- Email: [email protected]
Long-term growth of children with growth hormone deficiency and hypoglycemia
598
Clinical and laboratory observations
6. Brusilow S, Valle D. Allopurinol induced orotidinuria: a test of heterozygosity for ornithine transcarbamylase deficiency [Abstract]. Pediatr Res 1987;21:289A. 7. Spence JE, Maddalena A, O'Brien WE, et al. Prenatal diagnosis and heterozygote detection by DNA analysis in ornithine transcarbamylase deficiency. J PEDIATR 1989;114:582-8. 8. Bachmann C, Colombo JP. Diagnostic value of orotic acid excretion in heritable disorders of the urea cycle in hyperammonemia due to organic aciduria. Eur J Pediatr 1980;I 34:10913. 9. Hokanson JT, O'Brien WE, ldemoto J, Schafer IA. Carrier detection in OTC deficiency. J PEDIATR 1978;93:75-8. 10, Becroft DMO, Barry DMJ, Webster DR, Simmonds HA. Failure of protein loading tests to identify heterozygosity for
The Journal of Pediatrics October 1989
11.
12.
13.
14.
ornithine carbamoyltransferase deficiency. J Inherited Metab Dis 1984;7:157-9. Simell O, Perheentupa J, Rapola J, Visakorpi JK, Eskelin L-E. Lysinuric protein intolerance. Am J Med 1975;59:22940. Batshaw M, Brusilow S, Walser M. Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids. N Engl J Med 1975;292:1085-90. Kesner L, Aronson FL, Silverman M, Chan PC. Determination of orotic and dihydroorotic acid in bioIogical fluids and tissues. Clin Chem 1975;21:353-5. Evans JE, Tieckelman H, Naylor EW. Measurement of urinary pyrimidine bases and nucleosides by high-performance liquid chromatography. J Chromatogr 1979;163:29-36.
Long-term growth of children with growth hormone deficiency and hypoglycemia H e a t h e r J. D e a n , MD (Clinical Director), H. G. Friesen, MD (Chairman), a n d t h e m e m b e r s of t h e T h e r a p e u t i c Trial of G r o w t h H o r m o n e C o m m i t t e e From the Medical Research Council of Canada
Children with hypoglycemia caused by growth hormone deficiency commonly are brought to medical attention in the newborn period or early infancy because they have hypoglycemic seizures after a short fast. These children, presumably treated from infancy before growth failure occurs, provide an excellent model to test the long-term efficacy of early initiation of conventional G H dosage schedules. This is important because the final adult heights of children treated beginning at 11 or 12 years of age have averaged more than 2 SD or 12 to 14 cm less than the population m e a n / 5 We and others have speculated that the failure to achieve full catch-up growth and normal adult height is caused by late initiation of therapy. 6 Children treated at an earlier age show a greater growth response to therapy. METHODS
All children enrolled in the Medical Research Council of Canada Therapeutic Trial between January 1968 and January 1986 with documented spontaneous hypoglycemia (blood glucose levet <2.2 m m o t / L [40 m g / d l ] ) and G H deficiency were included in this retrospective analysis. 7 The
Presented in abstract form at the International Growth Hormone Symposium, Tampa, Fla., June 14-I8, 1987. Submitted for publication Oct. 10~ 1988; accepted April 27, 1989. Reprint requests: Heather J. Dean, MD, Department of Pediatrics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. 9/22/13505
children received hydrocortisone, thyroxine, and 1-desamino-8-D-arginine vasopressin (DDAVP) as required by diagnostic testing] Diagnosis of G H deficiency was based on peak serum G H levels of less than 5 # g / L after spontaneous hypoglycemia and at least one pharmacologic stimulation test, usually arginine infusion. In a few cases the subjects were less than 1 month of age, when random basal G H levels are normally greater than 5 u g / L . 8 All subjects received human pituitary G H 0.1 I U / k g to a maximum of 2 IU intramuscularly three times weekly (approximately 3 m g / w k ) continuously for at least 1 year.
