Clinical Endocrinology (1994) 41, 673-676

Turner’s syndrome with X-isochromosome and Hashimoto’s thyroiditis

M. de Kerdanet*, J. Lucast, F. Lemeet and M. Lecornu’ *Service d’Endocrinologie Pediatrique, Hdpital Sud CUR Rennes and tLaboratoire de Cyto-genetique, Hdpital de Pontchaillou CUR Rennes, France

(Received 3 February 1994; returned for revision 28 February 1994; finally revised 20 May 1994; accepted 13 July 1994)

Summary

roldltls in Turner’s syndrome compared with the general population is well known. We have attempted to establish clearly the more frequent association of thyroiditis with the X-lsochromosome, since previous reports of this aspect have Included only small numbers of patients. DESIGN Retrospective study of patlents with Turner’s syndrome investigated withln the past 12 years. PATIENTS Sixty-seven cases of Turner’s syndrome were reviewed. MEASUREMENTS Peripheral blood ieucocyte karyotype and screening for thyrold dlsturbances on the basls of clinical examinatlon and laboratory evaluation (antl- thyroglobulin and anti-mlcrosomal antlbodles, basal TSH levels and TSH levels after TRH stimulation) were made for each patient. RESULTS A diagnosis of thyroiditis, based on the asso- clation of positive antibody tltres, elevated TSH and an abnormal thyroid gland on clinical examinatlon, was established In 20.9% (14167) of cases. A significantly higher frequency of thyroidltls was found among the patlents presenting with an X-isochromosome (57.3%, 9/16), compared to patlents wlth other karyotypes (B8Y0, 5/51) (P = 0.0001). CONCLUSIONS Our results, obtalned by Investigatlon of a larger number of patients with an X-isochromosome karyotype than in previous reports, confirm conciuslvely that patients wlth X-isochromosome Turner’s syndrome have an increased risk of deveioplng thyrolditis.

OBJECTIVE The higher frequency Of Hashimoto’s thy-

Following observations made in our department and those found in the literature, we have for over 10 years

Correspondence: M. de Kerdanet, Service d’Endocrinologie Pediatrique, HBpital Sud CHR Rennes, 16 Boulevard de Bulgarie, BP 35056 Rennes-Cedex, France.

systematically screened patients with Turner’s syndrome for thyroid gland abnormalities. This association did not show a homogeneous distribution, but seemed to be stronger in those cases with an isochromosome of the long arm of X. In this study we have reviewed 67 cases in order to define the exact incidence of Hashimoto’s thyroiditis in the Turner population and to study its relation to karyotype. We have compared our results with those found in the literature.

Patlents and methods

Sixty-seven cases of Turner’s syndrome investigated within the past 12 years in our paediatric endocrinology depart- ment were retrospectively reviewed.

At the time of initial diagnosis, the age range varied from shortly after birth to 22 years, with a mean of 103 years. At the time of the present study, the age range was from 5.5 to 34 years with a mean of 19.3 years (some of these patients are no longer followed by our paediatric team since we pass on follow-up after 20 years of age).

Turner’s syndrome was diagnosed in all patients except one by peripheral blood leucocyte karyotypes (Cytogenetic Laboratory of CHR Rennes) performed on the basis of various clinical features of the syndrome found in our patients. The exception was diagnosed by the association of a typical clinical syndrome, gonadal dysgenesis of mixed type found at ovariectomy, and a 46,XX karyotype with the presence of the HY antigen.

Each of the 67 patients was screened by clinical examination and laboratory evaluation for thyroid abnorm- alities. Clinical examination looked for abnormalities of the thyroid gland on palpation (for example, gland induration, enlargement or atrophy following initial enlargement). Since overt hypothyroidism (elevated TSH levels and low T4) was often masked by thyroxine replacement instituted when compensated hypothyroidism (elevated TSH levels and normal T4) was found, we have not reported circulating T4 and T3 levels in this study.

Laboratory evaluation of thyroid function included determination of TSH levels, basal (normal rage 0-5 mU/1), and/or after TRH stimulation (7 pg/kg i.v., maximum 200pg, normal peak below 20mU/1, Ciba-Corning TSH kit, Pediatric Endocrinology Laboratory, CHR Rennes). In early patients, determination of anti-thyroid antibodies was performed by a radioimmunological assay for anti- thyroglobulin antibodies (considered positive when greater

673

674 M. de Kerdanet et a / . Clinical Endocrinology (1994) 41

Table 1 Karyotype distribution Study Cytogenetic Lab. total

(n = 67) (n = 150)

