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Prenatal Diagnosis of Thyroid Hormone Resistance

Institute of Endocrine Sciences, Inc. (C.A., L.P., R.R., D.M., P.B.P.), University of Milan, Ospedale Maggiore IRCCS, Istituto Clinico Humanitas, Istituto Auxologico Italiano, IRCCS, and Department of Obstretics and Gynecology (P.Z.), Ospedale S. Paolo, Milan, Italy; Department of Medicine (O.R., T.N.C., V.K.K.C.), University of Cambridge, U.K., and Departments of Pediatrics (F.B.) and Neonatal Intensive Care (F.C.), University of Brescia, Italy

Address all correspondence and request for reprints to: Paolo Beck-Peccoz, M.D., Istituto Clinico Humanitas, Via Manzoni, 56, 20089-Rozzano-Milano, Italy; E-mail: paolo.beck-peccoz{at}humanitas.it

	Abstract

Top Abstract Introduction Case Report Materials and Methods Results Discussion References

 
A 29-yr-old woman with pituitary resistance to thyroid hormones (PRTH) was found to harbor a novel point mutation (T337A) on exon 9 of the thyroid hormone receptor ß (TRß) gene. She presented with symptoms and signs of hyperthyroidism and was successfully treated with 3,5,3'-triiodothyroacetic acid (TRIAC) until the onset of pregnancy. This therapy was then discontinued in order to prevent TRIAC, a compound that crosses the placental barrier, from exerting adverse effects on normal fetal development. However, as the patient showed a recurrence of thyrotoxic features after TRIAC withdrawal, we sought to verify, by means of genetic analysis and hormone measurements, whether the fetus was also affected by RTH, in order to rapidly reinstitute TRIAC therapy, which could potentially be beneficial to both the mother and fetus. At 17 weeks gestation, fetal DNA was extracted from chorionic villi and was used as a template for PCR and restriction analysis together with direct sequencing of the TRß gene. The results indicated that the fetus was also heterozygous for the T337A mutation. Accordingly, TRIAC treatment at a dose of 2.1 mg/day was restarted at 20 weeks gestation. The mother rapidly became euthyroid, and the fetus grew normally up to 24 weeks gestation. At 29 weeks gestation mild growth retardation and fetal goiter were observed, prompting cordocentesis. Circulating fetal TSH was very high (287 mU/L) with a markedly reduced TSH bioactivity (B/I: 1.1 ± 0.4 vs 12.7 ± 1.2), while fetal FT4 concentrations were normal (8.7 pmol/L; normal values in age-matched fetuses: 5–22 pmol/L). Fetal FT3 levels were raised (7.1 pmo/L; normal values in age-matched fetuses: <4 pmol/L), as a consequence of 100% cross-reactivity of TRIAC in the FT3 assay method. To reduce the extremely high circulating TSH levels and fetal goiter, the dose of TRIAC was increased to 3.5 mg/day. To monitor the possible intrauterine hypothyroidism, another cordocentesis was performed at 33 weeks gestation, showing that TSH levels were reduced by 50% (from 287 to 144 mU/L). Furthermore, a simultaneous ultrasound examination revealed a clear reduction in fetal goiter. After this latter cordocentesis, acute complications occured, prompting delivery by cesarean section. The female neonate was critically ill, with multiple-organ failure and respiratory distress syndrome. In addition, a small goiter and biochemical features of hypothyroidism were noted transiently and probably related to the prematurity of the infant. At present, the baby is clinically euthyroid, without goiter, and only exhibits biochemical features of RTH. In summary, although further fetal studies in cases of RTH are necessary to determine whether elevated TSH levels with a markedly reduced bioactivity are a common finding, our data suggest transient biochemical hypothyroidism in RTH during fetal development. Furthermore, we advocate prenatal diagnosis of RTH and adequate treatment of the disease in case of maternal hyperthyroidism, to avoid fetal thyrotrope hyperplasia, reduce fetal goiter, and maintain maternal euthyroidism during pregnancy.

