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Dominant Inheritance of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity
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Mayo Clinic ROCHESTER, MINNESOTA
Vol.61
MARCH 1986
Dominant Inheritance of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity
J. AIDAN CARNEY, M.D., Ph.D., F.R.C.P.I., Section of Surgical Pathology; LOIS S. HRUSKA, M.S., Department of Medical Genetics; GARY D. BEAUCHAMP, M.D.*; HYMIE GORDON, M.D., Department of Medical Genetics
We describe a family in which lentigines were present in the index patient, in three of her seven siblings, in their mother, and in a niece (the daughter of an affected sister). Cutaneous myxomas were present in the index patient, in t w o of her brothers, and probably in their mother. In addition, the index patient had t w o cardiac myxomas, multiple myxoid mammary fibroadenomas, and the Cushing syndrome, and an affected brother had acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. Thus, at least one manifestation of the complex of myxomas, spotty pigmentation, and endocrine overactivity has occurred in three successive generations of this family. Both male and female family members were affected, and 5 of the 11 children of affected persons had the disorder. The karyotypes of t w o affected persons were normal. These observations are consistent with mendelian dominant inheritance of the syndrome.
T h e association of lentiginosis with cardiac a n d cutaneous m y x o m a s h a s been reported on several occasions, 1 2 b u t our recent clinical a n d pathologic review of the subject presented evidence t h a t the association w a s a broader one a n d m i g h t include s y n d r o m e s of endocrine overactivity a s well. 3 I n t h a t review, a variable complex of mucocutaneous, visceral, a n d endocrine disorders w a s de scribed in 40 patients (16 male a n d 24 female patients), each of w h o m h a d two or more of the following lesions: (1) cardiac myxoma, in a n y one
*Department of Cardiology, St. Luke's Hospital, Kansas City, Missouri. Address reprint requests to Dr. J. A. Carney, Department of Pathology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 61:165-172, 1986
or more of the cardiac c h a m b e r s , in 29 (72%), including 16 with single lesions a n d 13 with multiple lesions; (2) cutaneous myxoma, single or multiple, in 18 (45%); (3) mammary myxoid fibroadenoma, single or multiple, in 12 female p a t i e n t s (30%) (2 m a l e p a t i e n t s h a d gynecomastia); (4) spotty mucocutaneous pigmentation, in cluding lentigines a n d blue nevi (and occasionally junctional nevi a n d compound nevi) a n d combina tions of these, in 26 (65%); (5) primary pigmented nodular adrenocortical disease, in 18 p a t i e n t s (45%), including 11 with the C u s h i n g s y n d r o m e a n d 7 who were a s y m p t o m a t i c a n d whose lesion w a s found a t autopsy; (6) testicular tumors, char acteristically large-cell calcifying Sertoli cell tumors, usually bilateral a n d multicentric, in 9 of t h e 16 male patients (56%) (4 h a d sexual precocity); 165
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and (7) pituitary growth hormone-secreting tumor, which caused acromegaly or gigantism, in 4 (10%). The possibility that this complex might be heritable was suggested by the relatively young age (mean, 18 years) of the patients with the visceral lesions and the tendency of the lesions to be multicentric and to be bilateral when paired organs were affected. Moreover, the 40 patients included five pairs of first-degree relatives (Table 1). Because the relatives of affected patients had not always been examined systematically, we believe that this reported finding was probably only a minimal indication of the familial aggrega tion of the disorder. We now have had the opportunity to examine most of the first- and second-degree relatives of one of the patients (no. 14) included in our previous review.3 Our observations in this family are con sistent with dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. INVESTIGATION OF THE FAMILY The index patient, her father, and her maternal grandmother had been examined at our institu tion. Six of her seven siblings and all six nephews and nieces were examined in Kansas City. The investigation included a thorough physical exam ination with anthropometry and study of the skin in natural and ultraviolet light. In each case, a chest roentgenogram and a two-dimensional echo-
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cardiogram were obtained. Each person older than 6 years of age had a complete blood cell count, automated serum biochemical profile (so dium, potassium, calcium, phosphate, total pro tein, albumin, glucose, alkaline phosphatase, aspartate aminotransferase, bilirubin, uric acid, and creatinine), and plasma cortisol determinations on specimens collected in the morning and midafternoon. The karyotypes of three persons were examined. The mother and one of the brothers of the index patient were not examined, but they provided us with their medical records and color photographs of themselves. In the following ac count of the pedigree (Fig. 1), the results of the aforementioned investigations that are not stated were normal; only the abnormal findings are presented. Paternal Lineage.—The paternal grand father (1.1) was of Irish, French, and American Indian descent. He had had no known abnormal pigmentation. His death, at age 64 years, was attributed to pulmonary embolism, a complication of an old leg injury. The paternal grandmother (1.2) was of French and American Indian descent; she was reported to have had "stomach ulcers" at age 72 years and to have died of Hodgkin disease at age 75 years. The father (II.2) was healthy when we examined him at age 54 years; he had no abnormal pigmentation or any other clinical man ifestations of the complex. None of the 5 paternal uncles or aunts or the 11 paternal first cousins was known to have any abnormal pigmentation or other manifestation of the complex.
