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Case Reports

Indian Pediatrics 1998;35:778-782 

Generalized Resistance to Thyroid Hormones


Abdul Hamid Zargar
Bashir Ahmad Laway
Shariq Rashid Masoodi
Muzaffar Maqsood Wani*
Mir Ifitikhar Bashir
Arshad Iqbal Wani
Mohammad Salahuddin**

From the Departments of Endocrinology, Internal Medicine* and Immunology** Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India.

Reprint requests: Prof A.H. Zargar Post Box No.
1098, G.P.O. Srinagar 190 001, Kashmir, India.

Manuscript Received: November 20, 1997; Initial review completed: January 31, 1998; Revision Accepted: March 11, 1998.

 

Generalized resistance to thyroid hormones (GRTH) is an inherited syndrome of reduced target tissue sensitivity to thyroid hormones(1,2). Thyroid hormone resistance was first described in 1967 by Refetoff, Dewind, and De Groot in several siblings in a family with congenital deafness and dysgenetic stippled epiphyses; these siblings were evaluated with clinical suspicion of hypothyroidism but, surprisingly, their thyroid hormone levels were found markedly elevated(3). Because there were no signs or symptoms of thyrotoxicosis, the authors hypothesized the existence of target organ resistance to thyroid hormone to explain the clinical and biochemical findings. In this report we describe a family with generalized. thyroid hormone resistance with variable clinical picture in different siblings.

Case Report

This study was conducted on a couple with 3 children, namely,
A - 9 year male child, B - 5 year female child and C - one year female child. It was the second child B who was first brought to medical attention. She was referred to our endocrine clinic for evaluation of a small swelling in the neck, short stature, and high normal serum total triiodothyronine(T3), elevated total thyroxine (T4) and thyroid stimulating hormone (TSH) by a general practitioner who l1ad failed to interpret the hormone assay. In our clinic, we received a 5 year old female child, product of a consanguineous marriage, whose parents were primarily concerned about her short stature. She was second in birth order born by normal delivery of a full term pregnancy with uneventful neonatal history. At the age of 4 years, parents had noticed a small swelling in the front of neck and delay in her linear growth as compared to other sibs. She had no history of constipation, 'prolonged diarrhea, or vomiting. Clinical examination revealed a female child with pulse of 60 beats/minute, palpable thyroid gland (Grade II), without any features of rickets or malnutrition. Her anthropometric parameters are given in Table I. The systemic examination was unremarkable.

The investigations performed included complete hemogram, detailed urine and stool analysis, detailed serum biochemistry including blood glucose, blood urea nitrogen
(BUN), creatinine, bilirubin, aspartate aminotransferase (AST) alanine amionstransferase (ALT), calcium, phosphorus, and alkaline phosophataseand complete lipidogram. Radiology including X-ray skull, X-ray chest, and X-ray left wrist for bone age was performed.

In view of an available thyroid function test report with high normal total T3 and elevated total T4 and TSH and a possibility of thyroid hormone resistance, the parents and other siblings of the index case were also evaluated. Though being asymptomatic, they were explained about the possible genetic nature of this disorder and were evaluated with consent. All the above mentioned investigations were performed in the father, mother and two siblings of the index case. Fig. 1 shows the index case with two siblings.




TABLE I

Anthropometric Parameters and Thyroid Function Tests in the Subjects Studied

Cases  Chrono-
logic age
(yr) 
Height
(cm)
Height
age (yr) 
Bone
age (yr)
Total T3
Normal
value:
0.070-2.50
ng/ml
Total T4
Normal
value:
5.50-13.50
µg/dl
TSH
Normal
value:
00.50-6.50
'
µIU/ml)
 A 9 124 8 7

     2.82

14.14 1.20

B

5 98 3 3

i.*  1.82

18.62 2.14
         

i.*  1.82

16.67 2.14
         

iii.* 2.03

20.12 2.18
C 1 75 1 1

     2.64

15.28 1.81
D 32 176 - -

     2.16

18.00 0.79
E 28 158 - -

     1.34

9.00 1.09

* T3, T4 and TSH done on three occasions in the index case.
A: Elder brother B: Index case  C: Younger sister D: Father E. Mother



Hormone estimations done included total T3, total T4 and TSH (thrice in the index case) in the parents and the 2 siblings, and insulin tolerance test in the index case only. Insulin tolerance test was performed by giving 0.1 units/kg body weight of regular insulin intravenously and collecting samples for growth hormone and cortisol estimation at 0, 30, 60, 90 and 120 minutes(4).

All hormone estimations were done by sensitive radioimmunoassay; T3, T4, TSH, and growth hormone estimation was performed with radioimmunoassay kits supplied by Bharat Radioactive Isotope Technology, Mumbai, India, while cortisol estimation was done by commercially available kits from Diagnostic Products Corporation, Los Angeles, USA.

The details of anthropometric parameters of the family are given in Table 1. The baseline investigations-complete blood counts, ESR, biochemical parameters including blood glucose, urea nitrogen, creatinine, bilirubin, ALT, AST, calcium, phosphorus and alkaline phosphatase, and urine and stool analysis were within the normal range in all subjects. Only the index case had hypercholesterolemia (serum cholestrol 224 mg/dl). Roentgenogram of skull and chest also were normal. The bone age of the index case was 3 years.

