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Spectrum of Malignancy and Premalignancy in Carney Syndrome

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Spectrum of Malignancy and Premalignancy in Carney Syndrome American Journal of Medical Genetics 73:369–377 (1997) Spectrum of Malignancy and Premalignancy in Carney Syndrome Ngozi A. Nwokoro,1,2* Mary T. Korytkowski,3 Suzanne Rose,3 Michael B. Gorin,4 Mona Penles Stadler,2 Selma F. Witchel,5 and John J. Mulvihill2 1Department of Oral and Maxillofacial Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 2Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 3Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 4Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania 5Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania Carney syndrome is a rare, autosomal dom- neoplastic colonic polyps; inant, multi-system disorder comprising 8 subcapsular cataracts; follic- well-characterized findings, only 2 of which ular thyroid carcinoma need be present for a definitive diagnosis. Benign neoplasms are frequent, but malig- nancies are thought to be uncommon. We INTRODUCTION have studied a family to clarify the diagno- sis and spectrum of clinical manifestations Carney syndrome (MIM number 160980) is a rare, of the syndrome and to develop guidelines multi-system, pre-neoplastic syndrome diagnosed for management. The proposita, a 34-year- when at least 2 of the following 8 findings are present: old woman had classic findings of Carney cardiac myxoma, cutaneous myxoma, myxoid mam- syndrome, invasive follicular carcinoma of mary fibroadenoma, spotty mucocutaneous pigmenta- the thyroid gland, Barrett metaplasia of the tion including lentigines and blue nevi, primary pig- esophagus, neoplastic colonic polyps, bipo- mented nodular adrenocortical disease (Cushing syn- lar affective disorder, and atypical mesen- drome), testicular tumor, growth-hormone–secreting chymal neoplasm of the uterine cervix dis- pituitary adenoma, and psammomatous melanotic tinct from the myxoid uterine leiomyoma schwannoma [Carney et al., 1985, 1986a,b; Cook et al., usually seen in this syndrome. Although 1987; Kennedy et al., 1987; Carney, 1990]. Based on at thyroid gland neoplasm is rare in Carney least 56 certain cases, the mode of inheritance appears syndrome, this patient’s most aggressive to be autosomal dominant [Kennedy et al., 1991; Koop- manifestation was her thyroid carcinoma. man and Happle, 1991[. The diagnosis of Carney syndrome was es- Malignant neoplasms are infrequently seen in this tablished in her 9-year-old son and is a prob- disorder. Our 34-year-old proposita with Carney syn- able diagnosis in her 12-year-old daughter. drome had atypical malignant and premalignant neo- Endocrine manifestations were prominent plasms as did variously affected relatives. Taken to- in the family with at least 9 relatives in 3 gether, these findings expand our knowledge of the generations affected with various endo- syndrome. crine abnormalities. The findings in this family indicate that the spectrum of mani- CLINICAL REPORTS festations in this pleiotropic gene appar- ently includes a malignant course with pre- Detailed studies of the proposita and her 2 children malignant and endocrinologic disorders not (half sibs, Fig. 1) were conducted, including review of previously recognized. Am. J. Med. Genet. medical records and multi-disciplinary clinical and 73:369–377, 1997. © 1997 Wiley-Liss, Inc. laboratory evaluations. Family history and records of other relatives were also reviewed, but these individu- KEY WORDS: Carney syndrome; cardiac als were not personally examined. myxoma; Barrett metaplasia; The Proposita Individual III-6 (Fig. 2) presented at age 31 years *Correspondence to: Ngozi A. Nwokoro, Ph.D., M.D., Depart- because of an unusual multi-system syndrome. Now ment of Human Genetics, Graduate School of Public Health, A300 age 34 years, she is a gravida 4, para 2, aborta 2 woman Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261. with a history of multiple nevi, diffuse facial lentigines, Received 2 January 1996; Accepted 3 June 1997 and labial pigmentation, all apparent at an early age. © 1997 Wiley-Liss, Inc. 370 Nwokoro et al. Fig. 1. Pedigree. Symbols. At birth she had a large, multi-pigmented hairy patch vere palpitations. At surgery, 4 distinct right ventricu- across her left lower abdomen and, by age 2 years, had lar myxomas (1.8 × 1.5 × 1.1, 0.7 × 0.4 × 0.4, 0.6 × 0.6 developed several pigmented skin lesions and masses. × 0.5, and 1.4 × 0.9 × 0.8 cm) were found and resected. Since the age of 2 years, she had multiple removals of Cardiac symptoms resolved, and no additional masses cutaneous tumors, a hemangioma of the right lower have been seen on yearly echocardiographic evalua- eyelid, a peripheral myxoid tumor of the right lower tions. eyelid, fibromyxomatous lesions from the right axilla, Before the diagnosis of LAMB syndrome at age 30 and papillomas of the right nipple