Prenatal Diagnosis of Thyroid Hormone Resistance

Abstract

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 beta (TRbeta) 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 TRbeta 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 pmol/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 ofhypothyroidism 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 ...

Triiodothyroacetic acid in health and disease

“…A similar case was reported by Nicolini and coworkers (Nicolini et al 1996). In addition, Asteria and coworkers (Asteria et al 1999) reported on the use of TA 3 in the treatment of a pregnant woman with RTHβ because of suspected hypothyroidism in the fetus carrying the same heterozygous mutation in TRβ. In all three cases, the infant showed a normal neuro(psycho) logical development at 20-24 months of age.…”

“…In a subgroup of RTHβ patients, TA 3 is able to decrease TSH and consequently the high serum T 4 and T 3 levels. Since the thyromimetic effects of TA 3 itself do not fully compensate the reduction in endogenous TH levels, it alleviates the thyrotoxic symptoms including tachycardia, goiter, excessive sweating and behavioral problems (BeckPeccoz et al 1983, Lind & Eber 1986, Faglia et al 1987, Salmela et al 1988, Kunitake et al 1989, Smallridge et al 1989, Beck-Peccoz et al 1990, Aguilar Diosdado et al 1991 Crino et al 1992, Dulgeroff et al 1992, Ueda et al 1996, Darendeliler & Basx 1997, Radetti et al 1997, CliftonBligh et al 1998, Persani et al 1998, Asteria et al 1999, Kong et al 2005, Torre et al 2005, Wu et al 2006, Gurgel et al 2008, Santos et al 2008, Guran et al 2009, Anzai et al 2012, Ferrara et al 2012, Ramos-Prol et al 2013, Stagi et al 2014, Chatzitomaris et al 2015, Xue et al 2015. However, some patients do not respond to TA 3 treatment, which is assumed to depend on the type or location of the mutation (Hamon et al 1988, Persani et al 1998.…”

“…If TA 3 would be an effective therapy, it can be anticipated that early intervention may have effects on the neurocognitive phenotype. Although TA 3 readily crosses the placenta (Asteria et al 1999, Cortelazzi et al 1999, there are many medical Schematic representation of a T 3 target cell that relies on MCT8 for its TH uptake. The proposed working mechanism of TA 3 (and other TH analogues) in case of defective MCT8 entails cellular uptake in an MCT8-independent way, binding to the TRs and preferably degradation through similar pathways as TH, which are all fulfilled by TA 3 as outlined in this review.…”

Hyperthyroxinämie mit kardialer Symptomatik

“…1 We report on a 12 11 / 12 year old girl who was admitted to hospital with tachycardia. Laboratory tests showed high levels of serum free T3 and free T4 in the presence of non-suppressed TSH concentrations.…”

“…In einigen Untersuchungen konnte gezeigt werden, dass Trijodessigsäure (TRIAC), ein Metabolit des T3, bei Patienten mit Symptomen und Zeichen einer Hyperthyreose die Sekretion und Wirkung des TSH vermindern kann [1,2]. L-T4 wurde bei klinischen Symptomen einer Hypothyreose erfolgreich eingesetzt [6].…”