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November 7, 1990, Vol 264, No. 17 >
ARTICLE | November 7, 1990

Neonatal Detection of Generalized Resistance to Thyroid Hormone FREE

Roy E. Weiss, MD, PhD; Stefano Balzano, MD; Neal H. Scherberg, PhD; Samuel Refetoff, MD
[+] Author Affiliations

Reprint requests to Box 138, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637 (Dr Weiss).


JAMA. 1990;264(17):2245-2250. doi:10.1001/jama.1990.03450170093029
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Published online
Article
References

Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin. Often these test results are obtained because of short stature, decreased intelligence, and/or hyperactivity with learning disability noted in childhood and adolescence, or because of goiter in adulthood. We detected GRTH at birth by analysis of blood obtained during routine neonatal screening. The proposita, born to a mother with GRTH, had a thyrotropin level of 26 mU/L and a corresponding thyroxine concentration of 656 nmol/L (normal, 84 to 232 nmol/L). Administration of thyroid hormone in doses eightfold to 10-fold above replacement levels (liothyronine sodium, 21 μ/kg per day, and levothyroxine sodium, 44 μg/kg per day) were required to reduce serum thyrotropin to normal levels without induction of hypermetabolism. This case, and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH, suggest that measurement of thyroxine at birth, in conjunction with thyrotropin, could allow the early detection of GRTH.

(JAMA. 1990;264:2245-2250)

