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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 4  |  Page : 273-275

Neonatal “resistance to thyroid hormone (refetoff syndrome)” with novel THRB mutation

Department of Pediatrics, Texas Tech University Health Sciences Center; Department of Pediatrics, El Paso Children's Hospital, El Paso, Texas, USA

Date of Web Publication17-Oct-2017

Correspondence Address:
Devaraj Sambalingam
Department of Pediatrics, Texas Tech University Health Sciences Center, 4800 Alberta Avenue, El Paso 79905, Texas
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_75_17

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Context: Resistance to thyroid hormone (RTH) is an inherited condition with variable target tissue hyposensitivity. We report two cases of preterm neonates with Neonatal resistance to thyroid hormone syndrome, one with a novel mutation in the “Thyroid hormone receptor – Beta (THRB) gene. Case description: Case 1: A male extremely preterm neonate born at 25 weeks and birth weight of 647 grams. The routine newborn screen raised concerns for hypothyroidism and further labs revealed persistently elevated TSH, free T4. The thyroid antibodies were not elevated. MRI brain did not show a pituitary tumor. The baby had persistent tachycardia and poor weight gain. The baby died eventually due to late onset sepsis as a complication of prematurity at 6 weeks of life. DNA sequence testing revealed that one of the copies had c.1299delC mutation in the THRB gene which is predicted to be pathogenic but not reported in literature. Case 2: A very preterm baby girl born at 30 weeks investigated for thyroid dysfunction due to persistent tachycardia and as mother had recently been diagnosed with resistance to thyroid hormone showed Heterozygous positive for p.PRO453THR mutation in THRB gene. Conclusion: This is the first case report of resistance to TH in extremely/very preterm newborn and one of them with novel mutation, suggesting tissue level differential functional thyroid status. Both these heterozygous mutations affect both THRB1 and THRB2 as exon 10 is necessary for both the protein isoforms. With TSH and T4 being elevated and persistent tachycardia, we think that these newborns had “Pituitary specific RTH”.

Keywords: Neonatal resistance to thyroid hormone, Refetoff syndrome, thyroid hormone resistance

How to cite this article:
Sambalingam D, Rao KJ. Neonatal “resistance to thyroid hormone (refetoff syndrome)” with novel THRB mutation. J Clin Neonatol 2017;6:273-5

How to cite this URL:
Sambalingam D, Rao KJ. Neonatal “resistance to thyroid hormone (refetoff syndrome)” with novel THRB mutation. J Clin Neonatol [serial online] 2017 [cited 2021 Feb 26];6:273-5. Available from: https://www.jcnonweb.com/text.asp?2017/6/4/273/216914

  Introduction Top

Thyroid hormone receptor beta (TRβ1 and TRβ2), also known as nuclear receptor Subfamily 1, Group A, Member 2, is a nuclear receptor protein that in humans is encoded by the THRB gene at location 3p24.2. The gene spans over 376 kilobases and has 10 exons. Exons 3–10 code for TRβ1 and TRβ2 proteins. They are nuclear hormone receptors for triiodothyronine (T3). Mutations in this gene are known to be a cause of resistance to thyroid hormone (RTH), also known as Refetoff syndrome [1] characterized by goiter and high levels of circulating thyroid hormone (TH), with normal or slightly elevated thyroid-stimulating hormone (TSH). RTH is estimated to occur in approximately 1/40,000 newborn.[2] Many mutations have been reported in THRB from exons 5–10[3] but none in extremely/late preterm babies. Most of these mutations have autosomal dominant inheritance.

  Case Reports Top

Case 1

The patient is a newborn baby born at 25 weeks and 4 days gestation with a birth weight of 547 g. The baby was born to nonconsanguineous parents. The parents were healthy with no significant medical concerns. The baby was delivered due to severe maternal preeclampsia and intrauterine growth retardation. The baby had problems related to extreme prematurity including respiratory distress syndrome, TPN dependency, and sepsis.

The routine newborn screens (by mass spectrometry) reported an elevated TSH which was confirmed by laboratory tests [Table 1]. Differential diagnoses included either a TSH-secreting tumor (pituitary adenoma) or RTH. The thyroid antibodies (to thyroglobulin, thyroperoxidase, and TSH receptor) were not elevated. Ultrasound of the thyroid gland on day 11 of life showed diffusely enlargement. Magnetic resonance imaging (MRI) of the head on day 25 of life did not reveal a pituitary tumor. Interpretation of MRI results at this weight and gestational age was challenging due to the absence of reference values. The baby exhibited persistent tachycardia (140-170 bpm) and poor weight gain despite adequate calorie intake. The baby died due to fulminant gram-negative sepsis on day 30 of life.
Table 1: Thyroid-stimulating hormone and free thyroxine levels were elevated from birth (case 1)

