Research in DevelopmmtalDtkzbilities, Printed in the USA. All rights reserved.
Vol. 12. pp. 287-296,
1991
0891-4222/91 $3.00 + .OO copyright @ 1991 Pergmon Press plc
Thyroid Function in Down Syndrome Siegfried M. Pueschel, lvor M. D. Jackson, Peter Giesswein, M. Kelley Dean, and John C. Peuullo Child Development Center, Department of Pediatrics and the Division of Endocrinology Depaflment of Medicine, Rhode Island Hospital, Brown Unrversity Program in Medicine
The thyroid function of 181 patients with Down syndrome was investigated. When compared with a control group of 163 children we found T4 and FT4 levels to be significantly lower and T3 and TSH levels to be significantly higher in the Down syndrome population. Of the 181 patients with Down syndrome. 29 (16%) showed evidence of either uncompensated or compensated hypothyroidism: II (6%) had both low T4 and high TSH levels, 14 (8%) had only high TSH values, and 4 (2%) had only low T4 values. One of the patients with Down syndrome had a significantly elevated T4 level. Studying dflerent age groups. we observed a decline of the mean T4, FT4, T3, FT3, and TBG values with advancing age. T4. T3. and TSH blood levels obtained in 1988 were slightly but not significantly lower when compared with values from 1985. Because thyroid dysfunctions in patients with Down syndrome are more common than in the general population, periodic thyroid hormone function tests should be performed in persons with Down syndrome in particular as they advance in age. Thus, individuals with significantly abnormal results can be identified early before clinical symptoms become manifest. If patients with Down syndrome are found to have a thyroid hormone disorder, appropriate treatment should be forthcoming, which in turn will enhance their quality of life.
Many reports on thyroid dysfunction in persons with Down syndrome have been published in the medical literature (Pueschel & Rynders, 1982). The most common abnormality has been decreased thyroid hormone production by the thyroid gland, resulting in hypothyroidism (Aarskog, 1980; Criscuolo, Pert-one, Sinisi, Bellastella, & Faggiano, 1986; Cutler, BenezraObeiter, & Brink, 1986). Hyperthyroidism (Azizi, Chandler, Bozorgzadeh, & Braverman, 1974; Essen & Mautner, 1957; Hughes, Cameron, & Goonetilleke, 1982; Johnson & Cook, 1962) and thyroiditis in persons with Down syndrome (Hollingsworth, McKean, & Roeckel, 1974; Lobo, Khan, 287
288
S. M. Pueschel et al.
& Tews, 1980; Mallya, Isaacs, & Bayliss, 1979; McCulloch, Ince, & Kendall-Taylor, 1982) have also been reported. An increased prevalence of thyroid autoantibodies in children with Down syndrome and their mothers, as well as autoimmune processes leading to thyroid disorders have, been discussed by several authors (Hollingsworth et al., 1974; Hopwood, Robin, Foley, & Peake, 1978; Korsager, 1981). Moreover, associations of hypothyroidism and diabetes mellitus (Daniels & Simon, 1968; Ong & Schneider, 1976; Parkin, 1974), hypothyroidism and precocious sexual development (Floret, Thomas, & Claustrat, 1978; Pabst, Pueschel, & Hillman, 1967), hypothyroidism and goiter (Hollingsworth et al., 1974; Ruvalcaba, Ferrier, & Thuline, 1969), and autoimmune hypothyroidism and hypoparathyroidism (Blumberg & AvRuskin, 1987) have been reported in individuals with Down syndrome. Hypothyroidism in newborn children with Down syndrome identified through neonatal screening programs have also been described (Cutler et al., 1986; Fort et al., 1984). Thus, there are numerous reports on various forms of thyroid abnormalities in persons with Down syndrome occurring at different ages, occasionally in association with other disorders. This study was designed to investigate the prevalence of thyroid disorders, correlations between selected thyroid parameters, and longitudinal follow-up of a cohort of individuals with Down syndrome relative to their thyroid function. The clinical significance of this study lies in the profound effects that thyroid hormones exert on growth, development, and intellectual functions in human beings. Specifically, thyroid hormones stimulate many intracellular metabolic processes such as the energy-producing electron transfer in the respiratory enzyme systems of the mitochondria, the transcription of messenger RNA via cyclic AMP, and others. These processes are important for any person’s biological integrity including individuals with Down syndrome, In optimizing such intracellular processes in those individuals who have thyroid dysfunctions by substituting exogenous thyroid hormone, their quality of life can be markedly improved. SUBJECTS AND METHODS A cohort of 181 unselected patients with Down syndrome who are followed at the Child Development Center of Rhode Island Hospital, a University Affiliated Program, participated in this prospective study. Of the 181 individuals with Down syndrome, 172 had the cytogenetic diagnosis of trisomy 21, seven had translocation Down syndrome, and two had mosaicism. Enrolled in this study were 77 females with a mean age of 14.8 years (SD = 9.3) and 104 males with a mean age of 13.9 years (SD = 9.2).