REFERENCES

1 +
Lamberg BA, Liewendahl K.  Thyroid hormone resistance . Ann Clin Res. 1980;;12:243-253.
2 +
Weintraub BD, Gershengorn MC, Kourides IA, Fein H.  Inappropriate secretion of thyroid stimulating hormone . Ann Intern Med. 1981;;95:339-351.
3 +
Refetoff S.  Syndromes of thyroid hormone resistance . Am J Physiol. 1982;;243:E88-E98.
4 +
Refetoff S.  Thyroid hormone resistance syndromes . In: Ingbar SH, Braverman LE, eds. Werner's The Thyroid: A Fundamental and Clinical Text . New York, NY: JB Lippincott Co; 1986;:1292-1307.
5 +
Maberly GF, Eastman CJ, Smith HC, Waite K, Wilke TJ.  Thyroid hormone binding to putative nuclear receptors in human mononuclear blood cells . Aust J Exp Biol Med Sci. 1982;;60:113-115.
6 +
Kasai Y, Aritaki S, Utsunomiya N, Matsuno T.  Twin sisters with Refetoff's syndrome . J Jpn Pediatr Assoc. 1983;;87:1203-1212.
7 +
Pagliara AS, Caplan RH, Gundersen CB, Wickus GG, Elston ACV III.  Peripheral resistance to thyroid hormone in a family: heterogeneity of clinical presentation . J Pediatr. 1983;;103:228-232.
8 +
Guinet P, Tourniaire J, Fleury-Goyon MC, Brièire J, Navarro D, Chalendar D.  Le syndrome de résistance aux hormones thyroïdiennes . Med Int. 1984;;19:11-18.
9 +
Ohzeki T, Egi S, Egawa M, Hachimori K.  Thyroid hormone unresponsiveness in two siblings with intrauterine growth retardation and exophthalmos . Eur J Pediatr. 1984;;141:181-183.
10 +
Gheri RG, Bianchi R, Mariani G, et al.  A new case of familial partial generalized resistance to thyroid hormones: study of 3,5,3,-triiodothyronine (T3) binding to lymphocyte and skin fibroblast nuclei and in vivo conversion to thyroxine to T3 . J Clin Endocrinol Metab. 1984;;58:563-569.
11 +
Bajorunas DR, Rosner W, Kourides IA.  Use of bromocriptine in a patient with generalized resistance to thyroid hormone . J Clin Endocrinol Metab. 1984;;58:731-735.
12 +
Takamatsu J, Miki K, Isaji H, et al.  Resistance of peripheral tissues and pituitary to thyroid hormone . Endocrinol Jpn. 1984;;31:435-441.
13 +
Takamatsu J, Majima M, Miki K, Kuma K, Mozai T.  Serum ferritin as a marker of thyroid hormone action on peripheral tissues . J Clin Endocrinol Metab. 1985;;61:672-676.
14 +
Nemec J, Kopecky A, Váña S, Bednár J.  Rodinna rezistence k tyreoidalnim hormonum . Cesk Pediatr. 1984;;39:36-39.
15 +
Sisson JC, Hopwood NJ, Sauder SE, Shapiro B.  Patterns of prolactin secretion in the syndrome of general resistance to thyroid hormones . J Clin Endocrinol Metab. 1984;;58:1188-1192.
16 +
Menezes-Ferreira MM, Eil C, Wortsman J, Weintraub BD.  Decreased nuclear uptake of [125I] triiodo-L-thyronine in fibroblasts from patients with peripheral thyroid hormone resistance . J Clin Endocrinol Metab. 1984;;59:1081-1087.
17 +
Gharib H, Klee GG.  Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones . Mayo Clin Proc. 1985;;60:9-15.
18 +
Magner JA, Petrick P, Menezes-Ferreira MM, Stelling M, Weintraub BD.  Familial generalized resistance to thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125I] triiodothyronine to fibroblast nuclei . J Endocrinol Invest. 1986;; 9:459-470.
19 +
Hopwood NJ, Sauder SE, Shapiro B, Sisson JC.  Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis? Pediatrics. 1986;;78:1114-1122.
20 +
Hughes IA, Ichikawa K, DeGroot LJ, et al.  Non-adenomatous inappropriate TSH hypersecretion and euthyroidism requires no treatment . Clin Endocrinol. 1987;;27:475-483.
21 +
Elte JWF, Bos F, Docter R.  Familial generalized resistance to thyroid hormones: occurrence in three generations . Neth J Med. 1987;;31:218-227.
22 +
Sarne DH, Refetoff S, Rosenfield RL, Farriaux JP.  Sex-hormone binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes following short-term triidothyronine administration . J Clin Endocrinol Metab. 1988;;66:740-746.
23 +
Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG.  Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies . Am J Med. 1989;;86:289-296.
