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Dwarfism and mental retardation: The serum growth hormone response to hypoglycemia
136
Brief clinical and laboratory observations
say, A. M.: Neurological and electroencephalographic problems of the rubella epidemic of 1962, Brit. Med. J. 2: 1300, 1963. 11. Kenny, F. M., Michaels, R. H., and Davis, N. S.: Rubella encephalopathy: Later psychometric, neurologic, and encephalographic
Dwarfism and mental retardation." The serum grmvth hormone reqoonse to hypoglycemia S. Douglas Frasier, M.D.,*
Jean M. Hilburn, BIS., and Fred G. Smith, Jr., M.D. POMONA AND LOS ANGELES
CALIF.
N A S S O C I A T I O N between mental retardation and impaired growth has been recognized by several investigators? T h e pathogenesis of this association has not been elucidated. There is an extensive amount of information indicating that experimental brain lesions are associated with retardation of growth? Hypothalamic lesions in rats are
A
From the Pacific State Hospital, Pomona, The Los Angeles County-University of Southern California Medical Center, Department of Pediatrics, University of Southern California School of Medicine, and Department of Pediatrics, University of California School of Medicine. Supported by State of Cali[ornla Department of Mental Hygiene Grant No. 14-38. Presented in part at the Thirty-Eighth Meeting of the Society [or Pediatric Research, Atlantic City, N. J., May 4, 1968. The opinions or conclusions stated in this paper are those of the authors and are not to be construed as official or as necessarily reflecting the policy of the California Depart?nent of Mental Hygiene. *Present address: Children's Division 4E8, Los Angeles County-University of Soufhern California Medical Center, 1200 N. State St., Los Angeles, Calif. 90033.
The Journal of Pediatrics July 1970
evaluation of seven survivors, Amer. J. Dis. Child. 110: 374, 1965. 12. Meyer, H. M., Johnson, R. T., Jr., Crawford, I. P., Dascomb, H. E., and Rogers, N. G.: Central nervous system syndromes of "viral" etiology: A study of 713 cases, Amer. J. Med. 29: 334, 1960.
associated with both decreased pituitary content of growth hormone and reduced plasma levels of growth hormone. The acute increase in the serum concentration of growth hormone stimulated by hypoglycemia depends on an intact hypothalamic-pituitary system. Hypoglycemia induces pituitary release of growth hormone by stimulating the secretion of a hypothalamic growth hormone releasing factor. In order to study the possibility that growth retardation associated with mental deficiency might be due to abnormalities in secretion of growth hormone, we have investigated the response of serum growth hormone to hypoglycemia in mentally retarded patients at the Pacific State Hospital, Pomona, California. M A T E R I A L AND M E T H O D S Fifty-eight institutionalized subjects with mental retardation and short stature were studied. T h e diagnoses were representative o.f the Pacific State Hospital population, 1 with the exclusion of patients with Down's syndrome. There were 30 males and 28 females whose ages ranged from 3 years 1 month to 16 years 9 months (mean 11 years 10 months + 3 years 9 months S.D.). Sexual development was determined according to the standards of T a n n e r } There were 36 prepubertal (Stage I) and 33 pubertal ( > Stage I I ) subjects. Height was measured as previously described? The deviations from mean height for age and from height age were determined from standards developed by the Iowa Child Welfare Research Station? The height of test subjects was > 2 S.D. below the mean for age (range 2 to 8 S.D. below mean) and the height a g e / chronologic age ratio ( H A / C A ) was <
Volume 77 Number 1
0.75 (range 0.14 to 0.72; mean 0.55 + 0.12 S.D.). Serial measurements from 1 year 1 month to 5 years 5 months were available in 55 subjects. The growth rate varied from 1.1 to 7.4 cm. per year (mean 3.9 + 1.7 S.D.). Twenty-three institutionalized subjects with mental retardation and normal height were also studied. The diagnoses were comparable to those os test subjects. There were 12 male and 11 female subjects whose ages ranged from 5 years 9 months to 17 years (mean 10 years 11 months + 3 years 1 month S.D.). There were 14 prepubertal (Stage I) and 9 pubertal ( > Stage I I ) control subjects. T h e height was +_ 2 S.D. from the mean height for age and H A / C A was > 0.75 (range 0.76 to 1.18; mean 1.00 + .09 S.D.). Serial measurements from 1 year 2 months to 6 years 3 months were available in 21 subjects. T h e growth rate varied from 3.0 to 7.6 cm. per year (mean 5.6 +_ 1.1 S.D.). Studies were performed in the fasting ambulatory state. Hypoglycemia was induced b 7 the intravenous administration of 0.05 units per kilogram of crystalline insulin. Blood was obtained by multiple venipuncture at zero time and 15, 30, 60, 90, and 120 minutes after the administration of insulin. An aliquot of each sample was assayed Sot glucose concentration by the glucose oxidase method (Glucostat), and the remainder was allowed to clot at room temperature for 1 to 2 hours. The serum was separated and frozen at -20 ~ C. until assayed for growth hormone concentration by radioimmunoassay. 4 RESULTS
There were no significant differences in sex, age, or the level of sexual development between test and control subjects. As expected, growth rate and H A / C A were significantly lower in test subjects (Table I ) P eFor Tables I, II, III, and IV, order Document No. NAPS-00991 from ASIS National Auxiliary Publications Service, c / o CCM Information Sciences, Inc., 909 3rd Ave., New York, N. Y. 10022. Remit $2.00 for each microfiche or $5.00 for each photocopy.