Thyroid Function in Down Syndrome
289
During the cross-sectional study detailed investigations were carried out on 181 patients with Down syndrome. An interim history was obtained with focus on symptoms of hypo- and hyperthyroidism. (Usual clinical signs of hypothyroidism include lethargy, dry skin, constipation, muscle weakness, cold intolerance, longitudinal growth retardation, and decreased intellectual performance, whereas patients with hyperthyroidism present with emotional lability, nervousness, irritability, increased perspiration, heat intolerance, tremors, frequent bowel movements, prominent eyes, and often diffuse swelling in the anterior neck due to development of a goiter.) All patients with Down syndrome were examined by the principal investigator. As part of this examination, the anterior neck region was palpated for thyroid gland enlargement and particular attention was paid to other clinical characteristics usually associated with thyroid hormone disorders. Psychological evaluations were done on a subgroup of 56 patients using the Stanford-Binet Intelligence Scale or the Wechsler Intelligence Scale for Children-Revised, if permission was given by parents. Venous blood samples were obtained from all participants for duplicate examinations of thyroxine (T4), free thyroxine (FT4), triiodothyronine (T3), free triiodothyronine (FT3), triiodothyronine uptake (T3U), thyroid stimulating hormone (TSH), and thyroxine-binding globulin (TBG). Normal age-related ranges of various thyroid hormone parameters were obtained from Hung, August, and Glasgow (1982). In addition, antithyroglobulin antibody (ATA) titers and antimicrosomal antibody (AMA) titers were determined. During the longitudinal study 52 patients with Down syndrome had T4, T3, and TSH determinations both in 1985 and 1988. Venous blood samples were obtained from 163 age- and sex-matched patients without endocrine disorders seen at various outpatient cIinics of Rhode Island Hospital. Of the 163 patients, there were 69 females with a mean age of 14.2 years (SD = 8.6) and 94 males with a mean age of 13.5 years (SD = 9.4). T4, T3, and T3U were determined using radioimmunoassays obtained from Nuclear Medical Laboratories Organon, Teknika Corporation, Irving, TX. Free T4 was assayed using the gammacoat direct radioimmunoassay from Clinical Assays, Travenol-Genetech Diagnostics, Cambridge, MA. Free T3 was determined using the coat-a-count radioimmunoassay obtained from Diagnostic Products Corporation, Los Angeles, CA. TSH was estimated employing the TANDEM-R TSH immunoradiometric assay obtained from Hybritech, San Diego, CA. The determination of thyroid autoantibodies was carried out using Thymune-T and Thymune-M Hemagglutination kits obtained from the Wellcome Reagent Division of the Burroughs Wellcome Company, Greenville, NC. TBG was estimated by radioimmunoassay using a kit developed by the Nichols Institute, Los Angeles, CA.
S. M. Pueschel et al.
290
TABLE 1. Means (x) and Standard Deviations (SD) of Various Thyroid Hormone Parameters of Patients in the Down Syndrome (DS) and Control (C) Groups
GroupN
T4
Fr4
T3
Pg/~
wfd
ne/fl
X
SD
X
SD
X
T3U
Fr3 Pg/dl SD
X
SD
TSH
%
@U/ml ___
___ X
SD
X
SD
TBG
Pi# X
SD
DS
181 8.Ok2.2
1.520.4
145.5k32.7
2.9k0.8
31.3k2.4
6.9514
27.2T11.5
C
163 8.7f2.3
1.6f0.4
128.2f37.5
1.6kl.l
31.2zk4.4
2.8k7.8
29.4 f9.6
RESULTS
During the cross-sectional study 181 individuals with Down syndrome were compared with 163 control patients with regard to their T4, FI4, T3, FK3, T3U, TSH, and TBG blood levels. As noted in Table 1, there was a significant difference between the two groups for T4 (F = 8.914, df= 1, p = .003), T3 (F = 20.96, df= 1, p = .OOOl), and TSH (F = 10.362, df= 1, p = .0014). T4 levels were lower, whereas T3 and TSH levels were higher in the Down syndrome population when compared with equivalent data obtained from the control group. When the females of the Down syndrome cohort were compared with their male counterparts relative to the above mentioned parameters, no statistically significant differences were observed. Of the 181 patients with Down syndrome enrolled in the cross-sectional study, 29 subjects (16%) had evidence of decreased thyroid hormone function. The serum TSH was elevated (2 SD above mean) in 25 of these subjects (mean age 13.5 years, range 1 to 29 years) and was associated with a reduced T4 (2 SD below mean) in 11 (mean age 20.9 years, range 6 to 29 years). It is of note that there were four patients with a low T4 (3.9 to 5.3 pg/dl) in whom the TSH (2.3 to 6.1 @U/ml) and T3 (111 to 124 ng/dl) were normal. Only one of the 181 patients with Down syndrome had a significantly elevated T4 level (2 SD above mean). None of the patients in the Down syndrome group had thyroid gland enlargement. Of the 29 patients with laboratory evidence of hypothyroidism, 12 had dry and rough skin, 5 had a history of constipation, and 3 were said to be slow and lethargic. These “symptoms” are not more frequent in these patients than in the general cohort of persons with Down syndrome. In further analysis of the data, the individuals with Down syndrome were divided into five-year age groups, as shown in Table 2. Except for the TSH variable, there were statistically significant differences between most of the age groups in the different thyroid test categories. T4 (F = 19.297, df = 5, p = .OOOl), FT4 (F = 3.145, df= 5, p = .0097), T3 (F = 12.571, df= 5,
o-5 6-10 11-15 16-20 21-25 26-30
1 2 3 4 5 6
33 29 25 39 29 26
N
SD
1.6 2.0 1.9 2.0 1.5 1.5
X
10.2 + 9.0 + 8.6f 7.5 * 7.1* 6.7 +
SD
1.7 kO.4 1.5 * 0.3 1.3kO.3 1.5kO.5 1.5 i: 0.4 1.4 kO.3
X
ng/dl
clg/dl
173.7 It 21.2 159.9 f 39.1 141.0f 29.1 137.9 zk22.4 127.4 f 16.2 129.8 f 38.3
X
X
1 vs 3,4,5,6 2 vs 3,4,5,6
3.6 + 2.4 3.3 +-0.7 2.7 + 0.7 2.7 +_0.6 2.4 + 0.5 2.3 + 0.8
SD
Pg/dl
ngJdl SD
Fr3
T3
Nope.Post hoc tests thatare significant between specified groups (p < .05). Ivs 3,6 1 vs 3,4,5,6 1~~23456 , 13, 2 vs 3 2 vs 3,4,5,6 2 vs 3,4,5,6 3 vs 6
Age
Group
F‘T4
T4
(C) Groups According to Age
1 vs4 2 vs 4.5
30.6 +-2.4 30.3 +-2.5 31.4k2.8 32.0 +-2.2 31.6C 1.6 31.7 k2.8
SD
SD 3.7It 2.3 8.4 It 14.1 11.6+ 23.9 7.1* 16.2 6.2 + 12.3 5.3f 9.4
X
1 vs 4,5 2 vs 3,4,5
30.8 t 8.9 31.6 +- 12.8 25.0f 11.8 24.9 f. 12.0 24.9 -+ 9.3 25.8 _+12.3
SD
clgldl
W/ml
% X
TBG
TSH
T3U
X
TABLE 2. Means (X) and Standard Deviations (SD) of Various Thyroid Hormone Parameters of Patients in the Down Syndrome (DS) and Control
