Brief Clinical Report

Family With Graves Disease, Multinodular Goiter,Nonmedullary Thyroid Carcinoma, andAlveolar Rhabdomyosarcoma

Harriet A. Druker,1,2 Lidia Kasprzak,1,2 Louis R. Begin,3 Serge Jothy,3 Steven A. Narod,4 andWilliam D. Foulkes1,2,5*1Department of Human Genetics, McGill University, Montreal, Quebec, Canada2Department of Medicine, McGill University, Montreal, Quebec, Canada3Department of Pathology, McGill University, Montreal, Quebec, Canada4Women’s College Hospital, University of Toronto, Ontario, Canada5Cancer Prevention Research Unit, Jewish General Hospital, Montreal, Quebec, Canada

Benign thyroid disease is a risk factor fornonmedullary thyroid carcinoma [Houlstonand Stratton: Q J Med 88:685–693, 1995]. Wereport on a family with 7 members with be-nign and/or malignant thyroid neoplasia;one affected female died of a paravertebralalveolar rhabdomyosarcoma at age 20. Theoccurrence of thyroid nodular hyperplasia,nonmedullary thyroid cancer, and rhabdo-myosarcoma in the same family may be dueto chance, common environmental factors,or, most likely, genetic predisposition. Am.J. Med. Genet. 72:30–33, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: nonmedullary thyroid can-cer; multinodular goiter;family studies; rhabdomyo-sarcoma

INTRODUCTION

Multiple cases of the same tumor in a family mayindicate a common underlying genetic cause for thetumors, common environmental determinants, or both.Autosomal-dominant adolescent-onset multinodulargoiter appears to be a distinct hereditary syndrome[Couch et al., 1986]. In addition, there may be a geneticbasis to the susceptibility to papillary and other non-medullary thyroid carcinomas in a few of the affected

individuals. Familial nonmedullary thyroid cancercomprises about 5% of all thyroid cancers [Grossman etal., 1995] and, like familial multinodular goiter, an au-tosomal-dominant pattern of inheritance with reducedpenetrance in males has been proposed. An African-American family with 6 members with congenital goi-ter has been reported; 2 members developed follicularcarcinoma of the thyroid in their third decade, suggest-ing that these two disorders may also be causally re-lated [Cooper et al., 1981].

FAMILY STRUCTURE (FIG. 1)

The proposita (III-1) was diagnosed with nodular hy-perplasia and superimposed invasive follicular carci-noma (well-differentiated and confined within the thy-roid gland) at age 17, at which time she had a thyroid-ectomy. She is now 34 years old and has had norecurrences and is taking thyroid replacement therapy.Both her parents were of Ashkenazi Jewish descent.The father of the proposita (II-4) also had a left thyroidlobectomy at age 15 years for multinodular goiter andat age 37 was diagnosed with a well-differentiated fol-licular carcinoma of the right lobe of the thyroid. Therewas extension beyond the capsule with focal/limitedinvasion within perithyroid soft tissue. Associated re-gional lymph nodes were negative for neoplasia, butshowed epithelioid granulomas. The cancer was sur-rounded by nodular hyperplasia (multinodular goiter),including secondary changes in the form of hemor-rhage, calcification, and cystic degeneration. He is now61 years old and on thyroid replacement therapy.

All three of the proposita’s sibs had thyroid condi-tions. Her brother (III-2) presented at age 14 yearswith a multinodular goiter. He was clinically euthy-roid, but was biochemically hypothyroid and wastreated with L-thyroxine. Because of a persisting 4 × 3cm nodule in the left lobe of the thyroid gland, he un-

*Correspondence to: William D. Foulkes, Division of MedicalGenetics, Department of Medicine, L10-116, Montreal GeneralHospital, 1650 Cedars Ave., Montreal, Quebec H3G 1A4, Canada.E-mail: MDWF@musica.mcgill.ca

Received 8 July 1996; Accepted 31 March 1997

American Journal of Medical Genetics 72:30–33 (1997)

© 1997 Wiley-Liss, Inc.