Table 1.—Summary of Findings in Familial Cases of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity* Testicular Mammary Skin Sertoli Hypermyxoid pigmen cell Myxoma pituitarism Reference PPNAD Skin tumor tation tumors Cardiac Familyt 4 I. Sister Neg + + + + + Brother Neg Neg Neg + + + 5 II. Sister Neg + + + + + Sister Neg Neg Neg + + III. Mother Neg Neg 6 Neg Neg + + Son Neg Neg Neg + + + + Son Neg Neg Neg + + + + IV. Sister Current Neg + + + + + Neg Neg Neg Neg report Brother + + + V. Mother J-P + — + — — OrtonneJ Son + + *+ = present; — = not recorded or status unknown; Neg = examination for that condition revealed normal findings; PPNAD = primary pigmented nodular adrenocortical disease. tRoman numerals refer to Table 1 in reference 3. {Personal communication.
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Maternal Lineage.—The maternal grand father (1.3) was of German descent; he had died of a stroke at age 63 years. The maternal grand mother (1.4), who was 73 years of age, was of English descent. Her skin was normal and, except for recent acute bronchitis, she was healthy. The mother (II.3), 55 years of age, declined to be examined but provided information about herself. For as long as she could remember, she had had spots of dark pigment on her face, lips, backs of her hands, forearms, and genitalia. Photographs confirmed the presence of numerous dark brown or black lentigines on her face, especially under the eyes and across the bridge of the nose; similar spots were present on her lower lip. At age 24 years, she had had a partial thyroidectomy for "goiter"; at that time, a "growth" had been re moved from her right external auditory canal. A mass had been excised from her left breast when she was 28 years old. (Records of these procedures were not available.) At 55 years of age, she had undergone excision of a small nodule from her right lower eyelid; microscopic examination showed a lentigo, an epithelium-lined cyst (hidrocystoma), and myxoid stroma. The maternal uncle (II.4) was 53 years old. We did not examine him but, according to his sister (II.3), he was healthy and had no abnormal pig
mentation. The maternal first cousin (111.12), who was 24 years old, was not examined by us; he was said to be healthy and to have no abnormal pigmentation. Index Patient.—The index patient, a 34-yearold woman (III.3), had cutaneous lentigines (Fig. 2 A) and myxomas of the right lower eyelid and on the pinna of the left ear. She had undergone surgical removal of cardiac myxomas from her left ventricle and left atrium. The clinical findings are described in the detailed case reports (case 1). Siblings and Their Children.—A 35-year-old brother of the index patient (III.2) was healthy; he had no cutaneous or other manifestations of the complex. His three sons (nephews IV.l, 2, and 3), who were 14, 7, and 5 years old, respectively, also were found to be normal. Another brother (III.4), 30 years old, declined to be examined, but he provided us with medical records and photographs of his face. The latter showed typical facial lentiginosis, especially un der the eyes, on the cheeks, across the bridge of the nose, and on the lips. At age 8 years, he had had a dark facial lesion excised; microscopically, it was composed of "elongated, spindle-shaped, deeply pigmented cells"—findings consistent with blue nevus. At age 13 years, he had complained of a sensation of fullness in his right ear canal. Amass
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that was attached to the posterior wall and filled and obstructed the ear canal was excised. The lesion proved to be a ruptured squamous epithelium-lined cyst surrounded by myxoid stroma. The following year, an elevated cystic lesion that partially blocked the left ear canal was detected and excised. Microscopic examination showed it to be a myxoma with a trichofolliculoma-like component. When he was 19 years old, a 1.5-cm polypoid myxoma had been removed from the scalp. Recently, he had been examined by his home physician because of shortness of breath and a pressurelike sensation in the chest. Apart from the abnormal pigmentation, results of physi cal examination were normal, as were the findings on echocardiography. This man is married but has no children. A 28-year-old unmarried brother (III.5) was healthy and had no sign of the complex. A 27-year-old sister (III.6) was healthy but had extensive facial lentiginosis, mostly under the eyes, around the mouth, and also on the vermilion border of the upper lip; she had no conjunctival lesions. Her son (nephew IV.4), 5 years of age, was healthy. Her 3-year-old daughter (niece IV.5) had lentiginosis. Numerous small, dark brown-black lentigines were present around her eyes, across
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her cheeks, and on the bridge of her nose; she also had a cluster of lentigines below the right side of her lower lip but none on the vermilion borders of her lips (Fig. 2 Q . A streak of black pigmentation (2.2 by 1.0 cm) was noted over her right scapula. A tiny black pigmented spot was present on the lateral wall of her left axilla; a similar lesion was present on the back of her left thigh, and two more such spots were visible on the lateral aspect of her left knee. A 26-year-old brother (III.7) had extensive lentig inosis (Fig. 2 B); he had had several cutaneous myxomas excised, and he had had acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. His clinical findings are re corded in detail in the subsequent case reports (case 2). We examined his 9-day-old daughter (IV.6). She did not have lentiginosis but had a taillike appendage in the sacral area; no underly ing bony abnormality was noted on x-ray exami nation. Microscopic examination of the append age showed a fibrofatty core covered by normal epidermis. A 25-year-old sister (III.8) was mildly subnor mal mentally. She had a few common freckles on the bridge of her nose but no lentigines. A large (4.5-cm), round cafe au lait spot was present on the
