Acta PBdiatr 81: 1058-60. 1992
CASE REPORT
TSH-secreting pituitary macroadenoma in an 11-year-old girl A Avramides, A Karapiperis, E Triantafyllidou, S Vayas, A Moshidou and A Vyzantiadis Departments of Endocrinology, Radiology and the Laboratory of B Propedeutic Department of Medicine. Hippokration Hospital. Thessaloniki. Greece
Avramides A, Karapiperis A, Triantafyllidou E, Vayas S, Moshidou A, Vyzantiadis A. TSH-secreting pituitary macroadenoma in an 1 I-year-old girl. Acta Pzdiatr 1992;81:1058-60. Stockholm ISSN 0803-5253 Graves’ disease, multinodular toxic goiter or toxic adenoma are the usual causes of hyperthyroidism in children as well as in adults. We report a case of hyperthyroidism due to TSH-secreting pituitary macroadenoma in an 1 I-year-old girl. The patient was admitted to the Endocrine Department for pituitary function evaluation, five months after transfrontal adenomectomy and pituitary irradiation for a macroadenoma. On admission the patient was clinically hyperthyroid and the work-up established a diagnosis of hyperthyrodism due to TSH-secreting adenoma (high levels of TSH in the face of hyperthyroidism, no TSH response to TRH stimulation, diffuse thyroid goiter without eye signs orpretibial myxedema). Of interest in this case was the fact that (a) she is the youngest patient reported with hyperthyroidism due to a TSH-secreting macroadenoma and (b) hyperthyroidism was diagnosed after adenomectomy. 0 Hyperthyroidism, pituitary macroadenoma, TSH-secreting adenoma A Avramides, Chief of Endocrinology, Hippokration Hospital, 54642 Thessaloniki, Greece
The usual causes of hyperthyroidism in children are those seen in adults (Graves’ disease, multinodular toxic goiter and toxic adenoma) (1). TSH-secreting adenoma is a rare cause of hyperthyroidism. Such an adenoma is infrequent in adults (60 cases, age range 22-58 years) and has not been reported thus far in children (2-6). Characteristically, these adenomas are large, sometimes mixed, their diagnosis is often delayed and the hyperthyroidism they produce is difficult to control with antithyroid drugs.
Case report An 11-year-old girl was admitted to the Endocrine Department in November 1987 for assessment of pituitary function. Eight months prior to admission the patient had started having severe frontal headaches followed by polyuria, polydipsia and diplopia. She was admitted to another hospital, where hemianopia was noted. CAT scanning (Fig. 1) showed hydrocephalus due to a macroadenoma of the pituitary with suprasellar and right temporal lobe extension. A palliative Torkildsen shunt was performed and oral dexamethasone was given. The patient subsequently went to Erlangen, Germany where she was operated on by Professor Fahlbusch on July 23, 1987. A partial transfrontal adenomectomy was performed and the suprasellar extension of the adenoma to the right of the optic chiasm was removed. Histologically the specimen was adenoma
Fig. 1. Preoperative CAT scan of the pituitary showing an adenoma 48 x 62 x 58 mm invading the adjacent bone tissues ofthe sella turcica.
of pituitary in which immunohistochemistry revealed the presence of TSH- and FSH-secreting cells. Hyponatremia and a seizure complicated the postoperative course, during which paresis of the right oculomotor nerve also appeared. External irradiation was given because it had only been possible to partially remove the adenoma. There was some improvement in the paresis of the oculomotor and the patient was discharged on 30 mg of hydrocortisone and 400 mg of carbazepame daily.
1059
TSH-induced hyperthyroidism
ACTA PfiDIATR 8 I ( I 992)
Table 1 . GnRH and TRH test results in the patient, five months after adenomectomy. PRL=Prolactin.
Time (min)
FSH (3-12 mU/ml)a
LH (2-14 mU/ml)a
(< 6 pU/ml)B
PRL (60.6-606 pU/ml)B
GH (0-20 pU/ml)a
0 3 5
4 4 4
I1 10 8
515 666 485
30 28 36
0 30 60 a
TSH
Range of laboratory values.
Table 2. Endocrine work-up of patient five months after adenomectomy.
