A CASE OF FAMILIAL NONAUTOIMMUNE HYPERTHYROIDISM DURING PREGNANCY

Abstract

Objective:

Familial nonautoimmune hyperthyroidism (FNAH) is a rare disease. To date there are few, if any, reports of pregnancies in women with FNAH. Our objective here is to present such a case.

Methods:

Free thyroxine (free T4), free triiodothyronine (free T3), thyroid-stimulating hormone (TSH), and antibodies related to the thyroid were measured. Fetal thyroid function indicators including thyroid volume and ossification were checked using ultrasound. Thyroid-stimulating hormone receptor (TSHR) gene analyses were performed.

Results:

The patient was a 30-year-old woman with no past medical history. She was introduced to our hospital in the fifth gestational week for pregnancy care because her family history revealed that her mother had nonautoimmune hyperthyroidism with a TSHR-activating germ-line mutation (Asn406Ser). The serum free T4 was 1.88 ng/dL (normal, 0.62 to 1.19 ng/dL), free T3 was 3.27 pg/mL (normal, 2.55 to 3.88 pg/mL), TSH was 0.02 μIU/mL (normal, 0.007 to 3.619 μIU/mL), and TSHR was negative which were considered to be consistent with mild primary hyperthyroidism. Serum free T4, free T3, and TSH concentrations were monitored every 4 to 6 weeks with a peak free T4 of 2.23 ng/dL noted at gestational week 9. The patient had no signs related to hyperthyroidism throughout pregnancy. The patient delivered a 3,518 g girl at 40 weeks of gestation. Genetic analysis of her TSHR gene showed heterozygous Asn406Ser mutation. The offspring did not show any signs of prenatal hyperthyroidism, and thyroid function at day 6 after delivery revealed a free T4 of 2.41 ng/dL (normal, 1.83 to 2.91 ng/dL) and a TSH of 3.55 μIU/mL (normal, 0.51 to 4.57 μIU/mL).

Conclusion:

Women with FNAH and mild thyrotoxicosis prior to pregnancy may have continuous hyperthyroidism with additional change due to the series of human chorionic gonadotropin secretion during pregnancy.

INTRODUCTION

Nonautoimmune hyperthyroidism with a dominant activating mutation of the thyroid-stimulating hormone receptor gene (TSHR) is a rare disease (1,2) consisting of 3 categories: familial nonautoimmune hyperthyroidism (FNAH), persistent sporadic congenital hyperthyroidism (PSNAH) (3), and gestational thyrotoxicosis with enhanced human chorionic gonadotropin (hCG) sensitivity in the mutant thyrotropin receptor (4,5).

Patients with FNAH exhibit varying degrees of hyperthyroidism (2,6) and age at diagnosis (ranging from the neonatal period [7] to 60 years of age [8]), depending in part on the intensity of the activating mutation allele. Compared to patients with PSNAH, those with FNAH exhibit mild hyperthyroidism and late onset (3). However, no report is available regarding pregnant women with FNAH, while natural tendencies in their thyroid function, as well as maternal and fetal/neonatal management during and after pregnancy, has also remained unclear. We herein report on the gestational and postpartum course of a woman with FNAH who had a heterozygous Asn406Ser mutation while also observing for signs of fetal hyperthyroidism using transabdominal ultrasonography.

