Resistance to Thyroid Hormone Beta in a Patient Born to a Mother With Undiagnosed Graves’ Disease

Background/Objective Graves’ disease is an autoimmune disease associated with high levels of circulating thyroid hormones (THs). Resistance to thyroid hormone beta (RTHβ) caused by mutations in the thyroid hormone receptor beta (THRB) gene also can lead to high TH levels. Here, we describe 2 related cases, one of a woman with Graves’ disease, and her newborn with RTHβ. Case Report The woman was 27 years of age, with free thyroxine (T4) (FT4) >7.7 ng/dL (0.8-1.8), triiodothyronine of 1350 ng/dL (90-180), and undetectable thyrotropin (TSH), but no symptoms of thyrotoxicosis. She also had thyroglobulin antibodies of 65 (2-38). She was treated with methimazole and atenolol. The newborn neonatal screen showed a TSH of 43 mU/L [upper limit of normal 20 mU/L] and total T4 of 21.8 μg/dL (upper limit of normal 15). At 6 days of age, the newborn had a FT4 of 12.3 ng/dL (0.9-2.3), and unsuppressed TSH. The infant, at 3.5 months of age, was identified to harbor a THRB mutation (R438H) inherited from her father, but the brothers and mother had no THRB mutation. The newborn had tachycardia and delayed growth and was treated with atenolol and supplemental feeding, resulting in weight gain and reduced heart rate. Discussion The perinatal high FT4 and tachycardia could have been influenced by the elevated TH levels of the mother and the fetal RTHβ. Conclusion It is difficult to evaluate the etiology of neonatal hyperthyroidism when fetal RTHβ and maternal Graves’ disease are not diagnosed early at birth.


Introduction
Resistance to thyroid hormone is a clinical syndrome of reduced responsiveness of target tissues to thyroid hormone (TH). 1 The incidence of resistance to thyroid hormone is 1 case per 40 000 live births 2 and is commonly caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed resistance to thyroid hormone beta (RTHb). 3 The hallmark of RTHb is high circulating THdboth thyroxine (T4) and triiodothyronine (T3) 4 dwith unsuppressed thyrotropin (TSH). 5,6 The clinical presentations are variable, and it is common for RTHb individuals to have symptoms of TH deficiency and excess (eg, delayed growth and tachycardia). 5 Herein, we report 2 related cases, 1 of a mother and 1 of her newborn. The mother had undiagnosed Graves' disease, and had very high levels of circulating TH and antibodies for thyroglobulin but no thyrotoxic symptoms. 7 The newborn was a female with RTHb presenting delayed growth, tachycardia, and a mutation in the THRB gene inherited from the father. The elevated TH levels of the mother and the fetal RTHb could have influenced the perinatal high free T4 (FT4) and tachycardia. We conclude that it is difficult to make a differential diagnosis and evaluate the impact of neonatal hyperthyroidism caused by either fetal RTHb or maternal Graves' disease if both conditions are not diagnosed before birth.

Case Presentations
The first case is a woman of 27 years of age, who exhibited FT4 >7.7 ng/dL (0.8-1.8), total T3 of 1350 ng/dL (90-180), and non-detectable TSH (Fig. 1A), but had no symptoms of hyperthyroidism or any manifestation associated with autoimmune diseases, except feeling a little sweaty and having 1 to 3 bowel movements daily with soft stools. She denied jitteriness, racing heartbeats, heat intolerance, weight loss, and feeling short of breath. She denied any history of hypertension and reported unintentional weight fluctuations while in high school, losing 100 lbs. Further evaluation showed positive thyroglobulin antibodies with values of 65 ng/mL (2-38), confirming Graves' disease, but no additional information about her family history could be obtained. She was treated with methimazole and atenolol but was non-adherent to her medications. She had obesity and 3 previous C-sections. She received routine prenatal care without being checked for thyroid tests. The only thyroid function tests obtained in the woman were after 3.5 months of giving birth to a female newborn (the subject of the second case).
The second case is a female newborn born to unrelated parents at full term via emergency C-section for fetal tachycardia. At birth, the newborn measurements were appropriate for age: weight 3.785 Kg, length 51.5 cm, and head circumference 35 cm (Fig. 1C). She had patent ductus arteriosus, meconium aspiration, respiratory distress, and developed pulmonary hypertension, requiring intubation for 12 days. Moreover, she has neonatal thrombocytopenia and received antibiotics for suspected neonatal sepsis.
During her 3-month visit, while she continued to have a normal thyroid exam with no goiter by palpation (thyroid ultrasound not obtained), no jitteriness, and no proptosis. Her resting heart rate was 160/min (normal range 120-140). Her umbilical cord was still attached that eventually separated at 5 months of age. She also had excessive lanugo hair on her lower back that resolved at 5 months of age. At 3 months of age, her growth was delayed, gaining only 0.4 Kg in 5 weeks (normal weight gain is 2.5 kg during the first 3 months of age), and her weight and linear growth were arrested, going from the 21st and 32nd percentile at 2 months to the 11th and 21st percentile at 3 months, respectively (Fig. 1C). Her head circumference decreased from the 51st percentile to the 27th percentile and remained relatively steady afterward (Fig. 1C).
We further investigated the infant (at 3.5 months of age) and her family members by obtaining comprehensive thyroid testing and sequencing the THRB gene ( Fig. 1 A and B). The infant and her father had an RTHß phenotype (ie, elevated FT4 with unsuppressed TSH) confirmed by identifying a heterozygous missense mutation in exon 10 of the THRB gene (R438H; Fig. 1B). The father denied any symptoms of hyperthyroidism. Studying the family members of the infant was the reason why we studied the mother (first case), who, while having a marked elevation of circulating serum TH levels, had no THRB mutation. The 3 older siblings had serum thyroid tests in the normal range and no THRB mutation.