292
S. M. Pueschel et al.
p = .OOOl), FT3 (F = 17.748, d’= 5, p = .OOOl), T3U (F = 2.525, df = 5, p = .031), and TBG (F = 2.39, df = 5, p = .0398). At the bottom of Table 2 the statistical significance between the various age groups is indicated as determined by follow-up tests (Fisher & Scheffe F). A gradual decline of the mean T4, FT4, T3, FT3, and TBG values with advancing age was observed which did not change appreciably when patients with hypothyroidism were excluded. Figure 1 demonstrates graphically the decrease of T4 and T3 values over time. Table 3 depicts the correlation coefficients of various thyroid hormone variables and their statistical significance. ATA showed a significant negative correlation with T4 and FT4, and a positive correlation with TSH, whereas AMA was significantly negatively correlated with T4, FT4, T3, and FI’3.
T4 u%'dl
T3 w/'dl
zoo I9 180
170
160
150
140
30
120 .! 3
o-5
6-10
11-15 AGE
16-20
2l-25
26-30
.\'e;lrs
GROUPS
FIGURE 1. Graphic illustrations of the decline of T4 and T3 levels with advancing age in persons with Down syndrome.
Thyroid Function in Down Syndrome
Correlation
293
TABLE 3. Coetficients (CC) of Various Thyroid Hormone Variables aad Their Statistical Significance (p)* Fr4
T4
FT3
T3
T3u
TSH
TBG
cc
-.I99
- .186
-.110
-.I04
- .029
.333
-.lOO
Ccp
- .286 .Ol
- .200 02
- .212 .17
-206 .21
- .080 .72
.115 .OOOl - .082 .22
.008
.Ol
ATA
ATA P
.0003
.Ol
.32
.15
.31
*These are pairwise p-values; the usual precautions should he taken when interpreting a collection of pairwise tests on one set of data.
In order to study thyroid functions in patients with Down syndrome over time, we compared T4, T3, and TSH results from 1985 with those from 1988 in 52 subjects. As shown in Table 4 during the time period from 1985 to 1988 we observed a slight reduction in mean T4, T3, and TSH levels which, however, was not statistically significant. When we studied the children’s intellectual functioning in relation to the various thyroid hormone parameters, we did not find any significant correlations. The mean IQ of 56 patients with Down syndrome was 49 (SD = 11, range: 25 to 70). DISCUSSION
Although many studies concerning thyroid hormone function in persons with Down syndrome have been carried out in the past, our investigations presented in this report are more comprehensive than any previous studies performed; we examined the largest cohort with Down syndrome using numerous thyroid hormone parameters in both a cross-sectional and a Iongitudinal approach.
TABLE 4. T4, T3, and TSH Levels Obtained From the Same Individuals with Down Syndrome in 1985 and 1988 T4
T3
Wdl
ng/dl
YCU
N
X
SD
1985 1988
52 52
7.8 k 2.0 7.6 k 1.7
X
TSH
SD
144.7 _+27.6 133.8 + 28.5
NJ/ml X
SD
5.3 Ik7.0 4.9 f 6.9
294
S. M. Pueschel et al.
One of the main objectives of this investigation was to study the prevalence of thyroid dysfunction in individuals with Down syndrome. Of the 18 1 patients in the cross-sectional study group, 29 (14%) individuals with Down’s syndrome showed evidence of hypothyroidism. Twenty-five (14%) patients had significantly increased TSH levels, half of them had also significantly decreased T4 levels. Four (2%) patients had significantly low T4 levels with normal TSH and T3 levels. We do not have a ready explanation for the latter observation. Only one person with Down syndrome had a significantly increased T4 level without overt clinical signs of hyperthyroidism. The study group differed significantly from the control group in their T4, T3, and TSH levels. Even after excluding frank hypothyroid individuals from the study group, there was still a significant difference in T4, T3, and TSH levels between the two groups. This can be explained by the decreased thyroid hormone function of the individuals in the study group, some of whom had an autoimmune thyroid disorder. We observed high negative correlations between AMA and T4, FT4, as well as between ATA and T4, FT4. In addition, negative correlations were observed between AMA and T3 as well as FI3. When the patients in the Down syndrome cohort were subdivided into five-year age groups, there were significant differences between most of the groups, as shown in Table 2. Although slightly decreasing T4 and T3 values with advancing age are also observed in a normal population, the decline of thyroid hormone variables was more pronounced in our study population than in children who do not have Down syndrome, even when patients with hypothyroidism were excluded. This suggests that persons with Down syndrome may be at a higher risk of developing hypothyroidism as they get older. Concerning our longitudinal studies, the comparison of the 1985 with the 1988 thyroid hormone parameters did not show any significant difference between the mean T4, T3, and TSH values. Although marked changes are not expected over a 3-year time period, the prompt identification and effective treatment of patients with either compensated or uncompensated hypothyroidism may also have contributed to the slight changes. Since many features of hypothyroidism are similar to those observed in Down syndrome, it may be difficult at times to diagnose hypothyroidism in patients with Down syndrome on clinical grounds. Since symptoms of hypothyroidism are nonspecific and it is unlikely that a physician would have been able to make the clinical diagnosis of hypothyroidism in the 29 individuals with thyroid dysfunction, we recommend that periodic thyroid hormone function tests be performed in persons with Down syndrome, preferably on an annual basis. Early detection of thyroid hormone dysfunction and prompt treatment with thyroid hormone, if hypothyroidism is pre-
Thyroid Function in Down Syndrome
295
sent, not only may prevent further cognitive decline (Pueschel & Pezzullo, 1985). but also will enhance the patients’ overall development, as well as benefit their educational progress and vocational achievements. REFERENCES Aarskog, D. (1980). Community study of hypothyroidism in Down’s syndrome. British Medical Journai, 280, 1253.
