are not told the prevalence ofLJM in the diabetic control population, and thus cannot evaluate Soler and -
reported
Khardori’s observations statistically. From the data presented in this paper, it is difficult to prove that an association between benign breast disease, thyroid antibodies, and LJM, all of which are common in patients with diabetes, is more than fortuitous. Soler and Khardori state that "no association between diabetes mellitus and breast disease ... has been reported before"-this may be simply because it does not exist. Gartnavel General Hospital, 12 0YN
Glasgow G
J. G. LARKIN B. M. FRIER
ANTIBODIES TO PURKINJE CELLS AND PERIPHERAL NERVE IN OPOCLONIA
SIR,—Opoclonia (or opsoclonus), irregular jerky movements of the eyes, has long been postulated to have an immunological basis.6 The condition consistently improves if the patient is given corticotropin or corticosteroids;6. and increased CSF immunoglobulins7 and macrophage inhibition by neuroblastoma antigens8 have been reported. In a 10-month-old boy with opoclonia but no neuroblastoma we found serum IgG antibodies to neurofibrillary and membrane components of guineapig Purkinje cells with weak cytoplasmic staining and to axons of rat peripheral nerve. The boy walked at 8 months and ran at 9 months. A week after an otitis media infection, ataxia developed, followed within a day by bizarre eye movements. Immunofluorescence (IF) titres in his serum were 128 against fresh frozen sections of guineapig cerebellum and rat peripheral nerve. No significant reactions were found against human fetal thymus or guineapig adrenal medulla. He improved rapidly after intramuscular corticotropin. IF titres fell to 20, five weeks after therapy started. Before treatment the infant had had depressed cell-mediated immunity, as judged by skin tests. The time available before corticotropin therapy began did not permit evaluation of the anti-T-cell activity of his serum against his own or other T cells, but such an abnormality may have existed in view of the cross-antigenic relations between subsets ofT cells and Purkinje cells 9 and oligodendrocytes,1O and between natural killer cells and Humphrey LJ, Estes NC. Aspects of fibrocystic disease of the breast: Treatment with danazol. Postgrad Med J 1975; 55 (suppl 5): 48-51. 2. Hislop TG, Elwood JM. Risk factors for benign breast disease: a 30 year cohort study. Can Med Assoc J 1981; 124: 283-91. 3. Bright GM, Blizzard RM, Kaiser DL, Clark WL. Organ-specific autoantibodies in children with common endocrine diseases. J Pediatr 1982; 100: 8-14. 4. Riley WJ, Legotte DC, Rosenbloom AL. Thyroid autoimmunity in insulin-dependent diabetes mellitus: the case for routine screening. J Pediatr 1981; 99: 350-54. 5. Lawson PM, Maneschi F, Kohner EM. The relationship of hand abnormalities to diabetes and diabetic retinopathy Diabetes Care 1983; 6: 140-43. 6. Leder RM. The opsoclonus-myoclonus syndrome: a review of the literature. Bull Los Angeles Neurol Soc 1981; 46: 41-50. 7. Dyken P, Kolar O. Dancing eyes, dancing feet: Infantile polymyoclonia. Brain 1968; 1.
91: 305-20.
Graham-Pole J, Ogg L, Cochran AJ. Reactivity to neuroblastoma childhood cerebellar encephalopathy ("dancing eyes" syndrome). Lancet 1976; ii: 975-76. 9. Garson JA, Beverly PCL, Coakham HB, Harper EI. Monoclonal antibodies against human T lymphocytes label Purkinje neurones of many species. Nature 1982; 298: 375-77. 10. Oger J. A monoclonal antibody against human T suppressor lymphocytes binds specifically to the surface of cultured oligodendrocytes. Nature 1982; 295: 66-68. 8.
Stephenson JBP, extracts in
,