GH IGF-I SDS
Growth hormone Insulin-like growth factor 1 Standard deviation score
I
[
F
Sera were screened annually for G H antibodies. 7 None of the children had a G H antibody titer greater than 1:100 at any time. The standard deviation score for height was calculated on the basis of Tanner length and height standards for chronologic age. Student t test and two-way analysis of variance were used for data analysis. Subjecls. Fifty-four children (30 girls) from birth to 11 years of age were treated with G H for l to 14 years (mean _+ SD, 5.3 _+ 3.6). Forty-nine of the children are now receiving biosynthetic GH; of the remaining five subjects, one died and four chose to discontinue G H therapy because of poor growth response and resolution of sponta-
Volume 115 Number 4
Clinical and laboratory observations
Pretreatment
T a b l e . Prctreatment and follow-up SDS for height
599
Follow-up
0 A g e a t start of t r e a t m e n t
Prctreatment Follow-up Change inSDS Data
are expressed
All subjects (N = 54)
_<2 yr (n = 32)
- 4 . 1 + 0.3
- 4 . 5 • 0.3
-2.4 • 1.9 +1.5 + 0.3
-2.8 + 0.3 +1.7 _+ 0.3
as mean
II
> 2 yr (n = 22)
_+ 0.4 -2.4 + 0.4 +1.2 • 0.4
!
-3.6
_+ S E M .
.
_2 ~
-4 69 a 69
L
-6
§
t. r
,
I
|
m |e
"
,,
$
-8 neous hypoglycemia. Seventy-two percent (39/54) had idiopathic G H deficiency. In many of these cases the disorder was diagnosed before high-resolution computed tomography was widely available, so it is possible that structural abnormalities remain to be defined. Six children had septooptic dysplasia defined by computed tomographic scan. The nine remaining children had familial G H deficiency or a central nervous system tumor. Thirty-two (59%) of the children were 2 years of age or younger at the s t a r t of therapy. The mean age of this group at initiation of G H therapy was 1.5 _+ 0.2 years. The majority (89%) of these children had panhypopituitarism with multiple hormone replacement. Three of the children have persistent fasting hypoglycemia on G H therapy. RESULTS The mean SDS for height at the start of G H therapy for the whole group was -4.1 (Table). The mean SDS for height at the time of the analysis was - 2 . 4 . The SDS for height for children 2 years of age or younger at the start of therapy was not significantly different from that for children more than 2 years of age (Figure). The SDS for height significantly improved with G H treatment in children 2 years of age or younger (p <0.001). There was no statistical difference in the SDS for height between the children treated at a younger age and those treated at an older age ( - 2 . 8 vs - 2 . 4 respectively; Table). The mean duration of therapy was similar in the two groups. The younger children showed a greater improvement in SDS for height with longer duration of treatment (p <0.001). Only 24 of the 54 children have achieved a height within 2 SD of the mean for their chronologic age. There was no sex difference in pretreatment height or height aclaieved, even when the study groups were controlled for age at the start of treatment. Although the number of subjects was too small for statistical analysis, diagnosis and associated hormone treatment had no apparent effect on height achieved. DISCUSSION We hypothesized that the growth curves of children with conventional replacement doses of human G H from infancy would be identical to those of normal, healthy children. We presumed that in the majority of children with treated
-10 -12
<2 >2 Age at Treatment (yr)
--<2 >2 Age at Treatment (yr)
Figure. SDS for height (mean _+ SEM) by age at start of GH therapy. Each point represents a child before GH treatment (left) or in follow-up (right) at time of analysis.