Fig. 2. Photographs of some affected members of the family. A, Index patient (III.3) has spotty pigmentation below eye, on lacrimal caruncle, and on cheek, nose, and vermilion border of upper lip. B, Her brother (III.7) has pigmented spots on forehead, cheek, nose, and vermilion borders of lips. A single spot of pigmentation was present on right conjunctival semilunar fold. C, A niece (IV.5) has butterfly distribution of spotty pigmentation around eyes, across nose, and on the skin of the upper lip.
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anterior aspect of her left thigh; no other dyspigm e n t a t i o n w a s visible in n a t u r a l or ultraviolet light. Her only somatic developmental a n o m a l y w a s a slightly short left fourth toe. She h a d a n o r m a l female karyotype. A 23-year-old brother (ΙΠ.9) w a s h e a l t h y . He h a d no manifestation of t h e complex. Siblings III.10 a n d III.11 were s p o n t a n e o u s miscarriages during the first trimester of pregnancy.
REPORT OF CASES Case I.—The index patient (III.3), a 34-year-old woman, had come to our medical center in 1984 because of persistent headaches. She had had pigmented spots on her face and lips since birth. At age 14 years, she had undergone removal of a lesion from her right upper eyelid; microscopically, it was a "papilloma having a core of fibrovascular tissue." Recurrence of the eyelid lesion 3 years later necessitated another excision. At age 16 years, she had had pigmented lesions excised from her cheeks, upper lip, and left shoulder. The lesions on her cheeks were blue nevi; the others were lentigines. At age 19 years, two dark brown lesions had been removed from her lower lip. (Histologie slides of these lesions were not available.) She had begun to wear glasses for mild myopia at age 9 years. Her menarche was at age 12 years, and she had always menstruated normally. When the patient was 24 years old, a heart murmur had been detected during the course of a physical examination. 7 An echocardiogram demonstrated a mass in the left ventricle. On cardiac exploration, a smaller left atrial mass was found in addition to the left ventricular tumor; both tumors proved to be myxomas. At age 25 years, she had undergone removal of an asymptomatic lump from her left breast; histologically, the lesion was multicentric myxoid fibroadenoma. Dur ing the following year, two nodules had been excised from the skin on her back; microscopically, they were myxomas. At age 27 years, she had had lentigines excised from her perianal skin and vulva. In the same year, she had undergone a right thyroid lobectomy for a 1.5-cm follicular adenoma. When she was 32 years old, impaired hearing in her right ear had led to the discov ery of a pedunculated mass in the external auditory canal; histologically, this lesion was a myxoma with an epithelial component that resembled trichofolliculoma. At age 34 years, she had undergone excision of addi tional regions of myxoid fibroadenomatosis from both breasts. When she was examined at our institution, her heart and nervous system were normal. Two-dimensional echocardiography, high-resolution computed tomographic scanning of the thorax and head (including coro nal views through the pituitary area with use of a contrast medium), and electroencephalography showed normal findings; no recurrence of the cardiac myxomas
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was detected. Results of biochemical investigation of her pituitary-adrenal function were normal; specifi cally, the plasma cortisol levels were 8.2 /ug/dl in the morning (normal range, 7 to 25 //g/dl) and 8.5 //g/dl in the afternoon (normal range, 2 to 14 //g/dl). She had a normal female karyotype. Her headaches had been caused by an abscessed tooth. During the course of the examination, various mucocutaneous lesions were observed. Numerous small, dark brown pigmented spots were present on the central part of her face, especially on the cheeks, nose, and upper lip including the vermilion border (Fig. 2 A). Similar single spots of dark pigmentation were present on the conjunc tiva of the right medial canthus, on the inside of the right cheek, and on the right areola. Multiple spots were present on the labia minora and buttocks. A 2-mm, darkly pigmented, nontender, cystic nodule was noted on the anthelix of the left ear, and a small thickening was felt in the middle of the right lower eyelid, just below the eyelashes; these lesions were probably myxomas. Approximately 6 months later, the patient began to feel excessively tired; in addition, she became emotion ally labile, her menstruation was prolonged, a slight growth of hair appeared on her face, and she rapidly gained weight—from 78.0 kg to 89.5 kg. She had no other signs of the Cushing syndrome, and her blood pressure remained normal. Her optic fundi and visual fields were normal. Her urinary excretion of free cortisol was moderately elevated to 186//g/24 h (normal range, 24 to 108 /ug/24 h). The plasma cortisol levels were elevated in the afternoon (20 and 22 //g/dl), but the morning levels were normal (17 and 20 //g/dl). The serum concentrations of thyroid-stimulating hormone, thyroxine, triiodothyronine, testosterone, prolactin, and somatomedin C were normal, as were results of the glucose tolerance test and the serum levels of growth hormone in response to insulin and glucose. Thinsection imaging of the adrenal glands by computed tomography showed slight globular enlargement in the posterior limb of the left adrenal gland to a maximal diameter of approximately 5 mm, but the adrenal glands were not diffusely enlarged and otherwise ap peared normal. Repeat computed tomography of the head, with use of a contrast agent and including coronal sections of the pituitary fossa, revealed, in the right side of the pituitary fossa, a 5-mm zone of decreased density that rapidly equilibrated with the contrast medium; the appearance was suggestive of a microadenoma of the pituitary. Further investigations, however, indicated that the increased production of cortisol was not caused by hyperpituitarism. The plasma corticotropin level was 39 pg/ml, which is in the low-normal range for our laboratory (0 to 120 pg/ml). The production of cortisol was not suppressed by the administration of a large dose (16 mg) of dexamethasone, and the administration of metyrapone produced only a small increase in the plasma levels of 11-deoxycorticosteroids—from 2.2 to 5.2 //g/dl (normal range, 0 to 5 //g/dl). Therefore, although the patient probably had a microadenoma of the pituitary gland, we concluded that her hypercortisol-
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ism was of adrenal origin and was not dependent on production of corticotropin in the pituitary. In September 1985, bilateral adrenalectomy was per formed. The right and left adrenal glands weighed 3.5 and 4.7 g, respectively, and they had the characteristic gross and microscopic appearances of primary pigmented nodular adrenocortical disease. Case 2 . ^ A brother (III.7) of the index patient was 26 years old at the time of our examination. For as long as he could remember, he had had dark spots on his face and lips. When he was 16 years old, a "cyst" had been removed from his left shoulder. At 20 years of age, he had undergone excision of two lesions, one (which was pedunculated, fingerlike, and 5 cm long and 1 cm wide) from the skin of his perineum and another (a 7-mm nodule) from his left buttock. Histologically, both were myxomas; the perineal lesion had an epithelial compo nent that resembled trichofolliculoma. At age 18 or 19 years, he had become aware of an enlargement of his hands and feet and then of his head and face. On examination at another institution at age 21 years, he had been told that he had acromegaly. His plasma growth hormone level was increased, and tomograms of the sella turcica showed asymmetric enlarge ment and a thin floor. A pituitary tumor, removed by transsphenoidal hypophysectomy, proved to be an ade noma composed of growth hormone-producing cells. The signs of acromegaly subsequently subsided. At age 24 years, he had undergone excision of a lobulated myxoma from the skin of his right thigh. When we examined this patient, his general health was good, and no signs of acromegaly were evident. Physical examination of his heart disclosed normal findings, and chest roentgenography and twodimensional echocardiography confirmed these results. His entire face, but especially the infraorbital areas, had numerous dark brown and black lentigines (Fig. 2 B). Several black lentigines were present on his lips, including their vermilion borders. In each eye, a tiny lentigo was present on the bulbar conjunctiva near the medial canthus (on the conjunctival semilunar fold). A small, dusky pink swelling (presumably a myxoma) was noted on the posterior surface of the helix of the right ear. A small cluster of lentigines was present on the anterior chest wall, and others were present on the thighs and forearms. A small horizontal streak of pigmentation extended from the lateral angle of the left palpebral opening, and a similar streak of dark pigmen tation was noted on the top of his right shoulder. A small spot of dark pigmentation was also present on the dorsal surface of the glans penis. He had a normal male karyotype. DISCUSSION In t h i s family, lentigines were present in the index patient, in three of her seven siblings, in their mother, a n d in a niece (the d a u g h t e r of a n affected sister). Cutaneous m y x o m a s were present in t h e index patient, in two of her brothers, a n d probably in their mother. I n addition, t h e index p a t i e n t h a d
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two cardiac m y x o m a s , multiple myxoid m a m m a r y fibroadenomas, a n d t h e C u s h i n g syndrome, a n d a n affected brother h a d acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. T h u s , a t least one manifestation of t h e complex of m y x o m a s , spotty pigmentation, a n d endocrine overactivity h a s occurred in three suc cessive generations of t h e family we describe. Both m a l e a n d female family m e m b e r s were af fected, a n d 5 of the 11 children of affected persons h a d the disorder. The karyotypes of two affected persons were n o r m a l . These observations are con sistent with d o m i n a n t , probably autosomal, in heritance, but in the absence of male-to-male t r a n s m i s s i o n , the mode of inheritance is not yet certain. We are a w a r e of two other families (Table 