Brief clinical and laboratory observations
13 7
T h e degree of hypoglycemia attained was the same in both groups (Table II). T h e mean fasting serum growth hormone concentration was 5.7 + 1.2 (S.E.) ng. per milliliter in test subjects and 10.5 _+ 3.9 (S.E.) ng. per milliliter in control subjects. T h e mean peak serum growth hormone concentration and mean increase in the serum growth hormone concentration were 38.9 + 6.3 and 35.6 + 6.3 (S.E.) ng. per milliliter respectively, in test subjects. I n control subjects these values were 52.0 _+ 9.7 and 46.0 _+ 9.4 (S.E.) ng. per milliliter, respectively. The differences between test and control subjects are not statistically significant (Table I I I ) . The peak or increase in the serum growth hormone concentration was < 5 ng. per milliliter in 7 test subjects; values of this magnitude were not observed in any of the control subjects. This incidence of impaired response 4 was not statistically significant (Table I V ) . DISCUSSION
Mosier and associates 5 studied the thyroid uptake of radioactive iodine, plasma 17hydroxycortisteroid levels~ and 17-hydroxycortisteroid response to an infusion of adrenocorticotropin in 97 institutionalized dwarf subjects. They concluded that pituitary, thyroid, and adrenal insufficiency were not etiologic factors in growth failure associated with mental deficiency. Lowrey and associates 6 compared the fasting serum concentration of growth hormone in children with mental retardation and short stature, children with mental retardation and normal height, and children with both normal mentality and height. No differences were noted between these 3 groups. Milunsky and associates 7 have recently reported a normal plasma growth hormone response to insulin-induced hypoglycemia in 7 patients with mental deficiency and dwarfism (norie had Down's syndrome). O u r results also indicate that abnormalities in secretion of growth hormone, as refleeted by the response of serum growth hormone to insulin-induced hypoglycemia,
138
Brie[ clinical and laboratory observations
do not play a role in the pathogenesis of dwarfism associated with mental retardation. T h e observed growth hormone response was greater t h a n previously reported from this laboratory 4 and by other investigators. s-9 This m a y be due to differences in the standard g r o w t h h o r m o n e preparations employed or to the inclusion of pubertal subjects in this study, whereas previous studies were in prepubertal subjects. T h e observation of an impaired growth h o r m o n e response in 7 test subjects requires further consideration. T h e degree of hypoglycemia was comparable in responsive and nonresponsive individuals, as were diagnoses, age, sex distribution, and the level of sexual development. T h e r e were no differences in g r o w t h rate and in H A / C A between nonresponsive and responsive test subjects. G r o w t h retardation could not be related to the impaired response. This conclusion is consistent with previous observations of an impaired g r o w t h h o r m o n e response to hypoglycemia in children with normal g r o w t h h o r m o n e function. 9 SUMMARY
T h e serum g r o w t h h o r m o n e response to insulin-induced hypoglycemia was studied in 58 institutionalized mentally deficient subjects with g r o w t h retardation and in 23 institutionalized mentally retarded subjects with normal height. T h e fasting, peak, and increased serum concentrations of growth h o r m o n e were the same in these 2 groups. These studies indicate that functional abnormalities in growth h o r m o n e secretion do