hypoglycemia resulting from idiopathic G H deficiency the disorder would be diagnosed before 2 years of age, before growth failure had occurred, and t h e r e f o r e t h e s e children would provide a natural model to test the efficacy of the conventional G H dosage schedule. The children with idiopathic G H deficiency in the study ranged in age from birth to 11 years; only 59% of the whole group was less than 2 years of age at diagnosis. Overall, less than 50% of the children treated before 2 years of age reached a height greater than the 3rd percentile. This poor outcome cannot be attributed to growth-inhibiting G H antibodies, to genetic factors, at least as represented by parental stature, or to growth-limiting replacement doses of hydrocortisone. It is possible that the conventional three times weekly dosage schedule used for the past 20 years was suboptimal. For two reasons this unphysiologic dosage schedule was not widely challenged until recently. First, although serum G H concentrations reach a peak of 80 to 100 ~zg/L in 3 to 6 hours and return to baseline with 24 hours after an intramuscular injection of GH, 9 circulating insulin-like growth factor 1 levels are elevated at least three times as long} ~ Thus the biologic effect was assumed to be adequate. However, this analysis had an inherent bias because it was based on circulating I G F - I levels. We now realize that IGF-I is produced in many tissues and that a lag phase occurs between tissue production of IGF-I and its appearance in serum. Second, most children treated with G H had a doubling of growth velocity, which investigators accepted as a good clinical response. 7, 10 Our experience suggests that, although this conventional schedule was usually effective, it was not optimal. The optimal total weekly dose of G H remains unknown. The doses of biosynthetic G H used now are
600
Clinical and laboratory observations
at least twice as large as the doses of pituitary G H used in the past. In addition, the route a n d frequency of G H administration may be i m p o r t a n t variables in the growth response to G H and are under review. Now t h a t unlimited quantities of biosynthetic G H are available, long-term studies can be conducted to d e t e r m i n e the drug schedule that will allow GH-dificient children to reach their full adult height potential. These data will be available in another 20 years. Members of the Medical Research Council of Canada Therapeutic Trial of Growth Hormone Committee are as follows: in British Columbia, Dr. W. J. Tze, Dr. R. Couch, Dr. B. C. Boulton, and Dr. H. P. Marshall; in Alberta, Dr. R. G. McArthur, Dr. D. Stephure, Dr. P. M. Crockford, and Dr. E. E. McCoy; in Saskatchewan, Dr. J. W. Gerrard, Dr. G. Bruce, and Dr. M. Bala; in Manitoba, Dr. H. G. Friesen, Chairman, and Dr. H. J. Dean, Clinical Director (principal author); in Ontario, Dr. J. D. Bailey, Dr. J. Holland, Dr. D. S. Alexander, Dr. H. M. C. Heick, Dr. M. R. F. Jenner, and Dr. A. B. Macmillan; in Quebec, Dr. R. Collu, Dr. H. J. Guyda, Dr. K. Khoury, Dr. G. Leboeuf, and Dr. F. Szots; in the Maritime Region, Dr. S. Salisbury; and in Newfoundland, Dr. A. J. Davis. REFERENCES
1. Dean H J, MacTaggart TL, Fish DG, Friesen HG. Evaluation of the educational, vocational and marital status of growth hormone deficient (GHD) adults treated with growth hormone during childhood. Am J Dis Child 1985;139:1105-10. 2. Burns EC, Tanner JM, Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic
The Journal of Pediatrics October 1989
3.
4.
5.
6.
7.
8.
growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981 ; 137:155-64. Bourguignon JP, Vandweghe M, VanderschuerenLodeweyckx M, et ah Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset of puberty. J Clin Endocrinol Metab 1986;63:376-82. Joss E, Zuppinger K, Schwartz HP, Roten H. Final height of patients with pituitary growth failure and changes in growth variables after long term hormonal therapy. Pediatr Rcs 1983;17:676-9. Vanderschueren-Lodeweyckx M, Van Den Broeck J, Wolter R, Malvaux P. Early initiation of growth hormone treatment: influence on final height. Acta Paediatr Scand (Suppl) 1987;337:4-11. Josefsberg Z, Bauman B, Pertzelan A, Laron Z. Greater efficiency of human growth hormone therapy in children below five years of age with growth hormone deficiency. Hormone Res 1987;27:126-33. Guyda H J, Friesen HG, Bailey JD, Leboeuf G, Beck JC. Medical Research Council of Canada therapeutic trial of human growth hormone: first 5 years of therapy. Can Med Assoc J 1975;112:1301-9. Kaplan SL, Grumbach MM, Aubert ML. The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent Prog Horm Res 1976;32:161243.