derwent a complete left and partial right thyroid lobec-tomy 6 months later. A small nodule was found in theright lobe at operation. Pathological examination dem-onstrated nodular hyperplasia with no evidence of ma-lignancy. The second brother, III-3, was found clini-cally to have a slightly enlarged thyroid, but with nor-mal thyroid function. He had had a prophylacticsubtotal thyroidectomy at age 11 years; no noduleswere seen on pathological examination. The proposita’ssister (III-4) presented at age 10 with euthyroid mul-tinodular goiter, which was treated by a subtotal thy-roidectomy. Histologic study showed multinodular ad-enomatous hyperplasia. The nodules were benign, witha minor pseudopapillary pattern. She had a recurrentleft thyroid nodule at age 13 years. At surgery, twonodules were excised from the left superior thyroid poleand showed benign multinodular adenomatous hyper-plasia. She continued her thyroid replacement. At age20 years she complained of fatigue, weakness in herupper torso, and brachial paresis. She was diagnosedwith a paravertebral (C3-T1) alveolar rhabdomyosar-coma. The pathological diagnosis of rhabdomyosarco-ma was confirmed by immunohistochemistry, whichshowed that 5–10% of cells coexpressed desmin andmuscle-specific actin. Rare cells produced myoglobulin.The tumor cells were negative for epithelial and neu-ral-specific markers.

A paternal aunt (II-1) was also diagnosed with mul-tinodular goiter and had two subtotal thyroidectomiesat ages 13 and 21 years. She may have had an episodeof thyroiditis at age 35, in the remaining tissue of theleft lobe of her thyroid. She is currently on thyroid re-placement therapy. The nephew of the proposita (IV-1)had Down syndrome with trisomy 21. He had a slightlyelevated thyroid-stimulating hormone level at age 6years, but is clinically euthyroid and does not have agoiter. He is receiving thyroid replacement therapy. Noother paternal relatives had thyroid conditions; how-ever, the proposita’s paternal grandparents had carci-noma of the transverse colon (I-1) and fibroblastic cer-ebellar meningioma (I-2), verified by review of pathol-ogy reports.

On the maternal side of the family, the proposita’sgrandmother (I-4) had Graves disease, verified by fam-ily report. No other relatives have had thyroid condi-tions.

DISCUSSION

This family contains 5 individuals with nontoxic goi-ter, 2 of whom later developed nonmedullary thyroidcarcinoma and 1 of whom subsequently developed analveolar rhabdomyosarcoma. As far as we know, thiscombination of events has not been reported previ-

Fig. 1. Pedigree of the family. Numbers below symbols are individual numbers. Those affected by neoplasia have filled-in symbols. non-MTC,nonmedullary thyroid cancer. Individuals with multinodular goiter, but unaffected by non-MTC have cross-hatched symbols.

Familial Nonmedullary Thyroid Cancer 31

ously. It is possible that the pattern of disease seen inthis family can be explained by chance, or by commonenvironmental exposures which may have triggered athyroid condition, but it is more likely that there is acommon underlying genetic cause.

Thyroid conditions are most commonly sporadic.However, there have been several reports of familialoccurrence of thyroid neoplasia [Couch et al., 1986;Stoffer et al., 1986; Ron et al., 1991; Grossman et al.,1995]. These pedigrees include multiple affected rela-tives with early onset of the condition relative to thatexpected in the population. In the present family, theinterpretation of an autosomal-dominant pattern foradolescent multinodular goiter and nonmedullary thy-roid carcinoma is consistent with the observation ofvertical and male-to-male transmission. Our familydoes differ somewhat from the typical pedigree in thatmales and females are equally affected. Thyroid condi-tions are more common in females than in males [Ronet al., 1987]. This may be due to an increased level ofhormonal activity in females. For example, circulatingthyroid-stimulating hormone levels are elevated inpregnancy [Chan et al., 1975], and this hormone playsa role in nonmedullary thyroid cancer in experimentalanimals [Lindsay et al., 1966]. Women who have had atleast one child were shown to be twice as likely to de-velop thyroid cancer as nulliparous women [Miller etal., 1980]. Thus, thyroid conditions, even when autoso-mal in inheritance pattern, are generally thought to besex-influenced [Couch et al., 1986].

An increased incidence of thyroid disease was seen inover one third of thyroid cancer families [Stoffer et al.,1986; Grossman et al., 1995]. In at least some families,a predisposition to thyroid cancer may be conferredthrough the development of a precancerous state,analogous to colonic polyps in familial adenomatouspolyposis coli [Houlston and Stratton, 1995]. In 11families with an excess of thyroid cancer [Ozaki et al.,1988], 4 also had relatives with nodular goiter andGraves disease. In the large family reported by Couchet al. [1986], 2 individuals developed pathologicalchanges suggestive, but not diagnostic of, papillarythyroid cancer. It is interesting to note that Namba etal. [1990] found that RAS oncogene activation wasequally prevalent in benign and malignant thyroid neo-plasms (approximately 21% in each), although strictly,this cannot be taken as evidence of a causal relation-ship between benign and malignant thyroid disease.