Azizi, F., Chandler, H., Bozorgzadeh, H., & Braverman, L. E. (1974). The occurrence of hyperthyroidism in patients with Down’s syndrome. Johns Hopkins Medical Journal, 134.303-306. Blumberg, D., & AvRuskin, T. (1987). Down’s syndrome, autoimmune hypothyroidism, and hypoparathyroidism: A unique triad. American Journal of Diseases in Childhood, 141, 1149. Crkcuolo, T., Perrone, L., Sinisi, A. A., Bellastella, A., & Fag&to, M. (1986). Subclinical hypothyroidism in children with Down’s syndrome. Minerva Endocrinologica, 11,169-171. Cutler, A. T., Benezra-Obeiter, R., & Brink, S. J. (1986). Thyroid dysfunction in young children with Down syndrome. American Journal of Diseases of Children, 140,479-483. Daniels, D. M., & Simon, J. L. (1968). Down’s syndrome, hypothyroidism, and diabetes mellitus. Journal of Pediatrics, 72.691-699.
Esen, F. M., & Mautner, H. (1957). Hypo- and hyperthyroidism in mongolism. Archives of Pediatrics, 74,291-298.
Floret, D., Thomas, A., & Claus&at, B. (1978). Trisomy 21, myxedema due to thyroiditis with precocious puberty involvemenu Study of gonadotropins and pro&tin secretions. Pediatrics, 33,189-200.
Fort, l?, Lifshitz, F., Belhsario, R., Davis, J., Lanes, R., Pugiiese, M., Richman, R., Post, E. M., & David, R. (1984). Abnormalities of thyroid function in infants with Down syndrome. Journal of Pediatrics, 104,545-549.
Hollingsworth, D. R., McKean, H. E., & Roeckel, I. (1974). Goiter, immunological observations, and thyroid function tests in Down syndrome. American Journal of Diseases of Children, 127, 524-527.
Hopwood, N. J., Robin, B. S., Foley, T. P., & Peake, R. L. (1978). Thyroid antibodies in children and adolescents with thyroid disorders. Journal of Pediatrics, 93,57-61. Hughes, V. C., Cameron, I., & Goonetilleke, A. S. R. (1982). The prevalence of thyroid dysfunction in mentally handicapped inpatients. Journal of Mental Deficiency Research, 26, 115-120. Hung, W., August, G. P., & Glasgow, A. M. (1982). Pediatric endocrinology. New Hyde Park, NY: Medical Examination Publishing Co. Johnson, I. E., & Cook, A. R. (1962). Hyperthyroidism in patients with mongolism. Journal of Clinical Endocrinology and Metabolism, 22,665-668. Korsager, S. (1981). Autoimmunitet ved Down’s syndrom. Ugeskrift For Jaeger [Autoimmunity
in Down syndrome], 143, 1589-1591. Lobo, E. D., Khan, M., & Tews, I. (1980). Community study of hypothyroidism in Down’s syndrome. British Medical Journal, 280, 1253-1255. Mallya, R. K., Isaacs, A. J., & Bay&, R. (1979). Hashimoto’s thyroiditis presenting as T3 toxicosis. British Medical Journal, 2, 1535-1536. McCulloch, A. J., Ince, P. G., & Kendall-Taylor, P (1982). Autoimmune chronic active hepatitis in Down’s syndrome. Journal of Medical Genetics, 19.232-234. Ong, E. A., & Schneider, G. (1976). Down syndrome, hypothyroidism, and diabetes mellitus. American Journal of Diseases of Children, 130,335-336. Pabst, H. F., Pueschel, S. M., & Hillman, D. A. (1967). Etiologic interrelationship in Down’s syndrome, hypothyroidism, and precocious sexual development. Pedianics, 40.590-595. Parkin, J. M. (1974). Down’s syndrome, hypothyroidism, and diabetes mellitus. British Medical Journal, 2,384.
Pueschel, S. M., & Pezaullo, J. C. (1985). Thyroid dysfunction in Down syndrome. American Journal of Diseases of Children, 139.636639.
296
S. M. Pueschei et al.
Pueschel, S. M., & Rynders, J. (1982). Down syndrome: Advances in biomedicine and the behavioral sciences. Cambridge, MA: Ware Press Inc. Ruvalcaba, R. H. A., Ferrier, P. E., & Thuline, H. C. (1969). Incidence of goiter in patients with Down’s syndrome. American Journal of Diseases of Children, 118.451-453. Vladutiu, A. 0.. Chun, T. C., Victor, A., Gienau, L., & Bannerman, R. M. (1984). Down’s syndrome and hypothyroidism: A role for thyroid autoimmunity? Lancet, 1,1416.