Karyotype number (YO) number (”/I

X-monosomy (45 X) 25 37.3 63 42 Isochromosome-X 16 23.9 30 20

4 6, X , i fl s) 6 45,X/46,X,i(Xq) 10

45,X/46,X,rX I 46,X,delfl~) 4 46,X,X(Ag HY +) 1 45,X/46,X,idic Y 1

45,X/46,X,X 6

Structural disturbances 13 19.4 30 20

Mosaic without structural disturbances 13 19.4 21 18

45,X/46,X,Y 4 45,X/46,X,X/47X,X,X 2 45,X/4l,X,X,X 1

than 2.1 pg/l, Oris kit, same laboratory). However, another radioimmunological assay for anti-thyroglobulin and anti-microsomal antibodies was used for most patients (considered positive when greater than 100 U/ml, Henning- Berlin kit).

Thyroiditis was diagnosed by the association of (1) significantly positive antibody titres on a least two determinations (anti-thyroglobulin antibodies alone or, for most patients, with anti-nicrosomal antibodies); (2) significantly elevated TSH levels: basal (above 6 mU/l, i.e. mean $3 SD) and/or after TRH stimulation (peak value more than 25 mU/1, mean +3 SD); and (3) abnormal thyroid gland palpation: changes in volume or consistency.

We did not perform histological, scintigraphic or ultrasonographic examinations of the thyroid.

The chi-squared test with the Yates’ correction and variance analysis were used for statistical analysis.

Results

Karyotype distribution (Table 1 )

For the purpose of our study, patients were divided into four groups according to the various karyotypes observed: X-monosomy, X-isochromosome, structural disturbances of X-chromosome, and mosaics. For mosaic patients, the karyotypes depicted here do not take into account the proportion of each respective clone. For comparison, all Turner’s syndrome karyotypes ever recorded in our cytogenetics laboratory (n = 150) were divided into the same four groups.

Incidence of thyroid dysfunction (Table 2)

Positive anti-microsomal and/or anti-thyroglobulin anti- bodies were found in 18 of the 67 patients. TSH levels ranged from 1 to 31, and were greater than 6mU/1 in 16 cases (mean 10-8 i6-5mU/I). TSH peaks after TRH stimulation ranged from 4 to 100 (n = 43, and were above 25mU/1 in 10 cases (mean 52-5 i 28mU/1). An abnormal thyroid gland was found in 14 patients, with gland induration associated with enlargement (n = 10) or atrophy (n = 4). Overall, 21 patients presented with at least one type of thyroid disturbance (3 1 YO), thyroiditis was identified in 14 (20.9%) as defmed above.

Thyroiditis distribution

Age. No thyroiditis was found before the age of 10; mean age at time of diagnosis was 146 i 4 years (range 10-22).

Kuryotype. A statistically significant difference was found between the four groups (each compared to the three others) for mean basal TSH levels, TSH levels after TRH stimulation, and the number of cases with positive anti- thyroid antibodies. The incidence of thyroiditis was also significantly different in the four groups (P < 0.0001, chi- squared test) (Table 2).

Age and kuryotype. The mean age at the time of thyroiditis diagnosis was not different in the isochromosome group from the others (146 f 47.7 vs 14-5 i 3.3 years). Consider- ing all patients, the mean age was still not different between

Clinical Endocrinology (1994) 41 Thyroiditis and X-isochromosome 675

Table 2 Distribution of thyroid abnormalities according to karyotype

Karyotype

45,x Isochromosome Mosaic Structural disturbances Total population

n (YO) n (%) n (YO) n (YO) n (YO)

Number of cases with 2 (8) 1 1 (68.8) 4 (30.8) 1 (8) 18 (26.9)

Basal TSH (mU/l) 3.1 f 2.3 8.7 f 1.5 4.3 f 3.1 2.1 f 1.4 4.6 f 4.8

Number of cases with 2 I 4 1 16 (23.9)

TSH after TRH (mU/l) 18.4 f 15 36.1 f 28.8 23.8 f 26.1 16.1 f 8.1 22.6 f 21

Number of cases with 1 5 2 2 10 (15)

Number of 1 (4) 9 (56.3) 4 (30.8) 0 (0) 14 (20.9)

positive antibodies (P < 0~00Ol)t

(mean f SD) (P < 0~0001)t

values > 6

(mean peak f SD)

values > 25

thyroiditis cases

(P = 0,028)t

P = 0.021 * P = 0.0003* P = 0.55’ P = 0.092* P = 0~0001**

*Chi-squared test between *one group and the other three; **among the four groups. fVariance analysis, each group compared to the other three.

the two groups (at present 20.7 f 6.6 years for patients with isochromosome, 18.8 f 6.8 years for the other patients).