The occurrence of an autosomal-dominant inheri-tance pattern of nonmedullary thyroid carcinoma andbenign thyroid disease in this family suggests that in-dividual III-4 would have had an increased risk of de-veloping thyroid cancer had she lived beyond age 20years. The mean length of time between diagnosis ofgoiter and thyroid cancer was 11.6 years in the study ofRon et al. [1987]. In the study by Stoffer et al. [1986],the average age of diagnosis of familiar cases of papil-lary thyroid cancer was 37.8 ± 14.2 years (not signifi-cantly different from the average for sporadic cases).

As is well-documented, the occurrence of one cancermay predispose to the development of another [Tuckeret al., 1985]. In those with a primary cancer of thethyroid gland following a cancer elsewhere, central

nervous system tumors are more likely to be the pri-mary tumor than tumors at other sites [Hawkins et al.,1987; Tucker et al., 1991], and it has been suggestedthat the increased incidence of thyroid cancer followingchildhood cancer is due to radiation therapy for neuro-blastoma and other neural-derived tumours [Tucker etal., 1991]. In a study by de Vathaire et al. [1992], therisk of developing thyroid carcioma following neuro-blastoma was elevated fivefold compared with the riskafter any other childhood cancer, after adjusting fordifferences in sex, time elapsed since irradiation, andradiation dose to the thyroid. This prompted them tosuggest that, for their cases, an increased rate of thy-roid tumor formation was more important than thyroidgland radiosensitivity when determining the cause ofthe increased incidence of thyroid cancer. There wereno reported cases of thyroid cancer following nonirra-diated childhood cancers: in this model, irradiation ap-pears to be necessary but not sufficient for thyroid car-cinogenesis. It should be noted that small round-celltumors were exceedingly difficult to classify before thedevelopment of modern molecular diagnostic tech-niques. It is possible, therefore, that some small round-cell tumors previously classified as neuroblastomacould in fact represent rhabdomyosarcomas.

To our knowledge, this combination of familial thy-roid disease and rhabdomyosarcoma has never beenreported. We can suppose that the occurrence of boththyroid goiter and rhabdomyosarcoma in the same in-dividual (III-4) may be due to chance or to commonsusceptibility. It is possible that there may be genesthat predispose to both thyroid conditions, be they be-nign or malignant, and rhabdomyosarcoma in certainindividuals. There is a possible causal link betweennonmedullary thyroid carcinoma and rhabdomyosarco-ma. Some members of the PAX family of developmentalcontrol genes have oncogenic potential [Stuart andGruss, 1996], and PAX8 is expressed in the thyroid andregulates the thyroglobulin genes [Zannini et al.,1993]. PAX genes are widely expressed in the paraxialmesoderm, and family member III-4 reported here de-veloped a paravertebral alveolar rhabdomyosarcoma.PAX3 is translocated in alveolar rhabdomyosarcomas,but PAX3 is not known to have a role in thyroid devel-opment [Stuart and Gruss, 1996].

It is intriguing that both thyroid cancer and rhabdo-myosarcoma appear to be under hormonal influence.Dos Santos Silva and Swerdlow [1993] showed that attime of puberty there are marked increases in the in-cidence of both thyroid cancer in girls and rhabdomyo-sarcoma in both sexes, the latter being associated withthe increase in muscle bulk, which occurs earlier ingirls than boys [Tanner, 1989]. Therefore, the presenceof benign thyroid disease, diagnosed at age 13 years,and a rhabdomyosarcoma at age 20 years (which mayhave been present for some time) may have resultedfrom abnormal responses to normal hormonal changesin puberty, acting on predisposed cells.

ACKNOWLEDGMENTS

We thank Dr. V. Der Kaloustian for initially refer-ring the family to us and Dr. R. Tabah, Ms. O. Gins-

32 Druker et al.

burg, Dr. F.J. Holland, and Ms. N. Wong for clinicaland family information. Ms. L. Robb and other staffmembers of the Montreal Children’s Hospital contrib-uted clinical and technical information which was usedin preparing this report. The two referees made a num-ber of useful suggestions.

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