Vol. 12. pp. 287-296,
1991
0891-4222/91 $3.00 + .OO copyright @ 1991 Pergmon Press plc
Thyroid Function in Down Syndrome Siegfried M. Pueschel, lvor M. D. Jackson, Peter Giesswein, M. Kelley Dean, and John C. Peuullo Child Development Center, Department of Pediatrics and the Division of Endocrinology Depaflment of Medicine, Rhode Island Hospital, Brown Unrversity Program in Medicine
The thyroid function of 181 patients with Down syndrome was investigated. When compared with a control group of 163 children we found T4 and FT4 levels to be significantly lower and T3 and TSH levels to be significantly higher in the Down syndrome population. Of the 181 patients with Down syndrome. 29 (16%) showed evidence of either uncompensated or compensated hypothyroidism: II (6%) had both low T4 and high TSH levels, 14 (8%) had only high TSH values, and 4 (2%) had only low T4 values. One of the patients with Down syndrome had a significantly elevated T4 level. Studying dflerent age groups. we observed a decline of the mean T4, FT4, T3, FT3, and TBG values with advancing age. T4. T3. and TSH blood levels obtained in 1988 were slightly but not significantly lower when compared with values from 1985. Because thyroid dysfunctions in patients with Down syndrome are more common than in the general population, periodic thyroid hormone function tests should be performed in persons with Down syndrome in particular as they advance in age. Thus, individuals with significantly abnormal results can be identified early before clinical symptoms become manifest. If patients with Down syndrome are found to have a thyroid hormone disorder, appropriate treatment should be forthcoming, which in turn will enhance their quality of life.
Many reports on thyroid dysfunction in persons with Down syndrome have been published in the medical literature (Pueschel & Rynders, 1982). The most common abnormality has been decreased thyroid hormone production by the thyroid gland, resulting in hypothyroidism (Aarskog, 1980; Criscuolo, Pert-one, Sinisi, Bellastella, & Faggiano, 1986; Cutler, BenezraObeiter, & Brink, 1986). Hyperthyroidism (Azizi, Chandler, Bozorgzadeh, & Braverman, 1974; Essen & Mautner, 1957; Hughes, Cameron, & Goonetilleke, 1982; Johnson & Cook, 1962) and thyroiditis in persons with Down syndrome (Hollingsworth, McKean, & Roeckel, 1974; Lobo, Khan, 287
288
S. M. Pueschel et al.
& Tews, 1980; Mallya, Isaacs, & Bayliss, 1979; McCulloch, Ince, & Kendall-Taylor, 1982) have also been reported. An increased prevalence of thyroid autoantibodies in children with Down syndrome and their mothers, as well as autoimmune processes leading to thyroid disorders have, been discussed by several authors (Hollingsworth et al., 1974; Hopwood, Robin, Foley, & Peake, 1978; Korsager, 1981). Moreover, associations of hypothyroidism and diabetes mellitus (Daniels & Simon, 1968; Ong & Schneider, 1976; Parkin, 1974), hypothyroidism and precocious sexual development (Floret, Thomas, & Claustrat, 1978; Pabst, Pueschel, & Hillman, 1967), hypothyroidism and goiter (Hollingsworth et al., 1974; Ruvalcaba, Ferrier, & Thuline, 1969), and autoimmune hypothyroidism and hypoparathyroidism (Blumberg & AvRuskin, 1987) have been reported in individuals with Down syndrome. Hypothyroidism in newborn children with Down syndrome identified through neonatal screening programs have also been described (Cutler et al., 1986; Fort et al., 1984). Thus, there are numerous reports on various forms of thyroid abnormalities in persons with Down syndrome occurring at different ages, occasionally in association with other disorders. This study was designed to investigate the prevalence of thyroid disorders, correlations between selected thyroid parameters, and longitudinal follow-up of a cohort of individuals with Down syndrome relative to their thyroid function. The clinical significance of this study lies in the profound effects that thyroid hormones exert on growth, development, and intellectual functions in human beings. Specifically, thyroid hormones stimulate many intracellular metabolic processes such as the energy-producing electron transfer in the respiratory enzyme systems of the mitochondria, the transcription of messenger RNA via cyclic AMP, and others. These processes are important for any person’s biological integrity including individuals with Down syndrome, In optimizing such intracellular processes in those individuals who have thyroid dysfunctions by substituting exogenous thyroid hormone, their quality of life can be markedly improved. SUBJECTS AND METHODS A cohort of 181 unselected patients with Down syndrome who are followed at the Child Development Center of Rhode Island Hospital, a University Affiliated Program, participated in this prospective study. Of the 181 individuals with Down syndrome, 172 had the cytogenetic diagnosis of trisomy 21, seven had translocation Down syndrome, and two had mosaicism. Enrolled in this study were 77 females with a mean age of 14.8 years (SD = 9.3) and 104 males with a mean age of 13.9 years (SD = 9.2).