Discussion

The division of Turner’s syndrome patients into four groups on the basis of chromosomal abnormalities may appear somewhat artificial, but was necessary to provide homo- geneous groups for comparison.

The distributions of patients included in our study and of the 150 patients with Turner’s syndrome studied by our cytogenetics laboratory, according to chromosomal abnor- malities (X-monosomy, X-isochromosome, mosaic, and structural disturbances, Table l), were statistically identical (P < 0.0001, chi-squared test). We can therefore assume that no particular bias was present in our study with respect to the population evaluated. Nevertheless, the distribution observed among our patients differs slightly from the classic description of a Turner’s population: X-monosomy 55%, X-isochromosome 20% (Grouchy & Turleau, 1982). Comparison between our patients and those reported in the literature (eight studies, each including from 20 to 100 patients; 419 karyotypes (Pai et al., 1977; Germain & Plotnick, 1986; Gruneiro et al., 1987; Takano et al., 1986; Raiti et al., 1986; Brook et al., 1974; Ranke et al., 1987)) shows that fewer cases of X-monosomy were present in our study (37.5% compared with 40-82%, mean 65%), whereas the frequency of X-isochromosome was similar (23.9% compared with 4-40%, mean 13.6%). Differences in statistical analysis could explain such differences.

The clinical and laboratory indicators we used, in the absence of histology to confirm a diagnosis of thyroiditis, have been used by other authors (Gruneiro et al., 1982; Bastenie et al., 1980) and take into consideration biological and clinical variants of the disease. We started T4 therapy without waiting for the development of overt hypothyroidism.

The frequency of thyroiditis in this population of Turner’s syndrome patients was much higher than in the normal population. Rallison (1975) observed that thyroiditis frequency was 1.2% in a large population of normal American children aged 11-18 years, with a 2 : 1 female: male sex ratio. The thyroiditis frequency was significantly higher in the subgroup with an X-isochromosome than in the other three subgroups (P = 0.0001). Furthermore, frequency of thyroiditis in the 45,X group in our study was rather low, and significantly different (P = 0.021) from that observed in the other subgroups.

In our study, no case was found before the age of 10 years. In the normal population the frequency of thyroiditis increases with age up to the sixth decade, as does the sex ratio which reaches a maximum of 10 to 1 (Pai et al., 1977). Such an age related increase has also been observed in patients with Turner’s syndrome (Germain & Plotnick, 1986). Greater age, which is correlated with a higher frequency of thyroiditis, cannot explain the difference in our study between patients with the X-isochromosome and the other patients since we found no difference in mean age between the two groups.

Despite the well known increase in the frequency of Hashimoto’s thyroiditis in Turner’s syndrome compared to

676 M. de Kerdanet et al. Clinical Endocrinology (1994) 41

the general population (Williams et al., 1964; Pai et al., 1977; Bright et al., 1982), a more frequent association between thyroiditis and the X-isochromosome remained to be proved conclusively, since studies of this aspect concerned only small numbers of patients (Sparks & Motulsky, 1963; Pai et al., 1977; Zinman et al., 1984; Lecornu et al., 1988). Gruneiro et al. (1987) found (1) that among 49 patients with Turner’s syndrome, 26% had thyroiditis and (2) that of 11 patients with an X-isochromosome, 5 had thyroiditis (455%). Germain and Plotnick (1986) found in 100 patients with Turner’s syndrome that 22% had thyroid abnormalities, whereas among the 7 patients with an X-isochromosome thyroid dysfunction was present in 57%.

In our study the results obtained from a large number of patients with X-isochromosome karyotype confirm the increased risk of developing thyroiditis. These results, together with the fact that thyroiditis may interfere with the effects of growth hormone therapy, lead us and others (Germain & Plotnick, 1986), to encourage practitioners to look for thyroid function impairment in patients with Turner’s syndrome, especially those with an X-isochromosome.

Many different types of autoimmune disease have been observed in association with Turner’s syndrome (Chen et al., 1978; Nishimura et al., 1985; Balestrazzi et al., 1986; Manzione et al., 1988; Levesque et al., 1989) especially when an X-isochromosome karyotype was involved. Rather than being the disease of a single organ, it would seem that the mechanism leading to thyroiditis in Turner’s syndrome reflects the pathophysiological Grocess of autoimmunity linked with the presence of an abnormal X-chromosome. We wish to emphasize that X-isochromosome Turner’s syndrome patients could be considered as a model for research into the development of autoimmune disease.

References

Balestrazzi, P., Ferraccioli, G.F., Ambanelli, U. & Giovannelli, G. (1986) Juvenile rheumatoid arthritis in Turner’s syndrome. Clinical and Experimental Rheumatology, 461-62.