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DNA sequence testing from exon 3 to exon 10 of the THRB gene by DNA-PCR indicated the patient was positive for one of the copies of the c.1299delC mutation in the THRB gene. It was caused by deletion of cytosine at nucleotide c.1299 in exon 10 of the THRB gene. This single nucleotide deletion caused a frame shift of the coding sequence and premature truncation of the TRβ protein (p. Cys434Alafs*9). This mutation is neither listed in any of the online mutation databases nor described in literature. However, the c.1299delC mutation is predicted to be pathogenic according to the American College of Medical Genetics and Genomics guideline.[4] This mutation seems to affect both TRβ1 and TRβ2 as exon 10 is necessary for both the protein isoforms. In the reported cases of RTH due to THRB mutations, both partial and generalized resistances are as a result of dominant-negative mutations. Unfortunately, neither of the parents could be tested.

Case 2

The patient was a moderately preterm baby born at 30 weeks and 3 days gestation with a birth weight of 1236 g. The baby was delivered due to severe maternal preeclampsia by emergency cesarean section in good condition. Mother was diagnosed with possible RTH soon after this delivery, and she also had learning disability and was being treated for a chronic psychotic illness. Newborn screens (mass spectrometry) for the neonate were normal. The newborn was investigated because of the maternal history and persistent tachycardia. The baby was found to have elevated TSH and free T4 levels [Table 2].
Table 2: Thyroid-stimulating hormone and free thyroxine levels were elevated from birth (case 2)

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DNA sequence testing from exon 3 to exon 10 of the THRB gene was done after they and their flanking regions were amplified from genomic DNA by PCR. This showed that the patient was heterozygous positive for p. Pro453Thr mutation. The nucleotide change from adenosine to cytosine at position 1357 (c.1357C>A) leads to replacement of proline by threonine at amino acid position 453 in exon 10. This mutation has not been reported in preterm newborn and is known to be associated with autosomal dominant RTH [5],[6] (NCBI ClinVar ID: 12550). Both parents were further tested and only the mother had the same mutation. She was never investigated for her chronic psychotic illness and was not clinically hypothyroid until delivery.

  Discussion Top

RTH is usually a dominantly inherited condition resulting from variable target tissue hyposensitivity to TH.[7] There is no treatment available to correct the defect causing THRB. Delayed growth, delayed bone maturation, and learning disabilities, suggestive of hypothyroidism, can be present along with hyperactivity and tachycardia, compatible with thyrotoxicosis. In most cases, partial RTH is adequately compensated for by an increase in the endogenous supply of TH, and thus, treatment is not required.

This will be the first reported case of neonatal TH resistance in extremely preterm and very preterm newborn. Both cases were delivered preterm due to maternal preeclampsia, and maternal thyroid disease can cause preterm deliveries.[8] Among the 2 reported cases, case 1 was secondary to a novel mutation and is the first case of RTH in a very low birth weight baby. Earlier diagnosis was aided by newborn screening. Earlier diagnosis of case 2 with RTH was because of mother being diagnosed in the peripartum period with RTH. Whether pregnancy augments RTH is not known. Both these cases have heterozygous mutations in exon 10 and presented in the neonatal period. Both cases had persistent tachycardia with a baseline: 170–180/min (normal 120–160) and poor growth suggestive of at least partial hyperthyroidism at the tissue level. Screening hearing test (OAE) in the baby in case 2 was normal for both ears. Most cases detected in newborn are due to newborn screening results [9] without clinical symptoms. Serum bilirubin levels were normal for both babies described in the above cases.

Several alternatively spliced transcript variants encoding the same protein have been observed for this gene.[10] There are three human TRβ isoforms TRβ1, TRβ2, and TRβ4, which are differentially expressed in various tissues. TRβ1 is widely expressed in all human tissues but is prominent in brain, thyroid, kidney, and liver. TRβ2 is restricted to the hypothalamus, anterior pituitary, developing brain, cochlea (inner ear), and retina, wherein TRβ2 alone is crucial for the development of mid-wavelength cones photoreceptors, which play a significant role in circadian clock light entrainment and in phase shifting of the circadian oscillator.[11] TRβ4 isoform is expressed in various human tissues but is highly abundant in testis and skeletal muscle.

Feedback on hypothalamic thyrotropin-releasing hormone transcription needs THRB. N-terminally deleted TRβ1 impairs T3-dependent repression of hypothalamus.[12] Exons 5–10 are common determinants for TRβ1 and TRβ2, and many mRNA variants have been reported. Because of the nonsuppressed TSH and TH and signs of tissue level thyrotoxicosis, these cases just represent “Pituitary selective TH resistance-PRTH” (OMIM: 145650, MedGen UID: 333543). Despite striking differences among the clinical presentations of RTH, there is a lack of direct genotype–phenotype correlation, and almost identical THRB gene mutations have been observed in PRTH or GRTH (generalized RTH) patients.[13] The functional effect of most mutations to THRB appears to be reduction in TH binding and/or altering critical domains involved in transcriptional control.[14],[15],[16],[17],[18],[19],[20]

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Conflicts of interest

There are no conflicts of interest.