The details of total T3
total T4 and TSH are given in Table I. The peak growth hormone and cortisol after insulin induced hypoglycemia in the index case were 20.4 mg/ dl and 30.2 µg/dl, respectively.

Discussion

In 1942, Fuller Albright used the example of pseudohypoparathyroidism to introduce the concept of hormone resistance syndrome(5). Over the last half a century, clinical, biochemical and molecular studies of hormone resistance syndromes have flourished. The prevalence of thyroid hormone resistance and heterogeneity
of its clinical presentation are now becoming apparent, often resulting in varied and confusing clinical profiles, perhaps due to variable tissue sensitivity(2,6). Generalized resistance to thyroid hormones is a syndrome characterized by elevated 'serum free T3 free T4 and TSH levels and preservation of TSH response to thyroid hormone releasing hormone (TRH) in the absence of clinical manifestations of thyroid hormone excess(2,7,8). Some patients have severe pituitary as well as peripheral thyroid hormone resistance accompanied by signs and symptoms of hypothyroidism(3,8). More commonly, individuals have partial pituitary and peripheral resistance to thyroid hormones and are clinically euthyroid(3,9,10). Occasionally, resistance at the level of pituitary only has been reported; these individuals have symptoms of hyperthyroidism(1,11,12). Rarely selective peripheral resistance without pituitary resistance to thyroid hormones has been re- ported; these patients are clinically hypothyroid and have normal T 3 T4 and TSH levels(13).

 


Fig.
1. Photograph of the index case with two siblings.


The clinical features of GRTH can include attention deficit disorders, delayed skeletal maturation, tachycardia, a variety of somatic abnormalities, and altered metabolic response to thyroid hormones(2,14). Some individuals exhibit a curious combination of physical findings such as delayed skeletal maturation (suggestive of hypothyroidism) and tachycardia, (suggestive of hyperthyroidism), leading to the notion that the degree of hormone resistance varies in different organs(15).

Our index patient had a goiter and some features of hypothyroidism in the form of short stature, bradycardia, and delayed bone age with high normal total T3, elevated total T4 and normal levels of TSH (reproducible on three separate samples). In view of these findings we believe she had sufficient clinical and biochemical suggestion of GRTH. Elevated T3 and T4 could also occur in the presence of excessive(16) or abnormal thyroid binding proteins(17,18) but, in view of features of hypothyroidism (short stature, bradycardia and delayed bone age with palpable goiter), without any other overt cause of these findings, it appears logical to entertain a diagnosis of
GRTH.

On evaluation of rest of the family, elevated thyroid hormones were also found in father, brother, and sister of the index case (Table 1). This suggests an autosomal dominant pattern of inheritance of the disorder in this family. The inheritance pattern in most of the earlier reported families with GRTH is autosomal dominant(6,8,9,10). An autosomal recessive type of inheritance has been reported in only one family(19). Although, cases of sporadic occurrence have been suspected(13,20), it is probable that additional family members might have been found to be affected if studied carefully.

It has long been suspected that GRTH is caused by abnormalities in the human thyroid hormone receptor (hTRβ)(21). However, this hypothesis was confirmed only recently by the identification of mutations in . the hTRβ gene in patients with GRTH(22,23). These mutations alter single aminoacids located in the hormone-binding domain of the hTRβ, resulting in the expression of receptor proteins with either reduced(24) or no(25,26) T3 binding activity.
In individuals with GRTH who do not have goiter (as subjects A, C and D), thyroid hormone production is probably adequate to supply the peripheral tissues. This explains their adequate height age and bone age. The development of a goiter or symptoms of hypothyroidism in these individuals would suggest that the gland is not able to adequately compensate for the resistance to thyroid hormones.

It is suggested that every child who presents with hyperthyroxinemia should have
a serum TSH estimation done and, if it is not suppressed, should be evaluated to exclude thyroid hormone resistance before anti thyroid therapy is initiated. Once the diagnosis has been established, screening of other family members should be under- taken. Increased recognition and evaluation of patients with thyroid hormone resistance is important not only clinically, but should also provide fundamental insights into the regulation of TSH secretion and the action of thyroid hormones.
 

 References



1. Weintruab BD, Gershengorn MC, Kourides IA, Fein H. Inappropriate secretion of thyroid stimulating hormone. Ann Intern Med 1981; 95: 339-351.

2. Refetoff S. Syndromes of thyroid hormone resistance. Am
J Physiol 1982; 243: E88-E98.

3. Refetoff S, Dewind LT, DeGroot LJ. Familial syndrome combining deaf mutism, stippled epiphyses, goiter and abnormality high PBI: Possible target organ refractoriness to thyroid hormone.
J Clin Endocrinol Metab, 1967; 27: 279-294.

4. Wass JAH, Besser M. Tests of pituitary function. In: Endocrinology, 3rd edn. Ed. DeGroot LJ Philadelphia, W.B. Saunders Co, 1995; pp 487-496.

