Prenatal Diagnosis and Treatment of Dyshormonogenetic Fetal Goiter Due to Defective Thyroglobulin Synthesis1

Geraldo Medeiros-Neto, Victor Bunduki, Eduardo Tomimori, Simone Gomes, Meyer Knobel, Regina T. Martin and Marcelo Zugaib

Thyroid Unit, Division of Endocrinology and Fetal Pathology, Division of Obstetrics, University of São Paulo Medical School, 05403–900 São Paulo, Brazil

Address all correspondence and requests for reprints to: Geraldo Medeiros-Neto, Thyroid Unit, Hospital Das Clinicas, Av Dr Eneas Carvalho Aguiar, 155, Bloco 3–8 Andar, Sao Paulo, Brazil 05403–900, Phone: 55112125711, Fax: 55112115194, e-mail: consular@embratel.net.br.


    Introduction
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 Introduction
 Case report
 Discussion
 References
 
WE PRESENT a case of fetal dyshormonogenetic goiter with hypothyroidism, probably due to defective thyroglobulin synthesis, diagnosed by ultrasound and cordocentesis performed at 28 weeks of gestation.


    Case report
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 Introduction
 Case report
 Discussion
 References
 
The patient was a 27-yr-old white female referred to the Thyroid Unit of the Hospital das Clinicas, University of São Paulo Medical School at 23 weeks of gestation. A dating ultrasound examination indicated a large homogeneous mass in the anterior aspect of the fetal neck. The patient, clinically euthyroid, had no history of past thyroid disease. However, a first-born son (now 6 yr old) had a neonatal goiter, although thyroid tests were not performed at the time of birth. This child had developed normally, but the goiter increased in size. The local pediatrician recommended a daily dose of 50 µg of L-thyroxine. With this medication there was a visible reduction of the goiter size. Actual thyroid function studies of this child indicated euthyroidism with a very low serum thyroglobulin concentration (Table 1Go). The bone age was retarded (2 yr, 8 months) for a chronological age of 5 yr, 9 months. A recent ultrasound examination of the thyroid gland indicated an enlarged thyroid gland with a 1.0 x 1.2 cm solid nodule in the left lobe. The mother is married to a second-degree cousin (see Pedigree, Fig. 1Go), and a nephew was also born with goiter and hypothyroidism (treated with L-thyroxine). Pregnancy was confirmed in August 96 (12 weeks ± 5 days). A second routine ultrasound examination at 23 weeks of gestation identified a large fetal goiter. Fetal vitality was considered normal. Maternal thyroid function tests at 26 weeks indicated a normal serum total T3 and total T4, but a relatively low free T4 serum concentration (Table 1Go). Serum TSH and serum thyroglobulin (Tg) were within normal limits. Ultrasound of maternal thyroid was normal (estimated thyroid weight: 10.7 g). There were no circulating autoantibodies (anti-TPO, anti-Tg).


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Table 1. Laboratory data (thyroid function tests)

 


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Figure 1. Pedigree of the family. Note the consanguineous marriage, with two siblings with congenital goiter and hypothyroidism.

 
The patient was referred to the São Paulo University Hospital for further studies. At 26 weeks gestation a large homogeneous mass measuring approximately 34 mm in the transverse plane, 24 mm in the antero-posterior plane and 29 mm in the sagittal plane was identified by ultrasound examination in the anterior aspect of the fetal neck (Fig. 2Go). The location, consistency, and bilobed appearance of this mass were suggestive of fetal goiter (approximately 12.3 g). The amniotic fluid volume appeared normal. A cordocentesis was performed at 29 weeks confirming fetal hypothyroidism with serum TSH at 61.3 µIU/mL (normal < 10 µIU/mL) and free thyroxine at 0.2 ng/dL (normal: 0.5–1.1 ng/dL). As expected, serum total T3 and T4 were very low. Surprisingly, serum Tg was also very low (1.3 ng/mL) for such a large goiter, suggesting that the dyshormonogenetic goiter could be related to defective Tg synthesis and/or secretion. At 30 weeks gestation an intra-amniotic injection of 400 µg L-thyroxine (Synthroid, levothyroxine sodium USP for injection, Knoll Pharmaceutical, Mount Olive, NJ) was performed. Also, because of the relatively and persistently low maternal free T4, the mother was instructed to take 150 µg L-thyroxine, daily. After 4 weeks of the L-T4 injection, ultrasonographic studies confirmed the reduction of the goiter size (from a circumference of 12.5 cm to 4.8 cm).