24 +
Gross A, Schvartz C, Ostermann G, Leutenegger M.  About a familial history of global resistance to thyroid hormone . Program and abstracts of the Ninth International Thyroid Congress; September 1-6, 1985; São Paulo, Brazil . Abstract 365.
25 +
Marel GM, Zafar MS, Miller JM.  Peripheral and pituitary resistance to thyroid hormone in male members of a kindred . Endocrinology. 1982;;111: T49. Abstract.
26 +
Tisell L, Caidahl K, Liudstedt G, et al. Familial thyroid hormone resistance in three women treated for hyperthyroidism. Acta Endocrinol Suppl. 1983;256:61.
27 +
Fisher DA.  Thyroid physiology in the prenatal period and during childhood . In: Ingbar SH, Braverman LB, eds. The Thyroid. 5th ed. New York, NY: JB Lippincott Co; 1986;:1387-1395.
28 +
Bode HH, Danon M, Weintraub BD, Maloof F, Crawford JD.  Partial target organ resistance to thyroid hormone . J Clin Invest. 1973;;52:776-782.
29 +
Cooper DS, Ladenson PW, Nisula BC, Dunn JF, Chapman EM, Ridgway EC.  Familial thyroid hormone resistance . Metabolism. 1982;;31:504.
30 +
Refetoff S, Salazar A, Smith TJ, Scherberg NH.  The consequences of inappropriate treatment due to failure to recognize the syndrome of pituitary and peripheral tissue resistance to thyroid hormone . Metabolism. 1983;;32:822-834.
31 +
Bantle JP, Seeling S, Mariash CN, Ulstrom RA, Oppenheimer JH.  Resistance to thyroid hormones: a disorder frequently confused with Graves' disease . Arch Intern Med. 1982;;142:1867-1871.
32 +
Refetoff S, DeWind LT, DeGroot LJ.  Familial syndrome combining deaf-mutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone . J Clin Endocrinol Metab. 1967;;27:279-294.
33 +
Kaplowitz PB, D'Ercole AJ, Utiger RD.  Peripheral resistance to thyroid hormone in an infant . J Pediatr. 1981;;53:958-963.
34 +
Robin NI, Hagen SR, Collaço F, Refetoff S, Selenkow HA.  Serum tests for measurement of thyroid function . Hormones. 1971;;2:266-279.
35 +
Refetoff S.  Thyroid function tests and effects of drugs on the thyroid . In: DeGroot LJ, ed. Endocrinology . Philadelphia, Pa: WB Saunders Co; 1989;: 590-639.
36 +
Sakurai A, Takeda K, Ain K, et al.  Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor β . Proc Natl Acad Sci U S A. 1989;;86:8977-8981.
37 +
Sarne DH.  Peripheral tissue responses to T3 in generalized resistance to thyroid hormone (GRTH) . Endocrinology. 1988;;121:T74. Abstract.
38 +
Johnsonbaugh RE, Bryan N, Hierlwimmer UR, Georges LP.  Premature craniosynostosis: a common complication of juvenile thyrotoxicosis . J Pediatr. 1978;;93:188-191.
39 +
Fisher DA, Dussault JH, Foley TP, et al.  Screening for congenital hypothyroidism: results of screening one million North American infants . J Pediatr. 1979;;94:700-705.
40 +
Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH.  Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program . J Pediatr. 1986;;109:959-964.
41 +
Clorieux J, Desjardins M, Letarte J, Morissette J, Dussault JH.  Useful parameters to predict the eventual mental outcome of hypothyroid children . Pediatr Res. 1988;;24:6-8.
42 +
Sarne DH, Sobieszczyk S, Ain KB, Refetoff S.  Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short-term triiodothyronine suppression . J Clin Endocrinol Metab. 1990;;70:1305-1311.
43 +
Viscardi RM, Shea M, Sriwantanakul K, Mc-Cormick K.  Hyperthyroxinemia in newborns due to excess thyroxine-binding globulin . N Engl J Med. 1983;;309:897-899.
44 +
Griffiths KD, Virdi NK, Rayner PHW, Green A.  Neonatal screening for congenital hypothyroidism by measurement of plasma thyroxine and thyroid stimulating hormone concentrations . Br Med J. 1985;;291:117-120.
45 +
Ruiz M, Rajatanavin R, Young RA, et al.  Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis . N Engl J Med. 1982;;306:635-639.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