Thyroid Function in Down Syndrome
289
During the cross-sectional study detailed investigations were carried out on 181 patients with Down syndrome. An interim history was obtained with focus on symptoms of hypo- and hyperthyroidism. (Usual clinical signs of hypothyroidism include lethargy, dry skin, constipation, muscle weakness, cold intolerance, longitudinal growth retardation, and decreased intellectual performance, whereas patients with hyperthyroidism present with emotional lability, nervousness, irritability, increased perspiration, heat intolerance, tremors, frequent bowel movements, prominent eyes, and often diffuse swelling in the anterior neck due to development of a goiter.) All patients with Down syndrome were examined by the principal investigator. As part of this examination, the anterior neck region was palpated for thyroid gland enlargement and particular attention was paid to other clinical characteristics usually associated with thyroid hormone disorders. Psychological evaluations were done on a subgroup of 56 patients using the Stanford-Binet Intelligence Scale or the Wechsler Intelligence Scale for Children-Revised, if permission was given by parents. Venous blood samples were obtained from all participants for duplicate examinations of thyroxine (T4), free thyroxine (FT4), triiodothyronine (T3), free triiodothyronine (FT3), triiodothyronine uptake (T3U), thyroid stimulating hormone (TSH), and thyroxine-binding globulin (TBG). Normal age-related ranges of various thyroid hormone parameters were obtained from Hung, August, and Glasgow (1982). In addition, antithyroglobulin antibody (ATA) titers and antimicrosomal antibody (AMA) titers were determined. During the longitudinal study 52 patients with Down syndrome had T4, T3, and TSH determinations both in 1985 and 1988. Venous blood samples were obtained from 163 age- and sex-matched patients without endocrine disorders seen at various outpatient cIinics of Rhode Island Hospital. Of the 163 patients, there were 69 females with a mean age of 14.2 years (SD = 8.6) and 94 males with a mean age of 13.5 years (SD = 9.4). T4, T3, and T3U were determined using radioimmunoassays obtained from Nuclear Medical Laboratories Organon, Teknika Corporation, Irving, TX. Free T4 was assayed using the gammacoat direct radioimmunoassay from Clinical Assays, Travenol-Genetech Diagnostics, Cambridge, MA. Free T3 was determined using the coat-a-count radioimmunoassay obtained from Diagnostic Products Corporation, Los Angeles, CA. TSH was estimated employing the TANDEM-R TSH immunoradiometric assay obtained from Hybritech, San Diego, CA. The determination of thyroid autoantibodies was carried out using Thymune-T and Thymune-M Hemagglutination kits obtained from the Wellcome Reagent Division of the Burroughs Wellcome Company, Greenville, NC. TBG was estimated by radioimmunoassay using a kit developed by the Nichols Institute, Los Angeles, CA.
S. M. Pueschel et al.
290
TABLE 1. Means (x) and Standard Deviations (SD) of Various Thyroid Hormone Parameters of Patients in the Down Syndrome (DS) and Control (C) Groups
GroupN
T4
Fr4
T3
Pg/~
wfd
ne/fl
X
SD
X
SD
X
T3U
Fr3 Pg/dl SD
X
SD
TSH
%
@U/ml ___
___ X
SD
X
SD
TBG
Pi# X
SD
DS
181 8.Ok2.2
1.520.4
145.5k32.7
2.9k0.8
31.3k2.4
6.9514
27.2T11.5
C
163 8.7f2.3
1.6f0.4
128.2f37.5
1.6kl.l
31.2zk4.4
2.8k7.8
29.4 f9.6
RESULTS
During the cross-sectional study 181 individuals with Down syndrome were compared with 163 control patients with regard to their T4, FI4, T3, FK3, T3U, TSH, and TBG blood levels. As noted in Table 1, there was a significant difference between the two groups for T4 (F = 8.914, df= 1, p = .003), T3 (F = 20.96, df= 1, p = .OOOl), and TSH (F = 10.362, df= 1, p = .0014). T4 levels were lower, whereas T3 and TSH levels were higher in the Down syndrome population when compared with equivalent data obtained from the control group. When the females of the Down syndrome cohort were compared with their male counterparts relative to the above mentioned parameters, no statistically significant differences were observed. Of the 181 patients with Down syndrome enrolled in the cross-sectional study, 29 subjects (16%) had evidence of decreased thyroid hormone function. The serum TSH was elevated (2 SD above mean) in 25 of these subjects (mean age 13.5 years, range 1 to 29 years) and was associated with a reduced T4 (2 SD below mean) in 11 (mean age 20.9 years, range 6 to 29 years). It is of note that there were four patients with a low T4 (3.9 to 5.3 pg/dl) in whom the TSH (2.3 to 6.1 @U/ml) and T3 (111 to 124 ng/dl) were normal. Only one of the 181 patients with Down syndrome had a significantly elevated T4 level (2 SD above mean). None of the patients in the Down syndrome group had thyroid gland enlargement. Of the 29 patients with laboratory evidence of hypothyroidism, 12 had dry and rough skin, 5 had a history of constipation, and 3 were said to be slow and lethargic. These “symptoms” are not more frequent in these patients than in the general cohort of persons with Down syndrome. In further analysis of the data, the individuals with Down syndrome were divided into five-year age groups, as shown in Table 2. Except for the TSH variable, there were statistically significant differences between most of the age groups in the different thyroid test categories. T4 (F = 19.297, df = 5, p = .OOOl), FT4 (F = 3.145, df= 5, p = .0097), T3 (F = 12.571, df= 5,
o-5 6-10 11-15 16-20 21-25 26-30
1 2 3 4 5 6
33 29 25 39 29 26
N
SD
1.6 2.0 1.9 2.0 1.5 1.5
X
10.2 + 9.0 + 8.6f 7.5 * 7.1* 6.7 +
SD
1.7 kO.4 1.5 * 0.3 1.3kO.3 1.5kO.5 1.5 i: 0.4 1.4 kO.3
X
ng/dl
clg/dl
173.7 It 21.2 159.9 f 39.1 141.0f 29.1 137.9 zk22.4 127.4 f 16.2 129.8 f 38.3
X
X
1 vs 3,4,5,6 2 vs 3,4,5,6
3.6 + 2.4 3.3 +-0.7 2.7 + 0.7 2.7 +_0.6 2.4 + 0.5 2.3 + 0.8
SD
Pg/dl
ngJdl SD
Fr3
T3
Nope.Post hoc tests thatare significant between specified groups (p < .05). Ivs 3,6 1 vs 3,4,5,6 1~~23456 , 13, 2 vs 3 2 vs 3,4,5,6 2 vs 3,4,5,6 3 vs 6
Age
Group
F‘T4
T4
(C) Groups According to Age
1 vs4 2 vs 4.5
30.6 +-2.4 30.3 +-2.5 31.4k2.8 32.0 +-2.2 31.6C 1.6 31.7 k2.8
SD
SD 3.7It 2.3 8.4 It 14.1 11.6+ 23.9 7.1* 16.2 6.2 + 12.3 5.3f 9.4
X
1 vs 4,5 2 vs 3,4,5
30.8 t 8.9 31.6 +- 12.8 25.0f 11.8 24.9 f. 12.0 24.9 -+ 9.3 25.8 _+12.3
SD
clgldl
W/ml
% X
TBG
TSH
T3U
X
TABLE 2. Means (X) and Standard Deviations (SD) of Various Thyroid Hormone Parameters of Patients in the Down Syndrome (DS) and Control