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Figure 2. Ultrasound examination of the fetus at 26.2 weeks gestation. A large homogeneous mass measuring 3.4 x 2.4 x 2.9 cm was identified in the anterior aspect of the fetal neck, estimated to weigh 12.3 g (normal expected weight: 0.36 g).

 
The patient presented in active labor at 37.2 weeks and was delivered a female infant weighing 3,190 g, with APGAR score of 9 at 5 min. No evidence of airway obstruction was seen. The newborn thyroid volume was barely palpable (Fig. 3Go). Cord blood indicated an elevated serum T3 level of 129 ng/dL (normal: 35–60 ng/dL), a normal serum total T4 of 10.5 µg/dL (normal: 8.0–10.0 µg/dL), and a free T4 concentration of 0.9 ng/dL (normal: 0.5–1.1 µg/dL). Cord serum TSH was 41.6 µIU/mL (normal: <45 µIU/mL). Serum Tg was below the limit of detection (<0.5 ng/dL). The neonate was also submitted to ultrasonographic studies of the thyroid that indicated a slightly enlarged thyroid (1.8 mL). The neonate was discharged on the third day of life on levothyroxine 50 µg/day (15 µg/kg/day). At 9 months of age the infant continues on levothyroxine daily with normal growth and development.



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Figure 3. The neonate shortly after birth. There was no visible enlargement of the thyroid. No clinical or laboratory signs of hypothyroidism were present.

 

    Discussion
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 Introduction
 Case report
 Discussion
 References
 
Major advances in the understanding of the thyroid system ontogenesis in the fetus and new insights and diagnostic approaches to fetal thyroid dysfunction have been reported in the past two decades and reviewed recently (1). In addition, several important advances in molecular biology and molecular medicine have contributed to our understanding of the molecular genetics of congenital thyroid disorders, particularly those from the dyshormonogenetic group (2).

Neonatal screening programs for congenital hypothyroidism were introduced in the middle 1970s and have been largely successful in facilitating diagnosis of congenital hypothyroidism shortly after birth, followed by treatment in the first few weeks of life. Thyroid dysgenesis (including agenesis) accounts for about 75% of all cases of congenital hypothyroidism and, according to a recent editorial (3), may be related to somatic mutations in the TSH-receptor (or post-receptor defects) with a hypothetical unresponsiveness of the thyroid follicular cell to the endogenous TSH. Hypothalamic pituitary disorders and central hypothyroidism account for less than 5% of congenital hypothyroidism and include mutations in the Pit-1 gene and the TSH-beta subunit gene (4).

Dyshormonogenesis of the thyroid system represents about 10–20% of all cases of congenital hypothyroidism, and most of the neonates would exhibit a relatively large goiter (2). The two most common causes for dyshormonogenesis are the defective organification of iodine, frequently the result of mutations in the TPO gene, and the defective synthesis and secretion of thyroglobulin (2).

In the present case a defective synthesis and/or secretion of Tg was thought to be the cause of the fetal goiter because of the following: 1) the family pedigree indicated a consanguineous marriage favoring an autosomic recessive disorder, being the parents obligate heterozygous; 2) the fetal serum Tg was remarkably low for a very large goiter, in spite of an elevated fetal serum thyrotropin, and the neonate cord-blood concentration of Tg was below the limit of detection; 3) a first-born child from the same parents had a confirmed diagnosis of congenital goitrous hypothyroidism with a low serum Tg. Although all these data do not confirm the diagnosis, they may be considered as very suggestive of impaired synthesis of Tg as the molecular defect in this family.

Since the inception of screening for neonatal hypothyroidism a significant number of children have been treated with levothyroxine. Results after long-term follow-up have indicated satisfactory school performance, normal mean IQ values, and minimal motor dysfunction in treated children (5). However, specific defects in hearing-speech performance scales and minimal central nervous system deficits have been described (5). Severe hypothyroidism during fetal life, marked chemical hypothyroidism at birth, delayed treatment, and poor compliance with the prescribed levothyroxine treatment increase the risk for lower IQ values, usually detectable at school age. Specifically we have found evidence that defective organification of iodine due to mutations that would lead to the complete absence of TPO activity would result in a severely affected phenotype with mental retardation and stunted growth in spite of relatively early levothyroxine treatment (2).