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1 +
Lamberg BA, Liewendahl K.  Thyroid hormone resistance . Ann Clin Res. 1980;;12:243-253.
2 +
Weintraub BD, Gershengorn MC, Kourides IA, Fein H.  Inappropriate secretion of thyroid stimulating hormone . Ann Intern Med. 1981;;95:339-351.
3 +
Refetoff S.  Syndromes of thyroid hormone resistance . Am J Physiol. 1982;;243:E88-E98.
4 +
Refetoff S.  Thyroid hormone resistance syndromes . In: Ingbar SH, Braverman LE, eds. Werner's The Thyroid: A Fundamental and Clinical Text . New York, NY: JB Lippincott Co; 1986;:1292-1307.
5 +
Maberly GF, Eastman CJ, Smith HC, Waite K, Wilke TJ.  Thyroid hormone binding to putative nuclear receptors in human mononuclear blood cells . Aust J Exp Biol Med Sci. 1982;;60:113-115.
6 +
Kasai Y, Aritaki S, Utsunomiya N, Matsuno T.  Twin sisters with Refetoff's syndrome . J Jpn Pediatr Assoc. 1983;;87:1203-1212.
7 +
Pagliara AS, Caplan RH, Gundersen CB, Wickus GG, Elston ACV III.  Peripheral resistance to thyroid hormone in a family: heterogeneity of clinical presentation . J Pediatr. 1983;;103:228-232.
8 +
Guinet P, Tourniaire J, Fleury-Goyon MC, Brièire J, Navarro D, Chalendar D.  Le syndrome de résistance aux hormones thyroïdiennes . Med Int. 1984;;19:11-18.
9 +
Ohzeki T, Egi S, Egawa M, Hachimori K.  Thyroid hormone unresponsiveness in two siblings with intrauterine growth retardation and exophthalmos . Eur J Pediatr. 1984;;141:181-183.
10 +
Gheri RG, Bianchi R, Mariani G, et al.  A new case of familial partial generalized resistance to thyroid hormones: study of 3,5,3,-triiodothyronine (T3) binding to lymphocyte and skin fibroblast nuclei and in vivo conversion to thyroxine to T3 . J Clin Endocrinol Metab. 1984;;58:563-569.
11 +
Bajorunas DR, Rosner W, Kourides IA.  Use of bromocriptine in a patient with generalized resistance to thyroid hormone . J Clin Endocrinol Metab. 1984;;58:731-735.
12 +
Takamatsu J, Miki K, Isaji H, et al.  Resistance of peripheral tissues and pituitary to thyroid hormone . Endocrinol Jpn. 1984;;31:435-441.
13 +
Takamatsu J, Majima M, Miki K, Kuma K, Mozai T.  Serum ferritin as a marker of thyroid hormone action on peripheral tissues . J Clin Endocrinol Metab. 1985;;61:672-676.
14 +
Nemec J, Kopecky A, Váña S, Bednár J.  Rodinna rezistence k tyreoidalnim hormonum . Cesk Pediatr. 1984;;39:36-39.
15 +
Sisson JC, Hopwood NJ, Sauder SE, Shapiro B.  Patterns of prolactin secretion in the syndrome of general resistance to thyroid hormones . J Clin Endocrinol Metab. 1984;;58:1188-1192.
16 +
Menezes-Ferreira MM, Eil C, Wortsman J, Weintraub BD.  Decreased nuclear uptake of [125I] triiodo-L-thyronine in fibroblasts from patients with peripheral thyroid hormone resistance . J Clin Endocrinol Metab. 1984;;59:1081-1087.
17 +
Gharib H, Klee GG.  Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones . Mayo Clin Proc. 1985;;60:9-15.
18 +
Magner JA, Petrick P, Menezes-Ferreira MM, Stelling M, Weintraub BD.  Familial generalized resistance to thyroid hormones: report of three kindreds and correlation of patterns of affected tissues with the binding of [125I] triiodothyronine to fibroblast nuclei . J Endocrinol Invest. 1986;; 9:459-470.
19 +
Hopwood NJ, Sauder SE, Shapiro B, Sisson JC.  Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis? Pediatrics. 1986;;78:1114-1122.
20 +
Hughes IA, Ichikawa K, DeGroot LJ, et al.  Non-adenomatous inappropriate TSH hypersecretion and euthyroidism requires no treatment . Clin Endocrinol. 1987;;27:475-483.
21 +
Elte JWF, Bos F, Docter R.  Familial generalized resistance to thyroid hormones: occurrence in three generations . Neth J Med. 1987;;31:218-227.
22 +
Sarne DH, Refetoff S, Rosenfield RL, Farriaux JP.  Sex-hormone binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes following short-term triidothyronine administration . J Clin Endocrinol Metab. 1988;;66:740-746.
23 +
Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG.  Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies . Am J Med. 1989;;86:289-296.
24 +
Gross A, Schvartz C, Ostermann G, Leutenegger M.  About a familial history of global resistance to thyroid hormone . Program and abstracts of the Ninth International Thyroid Congress; September 1-6, 1985; São Paulo, Brazil . Abstract 365.
25 +
Marel GM, Zafar MS, Miller JM.  Peripheral and pituitary resistance to thyroid hormone in male members of a kindred . Endocrinology. 1982;;111: T49. Abstract.
26 +
Tisell L, Caidahl K, Liudstedt G, et al. Familial thyroid hormone resistance in three women treated for hyperthyroidism. Acta Endocrinol Suppl. 1983;256:61.
27 +
Fisher DA.  Thyroid physiology in the prenatal period and during childhood . In: Ingbar SH, Braverman LB, eds. The Thyroid. 5th ed. New York, NY: JB Lippincott Co; 1986;:1387-1395.
28 +
Bode HH, Danon M, Weintraub BD, Maloof F, Crawford JD.  Partial target organ resistance to thyroid hormone . J Clin Invest. 1973;;52:776-782.
29 +
Cooper DS, Ladenson PW, Nisula BC, Dunn JF, Chapman EM, Ridgway EC.  Familial thyroid hormone resistance . Metabolism. 1982;;31:504.
30 +
Refetoff S, Salazar A, Smith TJ, Scherberg NH.  The consequences of inappropriate treatment due to failure to recognize the syndrome of pituitary and peripheral tissue resistance to thyroid hormone . Metabolism. 1983;;32:822-834.
31 +
Bantle JP, Seeling S, Mariash CN, Ulstrom RA, Oppenheimer JH.  Resistance to thyroid hormones: a disorder frequently confused with Graves' disease . Arch Intern Med. 1982;;142:1867-1871.
32 +
Refetoff S, DeWind LT, DeGroot LJ.  Familial syndrome combining deaf-mutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone . J Clin Endocrinol Metab. 1967;;27:279-294.
33 +
Kaplowitz PB, D'Ercole AJ, Utiger RD.  Peripheral resistance to thyroid hormone in an infant . J Pediatr. 1981;;53:958-963.
34 +
Robin NI, Hagen SR, Collaço F, Refetoff S, Selenkow HA.  Serum tests for measurement of thyroid function . Hormones. 1971;;2:266-279.
35 +
Refetoff S.  Thyroid function tests and effects of drugs on the thyroid . In: DeGroot LJ, ed. Endocrinology . Philadelphia, Pa: WB Saunders Co; 1989;: 590-639.
36 +
Sakurai A, Takeda K, Ain K, et al.  Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor β . Proc Natl Acad Sci U S A. 1989;;86:8977-8981.
37 +
Sarne DH.  Peripheral tissue responses to T3 in generalized resistance to thyroid hormone (GRTH) . Endocrinology. 1988;;121:T74. Abstract.
38 +
Johnsonbaugh RE, Bryan N, Hierlwimmer UR, Georges LP.  Premature craniosynostosis: a common complication of juvenile thyrotoxicosis . J Pediatr. 1978;;93:188-191.
39 +
Fisher DA, Dussault JH, Foley TP, et al.  Screening for congenital hypothyroidism: results of screening one million North American infants . J Pediatr. 1979;;94:700-705.
40 +
Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH.  Detection of congenital hypopituitary hypothyroidism: ten-year experience in the Northwest Regional Screening Program . J Pediatr. 1986;;109:959-964.
41 +
Clorieux J, Desjardins M, Letarte J, Morissette J, Dussault JH.  Useful parameters to predict the eventual mental outcome of hypothyroid children . Pediatr Res. 1988;;24:6-8.
42 +
Sarne DH, Sobieszczyk S, Ain KB, Refetoff S.  Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short-term triiodothyronine suppression . J Clin Endocrinol Metab. 1990;;70:1305-1311.
43 +
Viscardi RM, Shea M, Sriwantanakul K, Mc-Cormick K.  Hyperthyroxinemia in newborns due to excess thyroxine-binding globulin . N Engl J Med. 1983;;309:897-899.
44 +
Griffiths KD, Virdi NK, Rayner PHW, Green A.  Neonatal screening for congenital hypothyroidism by measurement of plasma thyroxine and thyroid stimulating hormone concentrations . Br Med J. 1985;;291:117-120.
45 +
Ruiz M, Rajatanavin R, Young RA, et al.  Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis . N Engl J Med. 1982;;306:635-639.

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