High incidence of thyroid disturbances in 49 children with Turner syndrome

258

Clinical and laboratory observations

REFERENCES

1. Bilaniuk LT, Moshang T, Cara J, et al. Pituitary enlargement mimicking pituitary tumor. J Neurosurg 1985;63:39. 2. Yamada T, Tsukui T, Ikejiri K, et al. Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 1976; 42:817. 3. Vagenakis AG, Dole K, Braverman LE. Pituitary enlargement, pituitary failure and primary hypothyroidism. Ann Intern Med 1976;85:195. 4. LaFranchi SH, Hanna CE, Krainz PL. Primary hypothyroidism, empty sella, and hypopituitarism. J PED1ATR 1985; 108:571. 5. Leiba S, Landau B, Ber A. Target gland insufficiency and pituitary tumors. Acta Endocrinol 1969;60:112. 6. Bercu BB, Shulman D, Root AW, et al. Growth hormone (GH) provocative testing frequently does not reflect endogenous GH ser J Clin Endoerinol Metab 1986;63:709.

The Journal of Pediatrics August 1987

7. McVie R. Abnormal TSH regulation, pseudotumor cerebri, and empty sella after replacement therapy in juvenile hypothyroidism. J PED~ATR1984;105:768. 8. Arafah BM. Reversible hypopituitarism in patier/ts with large nonfunctioningpituitary adenomas. J Clin Endocrinol Metab 1986;62:1173. 9. Penny R, Blizzard RM. The possible influence of puberty on the release of growth hormone in three males with apparent isolated growth hormone deficiency. J Clin Endocrinol 1972;34:82. 10. Moshang T, Parks JS, Vaidya V, et al. Recovery from probable acquired growth hormone deficiency. Am J Dis Child 1974;127:397. 11. Rosenfield RL, Furlanetto RW. Physiologic testosterone or estradiol induction of puberty increases plasma somatomedinC. J PZOlATrt1985;107:415.

High incidence of thyroid disturbances in 49 children with Turner syndrome Laura Grul~eiro de Papendieck, M.D., Sonia Iorcansky, M.D., Roberto Coco, M.D., Marco A. Rivarola, M.D., and C~sar BergadO, M.D. From Centro de Investigaciones Endocrinol6gicas, Hospital de Nitros de Buenos Aires, Argentina

The association of thyroid disturbances with Turner syndrome has been described in adults ~-3and in children, 4,5 in whom a high incidence of thyroid antibodies has been found; however, thyroid function was not completely studied in these reports. Some disturbances of thyroid function might not be readily apparent. For example, a remarkable proportion of patients with chronic lymphocytic thyroiditis have increased serum levels of T S H or an exaggerated response to thyrotropin releasing hormone as an expression of subclinical hypothyroidism?, 7 We studied the incidence of thyroid disturbances in girls with Turner syndrome by measuring thyroid function and thyroid antibodies in patients with different chromosomal abnormalities. Supported by Consejo Nacional de Investigaciones Cientificas y T6enicas (Argentina). Submitted for publication July 8, 1986; accepted April 3, 1987. Reprint requests: Laura Grufieiro de Papendieck, M.D., Centro de Investigaciones Endocrinol6gicas, Hospital de Nifios de Buenos Aires, GaUo 1330, 1425 Buenos Aires, Argentina.

METHODS

Forty-nine girls with Turner syndrome, aged 2 to 17V2 years, were examined. The diagnosis was confirmed by analysis of the karyotype with G and T banding techniques in at least 50 peripheral blood metaphase cells. Either antithyroglobulin or antimicrosomal antibodies were RIA T3 T4 TRH TSH ATSH

Radioimmunoassay Triiodothyronine Thyroxine Thyrotropin-releasing hormone Thyroid-stimulating hormone Difference between basal and maximal TSH values in TRH stimulation test

determined using the tanned red cell technique (Sera Tek, Ames Division, Elkhart, Ind.); 1:100 was the lowest dilution tested, and any positive result was considered abnormal. Serum thyroxine and serum triiodothyronine were determined by radioimmunoassay with a commercial kit (Clinical Assays Inc., Cambridge, Mass.). Normal

Volume 111 Number 2

Clinical and laboratory observations

259

T a b l e . Frequency of different types Of thyroid abnormalities in three groups of children with Turner syndrome