The Journal o[ Pediatrics July 1970
not play a role in the pathogenesis of dwarfism associated with mental retardation. The authors wish to express their appreciation to Mrs. Evelyn Kline for her help in performing the insulin tolerance tests and to Mrs. Wilda Lyons for secretarial assistance. REFERENCES
1. Mosier, I{. D., Jr., Grossman, H. J., and Dingman, H. F.: Physical growth in mental defectives, Pediatrics 36: 465, 1965. 2. Tanner, J. M.: Growth at adolescence, ed. 2, Oxford, 1962, Blackwell Scientific Publications. 3. Jackson, R. L., and Kelly, H. G.: Growth charts for use in pediatric practice, J. PEDIAT. 27: 215, 1945. 4. Frasier, S. D.: The serum growth-hormone response to hypoglycemia in dwarfism, J. PEBIAT. 71: 625, 1967. 5. Mosier, H. D., Jr., Grossman, H. J., and Dingman, H. F.: Laboratory values in severely stunted mental defectives, Amer. J. Ment. Defic. 71" 230, 1966. 6. Lowrey, G. tI., Bacon, G. E., Fisher, S., and Knoller, H.: Fasting growth hormone levels in mentally retarded children of short stature, Amer. J. Ment. Defic. 73: 474, 1968. 7. Milunsky, A., Lowy, C., Rubenstein, A. H., and Wright, A. D.: Carbohydrate tolerance, growth hormone and insulin levels in mongolism, Develop. Med. Child. Neurol. 10: 25, 1968. 8. Kaplan, S. L., Abrams, C. A. L., Bell, J. J., Conte, F. A., and Grumbach, M. M.: Growth and growth hormone. I. Changes in serum level of growth hormone following hypoglycemia in 134 children with growth retardation, Pediat. Res. 2: 43, 1968. 9. Youlton, R., Kaplan, S. L., and Grumbaeh, M. M.: Growth and growth hormone. IV. Limitations of the growth hormone response to insulin and arginine and of the immunoreactive insulin response to arginlne in the assessment of growth hormone deficiency in children, Pediatrics 43: 989, 1969.
Brief clinical and laboratory observations
say, A. M.: Neurological and electroencephalographic problems of the rubella epidemic of 1962, Brit. Med. J. 2: 1300, 1963. 11. Kenny, F. M., Michaels, R. H., and Davis, N. S.: Rubella encephalopathy: Later psychometric, neurologic, and encephalographic
Dwarfism and mental retardation." The serum grmvth hormone reqoonse to hypoglycemia S. Douglas Frasier, M.D.,*
Jean M. Hilburn, BIS., and Fred G. Smith, Jr., M.D. POMONA AND LOS ANGELES
CALIF.
N A S S O C I A T I O N between mental retardation and impaired growth has been recognized by several investigators? T h e pathogenesis of this association has not been elucidated. There is an extensive amount of information indicating that experimental brain lesions are associated with retardation of growth? Hypothalamic lesions in rats are
A
From the Pacific State Hospital, Pomona, The Los Angeles County-University of Southern California Medical Center, Department of Pediatrics, University of Southern California School of Medicine, and Department of Pediatrics, University of California School of Medicine. Supported by State of Cali[ornla Department of Mental Hygiene Grant No. 14-38. Presented in part at the Thirty-Eighth Meeting of the Society [or Pediatric Research, Atlantic City, N. J., May 4, 1968. The opinions or conclusions stated in this paper are those of the authors and are not to be construed as official or as necessarily reflecting the policy of the California Depart?nent of Mental Hygiene. *Present address: Children's Division 4E8, Los Angeles County-University of Soufhern California Medical Center, 1200 N. State St., Los Angeles, Calif. 90033.