9. Frasier SD, Costin G, Ley SM, Kaplan SA. Plasma growth hormone concentrations after a single intramuscular injection of human growth hormone. Pediatr Res 1969;3:557-61. 10. Dean HJ, Kellett JG, Bala RM, et al. The effect of growth hormone treatment on somatomedin levels in growth hormone deficient children. J Clin Endocrinol Metab 1982;55:1167-73.
Changes in brain maturation detected by magnetic resonance imaging in congenital hypothyroidism Cresio Alves, MD, Margaret Eidson, MD, Howard Engle, MD, Jerome Sheldon, MD, and William W. Cleveland, MD From the Department of Pediatrics, Division of Pediatric Endocrinology, and the Department of Radiology, University of Miami School of Medicine, Miami, Florida
The impact of u n t r e a t e d congenital hypothyroidism on function of the nervous system is well known,1 but structural correlates by modern imaging techniques are not documented. This report describes the correlation of the changes detected on magnetic resonance imaging with the clinical
Submitted for publication March 27, 1989; accepted May 24, 1989. Reprint requests: William W. Cleveland, MD, ProfesSor of Pediatrics, University of Miami School of Medicine, PO Box 016820, Miami, FL 33101. 9/22/14223
MRI T1 T2 T3 T4 TSH
Magnetic resonance imaging Spin-lattice relaxation time Spin-spin relaxation time Triiodothyronine Thyroxine Thyroid-stimulating hormone
findings in an infant with hypothyroidism, including the response to treatment. CASE REPORT A 14-month-old girl was referred for evaluation of delayed growth and development. She had been born by normal spontane-
Clinical and laboratory observations
6. Brusilow S, Valle D. Allopurinol induced orotidinuria: a test of heterozygosity for ornithine transcarbamylase deficiency [Abstract]. Pediatr Res 1987;21:289A. 7. Spence JE, Maddalena A, O'Brien WE, et al. Prenatal diagnosis and heterozygote detection by DNA analysis in ornithine transcarbamylase deficiency. J PEDIATR 1989;114:582-8. 8. Bachmann C, Colombo JP. Diagnostic value of orotic acid excretion in heritable disorders of the urea cycle in hyperammonemia due to organic aciduria. Eur J Pediatr 1980;I 34:10913. 9. Hokanson JT, O'Brien WE, ldemoto J, Schafer IA. Carrier detection in OTC deficiency. J PEDIATR 1978;93:75-8. 10, Becroft DMO, Barry DMJ, Webster DR, Simmonds HA. Failure of protein loading tests to identify heterozygosity for
The Journal of Pediatrics October 1989
11.
12.
13.
14.
ornithine carbamoyltransferase deficiency. J Inherited Metab Dis 1984;7:157-9. Simell O, Perheentupa J, Rapola J, Visakorpi JK, Eskelin L-E. Lysinuric protein intolerance. Am J Med 1975;59:22940. Batshaw M, Brusilow S, Walser M. Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids. N Engl J Med 1975;292:1085-90. Kesner L, Aronson FL, Silverman M, Chan PC. Determination of orotic and dihydroorotic acid in bioIogical fluids and tissues. Clin Chem 1975;21:353-5. Evans JE, Tieckelman H, Naylor EW. Measurement of urinary pyrimidine bases and nucleosides by high-performance liquid chromatography. J Chromatogr 1979;163:29-36.
