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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3264-3266
Copyright © 1997 by The Endocrine Society

Original Studies

Thyroid Function in Rubinstein-Taybi Syndrome1

David P. Olson and Ronald J. Koenig

Division of Endocrinology and Metabolism (D.P.O., R.J.K.), University of Michigan Medical Center, Ann Arbor, Michigan 48109-0678

Address all correspondence and requests for reprints to: Dr. Ronald J. Koenig, University of Michigan Medical Center, 5560 MSRB-2, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0678. E-mail: rkoenig{at}umich.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Rubinstein-Taybi syndrome (RTS) is a genetic syndrome characterized by broad thumbs and halluces, growth retardation, mental retardation, and craniofacial abnormalities. This condition recently was found to be caused by mutations in the gene encoding cAMP response element-binding protein (CREB)-binding protein. As CREB-binding protein has been shown to be a critical coactivator for thyroid hormone receptors, it is plausible that RTS would be characterized by thyroid hormone resistance. In fact, features of RTS, such as mental retardation and short stature, are consistent with thyroid hormone deficiency or resistance. To assess the function of the thyroid axis in RTS, free T4 and TSH were measured in 12 subjects with this syndrome. The free T4 level was normal in all 12 (mean ± SD, 0.97 ± 0.20 ng/dL; normal range, 0.73–1.79), as was the TSH level (2.24 ± 0.87 µU/mL; normal range, 0.3–6.5). Thus, overt thyroid hormone resistance does not appear to be a typical feature of RTS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RUBINSTEIN-TAYBI syndrome (RTS) is a genetic syndrome, the main features of which include broad thumbs and halluces, mental retardation, growth retardation, developmental delay, microcephaly, and craniofacial abnormalities (1). The typical craniofacial abnormalities include a high arched palate, small mouth, thin upper lip, antimongoloid eye slant, high arched and heavy eyebrows, beaked nose, broad bridge of nose, mandibular recession, hypertelorism, and prominent forehead. Other clinical problems include cardiac abnormalities (2), keloid formation (1), skeletal abnormalities (1), increased risk of tumors (3), cryptorchidism (1), stiff awkward gait (1), nevus flammeus (1), and eye abnormalities (4). Recently, mutations in the gene encoding cAMP response element-binding protein (CREB)-binding protein (CBP) were found to cause RTS (5). CBP is a 265-kDa nuclear protein (6) that appears to be a transcriptional coactivator for multiple signaling pathways, including cAMP (6, 7), nuclear hormone receptors (8), STAT (signal transducer and activator of transcription) proteins (9), and activating protein-1 (7). Given that CBP appears to be a critical coactivator for thyroid hormone receptors (8), an abnormally functioning CBP may be expected to result in thyroid hormone resistance in RTS. Indeed, several features of RTS, such as mental retardation and growth retardation, could be caused at least in part by hypothyroidism at the target tissue level. Therefore, this study was designed to test the hypothesis that RTS is associated with thyroid hormone resistance.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Experimental subjects

Twelve subjects with classical RTS were studied. At the time of the study none of the subjects was taking any medicines, and all were in their basal state of health. The clinical features of the subjects are presented in Table 1Go.


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  		Table 1. Clinical features of 12 subjects with Rubinstein-Taybi syndrome

 
Methods

Serum free T4 and TSH were measured in the Clinical Chemistry Laboratory at the University of Michigan Medical Center using routine assays (ACS:180 Free T4 and TSH, Chiron Diagnostics, East Walpole, MA). The normal range for free T4 is 0.73–1.79 ng/dL, and that for TSH is 0.3–6.5 µU/mL. Four subjects came to the University of Michigan to have their blood drawn. The other eight subjects had their blood drawn by their local physicians, and the sera were shipped cold overnight for analysis at the University of Michigan the following day. Dynamic testing of thyroid function and radionuclide studies were not performed. Informed consent was obtained from the parents of all subjects. These studies were approved by the University of Michigan Medical School institutional review board.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum free T4 levels were normal in all subjects, with a mean and SD of 0.97 and 0.20 ng/dL (Fig. 1Go). Serum TSH levels also were normal in all subjects, with a mean and SD of 2.24 and 0.87 µU/mL (Fig. 1Go).



