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Metastatic Follicular Thyroid Carcinoma Arising from Congenital Goiter as a Result of a Novel Splice Donor Site Mutation in the Thyroglobulin Gene

Departments of Medicine (A.S.A.) and Genetics (E.Y.B., M.Z., Y.S.), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia

Address all correspondence and requests for reprints to: Yufei Shi, Department of Genetics (MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. E-mail: yufei{at}kfshrc.edu.sa.

	Abstract

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Context: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only a few mutations in the Tg gene have been described.

Objectives: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation.

Cases: Two siblings aged 21 and 19 yr presented with recurrent goiters for which they had undergone multiple thyroid surgeries since early childhood. The older sibling was diagnosed with metastatic follicular thyroid carcinoma at age 15 yr.

Methods: The entire coding region and intron-exon boundaries of the Tg gene were amplified and sequenced from the patients. We also sequenced the boundaries of exon 5 and intron 5 from both parents. RT-PCR amplification of a cDNA fragment encompassing exons 4–6 was also performed.

Results: A homozygous G to A point mutation at position +1 of the splice donor site of intron 5 (g.IVS5+1GA) was detected in both patients, whereas a monoallelic mutation was found in their parents. RT-PCR amplification of a cDNA fragment covering exons 4–6 revealed a 191-bp fragment in the patients and 351- and 191-bp fragments in the parents. Sequence analysis of these two fragments confirmed deletion of exon 5 in the 191-bp fragment.

Conclusions: Aberrant splicing occurred as a result of the g.IVS5+1GA mutation, which caused fusion of exons 4 and 6, resulting in the frame shift at codon position 141 and a premature stop codon at position 147 (FS141147X). The malignant transformation is likely a result of prolonged TSH stimulation.

	Introduction

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PRIMARY CONGENITAL HYPOTHYROIDISM affects about 1 in 3000 to 1 in 4000 infants (1). It is caused by thyroid gland dysgenesis (75–80%) or inborn errors of thyroid hormone synthesis, a condition commonly referred to as dyshormonogenesis (15–20%) (1, 2). In dyshormonogenesis, genetic defects in the genes involved in thyroid hormone synthesis such as mutations in the Na⁺/I^– symporter (3), thyroglobulin (Tg) (4), thyroperoxidase (TPO) (5), and thyroid oxidase 2 (6) lead to a wide spectrum of congenital goitrous hypothyroidism.

Tg is a large 660-kDa glycoprotein synthesized by the thyroid gland. It functions as a matrix where thyroid hormones (T₄ and T₃) are produced from the coupling of iodotyrosyl residues, catalyzed by TPO (7). The human Tg gene, located on chromosome 8q24, is 270 kb long and contains an 8307-bp coding sequence divided into 48 exons. The preprotein monomer is composed of a 19-amino-acid signal peptide, followed by a 2749-residue polypeptide. At least nine different Tg gene mutations in humans have been identified and linked to thyroid dyshormonogenesis (4, 8, 9, 10, 11, 12, 13, 14, 15). These mutations have recently been summarized by Vono-Toniolo et al. (16). They involve exons 4 (g.IVS3–3CG), 7 (p.R277X), 9 (p.FS362382X), 17 (p.C1245R), 22 (p.R1511X), 30 (g.IVS30+1GT), 33 (p.C1977S), 35 (g.IVS34–1GC), and 38 (p.R2223H). They lead to overt or compensated hypothyroidism and are usually accompanied by large goiters as a result of chronic stimulation of thyroid gland by TSH.

A few cases of thyroid carcinoma developing from dyshormonogenic goiters have been reported (17, 18, 19, 20). It has been suggested that constant and prolonged stimulation by TSH might result in the appearance of thyroid carcinoma (17, 19). In experimental studies, Morris et al. (21) found that prolonged exposure of transplanted thyroid tissue to excessive amounts of TSH in mice led to the development of malignant thyroid neoplasms with pulmonary metastases.

In the present report, we describe two brothers who presented with huge recurrent goiters and apparently mild hypothyroidism since childhood. One of them ultimately developed a widely metastatic follicular thyroid carcinoma. Molecular analysis revealed a novel 5' splice site homozygous mutation in the Tg gene of both affected siblings. Both parents were heterozygous for the same mutation, and no mutation was found in their unaffected brother.