1, families III a n d V) in which the mothers a n d one or two of their sons are affected, but we h a v e not yet encountered a family with a n affected father a n d son. If the mode of inheritance is Xlinked d o m i n a n t , the niece (IV.6) who is the d a u g h t e r of a n affected brother (III.7) of our index case should also be affected—but she is not. She is still a n infant, however; t h u s , signs of the syn drome m a y subsequently appear. When more fam ilies with this s y n d r o m e h a v e been investigated, this question should be resolved; currently, the autosomal d o m i n a n t mode of inheritance seems most likely. T h e phenotypes of the affected persons in this family were variable. Only t h e index p a t i e n t h a d five of t h e seven known components of the syn drome. T h u s far, in this family, only s h e h a s h a d cardiac m y x o m a , a n d only s h e a n d one brother (III.7) h a v e h a d endocrine overactivity. Such vari ability is a characteristic feature of the other familial cases we h a v e reviewed (Table 1). For instance, in family I, only one of t h e affected siblings h a d a cardiac m y x o m a ; a n d in family II, two sisters h a d cardiac m y x o m a s a n d pigmented nodular adrenocortical disease, but only one of these sisters h a d pigmented a n d m y x o m a t o u s cutaneous lesions. There is little doubt t h a t these different condi tions are associated pathogenically. T h e associa tion, albeit variable, of conditions a s u n c o m m o n a s cardiac m y x o m a s , pigmented nodular adreno cortical disease, a n d large-cell calcifying Sertoli cell t u m o r s of the testis in individual p a t i e n t s a n d in families surely c a n n o t be due to chance. In the family we describe, the fact t h a t the index patient h a d c a r d i a c m y x o m a s a n d one of her brothers h a d
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a growth hormone-secreting tumor of the pituitary is not likely to be coincidental because we have recently learned of another person, unrelated to this family, with cutaneous and mucocutaneous pigmentation, cutaneous myxomas, and a growth hormone-secreting pituitary adenoma (Edis AJ: Personal communication). Thus, in the terminol ogy introduced in the United States by Opitz and associates, 8 the associations that have been ob served in this family (and in others) can be regarded as a "formal-genesis syndrome," mean ing that the various conditions have a common pathogenesis. Because we do not know the basic mechanism responsible for these diverse manifes tations, we cannot yet regard them as constituting a "causal-genesis syndrome." The complex we have described 3 must be distin guished from two other syndromes in which lentigines are associated with other developmental anomalies and in which autosomal dominant inheritance has been demonstrated. It is ob viously not the same as the one described by Forney and colleagues, 9 in which the affected persons had pigmented skin lesions similar to those in our patients but had different cardiac lesions. Three affected members in that family had congenital mitral insufficiency (probably mi tral valve prolapse), not cardiac myxomas. More over, they had conductive deafness and skeletal anomalies, neither of which was observed in the current family or in the cases that we previously reviewed. The complex that we report also differs from the syndrome of lentiginosis and hypertrophic cardiomyopathy, 10 because cardiac and cu taneous myxomas are not components of that syndrome. Some persons with that syndrome may also have variable combinations of short stature, hypogonadism, and sensorineural deafness, none of which was observed in the syndrome that we are reporting. Two other recently described cases, however, are probably partial forms of the syndrome that we are reporting. In 1980, Atherton and asso ciates 1 described a 10-year-old boy with spotty lesions of the skin, subcutaneous myxoid neurofibromas, and a left atrial myxoma. They suggested that this disorder be referred to as the NAME syndrome (for nevi, atrial myxoma, myxoid neurofibroma, and ephelides). The boy's parents and his two older brothers were said to be "freckled," but presumably they were regarded as normal. In
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1984, Rhodes and colleagues 2 described a 13-yearold girl with lentigines, cutaneous and oral myxo mas, blue nevi, and a myxoma of the right atrium. They suggested that this combination be called the LAMB syndrome (for /entigines, atrial myx oma, mucocutaneous myxoma, and olue nevi). The physical findings in this patient's parents and siblings were essentially normal. These acronymic designations may be misleading. The char acteristic skin lesions are not ephelides or neurofibromas, and the cardiac myxomas may occur in the ventricles as well as in the atria. A statement about the genetics of the complex cannot be made confidently on the basis of the single family that we have examined and the other four families that have been described else where (Table 1). We cannot even speculate about whether the various manifestations of the com plex are the pleiotropic effects of a mutation at a single gene locus, with variable expression within and between families, or whether they are the effects of two or more closely linked genes. These issues can be resolved only after many more families have been investigated systematically. Nonetheless, at present, the heritable nature of the complex cannot be