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  		Figure 1. Serum free T4 and TSH levels in 12 patients with RTS. Normal ranges are indicated by the dashed lines. Free T4 and TSH were normal in all 12 subjects.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
CBP was originally described as a protein that binds phosphorylated CREB and functions as a critical coactivator of cAMP-regulated transcription by CREB (6). Since that time, CBP has been implicated as a transcriptional coactivator for numerous other nuclear signaling pathways, including those regulated by the nuclear hormone receptors (8), activating protein-1 (7), and STAT proteins (9). The exact mechanism by which CBP activates transcription is not known, although several activation domains have been identified (10). In addition, CBP recently has been demonstrated to possess histone acetyl transferase activity (11, 12), and thus, it may be involved in altering chromatin structure.

Mutations in the gene encoding CBP have been demonstrated to cause RTS (5). These mutations vary from large deletions to point mutations, and it is reasonable to speculate that the phenotypic diversity of RTS is at least in part explained by the diverse array of CBP mutations. However, it is not known whether all cases of RTS are caused by CBP mutations, and the current group of subjects was not tested for such mutations. In any case, as CBP appears to be involved in many transcription pathways, a diverse array of nuclear regulatory abnormalities may underlie the RTS phenotype. We hypothesized that one such abnormality would involve defective signaling by T3. This appeared attractive not only because CBP appears to be important in thyroid hormone receptor action (8), but also because some of the clinical features of RTS (e.g. mental retardation and growth retardation) are compatible with thyroid hormone deficiency (13) or resistance (14, 15) in early childhood. A large number of families with thyroid hormone resistance due to mutations in the T3 receptor ß-gene have been described (14, 15). The hallmark biochemical features of this condition are an elevated free T4 level with a high or high normal TSH level. Thus, we hypothesized that at least a subset of RTS subjects would have similar thyroid function test abnormalities. This would be of potential clinical importance, because appropriately timed therapy with T4 might then improve the clinical outcome.

In contrast to our expectations, all 12 RTS subjects had normal free T4 and TSH levels. The simplest interpretation is that thyroid hormone resistance is rarely if ever a clinical feature of RTS. One needs to consider several possible explanations for why this might be the case. First, RTS is an autosomal dominant syndrome. It is possible that 1 normal CBP allele is sufficient for normal thyroid hormone function. This could be because 1 allele of CBP produces a sufficient quantity of CBP for T3 receptors or because another protein can subserve a similar function. The CBP homolog p300 does have similar functions (8), although obviously 2 normal p300 alleles plus 1 normal CBP allele are not sufficient to prevent the occurrence of RTS. One also must note that serum levels of free T4 and TSH reflect homeostasis within the hypothalamic-pituitary-thyroid axis, but do not necessarily reflect thyroid hormone function in other organs. It thus remains possible that 1 normal CBP allele is sufficient for the function of the hypothalamic-pituitary-thyroid axis, but thyroid hormone function in other organs (e.g. cerebral cortex and bone) may not be normal.

In addition, the interpretation that normal thyroid function tests signify normal function of the hypothalamic-pituitary-thyroid axis may be simplistic. The TSH (16, 17, 18) and TRH (19) genes are negatively regulated by T3, but they also are positively regulated by cAMP (18, 20, 21). Under normal circumstances it is probably reasonable to view cAMP as a tonic stimulator of these genes, with T3-induced negative regulation imposed on top of that baseline stimulation. Given this, the CBP mutations may be expected to impair the tonic cAMP stimulation of TRH and TSH, and thus, T3 would down-regulate these genes from a lower baseline of expression than normal. This lower baseline expression would lead to decreased thyroid hormone secretion, which would result in hypothyroidism and, therefore, signal increased TRH and TSH secretion. (In this regard, it is interesting to note that the free T4 values in these RTS subjects hover about the lower portion of the normal range.) It is possible that the decrease in basal TSH secretion due to faulty cAMP signaling may more or less precisely balance the increase in TSH secretion due to hypothyroidism or thyroid hormone resistance, resulting in apparently normal free T4 and TSH levels. As there is no a priori reason why these opposing effects should precisely neutralize each other, however, it seems more likely that the correct interpretation is the simple one of RTS not being a thyroid hormone-resistant state. Understanding why this may be the case will provide insight into the physiological role of CBP in T3 action. In addition, as cAMP is a second messenger for TSH action, RTS might have been expected to be a TSH-resistant state, which also is not supported by the data. From a clinical perspective, there is currently no evidence to support the use of thyroid hormone therapy in RTS. The possibility that RTS may be associated with resistance to other nuclear hormone signaling pathways, such as retinoid, calcitriol, or steroid pathways, remains to be explored.


   Acknowledgments
 
We thank Dr. Jack H. Rubinstein for providing clinical information on a subset of the patients, and Dr. Jerome Gorski for advice.