	Subjects and Methods

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Subjects

The propositus is a 21-yr-old man who presented with recurrent goiter since 1.5 yr. At that time, the parents noticed a slowly growing lower neck swelling. They did not seek medical advice until he was 5 yr old and he underwent partial thyroidectomy for a large thyroid swelling. The swelling gradually recurred, and he needed another thyroid surgery at age 7 yr. After the second surgery, the patient was given L-T₄, 100 µg/d, but he was noncompliant, frequently missing his doses. The neck swelling recurred. He then had partial bilateral thyroidectomy at 15 yr old and was diagnosed with thyroid cancer. Baseline thyroid function tests and the details of these surgeries were not available. He presented to our hospital in June 2002, complaining of pain at the right upper thigh. Family history was significant for a brother with a similar condition of recurrent goiter since 1.5 yr old. He had two thyroid surgeries at 6 and 14 yr old. Both siblings had delayed milestones (e.g. crawling at age 15 months and walking at age 3 yr) and difficulty in their school performance, completing only the fourth and fifth grade, respectively. They are, however, independent, fully oriented, and have normal cognitive function. The parents are not affected but are first-degree relatives. The family pedigree and thyroid function profile are summarized in Fig. 1. On physical examination, he was severely hypothyroid with dysphonia and scars of previous thyroidectomy but no palpable neck masses. He had tenderness without swelling over the upper right femur. He was 158 cm tall and weighed 51 kg. Neck ultrasound revealed multiple thyroid nodules up to 3.7 cm in size. Fine-needle aspiration (FNA) of the thyroid nodules showed follicular cells with atypia. A diagnostic ¹²³I whole-body scan (WBS) revealed several foci in the neck, the skull, abdomen, and right upper femur. A chest computed tomography scan was negative. Magnetic resonance imaging of the right femur revealed a high signal intensity subtrochantric lesion of 4 x 2 cm size. FNA of this lesion confirmed the diagnosis of metastatic follicular thyroid cancer. The patient underwent completion thyroidectomy. The histopathological examination showed only hyperplastic nodules consistent with dyshormonogenesis (Fig. 2). He was treated with ¹³¹I three times: 190 mCi in August 2002, 190 mCi in September 2003, and 195 mCi in November 2004. Before each therapy, Tg was undetectable (<0.1 ng/dl) with negative Tg antibodies and TSH of more than 500 mU/liter. His last WBS in May 2005 showed marked improvement showing only a faint activity in the thyroid bed without evidence of any other abnormal uptake in the previously described skeletal sites. This was further confirmed by a negative bone scan. The evaluation of the other affected sibling revealed that he was 157 cm tall and weighed 41 kg. He had severe hypothyroidism (Fig. 1) secondary to previous thyroid surgeries and noncompliance with L-T₄ therapy. Repeated diagnostic WBS showed only residual tissue in the thyroid bed without evidence of distant metastases. FNA of residual thyroid tissue did not show malignancy. He had been treated with L-T₄, and his follow-up over the last 3 yr was unremarkable. The institutional review board has approved the study.

View larger version (13K): [in this window] [in a new window]   FIG. 1. Family pedigree, thyroid function tests, and Tg levels in the two affected siblings, their parents, and a healthy brother. FT4, Free T4; Abs, antibodies.

View larger version (131K): [in this window] [in a new window]   FIG. 2. Hyperplastic thyroid tissue removed at thyroidectomy. Hematoxylin and eosin staining shows thyroid micro- and macrofollicles with scanty colloid, and cytological atypia, which are consistent with dyshormonogenesis. Magnification, x20 (A) and x40 (B).

Genomic DNA from peripheral blood leukocytes was isolated following standard procedure. Tumor DNA from paraffin-embedded tissues was extracted as described previously (22).

DNA amplification and sequencing

The entire coding region of the Tg gene and intron-exon boundaries from the patients were amplified in 51 separate PCRs as detailed previously (14). Each successfully amplified fragment was directly sequenced using the BigDye Terminator V3.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA), and samples were run on the ABI prism 3100 sequencer. The H-RAS, K-RAS, and N-RAS codons 12, 13, and 61 were screened for mutations by direct sequencing of PCR fragments amplified from paraffin-embedded thyroid tumor DNA (22).

RNA isolation and RT-PCR amplification

Total RNA from 5 ml whole blood was isolated using TRIzol reagent (Invitrogen, Carlsbad, CA). Two micrograms of total RNA were reverse-transcribed into cDNA using the Promega RT system (Promega, Madison, WI). PCR was performed using a primer pair permitting amplification of exons 4–6. The primer sequences were 5'-ATGTGCAGCAGGTCCAGTGC-3' and 5'-TGTCTCAGCCAGTTCCCGCC-3'. PCR was carried out for 35 cycles of 94 C for 1 min (first cycle for 2 min), 60 C for 1 min, and 72 C for 1 min. RT-PCR products were resolved on 2% gel electrophoresis and visualized by ethidium bromide staining.