Long-term growth of children with growth hormone deficiency and hypoglycemia H e a t h e r J. D e a n , MD (Clinical Director), H. G. Friesen, MD (Chairman), a n d t h e m e m b e r s of t h e T h e r a p e u t i c Trial of G r o w t h H o r m o n e C o m m i t t e e From the Medical Research Council of Canada
Children with hypoglycemia caused by growth hormone deficiency commonly are brought to medical attention in the newborn period or early infancy because they have hypoglycemic seizures after a short fast. These children, presumably treated from infancy before growth failure occurs, provide an excellent model to test the long-term efficacy of early initiation of conventional G H dosage schedules. This is important because the final adult heights of children treated beginning at 11 or 12 years of age have averaged more than 2 SD or 12 to 14 cm less than the population m e a n / 5 We and others have speculated that the failure to achieve full catch-up growth and normal adult height is caused by late initiation of therapy. 6 Children treated at an earlier age show a greater growth response to therapy. METHODS
All children enrolled in the Medical Research Council of Canada Therapeutic Trial between January 1968 and January 1986 with documented spontaneous hypoglycemia (blood glucose levet <2.2 m m o t / L [40 m g / d l ] ) and G H deficiency were included in this retrospective analysis. 7 The
Presented in abstract form at the International Growth Hormone Symposium, Tampa, Fla., June 14-I8, 1987. Submitted for publication Oct. 10~ 1988; accepted April 27, 1989. Reprint requests: Heather J. Dean, MD, Department of Pediatrics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada. 9/22/13505
children received hydrocortisone, thyroxine, and 1-desamino-8-D-arginine vasopressin (DDAVP) as required by diagnostic testing] Diagnosis of G H deficiency was based on peak serum G H levels of less than 5 # g / L after spontaneous hypoglycemia and at least one pharmacologic stimulation test, usually arginine infusion. In a few cases the subjects were less than 1 month of age, when random basal G H levels are normally greater than 5 u g / L . 8 All subjects received human pituitary G H 0.1 I U / k g to a maximum of 2 IU intramuscularly three times weekly (approximately 3 m g / w k ) continuously for at least 1 year.
GH IGF-I SDS
Growth hormone Insulin-like growth factor 1 Standard deviation score
I
[
F
Sera were screened annually for G H antibodies. 7 None of the children had a G H antibody titer greater than 1:100 at any time. The standard deviation score for height was calculated on the basis of Tanner length and height standards for chronologic age. Student t test and two-way analysis of variance were used for data analysis. Subjecls. Fifty-four children (30 girls) from birth to 11 years of age were treated with G H for l to 14 years (mean _+ SD, 5.3 _+ 3.6). Forty-nine of the children are now receiving biosynthetic GH; of the remaining five subjects, one died and four chose to discontinue G H therapy because of poor growth response and resolution of sponta-
Volume 115 Number 4
Clinical and laboratory observations
Pretreatment
T a b l e . Prctreatment and follow-up SDS for height
599
Follow-up
0 A g e a t start of t r e a t m e n t
Prctreatment Follow-up Change inSDS Data
are expressed
All subjects (N = 54)
_<2 yr (n = 32)
- 4 . 1 + 0.3
- 4 . 5 • 0.3
-2.4 • 1.9 +1.5 + 0.3
-2.8 + 0.3 +1.7 _+ 0.3
as mean
II
> 2 yr (n = 22)
_+ 0.4 -2.4 + 0.4 +1.2 • 0.4
!
-3.6
_+ S E M .
.