   Footnotes
 
1 This work was supported in part by NIH Grant DK44155 and the General Clinical Research Center at the University of Michigan, which is funded by NIH Grant M01-RR-00042. Back

Received May 12, 1997.

Revised June 16, 1997.

Accepted June 26, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Rubinstein JH. 1990 Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957–1988. Am J Med Genet. 6(Suppl):3–16.
  2. Stevens CA, Bhakta MG. 1995 Cardiac abnormalities in the Rubinstein-Taybi syndrome. Am J Med Genet. 59:346–348.[CrossRef][Medline]
  3. Miller RW, Rubinstein JH. 1995 Tumors in Rubinstein-Taybi syndrome. Am J Med Genet. 56:112–115.[CrossRef][Medline]
  4. Roy FH, Summitt RL, Hiatt RL. 1968 Ocular manifestations of the Rubinstein-Taybi syndrome: case report and review of the literature. Arch Ophthal. 79:272–278.[Medline]
  5. Petrij F, Giles RH, Dauwerse HG, et al. 1995 Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 376:348–351.[CrossRef][Medline]
  6. Chrivia JC, Kwok RPS, Lamb N, Hagiwara M, Montminy MR, Goodman RH. 1993 Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 365:855–859.[CrossRef][Medline]
  7. Arias J, Alberts AS, Brindle P, et al. 1994 Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature. 370:226–229.[CrossRef][Medline]
  8. Chakravarti D, LaMorte VJ, Nelson MC, et al. 1996 Role of CBP/p300 in nuclear receptor signalling. Nature. 383:99–103.[CrossRef][Medline]
  9. Bhattacharya S, Eckner R, Grossman S, et al. 1996 Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature. 383:344–347.[CrossRef][Medline]
  10. Swope DL, Mueller CL, Chrivia JC. 1996 CREB-binding protein activates transcription through multiple domains. J Biol Chem. 271:28138–28145.[Abstract/Free Full Text]
  11. Bannister AJ, Kouzarides T. 1996 The CBP co-activator is a histone acetyltransferase. Nature. 384:641–643.[CrossRef][Medline]
  12. Ogryzko VV, Schlitz RL, Russanova V, Howard BH, Nakatani Y. 1996 The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 87:953–959.[CrossRef][Medline]
  13. Wellington H. 1995 Thyroid disorders of infancy and childhood. In: Becker KL, ed. Principles and practice of endocrinology and metabolism, 2nd ed. Philadelphia: Lippincott; 421–430.
  14. Refetoff S, Weiss RE, Usala SJ. 1993 The syndromes of resistance to thyroid hormone. Endocr Rev. 14:348–399.[CrossRef][Medline]
  15. Brucker-Davis F, Skarulis MC, Grace MB, et al. 1995 Genetic and clinical features of 42 kindreds with resistance to thyroid hormone: The National Institutes of Health Prospective Study. Ann Intern Med. 123:572–583.[Abstract/Free Full Text]
  16. Shupnik MA, Chin WW, Habener JF, Ridgway EC. 1985 Transcriptional regulation of the thyrotropin subunit genes by thyroid hormone. J Biol Chem. 260:2900–2903.[Abstract/Free Full Text]
  17. Bodenner DL, Mroczynski MA, Weintraub BD, Radovick S, Wondisford FE. 1991 A detailed functional and structural analysis of a major thyroid hormone inhibitory element in the human thyrotropin beta-subunit gene. J Biol Chem. 266:21666–21673.[Abstract/Free Full Text]
  18. Pennathur S, Madison LD, Kay TWH, Jameson JL. 1993 Localization of promoter sequences required for thyrotropin-releasing hormone and thyroid hormone responsiveness of the glycoprotein hormone alpha-gene in primary cultures of rat pituitary cells. Mol Endocrinol. 7:797–805.[Abstract/Free Full Text]
  19. Hollenberg AN, Monden T, Flynn TR, Boers ME, Cohen O, Wondisford FE. 1995 The human thyrotropin-releasing hormone gene is regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements. Mol Endocrinol. 9:540–550.[Abstract]
  20. Steinfelder HJ, Radovick S, Mroczynski MA, et al. 1992 Role of a pituitary-specific transcription factor (Pit-1/GHF-1) or a closely related protein in cAMP regulation of human thyrotropin-beta subunit gene expression. J Clin Invest. 89:409–419.
  21. Stevenin BS, Legradi G, Lee SL, Lechan RM. CREB activates TRH gene transcription and colocalizes with CBP in TRH neurons of the hypothalamic paraventricular nucleus. Proc of the 77th Annual Meet of The Endocrine Soc. 1995; 411.



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