	Results

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Sequence analysis of the Tg gene

All 48 exons and intron-exon boundaries of the Tg gene from the two patients were analyzed as well as 180 bp of the TG promoter. A novel homozygous G to A transition was observed at position +1 (g.IVS5+1GA), compared with the expected sequence (AT instead of GT) (Fig. 3). We then directly sequenced the boundary of exon 5 and intron 5 from both parents and their healthy brother. A heterozygous G to A transition at the same position was detected in both parents, and no change was found in the healthy brother (Fig. 3). These results indicate that both patients have inherited one copy of the g.IVS5+1GA from their father and another copy from their mother in an autosomal recessive mode.

View larger version (31K): [in this window] [in a new window]   FIG. 3. Identification of a homozygous splice donor site mutation in intron 5 of the Tg gene. Partial DNA sequence (coding strands) of exon 5 and intron 5. The arrow points to the G to A transversion in the splice donor site of intron 5. Biallelic mutations were present in both patients, whereas a monoallelic mutation was found in their parents. No mutation was found in the healthy son.

Because the g.IVS5+1GA mutation was in the splice donor consensus sequence, we expected that the spliceosome would use splice donor site of intron 4 and splice acceptor site of intron 5, resulting in the deletion of exon 5. To confirm this hypothesis, we performed RT-PCR analysis of total RNA (covering exons 4–6) isolated from peripheral blood of both patients and their father. As shown in Fig. 4A, a single 191-bp cDNA fragment (smaller than the expected 351 bp) was found in the patients, whereas both 191- and 351-bp fragments were present in their father, indicating a 160-bp deletion of Tg mRNA in the 191-bp fragment. DNA sequence analysis of the 191-bp fragment showed that the 160-bp fragment corresponding to exon 5 was indeed skipped entirely, resulting in the fusion of exons 4 and 6 (Fig. 4B). Exon 5 was present in the 351-bp cDNA fragment. The fusion of exons 4 and 6 causes a shift of the Tg reading frame and a premature stop codon six amino acids after exon 4 (Fig. 4C). Therefore, the patients would have a severely truncated Tg polypeptide chain, whereas their parents have both a truncated and normal copy of Tg polypeptide chain.

View larger version (19K): [in this window] [in a new window]   FIG. 4. Fusion of exons 4 and 6 of the Tg mRNA as a result of a splice donor site mutation in intron 5 of the Tg gene. A, Agarose gel electrophoresis of the RT-PCR products. Total RNA was isolated from peripheral blood leukocytes of the patients and their father. The RT-PCR fragments encompassing exons 4–6 were electrophoresed on a 2% agarose gel. The DNA size marker was a 100-bp DNA ladder. A single 191-bp cDNA fragment (smaller than the expected 351 bp) was found in the patients, and both a 191- and a 351-bp fragment were present in their father. B, Partial DNA sequence (coding strands) of the 191-bp cDNA fragment. The DNA sequence shows the fusion of exons 4 and 6. The line marks the boundary between exons 4 and 6. C, Schematic representation of the mutant Tg gene and mRNA. The G to A mutation at the splice donor site of intron 5 causes aberrant splicing by using normal splice donor site of intron 4 and the splice acceptor site of intron 5, resulting in the deletion of exon 5. The fusion of exons 4 and 6 leads to a reading frame shift at position R141 and a premature stop codon at position 147 (147X).

As reported in the literature, the prolonged stimulation by TSH as a result of dyshormonogenesis can result in the malignant transformation of thyroid goiter. One of our patients indeed developed metastatic follicular thyroid carcinoma. Because ras oncogene mutations at codons 12, 13, and 61 were frequently found in follicular thyroid carcinomas (22), we next screened for ras oncogene mutations by direct sequencing of PCR fragments amplified from the patients’ thyroid tumor DNA. No mutation was detected in codons 12, 13, and 61 of H-ras, K-ras, and N-ras oncogene (data not shown).

	Discussion

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Dyshormonogenesis as a result of defects in Tg synthesis causes congenital hypothyroidism characterized by intact iodide trapping, normal organification of iodide, and aberrant Tg protein expression (7). In the present study, we have described a family in whom a novel Tg mutation was found. The homozygous splice site mutation g.IVS5+1GA causes dyshormonogenesis with recurrent huge goiters in the two affected siblings. Their clinically unaffected parents were heterozygous for the mutation. In the older sibling, the clinical course was further complicated by the development of a widely metastatic follicular thyroid carcinoma. Their parents did not demonstrate any significant clinical and biochemical abnormality of Tg synthesis, confirming that a normal copy of the Tg gene is sufficient to compensate the functional loss of the defective copy of the Tg gene.