CASE REPORT

Written informed consent had been obtained from the patient, including consent to publish the findings. The patient was a 30-year-old woman with neither a medical history nor a record of hysterosalpingography. Immediately after being diagnosed with mild hyperthyroidism during infertility examinations, she became pregnant without any fertility treatment. Her family history revealed that her mother was diagnosed with nonautoimmune hyperthyroidism with a TSHR-activating germline mutation (Asn406Ser). The patient had 1 brother and 1 twin sister, both of whom had no medical problems but had not undergone thyroid testing (Fig. 1). The patient and her siblings had never been tested for the mutation that the patient's mother had. Upon diagnosis of hyperthyroidism, the patient was in her fifth week of gestation with no other symptoms having occurred except for nausea. Physical examination revealed that she was 166 cm tall, weighed 62.1 kg, had a pulse rate of 72 beats per minute, and had no goiter or ophthalmopathy. Thyroid function tests showed mild hyperthyroidism with a free thyroxine (free T4) level of 1.88 ng/dL (normal, 0.62 to 1.19 ng/dL), free triiodothyronine (free T3) level of 3.27 pg/mL (normal, 2.55 to 3.88 pg/mL), and thyroid-stimulating hormone (TSH) level of 0.02 μIU/mL (normal, 0.007 to 3.619 μIU/mL) (Table 1). Serum free T4, free T3, and TSH levels were measured using Lumipulse fT4-III, fT3-N, and TSH-III, respectively (Fujirebio, Tokyo, Japan). Trimester-specific reference ranges for serum free T4, free T3, and TSH during pregnancy were defined by our institute as shown in Table 1. TSHR antibodies, thyroglobulin antibodies, thyroid peroxidase antibodies, TSH-binding inhibitor immunoglobulin, and thyroid-stimulating antibodies were all negative. Ultrasonography revealed a normal-sized thyroid.

Fig. 1.

Family tree. The patient's mother had been diagnosed with nonautoimmune hyperthyroidism with a TSHR-activating germline mutation (Asn406Ser). The patient had 1 brother and 1 twin sister. P = proband TSHR = thyroid-stimulating hormone receptor.

Table 1.

Patient's Thyroid Function During Perinatal Period

Gestational week	Prepregnancy	5	9	17	22	29	35	5 weeks post
TSH (μIU/mL)	0.092	0.02	<0.021↓	<0.021↓	<0.021↓	<0.021↓	<0.021↓	<0.021↓
Normal range for TSH (μIU/mL)	0.546–4.118a	0.007–3.619b		0.135–2.269b		0.262–2.174b		0.546–4.118a
Free T3 (pg/mL)	3.07	3.27	4.8↑	3.74↑	4.41↑	3.96↑	3.28↑	3.31
Normal range for free T3 (pg/mL)	2.51–3.47a	2.55–3.88 b		2.24–3.33b		2.32–3.24b		2.51–3.47a
Free T4 (ng/dL)	1.77↑	1.88↑	2.23↑	1.49↑	1.59↑	1.8↑	1.76↑	1.66↑
Normal range for free T4 (ng/dL)	0.68–1.2a	0.62–1.19b		0.56–0.89b		0.52–0.90b		0.68–1.2a

Abbreviations: free T3 = free triiodothyronine; free T4 = free thyroxine; TSH = thyroid-stimulating hormone.

^aReference ranges from the manufacturer.

^bInstitutional reference ranges during pregnancy.

Mild hyperthyroidism was continuously observed throughout her pregnancy, even after the emesis, peaking at gestational week 9 (Table 1). No hypertension, high blood glucose levels, medication usage, or other symptoms were observed. Fetal development progressed well without growth restrictions and symptoms related to hyperthyroidism as evidence by a fetal heart beat that was appropriate for its gestational age, a normal thyroid volume, no signs of early ossification in the distal femoral epiphysis, and no hydrops. The patient delivered a baby girl weighing 3,518 g at 40 weeks of gestation via vaginal delivery. The patient's thyroid function tests at 5 weeks postpartum showed mild hyperthyroidism with a free T4 level of 1.66 ng/dL (normal, 0.68 to 1.20 ng/dL), a free T3 level of 3.31 pg/mL (normal, 2.51 to 3.47 pg/mL), and a TSH level of <0.021 μIU/mL (normal, 0.546 to 4.118 μIU/mL) (Table 1). The patient underwent TSHR gene analysis using peripheral blood following delivery, which revealed a heterozygous Asn406Ser mutation identical to that in her mother. The baby's thyroid function at day 6 after delivery revealed a free T4 of 2.41 ng/dL (normal, 1.83 to 2.91 ng/dL) and a TSH of 3.55 μIU/mL (normal, 0.51 to 4.57 μIU/mL). The baby's thyroid function has remained normal after follow-up at 6 months.