Patient T4 (nmol/l) Serum cortisol (pmol/l) At 08:OO At 20:OO Serum ACTH (pIU/ml) At 08:OO At 20:OO Urinary 17-ketosteroids (pmo1/24 h) (4 mol/l of cortisol) Synachten stimulation testa At 0 min 3h 6h 12 h 24 h
23 1
Laboratory range 60.5-170 0.13-0.68
0.27 0.1 I 20- 120 110
73 32.2
0.41 1.21 > 1.65 1.18 0.80
17.3-52.0
levels of thyroxine and TSH not responding to TRH stimulation. Carbimazole 40 mg/day and hydrocortisone 30 mg/day were administered orally. One month later she became euthyroid but her hyperthyroidism recurred at 14 and 20 months, when the dose of carbimazole was reduced to 5 mg/day. Repeat pituitary function assessment on March I , 1989 and on September 6, 1989 showed no significant change from the original work-up except that her initially increased G H levels had become normal. On repeat CAT scanning, the size of the pituitary adenoma was found to be reduced to 28 x 38 mm in diameter (half its preoperative size) and the visual fields showed mild improvement.
Discussion
Hyperthyroidism due to TSH-secreting adenoma is rare in adults and has not been described previously in children: there are 60 adult cases reported in the a Synachten 1 mg depot im. literature (age range 22-58 years) (2-5). The present case is the only child with hyperthyroidism due to a macroadenoma secreting TSH. On her admission to our Endocrine Department TSH secretion causing hyperthyroidism has been (January 1988), the patient was a hyperkinetic, well recognized as an entity only in the past 15 years, even developed girl with obvious divergent right strabismus, though there are reports of earlier cases (2-5). Crucial to no signs of adrenarche and prepubertal breasts (Tanner the diagnosis is the availability of a sensitive TSH assay. stage MI-M2). Heart rate was 125/min, blood pressure Diagnostic criteria include: signs and symptoms of 180/70 mmHg and the thyroid was enlarged with increased peripheral metabolic rate; diffuse goiter; homogenous consistency. Neurologic examination increased free thyroxine and triiodothyronine levels showed residual paretic signs of cranial nerves I1 and 111 with simultaneous increased serum TSH levels. and bitemporal hemianopia. The right eye showed great Increased TSH levels in the presence of hyperthyroidism diminution of vision (shadows only) with optic atrophy. is the hallmark of the disease, separating it from Visual acuity in the left eye was normal. common forms of hyperthyroidism, where suppressed Biochemical and hematologic values were normal levels of TSH not responding to TRH administration is except for a high alkaline phosphatase concentration the rule. (469 u/l (normal 80-310 u/l)), consistent with the The differential diagnosis should be made from patient’s age, and low concentrations of cholesterol thyroid hormone resistance (sporadic or familial), a (4.55 mmol/l(2.86-6.50 mmol/l)) and triglycerides (0.51 condition characterized by disturbance in the action of mmol/l (0.86-0.35 mmol/l)). Thyroid scintigraphy, thyroid hormones at the receptor or post-receptor level using 99Tc, showed a homogeneously enlarged thyroid (7, 8). Besides TSH, the pituitary adenoma may secrete with increased 20 min 99Tc uptake of 25% (normal other hormones, such as prolactin or growth hormone < 5 % ) . A CAT scan of the pituitary showed an and, especially the a subunit which is common in adenoma measuring 48 x 62 x 58 mm invading the adja- glycoprotein hormones (TSH, FSH, LH and hCG) (9). cent bone tissues of the sella turcica and the roof of the An increased ratio of a subunit/total TSH is another right eye. The third ventricle was virtually obliterated. characteristic finding in these cases (10, 11). TSHEndocrine work-up (Tables 1 and 2) revealed high secreting adenomas are usually large when they are
1060
A Avramides e[ al.