Splice site mutations in the Tg gene have been described previously (16). Ieiri et al. (4) described two siblings with a transversion in the splice acceptor site of intron 3 converting cytosine to guanine at position –3 (g.IVS3–3GC). This mutation leads to skipping of exon 4 without affecting the remainder of the reading frame (4). Targovnik et al. (9) reported two siblings with a 171-nucleotide deleted Tg mRNA (corresponding to exon 22) as a result of nonsense-mediated exon skipping. In the same family, Gutnisky et al. (14) reported a G to C mutation at position –1 of the splice acceptor site in intron 34 (g.IVS34–1GC), causing skipping of exon 35. This family is remarkable for two distinct compound heterozygous constellations (16). Neither mutation disrupted the reading frame and is potentially fully translatable into a Tg polypeptide chain. Targovnik et al. (8) also reported a point mutation in the splice donor site of intron 30 at position +1 (g.IVS30+1GT) from two siblings from a consanguineous family. This led to the skipping of exon 30 without affecting the reading frame and generation of a Tg molecule that lacks 46 amino acids (23). In contrast, the novel g.IVS5+1GA mutation we identified would cause a shift of the reading frame and result in a severely truncated Tg polypeptide chain. A similar Tg truncation R227X (C886T in exon 7) was reported by van de Graaf et al. (11). The truncation may explain the undetectable Tg found in our patients. However, it may be possible to detect low amounts of Tg with an antibody recognizing an amino-terminal epitope, given the presence of small amounts of colloid shown in the histology (Fig. 2).

Thyroid hormone synthesis involves a two-step modification of tyrosine residues. Iodination and the subsequent coupling reactions are catalyzed by thyroid peroxidase. The specific iodinated tyrosine residues that are involved in the coupling reaction can either accept (hormonogenic sites) or donate iodinated phenyl groups. The most important acceptor site in all vertebrate species is at Tyr5. For human Tg, three potential donor sites have been identified so far (Tyr130, Tyr847, and Tyr1488) (24). The truncated form of Tg described here harbors the acceptor Tyr5 and the donor Tyr130 residues as well as two putative N-linked glycosylation sites. Amino-terminal truncated glycosylated Tg fragments may be able to synthesize T₄ in vivo as illustrated in human (11) and the goitrous Dutch goat (25). This, together with an elevated TSH and goiter, may be able to partially compensate the Tg defect in our patients and may explain to some extent the ability of the remaining Tg protein to function as a substrate for thyroid hormone synthesis.

As reported earlier (17, 18, 19), malignant transformation from congenital goiter can occur if elevated TSH levels are present for a prolonged period of time. This is supported by the fact that nonsuppressed TSH seems to stimulate the growth of thyroid carcinoma (26, 27). Moreover, constitutively activating TSH receptor mutations are the underlying genetic defect in the majority of cases of toxic thyroid adenoma (28) and have also been reported in a few cases of thyroid carcinoma (29). Indeed, all the reported cases of thyroid carcinoma arising from dyshormonogenetic goiter had long-standing untreated congenital goiters and elevated TSH. Table 1 summarizes the genetic defects reported in the literature of thyroid cancer cases arising from dyshormonogenic goiters. Most of the reported cases were follicular thyroid carcinomas and were aggressive tumors with a tendency for early distant metastases. Because RAS mutations are common in follicular thyroid carcinoma (22), it was logical to screen for these mutations in our patient to understand the oncogenesis. Screening for all previously described mutations was negative, suggesting that the development of thyroid carcinoma in this patient is not a result of genetic defects in any of the RAS genes.

	Footnotes

 
First Published Online January 10, 2006

Abbreviations: FNA, Fine-needle aspiration; Tg, thyroglobulin; TPO, thyroperoxidase; WBS, whole-body scan.

Received October 19, 2005.

Accepted December 28, 2005.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alzahrani, A. S. Articles by Shi, Y. Search for Related Content PubMed PubMed Citation Articles by Alzahrani, A. S. Articles by Shi, Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Genetics Home Reference Hazardous Substances DB THYROGLOBULIN Medline Plus Health Information Thyroid Cancer Related Collections Thyroid Endocrine Oncology