292
S. M. Pueschel et al.
p = .OOOl), FT3 (F = 17.748, d’= 5, p = .OOOl), T3U (F = 2.525, df = 5, p = .031), and TBG (F = 2.39, df = 5, p = .0398). At the bottom of Table 2 the statistical significance between the various age groups is indicated as determined by follow-up tests (Fisher & Scheffe F). A gradual decline of the mean T4, FT4, T3, FT3, and TBG values with advancing age was observed which did not change appreciably when patients with hypothyroidism were excluded. Figure 1 demonstrates graphically the decrease of T4 and T3 values over time. Table 3 depicts the correlation coefficients of various thyroid hormone variables and their statistical significance. ATA showed a significant negative correlation with T4 and FT4, and a positive correlation with TSH, whereas AMA was significantly negatively correlated with T4, FT4, T3, and FI’3.
T4 u%'dl
T3 w/'dl
zoo I9 180
170
160
150
140
30
120 .! 3
o-5
6-10
11-15 AGE
16-20
2l-25
26-30
.\'e;lrs
GROUPS
FIGURE 1. Graphic illustrations of the decline of T4 and T3 levels with advancing age in persons with Down syndrome.
Thyroid Function in Down Syndrome
Correlation
293
TABLE 3. Coetficients (CC) of Various Thyroid Hormone Variables aad Their Statistical Significance (p)* Fr4
T4
FT3
T3
T3u
TSH
TBG
cc
-.I99
- .186
-.110
-.I04
- .029
.333
-.lOO
Ccp
- .286 .Ol
- .200 02
- .212 .17
-206 .21
- .080 .72
.115 .OOOl - .082 .22
.008
.Ol
ATA
ATA P
.0003
.Ol
.32
.15
.31
*These are pairwise p-values; the usual precautions should he taken when interpreting a collection of pairwise tests on one set of data.
In order to study thyroid functions in patients with Down syndrome over time, we compared T4, T3, and TSH results from 1985 with those from 1988 in 52 subjects. As shown in Table 4 during the time period from 1985 to 1988 we observed a slight reduction in mean T4, T3, and TSH levels which, however, was not statistically significant. When we studied the children’s intellectual functioning in relation to the various thyroid hormone parameters, we did not find any significant correlations. The mean IQ of 56 patients with Down syndrome was 49 (SD = 11, range: 25 to 70). DISCUSSION
Although many studies concerning thyroid hormone function in persons with Down syndrome have been carried out in the past, our investigations presented in this report are more comprehensive than any previous studies performed; we examined the largest cohort with Down syndrome using numerous thyroid hormone parameters in both a cross-sectional and a Iongitudinal approach.
TABLE 4. T4, T3, and TSH Levels Obtained From the Same Individuals with Down Syndrome in 1985 and 1988 T4
T3
Wdl
ng/dl
YCU
N
X
SD
1985 1988
52 52
7.8 k 2.0 7.6 k 1.7
X
TSH
SD
144.7 _+27.6 133.8 + 28.5
NJ/ml X
SD
5.3 Ik7.0 4.9 f 6.9
294
S. M. Pueschel et al.
One of the main objectives of this investigation was to study the prevalence of thyroid dysfunction in individuals with Down syndrome. Of the 18 1 patients in the cross-sectional study group, 29 (14%) individuals with Down’s syndrome showed evidence of hypothyroidism. Twenty-five (14%) patients had significantly increased TSH levels, half of them had also significantly decreased T4 levels. Four (2%) patients had significantly low T4 levels with normal TSH and T3 levels. We do not have a ready explanation for the latter observation. Only one person with Down syndrome had a significantly increased T4 level without overt clinical signs of hyperthyroidism. The study group differed significantly from the control group in their T4, T3, and TSH levels. Even after excluding frank hypothyroid individuals from the study group, there was still a significant difference in T4, T3, and TSH levels between the two groups. This can be explained by the decreased thyroid hormone function of the individuals in the study group, some of whom had an autoimmune thyroid disorder. We observed high negative correlations between AMA and T4, FT4, as well as between ATA and T4, FT4. In addition, negative correlations were observed between AMA and T3 as well as FI3. When the patients in the Down syndrome cohort were subdivided into five-year age groups, there were significant differences between most of the groups, as shown in Table 2. Although slightly decreasing T4 and T3 values with advancing age are also observed in a normal population, the decline of thyroid hormone variables was more pronounced in our study population than in children who do not have Down syndrome, even when patients with hypothyroidism were excluded. This suggests that persons with Down syndrome may be at a higher risk of developing hypothyroidism as they get older. Concerning our longitudinal studies, the comparison of the 1985 with the 1988 thyroid hormone parameters did not show any significant difference between the mean T4, T3, and TSH values. Although marked changes are not expected over a 3-year time period, the prompt identification and effective treatment of patients with either compensated or uncompensated hypothyroidism may also have contributed to the slight changes. Since many features of hypothyroidism are similar to those observed in Down syndrome, it may be difficult at times to diagnose hypothyroidism in patients with Down syndrome on clinical grounds. Since symptoms of hypothyroidism are nonspecific and it is unlikely that a physician would have been able to make the clinical diagnosis of hypothyroidism in the 29 individuals with thyroid dysfunction, we recommend that periodic thyroid hormone function tests be performed in persons with Down syndrome, preferably on an annual basis. Early detection of thyroid hormone dysfunction and prompt treatment with thyroid hormone, if hypothyroidism is pre-
Thyroid Function in Down Syndrome
295
sent, not only may prevent further cognitive decline (Pueschel & Pezzullo, 1985). but also will enhance the patients’ overall development, as well as benefit their educational progress and vocational achievements. REFERENCES Aarskog, D. (1980). Community study of hypothyroidism in Down’s syndrome. British Medical Journai, 280, 1253.