_2 ~
-4 69 a 69
L
-6
§
t. r
,
I
|
m |e
"
,,
$
-8 neous hypoglycemia. Seventy-two percent (39/54) had idiopathic G H deficiency. In many of these cases the disorder was diagnosed before high-resolution computed tomography was widely available, so it is possible that structural abnormalities remain to be defined. Six children had septooptic dysplasia defined by computed tomographic scan. The nine remaining children had familial G H deficiency or a central nervous system tumor. Thirty-two (59%) of the children were 2 years of age or younger at the s t a r t of therapy. The mean age of this group at initiation of G H therapy was 1.5 _+ 0.2 years. The majority (89%) of these children had panhypopituitarism with multiple hormone replacement. Three of the children have persistent fasting hypoglycemia on G H therapy. RESULTS The mean SDS for height at the start of G H therapy for the whole group was -4.1 (Table). The mean SDS for height at the time of the analysis was - 2 . 4 . The SDS for height for children 2 years of age or younger at the start of therapy was not significantly different from that for children more than 2 years of age (Figure). The SDS for height significantly improved with G H treatment in children 2 years of age or younger (p <0.001). There was no statistical difference in the SDS for height between the children treated at a younger age and those treated at an older age ( - 2 . 8 vs - 2 . 4 respectively; Table). The mean duration of therapy was similar in the two groups. The younger children showed a greater improvement in SDS for height with longer duration of treatment (p <0.001). Only 24 of the 54 children have achieved a height within 2 SD of the mean for their chronologic age. There was no sex difference in pretreatment height or height aclaieved, even when the study groups were controlled for age at the start of treatment. Although the number of subjects was too small for statistical analysis, diagnosis and associated hormone treatment had no apparent effect on height achieved. DISCUSSION We hypothesized that the growth curves of children with conventional replacement doses of human G H from infancy would be identical to those of normal, healthy children. We presumed that in the majority of children with treated
-10 -12
<2 >2 Age at Treatment (yr)
--<2 >2 Age at Treatment (yr)
Figure. SDS for height (mean _+ SEM) by age at start of GH therapy. Each point represents a child before GH treatment (left) or in follow-up (right) at time of analysis.
hypoglycemia resulting from idiopathic G H deficiency the disorder would be diagnosed before 2 years of age, before growth failure had occurred, and t h e r e f o r e t h e s e children would provide a natural model to test the efficacy of the conventional G H dosage schedule. The children with idiopathic G H deficiency in the study ranged in age from birth to 11 years; only 59% of the whole group was less than 2 years of age at diagnosis. Overall, less than 50% of the children treated before 2 years of age reached a height greater than the 3rd percentile. This poor outcome cannot be attributed to growth-inhibiting G H antibodies, to genetic factors, at least as represented by parental stature, or to growth-limiting replacement doses of hydrocortisone. It is possible that the conventional three times weekly dosage schedule used for the past 20 years was suboptimal. For two reasons this unphysiologic dosage schedule was not widely challenged until recently. First, although serum G H concentrations reach a peak of 80 to 100 ~zg/L in 3 to 6 hours and return to baseline with 24 hours after an intramuscular injection of GH, 9 circulating insulin-like growth factor 1 levels are elevated at least three times as long} ~ Thus the biologic effect was assumed to be adequate. However, this analysis had an inherent bias because it was based on circulating I G F - I levels. We now realize that IGF-I is produced in many tissues and that a lag phase occurs between tissue production of IGF-I and its appearance in serum. Second, most children treated with G H had a doubling of growth velocity, which investigators accepted as a good clinical response. 7, 10 Our experience suggests that, although this conventional schedule was usually effective, it was not optimal. The optimal total weekly dose of G H remains unknown. The doses of biosynthetic G H used now are
600
Clinical and laboratory observations
at least twice as large as the doses of pituitary G H used in the past. In addition, the route a n d frequency of G H administration may be i m p o r t a n t variables in the growth response to G H and are under review. Now t h a t unlimited quantities of biosynthetic G H are available, long-term studies can be conducted to d e t e r m i n e the drug schedule that will allow GH-dificient children to reach their full adult height potential. These data will be available in another 20 years. Members of the Medical Research Council of Canada Therapeutic Trial of Growth Hormone Committee are as follows: in British Columbia, Dr. W. J. Tze, Dr. R. Couch, Dr. B. C. Boulton, and Dr. H. P. Marshall; in Alberta, Dr. R. G. McArthur, Dr. D. Stephure, Dr. P. M. Crockford, and Dr. E. E. McCoy; in Saskatchewan, Dr. J. W. Gerrard, Dr. G. Bruce, and Dr. M. Bala; in Manitoba, Dr. H. G. Friesen, Chairman, and Dr. H. J. Dean, Clinical Director (principal author); in Ontario, Dr. J. D. Bailey, Dr. J. Holland, Dr. D. S. Alexander, Dr. H. M. C. Heick, Dr. M. R. F. Jenner, and Dr. A. B. Macmillan; in Quebec, Dr. R. Collu, Dr. H. J. Guyda, Dr. K. Khoury, Dr. G. Leboeuf, and Dr. F. Szots; in the Maritime Region, Dr. S. Salisbury; and in Newfoundland, Dr. A. J. Davis. REFERENCES
1. Dean H J, MacTaggart TL, Fish DG, Friesen HG. Evaluation of the educational, vocational and marital status of growth hormone deficient (GHD) adults treated with growth hormone during childhood. Am J Dis Child 1985;139:1105-10. 2. Burns EC, Tanner JM, Preece MA, Cameron N. Final height and pubertal development in 55 children with idiopathic
The Journal of Pediatrics October 1989
3.