Bastenie, P.A., Bonnyns, M. & VanHaelst, L. (1980) Grades of subclinical hypothyroidism in asymptomatic autoimmune thyroiditis revealed by the thyrotropin-releasing hormone test. Journal of Clinical Endocrinology and Metabolism, 51, 163-166.

Bright, G.M., Blizzard, R.M., Kaiser, D.M. &Clarke, W.L. (1982) Organ specific autoantibodies in children with common endo- crine diseases. Journal of pediatrics, 100,8-14.

Brook, C.G.D., Murset, G., Zachmann, M. & Prader, A. (1974) Growth in children with 45,XO Turner’s syndrome. Archives of Diseases in Childhood, 49,789-795.

Chen, H., Hoffman, W.H., Chang, C.H., Hart, Z. & Kaplan, J. (1978) Lymphocitic thyroiditis, myasthenia gravis and Turner syndrome. Birth Defects, 15, 137-147.

Germain, E.L. & Plotnick, L.P. (1986) Age-related anti-thyroid antibodies and thyroid abnormalities in Turner syndrome. Acta Pediatrica Scandinavia, 75,750-755.

Grouchy, J. de & Turleau, C. (1982) Syndrome de Turner. In Atlas des Maladies Chromosomiques, pp. 376-385. Expansion Scientifi- que FranMse, Paris.

Gruneiro de Papendieck, L., Jorcansky, S., COCO, R., Rivarola, M.A. & Bergada, C. (1987) High incidence of thyroid disturbances in 49 children with Turner syndrome. Journal of Pediatrics, 111, 258-261.

Gruneiro, D.E., Papendieck, L., Iorcansky, S., Rivarola, M.A. & Bergada, C. (1982) Variations in clinical, hormonal and serological expressions of chronic lymphocytic thyroiditis (CLT) in children and adolescents. Clinical Endocrinology, 16,

Lecornu, M., Treussard, I. & Jezequel, C. (1988) Thyroidite et syndrome de Turner. Archives Frangaises de Pidiatrie, 45,

Levesque, H., Cancel, A. & Courtois, H. (1989) Association syndrome de Turner-hypoparathyroide-diaMte. Presse Midi- cale, 18, 1166.

Manzione, N.C., Kram, M., Kram, E. & Das, K.M. (1988) Turner’s syndrome and inflammatory bowel disease: a case report with immunologic studies. American Journal of Gastroenterology, 83,

Nishimwa, H., Kino, M., Kubo, S. & Kawamura, K. (1985) Hasimoto’s thyroiditis and ulcerative colitis in a patient with Turner’s syndrome. Journal of the American Medical Association, 254,357.

Pai, G.S., Leach, D.C., Weiss, L., Wolf, C. & Van Dyke, D.L. (1977) Thyroid abnormalities in 20 children with Turner syndrome. Journal of Pediatrics, 91,267-269.

Raiti, S. , Moore, W.V., Van Vliet, G. & Kaplan, S.L. (1986) Growth-stimulating effects of human growth homone therapy in patients with Turner syndrome. Journal of Pediatrics, 109, 944- 949.

Rallison, M.L., Dobyns, B.M., Keating, R., Rall, J.E. & Tyler, F.H. (1975) Occurrence and natural history of chronic lymphocitic thyroiditis in childhood. Journal of Pediatrics, 86,675-682.

Ranke, M.B., Blum, W.F., Haug, F., Rosendahl, W., Attanasio, A., Enders, H., Gupta, D. & Bierich, J.R. (1987) Growth hormone, somatomedin levels and growth regulation in Turner’s syndrome. Acta Endocrinologica, 116, 305-313.

Sparkes, R.S. & Motulsky, A.G. (1963) Hashimoto’s disease in Turner’s syndrome with isochromosome X. Lancet, i, 946.

Takano, K., Hizuka, N. & Shizume, K. (1986) Growth homone treatment in Turner’s syndrome. Acta Pediatrica Scandinavia,

Williams, E.D., Engel, E. & Forbes, A.P. (1964) Thyroiditis and gonadal dysgensis. New England Journal of Medicine, 270,805.

Zinman, B., Kabiawu, S.I.O., Moross, T., Berg, J., Lupmanis, A., Markovic, V. & Gardner, H.A. (1984) Endocrine, cytogenetic and psychometric features of patients with X-isochromosome 46, X, i(Xq)Turner’s syndrome: a preliminary study in nine patients. Clinical and Investigative Medicine, 1, 135-141.

19-28.

411-412.

1294-1 297.

325(S~ppl.), 58-63.