ACTA P E D I A T R 81 (1992)
diagnosed, probably because small adenomas d o not tumors producing other hormones (prolactin, GH, etc.). cause symptoms and go unrecognized. Of the 60 This way, one may avoid delay in the diagnosis of these adenomas reported in the literature, only 2 were less rare cases. than 1 cm in diameter. (4) Stimulation and suppression tests are useful in the differential diagnosis of TSH-secreting adenomas versus References thyroid hormone resistance. In TSH-secreting adeno1. Toft AD. Hyperthyroidism. Clin Endocrinol Metab 1985;14299 2. Weintraub BD, Gershengorn MC, Kourides IA, Fein H. Inappromas, neither TRH stimulation increases nor exogenous priate secretion of thyroid-stimulating hormone. Ann Intern Med administration of T3 or T4 suppresses TSH secretion. In I98 1;95:339-5 I contrast, in patients with thyroid hormone resistance, 3. Duello TM, Halmi NS. Pituitary adenoma producing thyrotropin TRH stimulation increases TSH secretion and exogeand prolactin. An immunocytochemical and electron microscopic study. Virchows Arch 1977376255-65 nous T3 or T4 administration suppresses it (4).Gluco4. Afrasiabi A, Valenta L, Gwinup G. A TSH secreting pituitary cortoid administration suppresses TSH secretion in all tumour causing hyperthyroidism. Presentation of a case and cases (12). Somatostatin has mixed results (13). In two review of the literature. Acta Endocrinol (Copenh) 1979;92:448of four patients with TSH-secreting adenoma, somato54 statin administration caused partial suppression. 5. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin 1987;16765-92 Bromocriptine suppresses TSH in patients with thyroid 6. Seif FJ, Scherbaun W, Klingler W. Syndrome of elevated thyroid hormone resistance but has no effect on TSH-secreting hormone and TSH blood levels-a case report. Acta Endocrinol adenomas (4). (Copenh) 1978; (Suppl215) 87:81-2 The lack of FSH and LH response after GnRH 7. Bode HH, Danon M, Weintraub BD, Maloof F, Crawford JD. Partial target organ resistance to thyroid hormone. J Clin Invest stimulation in our patient was probably an indication of 1973;52:776-82 delay of puberty, due to partial destruction of the 8. Lamberg BA, Rosengard S,Leiwendhal K, Saarien P, Evered DC. pituitary by the adenoma. Transient G H elevation Familial partial peripheral resistance to thyroid hormones. Acta during the first admission of the patient could have been Endocrinol (Copenh) 1978;87:303- 12 due to psychological stress. Subsequent measurements 9. Vaitukaitis JL, Ross GT, Braunstein GD, Rayford PL. Gonadotropins and their subunits: basic and clinical studies. Recent Prog showed normal G H response and the patient’s growth Horm Res 1976;32:289-331 was normal. 10. Blackman MR, Weintraub BD, Kourides IA, Solano JT, Santner Hyperthyroidism due to TSH-secreting adenoma T, Rosen SW. Discordant elevation of the common alpha subunit differs from Graves’ disease in that there is no ophthalof the glycoprotein hormones compared to beta subunits in serum of uremic patients. J Clin Endocrinol Metab 1981;53:3948 mopathy, no pretibial myxedema and there are no thyroid-binding inhibiting immunoglobulins in patients I 1. Smallridge RC, Wartofsky L, Dimond RC. Inappropriate secretion of thyrotropin: discordance between the suppressive effects of with TSH hyperthyroidism (1 /l3), whereas thyroidcorticosteroids and thyroid hormone. J Clin Endocrinol Metab binding inhibiting immunoglobulins are almost always 1979;48:700-5 12. Reschini E, Giustina G, Cantalamessa L, Peracchi M. Hyperpresent (1 1/14) in patients with Graves’ disease (13). thyroidism with elevated plasma TSH levels and pituitary tumour: The interest in the case presented here lies in the fact with somatostatin. J Clin Endocrinol Metab 1976;43:924-7 that she is the only child reported in the literature with 13. study Kourides IA, Pekonen F, Weintraub BD. Absence of thyroid hyperthyroidism due to TSH-secreting adenoma, and binding immunoglobulins in patients with thyrotropin mediated her hyperthyroidism was diagnosed after adenomechyperthyroidism. J Clin Endocrinol Metab 1980;51:2714 tomy was performed. This case also demonstrates the need to measure TSH levels in all cases of clinical hyperthyroidism, as well as in patients with pituitary Received Nov. 29, 1991. Accepted May 5, 1992