  References Top

Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: Possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967;27:279-94.  Back to cited text no. 1
Refetoff S, Dumitrescu AM. Syndromes of reduced sensitivity to thyroid hormone: Genetic defects in hormone receptors, cell transporters and deiodination. Best Pract Res Clin Endocrinol Metab 2007;21:277-305.  Back to cited text no. 2
2017. Available from: http://www.omim.org/entry/190160. [Last accessed on 2017 Aug 20].  Back to cited text no. 3
Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008;10:294-300.  Back to cited text no. 4
Maciel LM, Magalhães PK. Thyroid hormone resistance detected by routine neonatal screening. Arq Bras Endocrinol Metabol 2010;54:723-7.  Back to cited text no. 5
Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z, et al. Apatient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab 2015;100:2511-4.  Back to cited text no. 6
Kopp P, Kitajima K, Jameson JL. Syndrome of Resistance to Thyroid Hormone: Insights into Thyroid Hormone Action. Vol. 211. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine New York; 1996. p. 49-61.  Back to cited text no. 7
Sheehan PM, Nankervis A, Araujo Júnior E, Da Silva Costa F. Maternal thyroid disease and preterm birth: Systematic review and meta-analysis. J Clin Endocrinol Metab 2015;100:4325-31.  Back to cited text no. 8
Weiss RE, Balzano S, Scherberg NH, Refetoff S. Neonatal detection of generalized resistance to thyroid hormone. JAMA 1990;264:2245-50.  Back to cited text no. 9
THRB Thyroid Hormone Receptor Beta. NCBI; 2016. Available from: http://www.ncbi.nlm.nih.gov/gene/7068?report=full_report. [Last accessed on 2017 Aug 20].  Back to cited text no. 10
Dkhissi-Benyahya O, Gronfier C, De Vanssay W, Flamant F, Cooper HM. Modeling the role of mid-wavelength cones in circadian responses to light. Neuron 2007;53:677-87.  Back to cited text no. 11
Guissouma H, Dupré SM, Becker N, Jeannin E, Seugnet I, Desvergne B, et al. Feedback on hypothalamic TRH transcription is dependent on thyroid hormone receptor N terminus. Mol Endocrinol 2002;16:1652-66.  Back to cited text no. 12
Beck-Peccoz P, Roncoroni R, Mariotti S, Medri G, Marcocci C, Brabant G, et al. Sex hormone-binding globulin measurement in patients with inappropriate secretion of thyrotropin (IST): Evidence against selective pituitary thyroid hormone resistance in nonneoplastic IST. J Clin Endocrinol Metab 1990;71:19-25.  Back to cited text no. 13
Usala SJ, Weintraub BD. Thyroid hormone resistance syndromes. Trends Endocrinol Metab 1991;2:140-4.  Back to cited text no. 14
Weiss RE, Refetoff S. Thyroid hormone resistance. Annu Rev Med 1992;43:363-75.  Back to cited text no. 15
Mixson AJ, Parrilla R, Ransom SC, Wiggs EA, McClaskey JH, Hauser P, et al. Correlations of language abnormalities with localization of mutations in the beta-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: Identification of four new mutations. J Clin Endocrinol Metab 1992;75:1039-45.  Back to cited text no. 16
Sakurai A, Miyamoto T, Refetoff S, DeGroot LJ. Dominant negative transcriptional regulation by a mutant thyroid hormone receptor-beta in a family with generalized resistance to thyroid hormone. Mol Endocrinol 1990;4:1988-94.  Back to cited text no. 17
Chatterjee VK, Nagaya T, Madison LD, Datta S, Rentoumis A, Jameson JL, et al. Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors. J Clin Invest 1991;87:1977-84.  Back to cited text no. 18
Adams M, Nagaya T, Tone Y, Jameson JL, Chatterjee VK. Functional properties of a novel mutant thyroid hormone receptor in a family with generalized thyroid hormone resistance syndrome. Clin Endocrinol (Oxf) 1992;36:281-9.  Back to cited text no. 19
Meier CA, Dickstein BM, Ashizawa K, McClaskey JH, Muchmore P, Ransom SC, et al. Variable transcriptional activity and ligand binding of mutant beta 1 3,5,3'-triiodothyronine receptors from four families with generalized resistance to thyroid hormone. Mol Endocrinol 1992;6:248-58.  Back to cited text no. 20


  [Table 1], [Table 2]

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