Group 1 45X Group 2 45X,46Xr(X) 45S,46Xi(Xq) 46Xi(Xq) Group 3 Mosaic

n

Goiter

Low T4

High TSH

Abnormal TRH

Thyroglobulin antibody

Microsomal antibody

25

4

~1

2

6

2

7

9 6

2 0 1 3

3 0 2 5

6 1 4 11"

2 1 3 6

7 1

5 20

3 1 0 4

4 12"

4

1

0

0

3

0

1

*Significantlydifferentfrom group i, P <0.05, chi-squaretest.

values in children were 9.2 + 1.6 /~g/dL and 138.8 + 37.7 ng/dL, respectively (n = 19). Thyroid-stimulating hormone was determined by R i A with a double-antibody technique. Reagents were supplied by the National Institute of Arthritis, Metabolism, and Digestive Diseases, Bethesda, Maryland. Results were expressed as microunits per milliliter of Human Thyrotr0piia Research Standard 68/38 supplied by the Medical Research Council, MillHill, England. The T R H stimulation test was carried out using 200 t~g intravenously administered synthetic TRH (TRH-ELEA). Serum TSH was determined before and 20, 30, and 60 minutes after T R H injection. Normal unstimulated TSH values in ~t group of 55 euthyroid control children were 2.3 + 1.1 # U / m L (mean +SD), and the maximal increment (ATSH) was 10.8 _+ 4.3 lzU/mL. A ATSH value >2 SD above the mean was considered an exaggerated response. Patients were divided according to karyotype into three groups: group 1, 45X (n = 25); group 2, structural abnormalities of the X chromosome (n = 20); and group 3, mosaicism without structural abnormalities (n = 4). Hypothyroidism was diagnosed On the basis of high basal TSH or exaggerated TSH response to TRH. Two subgroups could be distinguished: compensated hypothyroidism with high TSH or exaggerated TSH response to T R H and normal T4; and overt hypothyroidism with high TSH and low T4. In addition to overt hypothyroidism, thyroid abnormalities were defined as including the development of goiter, high thyroid antibody titers, elevated TSH values, or exaggerated TSH response to TRH. The chi-square test was used for statistical analysis. RESULTS Of the 49 patients, 20 had positive thyroid antibodies, 16 had compensated hypothyroidism, four had overt hypothyroidism, and nine had thyroid enlargement. Thirteen of the

20 patients with positive thyroid antibodies had altered thyroid function: 11 had compensated and two had overt hypothyroidism. NeVertheless, seven of 49 patients had thyroid function abnormalities with negative thyroid antibodies (five compensated and two overt hypothyroidism). Therefore, a total of 27 (55%) patients had thyroid disturbances. Three groups of patients could be distinguished on the basis of different chromosomal abnormalities (Table). Group 1: Patients with 45X karyotype (n = 25). Five patients older than 13 years of age were given estrogen replacement therapy for 3 to 4 years. Three patients had slight thyroid gland enlargement, one with compensated hypothyroidism and two without functional abnormalities. Another patient had an enlarged, bosselated thyroid gland with increased firmness and overt hypothyroidism. Six of 25 patients had hypothyroidism, five compensated and one overt; three of these six patients had negative antibody titers. In four patients, high antibody titers were demonstrated without thyroid function disturbances. Thus a total of 10 (40%) patients in this group had thyroid abnormalities. Group 2: Patients with structural abnormalities of X chromosome (n = 20). Patients were subdMded according to the type of X Chromosome disturbance: nine patients had 45X,46r(X), six had 45X,46Xi(Xq), and five had 46Xi(Xq) kary0type. Five patients older than 13 years of age received replacement doses of conjugated estrogens. Four patients had thyroid gland enlargement. Eleven patients had hormonal dysfunction, eight compensated and three overt hypothyroidism. Two of these patients had negative antibody titers, and t h r e e had high thyroid antibodies without other functional disturbances. Thyroid disturbances occurred in eight to nine patients with 45X,46Xi(X) karyotype, in four of five with 46Xiq(X), and two of six with 45X,46iq(X) chromosomal constitu-