CASE REPORT
TSH-secreting pituitary macroadenoma in an 11-year-old girl A Avramides, A Karapiperis, E Triantafyllidou, S Vayas, A Moshidou and A Vyzantiadis Departments of Endocrinology, Radiology and the Laboratory of B Propedeutic Department of Medicine. Hippokration Hospital. Thessaloniki. Greece
Avramides A, Karapiperis A, Triantafyllidou E, Vayas S, Moshidou A, Vyzantiadis A. TSH-secreting pituitary macroadenoma in an 1 I-year-old girl. Acta Pzdiatr 1992;81:1058-60. Stockholm ISSN 0803-5253 Graves’ disease, multinodular toxic goiter or toxic adenoma are the usual causes of hyperthyroidism in children as well as in adults. We report a case of hyperthyroidism due to TSH-secreting pituitary macroadenoma in an 1 I-year-old girl. The patient was admitted to the Endocrine Department for pituitary function evaluation, five months after transfrontal adenomectomy and pituitary irradiation for a macroadenoma. On admission the patient was clinically hyperthyroid and the work-up established a diagnosis of hyperthyrodism due to TSH-secreting adenoma (high levels of TSH in the face of hyperthyroidism, no TSH response to TRH stimulation, diffuse thyroid goiter without eye signs orpretibial myxedema). Of interest in this case was the fact that (a) she is the youngest patient reported with hyperthyroidism due to a TSH-secreting macroadenoma and (b) hyperthyroidism was diagnosed after adenomectomy. 0 Hyperthyroidism, pituitary macroadenoma, TSH-secreting adenoma A Avramides, Chief of Endocrinology, Hippokration Hospital, 54642 Thessaloniki, Greece
The usual causes of hyperthyroidism in children are those seen in adults (Graves’ disease, multinodular toxic goiter and toxic adenoma) (1). TSH-secreting adenoma is a rare cause of hyperthyroidism. Such an adenoma is infrequent in adults (60 cases, age range 22-58 years) and has not been reported thus far in children (2-6). Characteristically, these adenomas are large, sometimes mixed, their diagnosis is often delayed and the hyperthyroidism they produce is difficult to control with antithyroid drugs.
Case report An 11-year-old girl was admitted to the Endocrine Department in November 1987 for assessment of pituitary function. Eight months prior to admission the patient had started having severe frontal headaches followed by polyuria, polydipsia and diplopia. She was admitted to another hospital, where hemianopia was noted. CAT scanning (Fig. 1) showed hydrocephalus due to a macroadenoma of the pituitary with suprasellar and right temporal lobe extension. A palliative Torkildsen shunt was performed and oral dexamethasone was given. The patient subsequently went to Erlangen, Germany where she was operated on by Professor Fahlbusch on July 23, 1987. A partial transfrontal adenomectomy was performed and the suprasellar extension of the adenoma to the right of the optic chiasm was removed. Histologically the specimen was adenoma
Fig. 1. Preoperative CAT scan of the pituitary showing an adenoma 48 x 62 x 58 mm invading the adjacent bone tissues ofthe sella turcica.
of pituitary in which immunohistochemistry revealed the presence of TSH- and FSH-secreting cells. Hyponatremia and a seizure complicated the postoperative course, during which paresis of the right oculomotor nerve also appeared. External irradiation was given because it had only been possible to partially remove the adenoma. There was some improvement in the paresis of the oculomotor and the patient was discharged on 30 mg of hydrocortisone and 400 mg of carbazepame daily.
1059
TSH-induced hyperthyroidism
ACTA PfiDIATR 8 I ( I 992)
Table 1 . GnRH and TRH test results in the patient, five months after adenomectomy. PRL=Prolactin.
Time (min)
FSH (3-12 mU/ml)a
LH (2-14 mU/ml)a
(< 6 pU/ml)B
PRL (60.6-606 pU/ml)B
GH (0-20 pU/ml)a
0 3 5
4 4 4
I1 10 8
515 666 485
30 28 36
0 30 60 a
TSH
Range of laboratory values.
Table 2. Endocrine work-up of patient five months after adenomectomy.