and right labia. Ex- years, she presented to the endocrine clinic for further cised lesions from her checks included an angiofi- evaluation of a thyroid nodule involving the lower pole broma, a myxoma, cavernous hemangiomas, and a se- of the right lobe. Results of thyroid function studies baceous adenoma. Results of punch biopsies showed were normal. Fine-needle aspiration biopsy of the nod- myxofibroma and papilloma of the right occipital re- ule was performed on 2 occasions 6 months apart. The gion, keloid of the right ear lobe, focal dermal mucino- first was performed at an outside hospital and was re- sis of the back and the right nipple, focal dermal mu- ported as benign. A second, reported as adequate for cinosis or myxoma of the right buttock, and labial len- interpretation, showed clumps of atypical—probably tigo. Hirsutism of face, trunk, and limbs, was first benign—follicular epithelial cells. The continued noted at age 10 years, required frequent shaving as a growth of the nodule despite measured thyrotropin teenager, worsened by age 27 years, and continues to (TSH) levels of 0.3–0.5 IU/ml (normal 4 0.5–5 IU/ml) be a major cosmetic problem. Dermatological evalua- prompted surgical excision of the nodule in July 1992. tion at 30 years led to a diagnosis of LAMB syndrome A frozen section demonstrated follicular carcinoma, [Rhodes et al., 1984]. Skin biopsy results prompted an and a total thyroidectomy was performed. Histopatho- evaluation for the presence of cardiac myomas by echo- logical examination showed a 3.0 cm follicular thyroid cardiography. This showed right ventricular tumors carcinoma with angiolymphatic invasion and extensive that were thought to account for the several years’ his- parenchymal infiltration with a separate adjacent 0.5 tory of easy fatiguability, increasing dyspnea, and se- cm encapsulated follicular carcinoma in the right lobe. Malignancy in Carney Syndrome 371 DST, suboptimal suppression of UFC was observed (UFC 4 52 mg/day) with normal suppression of 17- hydroxycorticosteroids. An overnight high-dose DST (8 mg at night) was associated with a paradoxical rise in plasma cortisol. A repeat 24-hour UFC 6 months later was normal at 84 mg/day. An abdominal CT scan showed bilateral nodular adrenal enlargement, a find- ing well documented in Carney syndrome [Carney and Young, 1992]. Although repeat UFC remained normal, there were low plasma levels of dehydroepiandros- terone (DHEA, 18 ng/dl; normal 4 130–980 ng/dl) and dehydroepiandrosterone sulfate (DHEA-S, <5 mg/dl; normal 4 50–542 mg/dl), suggesting autonomously functioning adrenals [Braithwaite et al., 1989]. As part of an evaluation for hirsutism, plasma growth hormone (GH) and somatomedian-C (SM-C, IGF-1) were measured in addition to circulating andro- gens. Despite the absence of clinical findings of acro- megaly, the patient’s SM-C level was elevated at 616 ng/ml (normal 4 114–492 ng/ml), with a normal GH of 2.7 ng/ml. Abnormal GH secretion was further verified during a 3-hour oral glucose tolerance test in which a basal GH level of 8.5 ng/ml failed to suppress to <2 mg/ml. Measurement of growth-hormone–releasing hormone was normal (39 pg/ml). Magnetic resonance imaging (MRI) of the pituitary was normal. These en- docrine findings are shown in Table I. Gastrointestinal findings included chronic cholecys- titis and cholelithiasis, erosive esophagitis, gastritis, duodenitis, duodenal ulcer, colitis, and colonic polyps. The endoscopic impression of Barrett metaplasia, i.e., TABLE I. Results of Studies of Pituitary-Adrenal Function in Fig. 2. The proposita at age 32 years. the Proposita* ACTH UFC 17-OHCS Cortisol There was also a 0.5 cm follicular adenoma in the left (pg/ml) (mg/day) (mg/d) (mg/dl) lobe. Because of the size and aggressiveness of the thy- Adrenal testing 18 134 15 8 roid neoplasm, 150 mCi of 131I was administered in Baseline August 1992 to ablate any remaining thyroid tissue. Dexamethasone 52 1.3 12 (2 mg/d) Day 2 Although there was a lack of uptake on a pre-treatment Dexamethasone 16 131 I, a second dose of 150 mCi was given in March 1993 (8 mg at 11 PM) Day 3 because of an elevated thyroglobulin level of 325 ng/ml (normal 4 5–50 ng/ml). A post-treatment scan demon- Pituitary Testing 0 min 30 min 60 min 120 min 180 min strated an area of focal increased uptake in the neck OGTT Glucose (mg/dl) 89 133 92 64 75 slightly to the right of the midline. Despite continued GH (ng/ml) 8.9 6.1 5.0 7.5 suppressive therapy with L-thyroxine to maintain the L-DOPA (500 mg PO) TSH level at <0.03 IU/ml, the elevation in serum thy- GH (ng/ml) 6.0 3.3 14.7 3.8 roglobulin persisted. A recent sonogram of the neck 30 days demonstrated three solid masses in the anterior neck, Baseline (ng/dl) a finding confirmed by computed tomography (CT) Octreotide scan. These lesions were excised, and the histopatho- GH 5.3 4.9 logical findings were those of aggressive follicular car- SM-C 695 524 cinoma.
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