	Introduction

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IT IS recognised that RTH is a dominantly inherited condition associated with mutations in the binding domain of the TRß gene (1, 2). About 78 different receptor mutations have been reported at present, without a clear relationship between genotype and phenotype (3, 4, 5). Two major forms of RTH have been described on the basis of the clinical features: generalized RTH (GRTH) in clinically euthyroid individuals and predominant pituitary RTH (PRTH) in subjects with thyrotoxic features. The biochemical hallmark of both forms of RTH is the presence of elevated FT3 and FT4 levels with unsuppressed TSH concentrations (2, 6). Abnormal responses of TSH and circulating thyroid hormones to T3 suppression (2, 7, 8, 9), as well as increased TSH bioactivity are also features of this rare disorder (10). Altough the biochemical and clinical phenotype of RTH has been well characterized in the adult population, few data are available during the neonatal period (11, 12). Notably, there are no reports in the literature of thyroid function and the physiopathology of the hypothalamic-pituitary-thyroid axis in RTH patients during the fetal life.

With regard to the treatment of RTH, it has been reported that the administration of TRIAC, a thyroid hormone analog, to patients presenting with symptoms and signs of hyperthyroidism is useful in inhibiting the secretion and biological activity of TSH with minimal thyromimetic effects at the level of peripheral tissues (2, 9, 13, 14). As a consequence, TRIAC is generally able to restore euthyroidism and to reduce goiter size in PRTH patients. Recently, it has been shown that TRIAC binds TRß1 with higher affinity than T3, selectively augmenting the function of this receptor (15). Furthermore, cotransfection experiments indicate that TRIAC is more effective than T3 in enhancing the function of mutant TRß1 or overcoming its dominant negative effect, thus providing further experimental support for its use in RTH patients (15).

Heretofore, no data have been available concerning the use of TRIAC during pregnancy in RTH patients. It is not known whether this drug, which crosses the placental barrier (16, 17), can adversely affect the development of a normal fetus or can be beneficial for the growth of an affected RTH fetus.

In this paper, we report the studies carried out in a PRTH patient harboring a novel TRß gene mutation who was successfully treated with TRIAC until the onset of pregnancy, after which therapy was discontinued to avoid potential side effects. However, the recurrence of hyperthyroidism in the patient after TRIAC withdrawal necessitated rapid reintroduction of the treatment and prompted prenatal diagnosis and monitoring of fetal thyroid status during pregnancy.

	Case Report

Top Abstract Introduction Case Report Materials and Methods Results Discussion References

 
In 1993, a 26-yr-old female patient with PRTH was studied. She presented with symptoms and signs of hyperthyroidism, such as anxiety, tachycardia, insomnia, and tremor. The biochemical picture was characterized by elevated serum free T4 and free T3 concentrations (26 pmol/L and 10.2 pmol/L, respectively) associated with an inappropriately normal TSH (1.1 mU/L) level. The TSH response to TRH was exagerated (15.6 mU/L at peak), and thyroid ultrasound was normal. PCR amplification and direct sequencing of the TRß gene from genomic DNA extracted from the peripheral blood leukocytes of the patient indicated heterozygosity for a single nucleotide substitution corresponding to a threonine to alanine mutation at codon 337 (T337A) of the receptor.

Due to the presenting thyrotoxic features, the patient was successfully treated with TRIAC at a dose of 2.1 mg/day for 3 yr, up to the onset of pregnancy. At that time the therapy was discontinued, as TRIAC, which crosses the placental barrier, could have adversely affected the development of a normal fetus. However, after TRIAC withdrawal the patient developed recurrent hyperthyroidism, prompting a rapid fetal genotyping to determine whether it was also affected, enabling reinstitution of TRIAC therapy to restore maternal euthyroidism and for potentially beneficial effects in an affected RTH fetus.

A written informed consent to all procedures done was been obtained by the propositus, and the study was approved by our institutional ethical committee.