doubted. Therefore, should any patient be encountered with two or more compo nents of the syndrome, the first-degree relatives of the patient should immediately be investigated. The critical importance of this approach is exemplified by our recent experience with a family that was previously described by Proppe and Scully6 (family III in Table 1). In the original report of large-cell calcifying Sertoli cell tumor of the testis, these authors described two brothers who had this tumor and also had cardiac myxoma and nodular adrenocortical hyperplasia. Because we recognized that the adrenal disorder was pri mary pigmented nodular adrenocortical disease, we inquired further and learned that both young men had had cutaneous and mucocutaneous spotty pigmentation. We were able to locate their parents, and we recommended that they be investigated for the syndrome. The father had no mucocutaneous pigmentation, and his echocardiogram was nor mal. The mother, 58 years old, was asymptomatic but had the characteristic cutaneous and mucocu taneous pigmentation on her face, lips, conjunc tiva, labia minora, and clitoris. Tests of her adre nocortical function yielded normal results, but an echocardiogram showed a left atrial filling defect,
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which proved to be caused by a myxoma. The clinical and echocardiographic findings in the two maternal aunts and the maternal grandmother were normal; the paternal grandfather has died but had no obvious signs of the complex. This family indicates the heritable nature of the condi tion and also its variable expressivity. More im portant, it justifies our recommendation that the first-degree relatives of patients with this syn drome should be thoroughly investigated. At present, we recommend that first-degree rela tives (parents, siblings, and children) of affected persons have a complete physical examination, including examination of the cardiovascular sys tem, study of the skin in natural and ultraviolet light, and palpation of the testes. An echocardiogram should be done in all cases. Adrenal function should be tested by determining the 24-hour excre tion of free cortisol in the urine (in one report, a patient had massive intermittent hypercortisolemia but no Cushing syndrome 11 ). Until future experience teaches us differently, we recommend that these investigations be repeated every year. ACKNOWLEDGMENT We thank the following colleagues who provided clinical information, echocardiograms, or histologic slides for the study: J. L. Booth, L. R. Christie, J. D. Lott, G. A. Oliver, C. Siqueira, A. Starr, and G. Starr.
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REFERENCES 1. Atherton DJ, Pitcher DW, Wells RS, MacDonald DM: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syn drome. Br J Dermatol 103:421-429, 1980 2. Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR: Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the "LAMB" syndrome. J Am Acad Dermatol 10:72-82,1984 3. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW: The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64:270283, 1985 4. Schweizer-Cagianut M, Salomon F, Hedinger CE: Pri mary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch [A] 397:183-192, 1982 5. Barlow JF, Abu-Gazeleh S, Tarn GE, Wirtz PS, Ofstein LC, O'Brien CP, Woods GL, Drymalski WG: Myxoid tumor of the uterus and right atrial myxomas. SD J Med 36:9-13, July 1983 6. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 74:607-619, 1980 7. Morgan DL, Palazola J, Reed W, Bell HH, Kindred LH, Beauchamp GD: Left heart myxomas. Am J Cardiol 40:611-614, 1977 8. Opitz JM, Herrmann J, Pettersen JC, Bersu ET, Colacino SC: Terminological, diagnostic, nosological, and anatomical-developmental aspects of developmental de fects in man. Adv Hum Genet 9:71-164, 1979 9. Forney WR, Robinson SJ, Pascoe DJ: Congenital heart disease, deafness, and skeletal malformations: a new syndrome? J Pediatr 68:14-26, 1966 10. Polani PE, Moynahan EJ: Progressive cardiomyopathic lentiginosis. Q J Med 41:205-239, 1972 11. Rosenzweig JL, Lawrence DA, Vogel DL, Costa J, Gorden P: Adrenocorticotropin-independent hypercortisolemia and testicular tumors in a patient with a pituitary tumor and gigantism. J Clin Endocrinol Metab 55:421-427,1982
Mayo Clinic ROCHESTER, MINNESOTA
Vol.61
MARCH 1986
Dominant Inheritance of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity
J. AIDAN CARNEY, M.D., Ph.D., F.R.C.P.I., Section of Surgical Pathology; LOIS S. HRUSKA, M.S., Department of Medical Genetics; GARY D. BEAUCHAMP, M.D.*; HYMIE GORDON, M.D., Department of Medical Genetics
We describe a family in which lentigines were present in the index patient, in three of her seven siblings, in their mother, and in a niece (the daughter of an affected sister). Cutaneous myxomas were present in the index patient, in t w o of her brothers, and probably in their mother. In addition, the index patient had t w o cardiac myxomas, multiple myxoid mammary fibroadenomas, and the Cushing syndrome, and an affected brother had acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. Thus, at least one manifestation of the complex of myxomas, spotty pigmentation, and endocrine overactivity has occurred in three successive generations of this family. Both male and female family members were affected, and 5 of the 11 children of affected persons had the disorder. The karyotypes of t w o affected persons were normal. These observations are consistent with mendelian dominant inheritance of the syndrome.