DISCUSSION

We herein report a case of a pregnant woman with FNAH who had a heterozygous Asn406Ser mutation and we observed the natural course of her and her offspring's thyroid function during pregnancy and postpartum. The patient showed mild hyperthyroidism prior to and throughout her pregnancy, which peaked at gestational week 9 and returned to the same level following delivery. Although no signs of hyperthyroidism had been observed in her offspring during the prenatal or neonatal period, we do not know whether her offspring carried the same genetic abnormality.

Several aspects of this case report are discussed in the following paragraphs. First, our patient exhibited mild hyperthyroidism throughout her pregnancy, which peaked at gestational week 9. This additional change may be because of the effect of gestational transient hyperthyroidism due to placental hCG secretion during pregnancy. Owing to the mild hyperthyroidism in the present case, no clinical symptoms had been observed. As such, the patient required no treatment during pregnancy. Had symptoms, such as tachycardia, hypertensive disorders of pregnancy, gestational diabetes mellitus, or imminent premature birth appeared, treatment with antithyroid drugs may have been required. Given that antithyroid drugs can be transferred to the fetus via the placenta, it is necessary that mothers receive the minimum dose and that fetal thyroid function is monitored using transabdominal ultrasound, regardless of whether the fetus is a carrier. Of course, had the fetus been a carrier, such treatment could have been for both the mother and fetus. The patient did not undergo TSHR gene analysis until after delivery, because the same mutation that the patient's mother had was strongly suspected, and we did not need the exact diagnosis for the management during pregnancy. TSHR gene analysis for the offspring may be needed in the future, if she presents with hyperthyroidism or if she desires the results.

A second aspect of this case is that the baby did not present with any signs of hyperthyroidism from the neonatal period until 6 months of age. Thus far, the natural course of FNAH has remained unclear, especially during the prenatal period and early life. Although 1 study had presented a case of FNAH diagnosed at 20 months old with tachycardia however, the clinical record showed that the patient was born through emergency caesarian section at 35 weeks of gestation due to fetal tachycardia (9). This indicated that the patient would have already had hyperthyroidism at 35 weeks of gestation. In addition, 10 cases had been reported to have been diagnosed up to 1 year after the birth in families with FNAH (7,9–15). Symptoms leading to the diagnosis of hyperthyroidism included diarrhea, loss of body weight, and tachycardia. Excessive body height or/and excessive bone age, incessant crying, premature craniosynostosis, fixed eye deviation, etcetera, were found upon diagnosis. Some of the infants' parents had already recalled observing diarrhea, poor weight gain, inability to fall asleep, or irritability a few days after birth, which often predates diagnosis. One such case was diagnosed at birth given that the patient's elder brother and father were diagnosed with FNAH, while a thyroid function test had been performed at birth (12). The aforementioned reports indicate that hyperthyroidism in FNAH may have appeared much earlier than at the time of diagnose, with some cases perhaps developing hyperthyroidism from the prenatal, neonatal, or early in childhood period. Careful and continued observations are necessary starting from the intrauterine period up to adulthood considering that excess thyroid hormone among those carrying the same abnormal genotype have a considerable impact on their growth and development.

CONCLUSION

We herein report, for the first time, the thyroid function course of a pregnant woman with FNAH and her offspring. Women with FNAH and mild thyrotoxicosis prior to pregnancy may have continuous hyperthyroidism with additional change probably due to the series of hCG secretion during pregnancy. Careful long-term follow-up starting from the prenatal period is needed for the offspring of the patients with FNAH.

Abbreviations

FNAH

familial nonautoimmune hyperthyroidism

free T3

free triiodothyronine

free T4

free thyroxine

hCG

human chorionic gonadotropin

TSH

thyroid-stimulating hormone

TSHR

thyroid-stimulating hormone receptor