	Materials and Methods

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Extraction, direct sequencing and restriction analysis of maternal and fetal DNA

Maternal genomic DNA was extracted from peripheral blood leukocytes using standard techniques. Exon 9 of the TRß gene was amplified by PCR using flanking intronic primers (sense primer: 5'-AGT GAA TTC ACA GAA GGT TAT TCC TAT TGC-3'; antisense primer: 5'-GAT CTG CAG GCT CTT TGG ATG CCC ACT AAC-3'). PCR was performed using 1 µg genomic DNA and 10 pmol of each primer in 50 mL reaction volume containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 500 mM dNTPs, and 0.5 U Taq polymerase (Perkin Elmer Cetus, Norwalk, CT). The reaction conditions were denaturation at 94 C for 3 min, then annealing at 55 C for 30 s, followed by 30 cycles of extension at 72 C for 30 s, denaturation at 94 C for 30 s, and annealing at 60 C for 60 s.

The PCR product was sequenced directly using an internal intronic primer (5'-GTA TGT TGT TCC TGA CTG GC-3') by dideoxy-nucleotide method (Thermosequenase-Amersham Kit Milan, Italy), according to the manufacturer’s instructions.

The presence of the mutation was verified by at least two independent PCR and sequencing reactions.

The prenatal diagnosis of RTH was performed at 17 week_s gestation on fetal DNA extracted by standard methods from chorionic villi. As the presence of the T337A mutation abolishes a restriction site for Mae III, normally present on the wild-type allele, PCR amplicon encompassing exon 9 of TRß was digested with this enzyme and analysed by agarose gel electrophoresis. The result was also confirmed by direct sequencing. Maternal and paternal DNA were used as controls.

Mutagenesis and plasmids

The T337A mutation was generated by site directed mutagenesis of the wild-type hTRß1 cDNA in M13 mp18 as previously described (18) and confirmed by sequencing of individual phage plaques. Both wild-type and mutant receptor cDNAs were subcloned into a vector downstream of the Rous sarcoma virus (RSV) enhancer and promoter for transient transfection assays. The reporter plasmid MAL-TKLUC contains a positively regulated thyroid response element (TRE) from the malic enzyme gene inserted upstream of the viral thymidine kinase gene promoter and luciferase cDNA. The internal control plasmid BOS-ßgal contains the elongation factor-1, a promoter driving expression of the ß-galactosidase gene (19).

Cell culture and transfection assay

JEG-3 cells were cultured in Optimem (Gibco BRL, Paisley, Scotland) containing 2% (vol/vol) fetal calf serum and 1% (vol/vol) Penicillin, Streptomycin, and Fungizone (Gibco BRL, Paisley, Scotland), and 18 h before transfection the medium was changed to Optimem with 2% resin-stripped fetal calf serum. Twenty-four well plates of cells were transfected by a 5 h exposure to calcium phosphate. Cells were exposed to 2 µg MAL-TK-LUC reporter plasmid, together with 100 ng wild-type or mutant receptor expression vector and 100 ng BOS-ßgal. After a further 36 h, with T3 as appropriate, the cells were lysed and extracts assayed for luciferase and ß-galactosidase activity. Luciferase activity was measured using an Autolumat LB 953 luminometer (Berthold, Stevenage, UK) and values normalized with ß-galactosidase activity to correct for transfection efficiency.

T3 binding assay

For the measurement of receptor hormone binding affinity, wild-type and mutant receptor proteins were synthesized from cDNA templates in pGEM7Z using the Promega Corp. TNT coupled transcription and translation system (Promega Corp., Southampton, UK). The ligand binding affinities of in vitro translated wild-type and mutant receptors was measured with ¹²⁵I-T3 in a filter binding assay as previously described (20). Scatchard analyses were performed to generate affinity constants (Ka), and the results are the mean of three or more separate determinations.

Cordocentesis and fetal ultrasonography

Fetal blood was sampled from the placental insertion of the cord by a 22-gauge heparinized needle guided by ultrasonography (Ansaldo 450, equipped with Convex 5 MHz sector transducer) and under aseptic conditions using the technique first described by Daffos et al. (21). This method allows access to the fetal circulation and permits detailed study of fetal biochemistry and metabolism. The reliability of fetal sampling was assessed by analysis of red cell volume with a Coulter counter and confirmed by Kleihauer smears.

Ultrasound examinations were performed using an Ansaldo AU 4 sonograph with Convex 3.5 MHz probe.