T h e association of lentiginosis with cardiac a n d cutaneous m y x o m a s h a s been reported on several occasions, 1 2 b u t our recent clinical a n d pathologic review of the subject presented evidence t h a t the association w a s a broader one a n d m i g h t include s y n d r o m e s of endocrine overactivity a s well. 3 I n t h a t review, a variable complex of mucocutaneous, visceral, a n d endocrine disorders w a s de scribed in 40 patients (16 male a n d 24 female patients), each of w h o m h a d two or more of the following lesions: (1) cardiac myxoma, in a n y one
*Department of Cardiology, St. Luke's Hospital, Kansas City, Missouri. Address reprint requests to Dr. J. A. Carney, Department of Pathology, Mayo Clinic, Rochester, MN 55905. Mayo Clin Proc 61:165-172, 1986
or more of the cardiac c h a m b e r s , in 29 (72%), including 16 with single lesions a n d 13 with multiple lesions; (2) cutaneous myxoma, single or multiple, in 18 (45%); (3) mammary myxoid fibroadenoma, single or multiple, in 12 female p a t i e n t s (30%) (2 m a l e p a t i e n t s h a d gynecomastia); (4) spotty mucocutaneous pigmentation, in cluding lentigines a n d blue nevi (and occasionally junctional nevi a n d compound nevi) a n d combina tions of these, in 26 (65%); (5) primary pigmented nodular adrenocortical disease, in 18 p a t i e n t s (45%), including 11 with the C u s h i n g s y n d r o m e a n d 7 who were a s y m p t o m a t i c a n d whose lesion w a s found a t autopsy; (6) testicular tumors, char acteristically large-cell calcifying Sertoli cell tumors, usually bilateral a n d multicentric, in 9 of t h e 16 male patients (56%) (4 h a d sexual precocity); 165
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and (7) pituitary growth hormone-secreting tumor, which caused acromegaly or gigantism, in 4 (10%). The possibility that this complex might be heritable was suggested by the relatively young age (mean, 18 years) of the patients with the visceral lesions and the tendency of the lesions to be multicentric and to be bilateral when paired organs were affected. Moreover, the 40 patients included five pairs of first-degree relatives (Table 1). Because the relatives of affected patients had not always been examined systematically, we believe that this reported finding was probably only a minimal indication of the familial aggrega tion of the disorder. We now have had the opportunity to examine most of the first- and second-degree relatives of one of the patients (no. 14) included in our previous review.3 Our observations in this family are con sistent with dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. INVESTIGATION OF THE FAMILY The index patient, her father, and her maternal grandmother had been examined at our institu tion. Six of her seven siblings and all six nephews and nieces were examined in Kansas City. The investigation included a thorough physical exam ination with anthropometry and study of the skin in natural and ultraviolet light. In each case, a chest roentgenogram and a two-dimensional echo-
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cardiogram were obtained. Each person older than 6 years of age had a complete blood cell count, automated serum biochemical profile (so dium, potassium, calcium, phosphate, total pro tein, albumin, glucose, alkaline phosphatase, aspartate aminotransferase, bilirubin, uric acid, and creatinine), and plasma cortisol determinations on specimens collected in the morning and midafternoon. The karyotypes of three persons were examined. The mother and one of the brothers of the index patient were not examined, but they provided us with their medical records and color photographs of themselves. In the following ac count of the pedigree (Fig. 1), the results of the aforementioned investigations that are not stated were normal; only the abnormal findings are presented. Paternal Lineage.—The paternal grand father (1.1) was of Irish, French, and American Indian descent. He had had no known abnormal pigmentation. His death, at age 64 years, was attributed to pulmonary embolism, a complication of an old leg injury. The paternal grandmother (1.2) was of French and American Indian descent; she was reported to have had "stomach ulcers" at age 72 years and to have died of Hodgkin disease at age 75 years. The father (II.2) was healthy when we examined him at age 54 years; he had no abnormal pigmentation or any other clinical man ifestations of the complex. None of the 5 paternal uncles or aunts or the 11 paternal first cousins was known to have any abnormal pigmentation or other manifestation of the complex.