4.
5.
6.
7.
8.
growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr 1981 ; 137:155-64. Bourguignon JP, Vandweghe M, VanderschuerenLodeweyckx M, et ah Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset of puberty. J Clin Endocrinol Metab 1986;63:376-82. Joss E, Zuppinger K, Schwartz HP, Roten H. Final height of patients with pituitary growth failure and changes in growth variables after long term hormonal therapy. Pediatr Rcs 1983;17:676-9. Vanderschueren-Lodeweyckx M, Van Den Broeck J, Wolter R, Malvaux P. Early initiation of growth hormone treatment: influence on final height. Acta Paediatr Scand (Suppl) 1987;337:4-11. Josefsberg Z, Bauman B, Pertzelan A, Laron Z. Greater efficiency of human growth hormone therapy in children below five years of age with growth hormone deficiency. Hormone Res 1987;27:126-33. Guyda H J, Friesen HG, Bailey JD, Leboeuf G, Beck JC. Medical Research Council of Canada therapeutic trial of human growth hormone: first 5 years of therapy. Can Med Assoc J 1975;112:1301-9. Kaplan SL, Grumbach MM, Aubert ML. The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function. Recent Prog Horm Res 1976;32:161243.
9. Frasier SD, Costin G, Ley SM, Kaplan SA. Plasma growth hormone concentrations after a single intramuscular injection of human growth hormone. Pediatr Res 1969;3:557-61. 10. Dean HJ, Kellett JG, Bala RM, et al. The effect of growth hormone treatment on somatomedin levels in growth hormone deficient children. J Clin Endocrinol Metab 1982;55:1167-73.
Changes in brain maturation detected by magnetic resonance imaging in congenital hypothyroidism Cresio Alves, MD, Margaret Eidson, MD, Howard Engle, MD, Jerome Sheldon, MD, and William W. Cleveland, MD From the Department of Pediatrics, Division of Pediatric Endocrinology, and the Department of Radiology, University of Miami School of Medicine, Miami, Florida
The impact of u n t r e a t e d congenital hypothyroidism on function of the nervous system is well known,1 but structural correlates by modern imaging techniques are not documented. This report describes the correlation of the changes detected on magnetic resonance imaging with the clinical
Submitted for publication March 27, 1989; accepted May 24, 1989. Reprint requests: William W. Cleveland, MD, ProfesSor of Pediatrics, University of Miami School of Medicine, PO Box 016820, Miami, FL 33101. 9/22/14223
MRI T1 T2 T3 T4 TSH
Magnetic resonance imaging Spin-lattice relaxation time Spin-spin relaxation time Triiodothyronine Thyroxine Thyroid-stimulating hormone
findings in an infant with hypothyroidism, including the response to treatment. CASE REPORT A 14-month-old girl was referred for evaluation of delayed growth and development. She had been born by normal spontane-