Azizi, F., Chandler, H., Bozorgzadeh, H., & Braverman, L. E. (1974). The occurrence of hyperthyroidism in patients with Down’s syndrome. Johns Hopkins Medical Journal, 134.303-306. Blumberg, D., & AvRuskin, T. (1987). Down’s syndrome, autoimmune hypothyroidism, and hypoparathyroidism: A unique triad. American Journal of Diseases in Childhood, 141, 1149. Crkcuolo, T., Perrone, L., Sinisi, A. A., Bellastella, A., & Fag&to, M. (1986). Subclinical hypothyroidism in children with Down’s syndrome. Minerva Endocrinologica, 11,169-171. Cutler, A. T., Benezra-Obeiter, R., & Brink, S. J. (1986). Thyroid dysfunction in young children with Down syndrome. American Journal of Diseases of Children, 140,479-483. Daniels, D. M., & Simon, J. L. (1968). Down’s syndrome, hypothyroidism, and diabetes mellitus. Journal of Pediatrics, 72.691-699.
Esen, F. M., & Mautner, H. (1957). Hypo- and hyperthyroidism in mongolism. Archives of Pediatrics, 74,291-298.
Floret, D., Thomas, A., & Claus&at, B. (1978). Trisomy 21, myxedema due to thyroiditis with precocious puberty involvemenu Study of gonadotropins and pro&tin secretions. Pediatrics, 33,189-200.
Fort, l?, Lifshitz, F., Belhsario, R., Davis, J., Lanes, R., Pugiiese, M., Richman, R., Post, E. M., & David, R. (1984). Abnormalities of thyroid function in infants with Down syndrome. Journal of Pediatrics, 104,545-549.
Hollingsworth, D. R., McKean, H. E., & Roeckel, I. (1974). Goiter, immunological observations, and thyroid function tests in Down syndrome. American Journal of Diseases of Children, 127, 524-527.
Hopwood, N. J., Robin, B. S., Foley, T. P., & Peake, R. L. (1978). Thyroid antibodies in children and adolescents with thyroid disorders. Journal of Pediatrics, 93,57-61. Hughes, V. C., Cameron, I., & Goonetilleke, A. S. R. (1982). The prevalence of thyroid dysfunction in mentally handicapped inpatients. Journal of Mental Deficiency Research, 26, 115-120. Hung, W., August, G. P., & Glasgow, A. M. (1982). Pediatric endocrinology. New Hyde Park, NY: Medical Examination Publishing Co. Johnson, I. E., & Cook, A. R. (1962). Hyperthyroidism in patients with mongolism. Journal of Clinical Endocrinology and Metabolism, 22,665-668. Korsager, S. (1981). Autoimmunitet ved Down’s syndrom. Ugeskrift For Jaeger [Autoimmunity
in Down syndrome], 143, 1589-1591. Lobo, E. D., Khan, M., & Tews, I. (1980). Community study of hypothyroidism in Down’s syndrome. British Medical Journal, 280, 1253-1255. Mallya, R. K., Isaacs, A. J., & Bay&, R. (1979). Hashimoto’s thyroiditis presenting as T3 toxicosis. British Medical Journal, 2, 1535-1536. McCulloch, A. J., Ince, P. G., & Kendall-Taylor, P (1982). Autoimmune chronic active hepatitis in Down’s syndrome. Journal of Medical Genetics, 19.232-234. Ong, E. A., & Schneider, G. (1976). Down syndrome, hypothyroidism, and diabetes mellitus. American Journal of Diseases of Children, 130,335-336. Pabst, H. F., Pueschel, S. M., & Hillman, D. A. (1967). Etiologic interrelationship in Down’s syndrome, hypothyroidism, and precocious sexual development. Pedianics, 40.590-595. Parkin, J. M. (1974). Down’s syndrome, hypothyroidism, and diabetes mellitus. British Medical Journal, 2,384.
Pueschel, S. M., & Pezaullo, J. C. (1985). Thyroid dysfunction in Down syndrome. American Journal of Diseases of Children, 139.636639.
296
S. M. Pueschei et al.
Pueschel, S. M., & Rynders, J. (1982). Down syndrome: Advances in biomedicine and the behavioral sciences. Cambridge, MA: Ware Press Inc. Ruvalcaba, R. H. A., Ferrier, P. E., & Thuline, H. C. (1969). Incidence of goiter in patients with Down’s syndrome. American Journal of Diseases of Children, 118.451-453. Vladutiu, A. 0.. Chun, T. C., Victor, A., Gienau, L., & Bannerman, R. M. (1984). Down’s syndrome and hypothyroidism: A role for thyroid autoimmunity? Lancet, 1,1416.