Patient T4 (nmol/l) Serum cortisol (pmol/l) At 08:OO At 20:OO Serum ACTH (pIU/ml) At 08:OO At 20:OO Urinary 17-ketosteroids (pmo1/24 h) (4 mol/l of cortisol) Synachten stimulation testa At 0 min 3h 6h 12 h 24 h
23 1
Laboratory range 60.5-170 0.13-0.68
0.27 0.1 I 20- 120 110
73 32.2
0.41 1.21 > 1.65 1.18 0.80
17.3-52.0
levels of thyroxine and TSH not responding to TRH stimulation. Carbimazole 40 mg/day and hydrocortisone 30 mg/day were administered orally. One month later she became euthyroid but her hyperthyroidism recurred at 14 and 20 months, when the dose of carbimazole was reduced to 5 mg/day. Repeat pituitary function assessment on March I , 1989 and on September 6, 1989 showed no significant change from the original work-up except that her initially increased G H levels had become normal. On repeat CAT scanning, the size of the pituitary adenoma was found to be reduced to 28 x 38 mm in diameter (half its preoperative size) and the visual fields showed mild improvement.
Discussion
Hyperthyroidism due to TSH-secreting adenoma is rare in adults and has not been described previously in children: there are 60 adult cases reported in the a Synachten 1 mg depot im. literature (age range 22-58 years) (2-5). The present case is the only child with hyperthyroidism due to a macroadenoma secreting TSH. On her admission to our Endocrine Department TSH secretion causing hyperthyroidism has been (January 1988), the patient was a hyperkinetic, well recognized as an entity only in the past 15 years, even developed girl with obvious divergent right strabismus, though there are reports of earlier cases (2-5). Crucial to no signs of adrenarche and prepubertal breasts (Tanner the diagnosis is the availability of a sensitive TSH assay. stage MI-M2). Heart rate was 125/min, blood pressure Diagnostic criteria include: signs and symptoms of 180/70 mmHg and the thyroid was enlarged with increased peripheral metabolic rate; diffuse goiter; homogenous consistency. Neurologic examination increased free thyroxine and triiodothyronine levels showed residual paretic signs of cranial nerves I1 and 111 with simultaneous increased serum TSH levels. and bitemporal hemianopia. The right eye showed great Increased TSH levels in the presence of hyperthyroidism diminution of vision (shadows only) with optic atrophy. is the hallmark of the disease, separating it from Visual acuity in the left eye was normal. common forms of hyperthyroidism, where suppressed Biochemical and hematologic values were normal levels of TSH not responding to TRH administration is except for a high alkaline phosphatase concentration the rule. (469 u/l (normal 80-310 u/l)), consistent with the The differential diagnosis should be made from patient’s age, and low concentrations of cholesterol thyroid hormone resistance (sporadic or familial), a (4.55 mmol/l(2.86-6.50 mmol/l)) and triglycerides (0.51 condition characterized by disturbance in the action of mmol/l (0.86-0.35 mmol/l)). Thyroid scintigraphy, thyroid hormones at the receptor or post-receptor level using 99Tc, showed a homogeneously enlarged thyroid (7, 8). Besides TSH, the pituitary adenoma may secrete with increased 20 min 99Tc uptake of 25% (normal other hormones, such as prolactin or growth hormone < 5 % ) . A CAT scan of the pituitary showed an and, especially the a subunit which is common in adenoma measuring 48 x 62 x 58 mm invading the adja- glycoprotein hormones (TSH, FSH, LH and hCG) (9). cent bone tissues of the sella turcica and the roof of the An increased ratio of a subunit/total TSH is another right eye. The third ventricle was virtually obliterated. characteristic finding in these cases (10, 11). TSHEndocrine work-up (Tables 1 and 2) revealed high secreting adenomas are usually large when they are
1060
A Avramides e[ al.