The Journal of Pediatrics July 1970
evaluation of seven survivors, Amer. J. Dis. Child. 110: 374, 1965. 12. Meyer, H. M., Johnson, R. T., Jr., Crawford, I. P., Dascomb, H. E., and Rogers, N. G.: Central nervous system syndromes of "viral" etiology: A study of 713 cases, Amer. J. Med. 29: 334, 1960.
associated with both decreased pituitary content of growth hormone and reduced plasma levels of growth hormone. The acute increase in the serum concentration of growth hormone stimulated by hypoglycemia depends on an intact hypothalamic-pituitary system. Hypoglycemia induces pituitary release of growth hormone by stimulating the secretion of a hypothalamic growth hormone releasing factor. In order to study the possibility that growth retardation associated with mental deficiency might be due to abnormalities in secretion of growth hormone, we have investigated the response of serum growth hormone to hypoglycemia in mentally retarded patients at the Pacific State Hospital, Pomona, California. M A T E R I A L AND M E T H O D S Fifty-eight institutionalized subjects with mental retardation and short stature were studied. T h e diagnoses were representative o.f the Pacific State Hospital population, 1 with the exclusion of patients with Down's syndrome. There were 30 males and 28 females whose ages ranged from 3 years 1 month to 16 years 9 months (mean 11 years 10 months + 3 years 9 months S.D.). Sexual development was determined according to the standards of T a n n e r } There were 36 prepubertal (Stage I) and 33 pubertal ( > Stage I I ) subjects. Height was measured as previously described? The deviations from mean height for age and from height age were determined from standards developed by the Iowa Child Welfare Research Station? The height of test subjects was > 2 S.D. below the mean for age (range 2 to 8 S.D. below mean) and the height a g e / chronologic age ratio ( H A / C A ) was <
Volume 77 Number 1
0.75 (range 0.14 to 0.72; mean 0.55 + 0.12 S.D.). Serial measurements from 1 year 1 month to 5 years 5 months were available in 55 subjects. The growth rate varied from 1.1 to 7.4 cm. per year (mean 3.9 + 1.7 S.D.). Twenty-three institutionalized subjects with mental retardation and normal height were also studied. The diagnoses were comparable to those os test subjects. There were 12 male and 11 female subjects whose ages ranged from 5 years 9 months to 17 years (mean 10 years 11 months + 3 years 1 month S.D.). There were 14 prepubertal (Stage I) and 9 pubertal ( > Stage I I ) control subjects. T h e height was +_ 2 S.D. from the mean height for age and H A / C A was > 0.75 (range 0.76 to 1.18; mean 1.00 + .09 S.D.). Serial measurements from 1 year 2 months to 6 years 3 months were available in 21 subjects. T h e growth rate varied from 3.0 to 7.6 cm. per year (mean 5.6 +_ 1.1 S.D.). Studies were performed in the fasting ambulatory state. Hypoglycemia was induced b 7 the intravenous administration of 0.05 units per kilogram of crystalline insulin. Blood was obtained by multiple venipuncture at zero time and 15, 30, 60, 90, and 120 minutes after the administration of insulin. An aliquot of each sample was assayed Sot glucose concentration by the glucose oxidase method (Glucostat), and the remainder was allowed to clot at room temperature for 1 to 2 hours. The serum was separated and frozen at -20 ~ C. until assayed for growth hormone concentration by radioimmunoassay. 4 RESULTS
There were no significant differences in sex, age, or the level of sexual development between test and control subjects. As expected, growth rate and H A / C A were significantly lower in test subjects (Table I ) P eFor Tables I, II, III, and IV, order Document No. NAPS-00991 from ASIS National Auxiliary Publications Service, c / o CCM Information Sciences, Inc., 909 3rd Ave., New York, N. Y. 10022. Remit $2.00 for each microfiche or $5.00 for each photocopy.