Although prenatal treatment of fetal hypothyroidism may be considered controversial, treatment of the fetus with a large goiter is indicated because of the morbidity associated with obstruction to the trachea and mechanical problems during delivery. As pointed out by Abuhamad et al. (6), intra-amniotic administration of levothyroxine presents the least invasive approach to fetal treatment. These authors introduced fetal therapy with levothyroxine providing weekly intra-amniotic injections at a dose of 10 µg/kg of estimated fetal weight (total: seven intra-amniotic injections). A repeated cordocentesis at 35 weeks gestation showed normalization of fetal thyroid function and decrease of the fetal goiter. Six other reports [see Abuhamad et al. (6) and references therein] on fetal treatment with levothyroxine administered intra-amniotically (Table 2Go) indicated that only one injection of L-T4 was done (3 reports) or multiple weekly injections of L-T4 were preferred (2–7 intra-amniotic injections, at weekly intervals, 4 reports). The total amount of levothyroxine introduced into the fetal circulation was calculated to be between 250 µg and 1500 µg L-T4 (7). Even when a single intra-amniotic injection was administered, there was a rapid decrease in the fetal goiter size (8).


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Table 2. Prenatal thyroid hormone treatment for fetal hypothyroidism1

 
Our case differs from those previously reported cases in that the diagnosis of congenital hypothyroidism occurred relatively early in gestation, as in the case presented by Abuhamad et al. (6). In view of the morbidity associated with repeated intra-amniotic injections we decided for a single injection of 400 µg levothyroxine. Also we did not attempt to obtain fetal blood for repeated thyroid function testing, but followed the decrease of the fetal goiter by ultrasonography. The results confirmed that a single levothyroxine injection can decrease the size of the fetal goiter and that the neonate would have no visible or palpable goiter and would present normal thyroid function. This case and previously reported cases demonstrate that congenital goitrous hypothyroidism can be corrected following diagnosis and prenatal treatment with intra-amniotic injection of thyroxine. Careful follow-up of this and other cases will confirm that subtle deficits of the central nervous system can be prevented by prenatal treatment.


    Acknowledgments
 
We acknowledge the technical work of Maria Silvia Cardia and Jacyra M. Lima as well as the expert secretarial work of Maria Suzette Pott.


    Footnotes
 
1 This work was made possible through the continuous financial support of Klabin & Irmãos (São Paulo, Brazil) and by Research Grant 96/00998–4 from FAPESP (São Paulo, Brazil). Back

Received August 21, 1997.

Accepted September 2, 1997.


    References
 Top
 Introduction
 Case report
 Discussion
 References
 

  1. Fischer DA. 1997 Fetal thyroid function diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol. 40:16–31.[CrossRef][Medline]
  2. Medeiros-Neto GA, Stanbury JB. 1994 Inherited disorders of the thyroid system. Boca Raton, FL: CRC Press; 1–218.
  3. Abramowicz MJ, Vassart G, Refetoff S. 1997 Probing the cause of thyroid dysgenesis. Thyroid. 7:325–336.[Medline]
  4. Medeiros-Neto GA, Herodotou DT, Rajan S, et al. 1996 A circulating biologically inactive thyrotropin caused by a mutation in the beta subunit gene. J Clin Invest. 97:1250–1256.[Abstract/Free Full Text]
  5. Illig R, Largo RH, Qin Q, Torresani T, Rochiccioli P, Larson A. 1987 Mental development in congenital hypothyroidism after neonatal screening. Arch Dis Child. 62:1050–1055.[Medline]
  6. Abuhamad AZ, Fisher DA, Worsof SL, et al. 1995 Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case report and review of the literature. Ultrasound Obstet Gynecol. 6:368–371.[CrossRef][Medline]
  7. Davidson KM, Richards DA, Schatz DA, Fisher DA. 1991 Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med. 234:543–546.
  8. Noia G, De Santis M, Tocci A, Maussier L, Caruso A, Mancuso S. 1992 Early prenatal diagnosis and therapy of fetal hypothyroid goiter. Fetal Diagn Ther. 7:138–143.[Medline]