Immunoradiometric Assay and measurement of TSH bioactivity

Circulating levels of fetal and maternal TSH, FT4 and FT3 were measured by means of ultrasensitive time-resolved and specific immunofluorimetric assay, using Delfia technology (Delfia® Pharmacia SpA, Milan, Italy).

Maternal and fetal circulating TSH was immunoconcentrated and bioassayed using Chinese Hamster Ovary cells expressing human TSH receptor (CHO-R), as previously described (22).

	Results

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Genetic studies on maternal DNA

Direct sequencing of the TRß gene in the mother indicated heterozygosity for a G to A substitution at nucleotide 1296 in exon 9. This corresponds to a threonine to alanine substitution at codon 337 in the predicted protein sequence.

The ligand-binding affinity of the mutant receptor protein was impaired. Its affinity constant (Ka) was 60% (1.32 x 10¹⁰ M^-1) of the wild-type receptor, which bound T3 with an affinity of 2.2 x 10¹⁰ M^-1.

The function of the T337A mutant receptor was tested by assaying its ability to activate a reporter gene (MAL-TK-LUC) containing a positive TRE in a hormone-dependent manner (Fig. 1). In comparison to the wild-type receptor, the T337A mutant exhibited impaired function with a right-shifted activation profile, but at saturating T3 concentrations (1000 nM) it attained maximal activation comparable to the wild-type receptor.

View larger version (18K): [in this window] [in a new window]   Figure 1. T3-dependent activity of wild-type and T337A mutant receptors on the direct repeat Malic Enzyme TRE. JEG-3 cells were transfected with 500 ng MAL-TK-LUC, 100 ng receptor expression vector, and 100 ng BOS-ßgal. Luciferase activity was measured after exposure to varying concentrations of T3 (0–1000 nM) and normalized for ß-galactosidase activity. The maximum corrected luciferase activity achieved by wild-type receptor () was defined as 100%, and activation by T337A mutant (•) was calculated relative to this. The data shown are the mean of three or more experiments, each done in triplicate.

View larger version (31K): [in this window] [in a new window]   Figure 2. Dominant negative inhibition of wild-type receptor activity by T337A mutant receptor. JEG-3 cells were transfered with 500 ng MAL-TK-LUC, 100 ng BOS-ßgal, and either 100 ng wild-type receptor expression vector alone (white bars) or 50 ng each wild-type and mutant receptor vectors (shaded bars). Corrected luciferase activity was measured after incubation with 1 nM or 1000 nM T3. The maximum fold induction of reporter gene activity achieved by wild-type receptor at 1000 nM T3 was normalized to 100%, and all others values were calculated relative to this.

As shown on the agarose gel depicted in Fig. 3, digestion of maternal and fetal DNA with Mae III produced two fragments of 229 and 184 bp from the wild-type allele together with a 413 bp fragment from the mutant allele resistant to digestion with the above mentioned enzyme. In contrast, paternal DNA digestion showed only bands of 229 and 184 bp, corresponding to two normal alleles.

View larger version (27K): [in this window] [in a new window]   Figure 3. Restriction analysis of exon 9 of the TRß1 gene performed by Mae III. In the upper part of the figure is shown the schematic representation of PCR product of 413 bp, corresponding to exon 9 and part of the 5' and 3'-flanking region. Mae III is able to cut this product in two other fragments of 229 and 184 bp in the wild-type allele, while the presence of the mutation (T337A) leads to the lack of this restriction site. As shown on the pedigree and on the agarose gel (2%), both the mother and the fetus present the wild-type allele represented by the two bands of 229 and 184 bp and the mutant allele of 413 bp undigested by Mae III. The father shows only two bands of 229 and 184 bp, consisting of both normal alleles.

Fetal biochemical and ultrasound studies during TRIAC therapy

As the mother exhibited a recurrence of thyrotoxic features and the fetus was also affected by RTH, TRIAC therapy was reestablished at 20 weeks gestation in a dose of 2.1 mg/day (Table 1). Four weeks later ultrasonography showed a healthy fetus, normal for gestational age, without goiter. No investigations were done at that time.