Brief clinical and laboratory observations
13 7
T h e degree of hypoglycemia attained was the same in both groups (Table II). T h e mean fasting serum growth hormone concentration was 5.7 + 1.2 (S.E.) ng. per milliliter in test subjects and 10.5 _+ 3.9 (S.E.) ng. per milliliter in control subjects. T h e mean peak serum growth hormone concentration and mean increase in the serum growth hormone concentration were 38.9 + 6.3 and 35.6 + 6.3 (S.E.) ng. per milliliter respectively, in test subjects. I n control subjects these values were 52.0 _+ 9.7 and 46.0 _+ 9.4 (S.E.) ng. per milliliter, respectively. The differences between test and control subjects are not statistically significant (Table I I I ) . The peak or increase in the serum growth hormone concentration was < 5 ng. per milliliter in 7 test subjects; values of this magnitude were not observed in any of the control subjects. This incidence of impaired response 4 was not statistically significant (Table I V ) . DISCUSSION
Mosier and associates 5 studied the thyroid uptake of radioactive iodine, plasma 17hydroxycortisteroid levels~ and 17-hydroxycortisteroid response to an infusion of adrenocorticotropin in 97 institutionalized dwarf subjects. They concluded that pituitary, thyroid, and adrenal insufficiency were not etiologic factors in growth failure associated with mental deficiency. Lowrey and associates 6 compared the fasting serum concentration of growth hormone in children with mental retardation and short stature, children with mental retardation and normal height, and children with both normal mentality and height. No differences were noted between these 3 groups. Milunsky and associates 7 have recently reported a normal plasma growth hormone response to insulin-induced hypoglycemia in 7 patients with mental deficiency and dwarfism (norie had Down's syndrome). O u r results also indicate that abnormalities in secretion of growth hormone, as refleeted by the response of serum growth hormone to insulin-induced hypoglycemia,
138
Brie[ clinical and laboratory observations
do not play a role in the pathogenesis of dwarfism associated with mental retardation. T h e observed growth hormone response was greater t h a n previously reported from this laboratory 4 and by other investigators. s-9 This m a y be due to differences in the standard g r o w t h h o r m o n e preparations employed or to the inclusion of pubertal subjects in this study, whereas previous studies were in prepubertal subjects. T h e observation of an impaired growth h o r m o n e response in 7 test subjects requires further consideration. T h e degree of hypoglycemia was comparable in responsive and nonresponsive individuals, as were diagnoses, age, sex distribution, and the level of sexual development. T h e r e were no differences in g r o w t h rate and in H A / C A between nonresponsive and responsive test subjects. G r o w t h retardation could not be related to the impaired response. This conclusion is consistent with previous observations of an impaired g r o w t h h o r m o n e response to hypoglycemia in children with normal g r o w t h h o r m o n e function. 9 SUMMARY
T h e serum g r o w t h h o r m o n e response to insulin-induced hypoglycemia was studied in 58 institutionalized mentally deficient subjects with g r o w t h retardation and in 23 institutionalized mentally retarded subjects with normal height. T h e fasting, peak, and increased serum concentrations of growth h o r m o n e were the same in these 2 groups. These studies indicate that functional abnormalities in growth h o r m o n e secretion do
The Journal o[ Pediatrics July 1970
not play a role in the pathogenesis of dwarfism associated with mental retardation. The authors wish to express their appreciation to Mrs. Evelyn Kline for her help in performing the insulin tolerance tests and to Mrs. Wilda Lyons for secretarial assistance. REFERENCES
1. Mosier, I{. D., Jr., Grossman, H. J., and Dingman, H. F.: Physical growth in mental defectives, Pediatrics 36: 465, 1965. 2. Tanner, J. M.: Growth at adolescence, ed. 2, Oxford, 1962, Blackwell Scientific Publications. 3. Jackson, R. L., and Kelly, H. G.: Growth charts for use in pediatric practice, J. PEDIAT. 27: 215, 1945. 4. Frasier, S. D.: The serum growth-hormone response to hypoglycemia in dwarfism, J. PEBIAT. 71: 625, 1967. 5. Mosier, H. D., Jr., Grossman, H. J., and Dingman, H. F.: Laboratory values in severely stunted mental defectives, Amer. J. Ment. Defic. 71" 230, 1966. 6. Lowrey, G. tI., Bacon, G. E., Fisher, S., and Knoller, H.: Fasting growth hormone levels in mentally retarded children of short stature, Amer. J. Ment. Defic. 73: 474, 1968. 7. Milunsky, A., Lowy, C., Rubenstein, A. H., and Wright, A. D.: Carbohydrate tolerance, growth hormone and insulin levels in mongolism, Develop. Med. Child. Neurol. 10: 25, 1968. 8. Kaplan, S. L., Abrams, C. A. L., Bell, J. J., Conte, F. A., and Grumbach, M. M.: Growth and growth hormone. I. Changes in serum level of growth hormone following hypoglycemia in 134 children with growth retardation, Pediat. Res. 2: 43, 1968. 9. Youlton, R., Kaplan, S. L., and Grumbaeh, M. M.: Growth and growth hormone. IV. Limitations of the growth hormone response to insulin and arginine and of the immunoreactive insulin response to arginlne in the assessment of growth hormone deficiency in children, Pediatrics 43: 989, 1969.