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,
05403900 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 38 Andar, Sao Paulo, Brazil 05403900, Phone: 55112125711, Fax: 55112115194, e-mail: consular@embratel.net.br.
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Introduction
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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.
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Case report
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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 1
). 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. 1
), 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 1
). 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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Figure 1. Pedigree of the family. Note the
consanguineous marriage, with two siblings with congenital goiter and
hypothyroidism.
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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. 2
). 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: 0.51.1 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).
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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. 3
). Cord blood
indicated an elevated serum T3 level of 129 ng/dL (normal:
3560 ng/dL), a normal serum total T4 of 10.5 µg/dL
(normal: 8.010.0 µg/dL), and a free T4 concentration of
0.9 ng/dL (normal: 0.51.1 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.
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Discussion
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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 1020% 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 2
) indicated that only one injection of
L-T4 was done (3 reports) or multiple weekly injections of L-T4 were
preferred (27 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).
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.
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Acknowledgments
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We acknowledge the technical work of Maria Silvia Cardia and
Jacyra M. Lima as well as the expert secretarial work of Maria Suzette
Pott.
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Footnotes
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1 This work was made possible through the continuous financial support
of Klabin & Irmãos (São Paulo, Brazil) and by Research
Grant 96/009984 from FAPESP (São Paulo, Brazil). 
Received August 21, 1997.
Accepted September 2, 1997.
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