ACTA P E D I A T R 81 (1992)
diagnosed, probably because small adenomas d o not tumors producing other hormones (prolactin, GH, etc.). cause symptoms and go unrecognized. Of the 60 This way, one may avoid delay in the diagnosis of these adenomas reported in the literature, only 2 were less rare cases. than 1 cm in diameter. (4) Stimulation and suppression tests are useful in the differential diagnosis of TSH-secreting adenomas versus References thyroid hormone resistance. In TSH-secreting adeno1. Toft AD. Hyperthyroidism. Clin Endocrinol Metab 1985;14299 2. Weintraub BD, Gershengorn MC, Kourides IA, Fein H. Inappromas, neither TRH stimulation increases nor exogenous priate secretion of thyroid-stimulating hormone. Ann Intern Med administration of T3 or T4 suppresses TSH secretion. In I98 1;95:339-5 I contrast, in patients with thyroid hormone resistance, 3. Duello TM, Halmi NS. Pituitary adenoma producing thyrotropin TRH stimulation increases TSH secretion and exogeand prolactin. An immunocytochemical and electron microscopic study. Virchows Arch 1977376255-65 nous T3 or T4 administration suppresses it (4).Gluco4. Afrasiabi A, Valenta L, Gwinup G. A TSH secreting pituitary cortoid administration suppresses TSH secretion in all tumour causing hyperthyroidism. Presentation of a case and cases (12). Somatostatin has mixed results (13). In two review of the literature. Acta Endocrinol (Copenh) 1979;92:448of four patients with TSH-secreting adenoma, somato54 statin administration caused partial suppression. 5. Smallridge RC. Thyrotropin-secreting pituitary tumors. Endocrinol Metab Clin 1987;16765-92 Bromocriptine suppresses TSH in patients with thyroid 6. Seif FJ, Scherbaun W, Klingler W. Syndrome of elevated thyroid hormone resistance but has no effect on TSH-secreting hormone and TSH blood levels-a case report. Acta Endocrinol adenomas (4). (Copenh) 1978; (Suppl215) 87:81-2 The lack of FSH and LH response after GnRH 7. Bode HH, Danon M, Weintraub BD, Maloof F, Crawford JD. Partial target organ resistance to thyroid hormone. J Clin Invest stimulation in our patient was probably an indication of 1973;52:776-82 delay of puberty, due to partial destruction of the 8. Lamberg BA, Rosengard S,Leiwendhal K, Saarien P, Evered DC. pituitary by the adenoma. Transient G H elevation Familial partial peripheral resistance to thyroid hormones. Acta during the first admission of the patient could have been Endocrinol (Copenh) 1978;87:303- 12 due to psychological stress. Subsequent measurements 9. Vaitukaitis JL, Ross GT, Braunstein GD, Rayford PL. Gonadotropins and their subunits: basic and clinical studies. Recent Prog showed normal G H response and the patient’s growth Horm Res 1976;32:289-331 was normal. 10. Blackman MR, Weintraub BD, Kourides IA, Solano JT, Santner Hyperthyroidism due to TSH-secreting adenoma T, Rosen SW. Discordant elevation of the common alpha subunit differs from Graves’ disease in that there is no ophthalof the glycoprotein hormones compared to beta subunits in serum of uremic patients. J Clin Endocrinol Metab 1981;53:3948 mopathy, no pretibial myxedema and there are no thyroid-binding inhibiting immunoglobulins in patients I 1. Smallridge RC, Wartofsky L, Dimond RC. Inappropriate secretion of thyrotropin: discordance between the suppressive effects of with TSH hyperthyroidism (1 /l3), whereas thyroidcorticosteroids and thyroid hormone. J Clin Endocrinol Metab binding inhibiting immunoglobulins are almost always 1979;48:700-5 12. Reschini E, Giustina G, Cantalamessa L, Peracchi M. Hyperpresent (1 1/14) in patients with Graves’ disease (13). thyroidism with elevated plasma TSH levels and pituitary tumour: The interest in the case presented here lies in the fact with somatostatin. J Clin Endocrinol Metab 1976;43:924-7 that she is the only child reported in the literature with 13. study Kourides IA, Pekonen F, Weintraub BD. Absence of thyroid hyperthyroidism due to TSH-secreting adenoma, and binding immunoglobulins in patients with thyrotropin mediated her hyperthyroidism was diagnosed after adenomechyperthyroidism. J Clin Endocrinol Metab 1980;51:2714 tomy was performed. This case also demonstrates the need to measure TSH levels in all cases of clinical hyperthyroidism, as well as in patients with pituitary Received Nov. 29, 1991. Accepted May 5, 1992