26 0

Clinical and laboratory observations

tion. A total of 14 (70%) patients in this group had thyroid disturbances. Group 3: Patients with mosaicism without structural abnormalities (n = 4). The karyotypes of the four patients were 45X,46XX,47XXX, 45X,47XXX, 45X,46XX, and 45X,46qnXY. One patient had slight thyroid gland enlargement. Three had compensated hypothyroidism, and only one of these patients had elevated thyroid antibodies. Thus three of four patients had thyroid disturbances. An increased frequency of thyroid alterations was not found in patients receiving estrogen therapy in any of the groups. DISCUSSION In 1964, Williams et al. 1 investigated the incidence of chronic lymphocytic thyroiditis in adult patients with gonadal dysgenesis. They found that three of 25 patients had thyroid disease and 13 had antithyroid antibodies, with the same frequency in patients with positive and negative chromatin. Pai et al. 4 found high thyroid antibody titers in nine of 20 patients with Turner syndrome; three who had structural abnormalities of the X chromosome were hypothyroid. Bright et al? reported high antithyroid antibodies in 21 of 24 girls with gonadal dysgenesis. These authors found that the prevalence of these antibodies Was similar to that in patients with immunologic thyroid disorders and higher than in patients with diabetes mellitus. However, in these reports there is limited information on the functional status of the thyroid gland. In agreement with former reports, we found a high incidence of positive antibody titers in our patients. We also found a higher frequency of alterations of thyroid function in a group of patients with structural abnormalities of the X chromosome. Fui'thermore, seven of our patients with negative antibody titers had thyroid abnormalities. The possibility of negative antibody titers in chronic lymphocytic thyroiditis has been described by us 8 and by others?.1~ Many of our patients had elevation of TSH or an exaggerated response to TRH; the latter is considered to be a sensitive indicator of disturbed thyroid function. 6 However, the abnormal TRH test by itself might be either a reflection of a minor control abnormality of the hypothalamic-pituitary-thyroid axis or the first stage in the subsequent development of primary hypothyroidism. We are at present studying the significance of this abnormal test by long-term follow-up of the clinical course. A partial impairment of thyroid function might not be diagnosed because many patients are in a state of compensated hypothyroidism with normal serum T4 concentration and are clinically euthyroid. That only nine of 49 patients had goiter is also of interest, because there is a high frequency

The Journal of Pediatrics August 1987

of thyroid enlargement in chronic lymphocytic thyroiditis. 1~ Previous reports have found an equal frequency of thyroid abnormalities in different groups of patients with Turner syndrome. However, we found a greater frequency of thyroid disturbances in a group of patients with structural abnormalities of the X chromosome than in those with 45X karyotype (P <0.05, chi-square test). To explain the association of thyroid disturbances with Turner syndrome, Williams et al. ~ postulated a recessive gene located on a short arm of the X chromosome. The Xiq found in some of their patients indicated a possible role for some additional factor carried on the long arm of the X chromosome. Our findings in four patients with single 46,Xiq cell line would support this hypothesis: Thus we have confirmed previous reports that the absence of one X chromosome is associated with a high frequency of thyroid abnormalities, but in addition it seems that excessive genetic material of the X chromosome (duplication or triplication) favors even more the production of thyroid disturbances. An important question is the role of the X chromosome in chronic lymphocytic thyroiditis, in view of its greater frequency in women. The recent discovery of B cell genes on the X chromosome helps to explain the female preponderance in autoimmune disease. H On the other hand, chronic lymphocytic thyroiditis occurs with great frequency in patients with Down syndrome? ~ This also has led to the hypotheses that the formation of autoantibodies results in a chromosome derangement or that the chromosome abnormalities may produce the immunologic disturbance. We believe it is important to detect these thyroid abnormalities in patients with Turner syndrome even though they may not be clinically obvious. These patients are already at risk of genetically low growth potential, even without hypothyroidism. Finally, estrogen and anabolic steroids are sometimes given in an attempt to improve growth velocity, but the efficacy of these treatments cannot be evaluated if thyroid function is not adequately controlled.

REFERENCES 1. Williams ED, Engel E, Forbes AP. Thyroiditis and gonadal dysgenesis. N Engl J Med 1964;270:805. 2. Sparkes RS, Motulsky AB. Hashimoto's disease in Turner's syndrome with isochromosome X. Lancet 1963;1:947. 3. Engel E, Forbes AP. Cytogenetic and clinical findings in 48 patients with congenitally defective or absent ovaries. Medicine 1965;44:135. 4. Pai GS, Leach DC, Weiss L., Wolf CH, Van Dyke DL. Thyroid abnormalities in 20 children with Turner's syndrome. J PEDIATR 1977;91:267. 5. Bright GM, Robert M, Blizzard RD, Kaiser DL, Clark WL.