Discussion
The woman presented in the first case had very high TH levels but no thyrotoxic symptoms. Thus, it was pertinent to study her THRB gene, which showed no mutation, ruling out maternal RTHß. Individuals with RTHb due to heterozygous mutations in the THRB gene maintain euthyroidism at the expense of high serum TH levels. When pregnant, their high serum TH is congruent with similarly affected fetuses carrying the mutant THRB gene. In our second case, the newborn inherited her mutant allele from the father. Under this circumstance, fetal development might be jeopardized because of the exposure to subphysiological TH levels derived from a mother without RTHß. 9,10 For example, there is a higher prevalence of goiter and short stature in children with RTHß born to normal mothers than those born to affected mothers. 11 However, the circumstances presented here are atypical. Although the mother had no RTHß, she had very high levels of T4, which could have been congruent with the affected newborn carrying a mutant THRB gene. 3,5 The normal newborn weight at birth supports this possibility.
Approximately 1% to 5% of neonates born to mothers with Graves' disease may exhibit transient neonatal hyperthyroidism. If present, the fetus' clinical manifestations are highly predictive of fetus hyperthyroidism. 12,13 Tachycardia and goiter are among the main symptoms. Because the newborn had RTHb, it is unclear whether the high maternal TH levels had an impact during pregnancy or at birth. Indeed, the newborn had a typical case of RTHb caused by the THRB gene mutation R438H. This previously identified mutation decreases the receptor affinity for T3 to 23% of the normal (wild type) receptor (R438H Ka ¼ 0.51 vs wild type Ka ¼ 2.2). 14 The resulting phenotype is usually hyperthyroid, with unsuppressed TSH. However, the clinical features of both hypothyroidism (growth delay) and hyperthyroidism (tachycardia) are expected. 5 Highlights This is a rare case of neonatal resistance to thyroid hormone beta with maternal thyrotoxicosis. The newborn inherited the mutant thyroid hormone receptor beta allele from the father. At birth, the newborn exhibited very high FT4 values, rapidly dropping during the first days of life. The infant exhibits symptoms of both thyroid hormone deficiency and excess. Treatment with atenolol and supplemental feeding improved her tachycardia and growth delay.

Clinical Relevance
In a case of a newborn with resistance to thyroid hormone beta (RTHb), born to a mother with Graves' disease, it is difficult to evaluate the differential impact of the fetal RTHb and maternal Graves' disease on the neonate's hyperthyroidism if both conditions are not diagnosed before birth.
During her first days of life, the newborn exhibited very high FT4 values that reached~534% above the ULN. However, from 12 days of age, the FT4 values were~113% above the ULN. A similar drop in FT4 levels was described in a neonate with RTHb born to a mother with Graves' disease. 15 There are 2 possible mechanisms for the increase in TH levels in an infant born to a mother with active Graves' disease. Passage of TH or thyroid stimulating immunoglobulin across the placenta. However, the rapid drop in the FT4 values suggests that the former was at play, adding to the increased TH levels associated with the RTHB phenotype of the newborn in the first few days of life. Additionally, the newborn at 2 days of life exhibited a TSH of~200% ULN, incompatible with the transplacental passage of blocking antibodies, which undetectable TSH usually accompanies.
Similarly, the neonatal tachycardia and respiratory distress of the newborn could have been influenced by the transplacental passage of TH and elevated TH levels associated with the RTHb phenotype of the newborn. Regardless, treatment with atenolol may be prescribed. 16 This is a rare case of a neonatal RTHß complicated by coincidental maternal uncontrolled Graves' disease. It can be difficult to evaluate the etiology of neonatal hyperthyroidism when fetal RTHb and maternal Graves' disease are not diagnosed early at birth.

Disclosure
The authors have no multiplicity of interest to disclose.