The maternal TSH ranged from 0.41 to 0.7 mU/L with serum FT4 levels of 10.3 to 12 pmol/L between 24 and 33 weeks of pregnancy.

The measurement of fetal TSH biological activity on CHO-R cells showed a very low ratio between the bioactivity and the immunoreactivity of circulating TSH (B/I: 1.1 ± 0.4) as compared with that found in age-matched normal fetuses (B/I: 12.7 ± 1.2).

Because of the unexpectedly high fetal TSH levels, the maternal TRIAC dose was increased to 3.5 mg/day to reduce the TSH concentrations and goiter size in the fetus. As the very raised TSH values and fetal goiter strongly suggested the presence of concomitant intrauterine primary hypothyroidism, another cordocentesis was performed at 33 weeks gestation, which showed TSH concentrations reduced by 50%, to 144 mU/L. Concomitant ultrasonography revealed a clear reduction in the size of the goiter (thyroid circumference: 55 mm; normal value 48.6–65.8 at 33 weeks gestation). However, during this cordocentesis, several acute life-threatening fetal complications occurred, necessitating a prompt cesarean section at 33 weeks gestation.

At birth, the female newborn exhibited a small goiter and was critically ill with multiple-organ failure encompassing brain, heart, and lung. The Apgar score was very low (1 at 1 min and 3 at 5 min), and the most important clinical problem was the respiratory insufficiency due to respiratory distress syndrome, which required continuous positive airway pressure ventilation. The biochemical picture in the newborn was characterized by persistently elevated TSH concentrations (107.5 mU/L) together with free thyroid hormone levels in the hypothyroid range (FT4: 3.2 pmol/L; FT3: 3.5 pmol/L) (Table 1).

Consequently, L-T4 treatment at a dose of 10 µg/kg/day was started. After two months of treatment, the neonate showed high FT4 and FT3 levels in the presence of normal TSH values (2.0 mU/L) and was clinically euthyroid (Table 1). L-T4 therapy was therefore discontinued, and a month later the biochemical picture was totally compatible with RTH. At present, the 2-yr-old baby is euthyroid, without goiter, and has a normal stature and normal mental development.

	Discussion

Top Abstract Introduction Case Report Materials and Methods Results Discussion References

 
In the present study, we have described the presence of RTH, antenatally diagnosed, in a fetus whose mother was affected by the disease. We have shown that both mother and her fetus are heterozygous for a novel mutation, T337A, which localizes to a central cluster of RTH mutations ( 310 to 349) in the ligand binding domain of TRß. Functional studies indicate that this mutant binds T3 with a lower affinity than wild-type receptor, is transcriptionally impaired with a right-shifted activation profile, and inhibits wild-type receptor function in a dominant negative-manner. Thus, properties of the T337A mutant are analogous to those of the others RTH mutants described hitherto, indicating that it is casually linked to the RTH phenotype in this family. However, although both the mother and child harbored the same receptor defect, they exhibited divergent clinical features, with hyperthyroidism in the mother and euthyroidism in the neonate, underscoring the variable clinical phenotype in this disorder.

Although RTH has been well characterized clinically and biochemically in the adult population, no cases of RTH have been studied during fetal life, and there are very few examples of neonatal diagnosis of the disorder reported. In the few neonates studied heretofore, the biochemical picture seen at birth has appeared similar to that found in adulthood. Thus, RTH newborns can present with either borderline elevated (11) or high TSH concentrations (12) associated with increased total T4 levels. However, it should be noted that this biochemical finding is not specific for RTH, as it is also seen in other clinical conditions, such as inherited TBG excess or familial dysalbuminemic hyperthyroxinemia. Accordingly, further investigations, such as the measurement of serum TBG or free T4 concentrations are required to differentiate RTH from other conditions. In another RTH case, TSH concentrations measured at birth were in the normal range (11), and total T4 was not measured, highlighting the need to measure both these parameters to diagnose the disorder. On the basis of these observations it is clear that the current screening programs for the congenital hypothyroidism are not appropriate for early detection of RTH, as they usually rely on the measurement of only TSH on dried blood spot samples. On the other hand, the low frequency of the disorder and the rarity of clinical complications in RTH cases in the neonatal period suggest that there is no indication for prenatal or early diagnosis of the disease except in the case of a homozygous (25) or a compound heterozygous TRß defect. In our case the need to treat maternal hyperthyroidism prompted prenatal diagnosis of the disease.