5. Albright F, Burnett CH, Smith PH, Parson W. Pseudohypoparathyroidism-An example of 'Seabright-Bantam Syndrome'.
J Clin Endocrinol Metab. 1942; 30: 922-932.

6. Pagliara AS, Caplan RH, Gunderson CB, Wickus GG, Elston AC. Peripheral resistance to thyroid hormone in a family: Heterogeneity of clinical presentation.
J Pediatr 1983; 103: 228-232.

7. Refetoff S, Thyroid hormone resistance syndromes. In: Werner's The Thyroid: A fundamental and Clinical Text. Eds Ingbar SH, Braverman LE. New York, Lippincott, 1986; pp 1292-1307.

8. Linde R, Alexander N, Island DP, Rabin D. Familial insensitivity of the pituitary and periphery to thyroid hormone: A case report in two generations and a review of the literature. Metabolism 1982; 31: 510- 513.

9. Gharib H, Klee GC. Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones. Mayo Clin Proc. 1985; 60: 9-15.

10. Magner JA, Petrick P, Menezes-Ferreira M, Stelling M, Weintraub BD. Familial generalized resistance to thyroid hormons: Reports of three kind reds and correlation of patterns of affected tissue with the binding of 112s triodothyronine to fibroblast nuclei.
J Endocrinop Invest. 1986; 9: 459-469.

11. Spanheimer RG, Bar RS, Hayford Je. Hyperthyroidism caused by inappropriateate thyrotrophin hypersecretion: Studies in patients with selective pituitary resistance to thyroid hormones. Arch Intern Med 1982; 142: 1283-1286.

12. RosIer A, Letvin Y, Hage C, Gross J, Cerasi E. Familial hyperthyroidism due to inappropriate thyrotropin secretion successfully treated with triiodothyronine.
J Clin Endocrinol Metab 1982; 54: 76-82.

13. Kaplan MM, Swartz SL, Larsen PR. Partial peripheral resistance to thyroid hormone. AmJ Med 1981; 70: 1115-1121.

14. Same DH, Sobieszczyk S, Ain KB, Refetoff S. Serum thyrotrophin and prolactin in the syndrome of generalized resistance to thyroid hormone; responses to the thyrotropin releasing hormone and short term triiodothyronine suppression. J
Clin Endocrinol Metab 1990; 70: 1305- 1311.

15. Jameson JL. Thyroid hormone resistance: Pathophysiology at the molecular level.
J Clin Endocrinol Metab 1992; 74: 708-711.

16. Viscardi RM, Shea M, Sriwantanaku K, Mc Cormick K. Hyperthyroxinemia in newborns due to excess thyroxine-binding globulin. N Engl
J Med 1983; 309: 897- 899.

17. Borst GC, Premachandra BN, Burnam KG, Eilc. Euthyroid familial hyperthyroxinernia due to abnormal thyroid hormone binding protein. Am
J Med 1982; 73: 283-289.

18. Barlow JW, Csicsmann JM, White EL, Funder JW, Stockigt JR. Familial euthyroid thyroxine excess: Characterization of abnormal intermediate affinity thyroxine binding to albumin.
J Clin Endocrinol Metab 1982; 55: 244-250.

19. Refetoff S, DeGroot LJ, Barsano CP. Defective thyroid hormone feedback regulation in the syndrome of peripheral resistance to thyroid hormone.
J Clin Endocrinol Metab 1980; 51: 41-45.

20. Maenpaa J, Liewendahl K. Peripheral in- 'sensitivity to thyroid hormones in an euthyroid girl with goiter. Arch Dis Child 1980; 55: 207-212.

21. Refetoff S, DeGroot LJ, Benard B, DeWind LT. Studies of sibship with apparent hereditary resistance to the intracellular action of thyroid hormone. Metabolsim 1972; 21: 723-756

22. Burman KD, Djuh W, Nicholson D. Rhooms P, Wartofsky L. Identification of a unique mutation in affected members of a family with the syndrome of generalized thyroid hormone resistance [Abstract 848]. In: Proceedings of the 73rd Annual Meeting of the Endocrine Society 1991; p 242.

23. Usala SJ, Wondisford FE, Watson TL, Menke JB, Weintraub BD. Thyroid hormone and DNA binding properties of a mutant C-erbAβ receptor associated with generalized thyroid hormone resistance. Biochem Biophys Res Commun 1990; 171: 575-580.

24. Takeda K, Balzano S, Sakurai A, DeGroot LJ, Refetoff S. Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutation in the thyroid hormone receptr
β-gene and the detection of a new mutation. J Clin Invest 1990; 87: 496-502.

25. Sakurai A, Takeda K, Ain K, Ceccarelli P, Nakai A, Seinu S, 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 USA 1989; 86: 8977- 8981.

26. Usala SJ, Menke JB, Watson TL,
Wondisford FE, Weintraub BD, Berard
J et al. A homozygous deletion in the c-verb Aβ thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance; isolation and characterization of the mutant receptor. Mol Endocrinol1991; 5: 327-335.
 

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