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Organ-specificautoantibodies in children with common endocrine diseases. J PEDIATR1982;100:8. 6. Bestenie PA, Bonnyns M, Vanhaelst L. Grades of subclinical hypothyroidism in asymptomatic autoimmune thyroiditis revealed by the thyrotropin releasing hormone test. J Clin Endocrinol Metab 1980;51:163. 7. Gordin A, Saarinen P, Pelkonnen R, Lambert BA. Serum thyrotropin response to thyrotropin releasing hormone in symptomlessautoimmune thyroiditis and borderline and overhypothyroidism. Acta Endocrinol 1974;75:274. 8. Grufieiro de Papendieck L, Iorcansky S, Rivarola MA, Bergadfi. C. Variations in clinical, hormonal and serological expressions of chronic lymphocytic thyroiditis (CLT)

Clinical and laboratory observations

9.

10.

11. 12.

26 1

in children and adolescents. Clin Endocrinol (Oxf) 1982; 16:19. Loeb PB, Drasb AL, Kenny FM. Prevalence of low titre and "negative" antithyroglobulin antibodies in biopsy proved juvenile Hashimoto's thyroiditis. Pediatrics 1973;82:17. Rallison ML, Dobyns BM, Keating FR, Rall JE, Zyler FH. Occurrence and natural history of chronic lymphocytic thyroiditis in childhood. J PEDIATR1975;86:675. Burtnan KD, Baker JR. Immuno mechanisms in Graves' disease. Endocrin Rev 1985;6:183. Hollingsworth DR, McKean HE, Roeckel I. Goiter, immunological observations, and thyroid function tests in Down's syndrome. Am J Dis Child 1974;127:524.

Self-limited neonatal hyperparathyroidism in familial hypocalciuric hypercalcemia Lyman A. Page, M.D., and James E. Haddow, M.D. From the Division of PediQtric and Adolescent Endocrinology, Maine Medical Center, Portland, and the Departments of Pediatrics, University of Vermont College of Medicine, Burlington, and Southern Maine Medical Center, Biddeford

Neonatal hyperparathyroidism is generally severe, requiring surgical intervention,~-3 and has been associated with familial hypocalciuric hypocalcemia.4-8 Recently, three patients with clinically benign neonatal hypercalcemia have been described?,3,9 One of these 3 had normal serum levels of parathyroid hormone. The report of another, 2 who appears to have had neonatal hyperparathyroidism in FHH, was not well documented and the patient was thought to be a member of a family with familial hyperparathyroidism. The third 9 report was second-hand. In another infant in a family with FHH, only partial parathyroidectomy was performed, at 12 months of age, and the N H P improved1~ such treatment usually would be inadequate. We present a baby with symptomatic hyperparathyroidism who improved and thrived without surgical intervention. The patient, his father, paternal grandmother, and a half-uncle have FHH. Studies of the patient and his family have also provided new information on the early course of F H H and its various neonatal presentations. METHODS

Routine laboratory tests were performed by standard techniques in the clinical laboratories of Maine Medical

Submitted for publication March 20, 1987; accepted March 23, 1987. Reprint requests: Lyman A. Page, M.D., 157 Pine St., Portland, ME 04102.

Center and Southern Maine Medical Center. Urinary clearance ratios were calculated from simultaneous collections of blood and urine. Serum PTH assays in the patient and his father were performed by SmithKline Clinical Laboratories by radioimmunoassay, using antiserum to the C-terminal and mid-region of the hormone. The lower limit of detection is 50 pg/mL, and the adult normal value (for normal serum calcium) is 173 _+ 83 pg/mL (1 SD). Infant normal values are thought to be comparable. The PTH assays in the patient's paternal grandmother and half-uncle were performed by BioScience Laboratories, who give the same normal range.

FHH NHP PTH

CASE

Familial hypocalciuric hypocalcemia Neonatal hyperparathyroidism Parathyroid hormone

REPORT

This infant boy was born to unrelated parents after 42 weeks of clinically normal gestation; cesarean section was performed because of mild fetal distress. He appeared normal in the nursery, but had no bowel movementsfor 2 weeks. Physical findingsat that time included mild pectus excavatum, mottled skin, right inguinal hernia, and right undescended testis. X-ray studies revealed a normal colon, but abnormalities of the bones including metaphyseal widening, demineralization, subperiosteal resorption, and metaphyseal irregularity and varus angulation at the hips (Fig. 1, A); the calvarium was thin. Serum calcium concentration was 11