As the fetus showed growth retardation and goiter from 29 weeks gestation, fetal thyroid function and growth were monitored by measuring TSH and free thyroid hormone concentrations by cordocentesis and ultrasound examinations, respectively. Testing performed during maternal TRIAC administration showed very high circulating TSH levels (287 mU/L), compatible with primary hypothyroidism (PH). Markedly reduced TSH bioactivity (B/I:1.1 ± 0.4 vs. 12.7 ± 1.2, P < 0.001) was also observed, consistent with this diagnosis (26). It is unlikely that these features were caused by TRIAC therapy as, in congenital hypothyroid fetuses, we demonstrated that TRIAC administration to the mother was capable to reduce the TSH hypersecretion and the size of fetal goiter (17). The transplacental passage of maternal TSH receptor blocking antibodies can be also excluded the presence of fetal goiter.

On the basis of these findings, the possible coexistence of RTH and PH in the fetus was suspected. Such an association could have had dramatic consequences on fetal development, expecially at a neurological level, and thus required a close monitoring with further cordocentesis. However, at postnatal follow-up the biochemical picture altered to that typical of RTH alone. Accordingly, high intrauterine TSH levels with reduced bioactivity may be a feature of RTH per se. The TSH hypersecretion in RTH fetuses may be explained by impaired feedback action of thyroid hormone due to the receptor defect, resulting in low thyroid hormone circulating levels, as in fetuses with congenital hypothyroidism (27) or maternal hypothyroidism induced by PTU administration (28, 29). The decreased TSH bioactivity may be due to impaired thyroid hormone dependent regulation of genes coding for glycosyltransferases involved in the posttranslational modification of pituitary TSH during fetal life (30, 31). In addition, maternal TRIAC administration may also have played a role in reducing TSH bioactivity by modulating the glycosylation of terminal sugar residues (32).

Our case also illustrates the effectiveness of TRIAC administration in both the mother and the fetus. Thus, this agent was able to both restore euthyroidism by attenuating maternal thyrotoxic symptoms and also inhibit fetal TSH secretion by 50%, consequently reducing the fetal goiter markedly. Moreover, TRIAC did not alter fetal heart rate, which was normal before and during treatment.

A surprising finding was the transient hypothyroidism observed in our patient at birth. This may have been related to the prematurity (33 weeks gestation) of the infant. The neonatal hypothyroxinemia might be related to a "sick euthyroid" state associated with impaired oxygenation and metabolism caused by the respiratory distress syndrome. The prompt initiation of L-T4 treatment postnatally was aimed at restoring euthyroidism rapidly to avert adverse sequelae including mental retardation (33, 34). After later L-T4 withdrawal, the patient remained euthyroid, confirming that the hypothyroidism was transient, and the biochemical picture became consistent with RTH alone.

In summary, we have described a novel mutation in the TRß gene associated with the divergent phenotypes of RTH with hyperthyroid features in the mother and intrauterine hypothyroidism in the fetus, and we have confirmed the feasibility of prenatal diagnosis of RTH on chorionic villus sampling using molecular genetic techniques, according to previous data (35).

Finally, our observations suggest a biochemical phenotype of transient hypothyroidism in RTH during fetal development. Although further studies in a larger series of RTH cases in pregnancy are necessary to determine whether high circulating TSH levels with markedly reduced bioactivity are common findings in RTH fetuses, prenatal diagnosis and antenatal TRIAC therapy in this case may have prevented fetal thyrotrope hyperplasia, reduced the fetal goiter, and assured the euthyroid state in the mother during pregnancy.

	Acknowledgments

 
The authors would like to thank Associazìone per la Ricerca in Endocrinologia Clinìca, Milan, Italy, for partially supporting this investigation.

Received July 15, 1998.

Revised October 5, 1998.

Accepted October 22, 1998.

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