Table 1.—Summary of Findings in Familial Cases of the Complex of Myxomas, Spotty Pigmentation, and Endocrine Overactivity* Testicular Mammary Skin Sertoli Hypermyxoid pigmen cell Myxoma pituitarism Reference PPNAD Skin tumor tation tumors Cardiac Familyt 4 I. Sister Neg + + + + + Brother Neg Neg Neg + + + 5 II. Sister Neg + + + + + Sister Neg Neg Neg + + III. Mother Neg Neg 6 Neg Neg + + Son Neg Neg Neg + + + + Son Neg Neg Neg + + + + IV. Sister Current Neg + + + + + Neg Neg Neg Neg report Brother + + + V. Mother J-P + — + — — OrtonneJ Son + + *+ = present; — = not recorded or status unknown; Neg = examination for that condition revealed normal findings; PPNAD = primary pigmented nodular adrenocortical disease. tRoman numerals refer to Table 1 in reference 3. {Personal communication.
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Maternal Lineage.—The maternal grand father (1.3) was of German descent; he had died of a stroke at age 63 years. The maternal grand mother (1.4), who was 73 years of age, was of English descent. Her skin was normal and, except for recent acute bronchitis, she was healthy. The mother (II.3), 55 years of age, declined to be examined but provided information about herself. For as long as she could remember, she had had spots of dark pigment on her face, lips, backs of her hands, forearms, and genitalia. Photographs confirmed the presence of numerous dark brown or black lentigines on her face, especially under the eyes and across the bridge of the nose; similar spots were present on her lower lip. At age 24 years, she had had a partial thyroidectomy for "goiter"; at that time, a "growth" had been re moved from her right external auditory canal. A mass had been excised from her left breast when she was 28 years old. (Records of these procedures were not available.) At 55 years of age, she had undergone excision of a small nodule from her right lower eyelid; microscopic examination showed a lentigo, an epithelium-lined cyst (hidrocystoma), and myxoid stroma. The maternal uncle (II.4) was 53 years old. We did not examine him but, according to his sister (II.3), he was healthy and had no abnormal pig
mentation. The maternal first cousin (111.12), who was 24 years old, was not examined by us; he was said to be healthy and to have no abnormal pigmentation. Index Patient.—The index patient, a 34-yearold woman (III.3), had cutaneous lentigines (Fig. 2 A) and myxomas of the right lower eyelid and on the pinna of the left ear. She had undergone surgical removal of cardiac myxomas from her left ventricle and left atrium. The clinical findings are described in the detailed case reports (case 1). Siblings and Their Children.—A 35-year-old brother of the index patient (III.2) was healthy; he had no cutaneous or other manifestations of the complex. His three sons (nephews IV.l, 2, and 3), who were 14, 7, and 5 years old, respectively, also were found to be normal. Another brother (III.4), 30 years old, declined to be examined, but he provided us with medical records and photographs of his face. The latter showed typical facial lentiginosis, especially un der the eyes, on the cheeks, across the bridge of the nose, and on the lips. At age 8 years, he had had a dark facial lesion excised; microscopically, it was composed of "elongated, spindle-shaped, deeply pigmented cells"—findings consistent with blue nevus. At age 13 years, he had complained of a sensation of fullness in his right ear canal. Amass
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that was attached to the posterior wall and filled and obstructed the ear canal was excised. The lesion proved to be a ruptured squamous epithelium-lined cyst surrounded by myxoid stroma. The following year, an elevated cystic lesion that partially blocked the left ear canal was detected and excised. Microscopic examination showed it to be a myxoma with a trichofolliculoma-like component. When he was 19 years old, a 1.5-cm polypoid myxoma had been removed from the scalp. Recently, he had been examined by his home physician because of shortness of breath and a pressurelike sensation in the chest. Apart from the abnormal pigmentation, results of physi cal examination were normal, as were the findings on echocardiography. This man is married but has no children. A 28-year-old unmarried brother (III.5) was healthy and had no sign of the complex. A 27-year-old sister (III.6) was healthy but had extensive facial lentiginosis, mostly under the eyes, around the mouth, and also on the vermilion border of the upper lip; she had no conjunctival lesions. Her son (nephew IV.4), 5 years of age, was healthy. Her 3-year-old daughter (niece IV.5) had lentiginosis. Numerous small, dark brown-black lentigines were present around her eyes, across
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her cheeks, and on the bridge of her nose; she also had a cluster of lentigines below the right side of her lower lip but none on the vermilion borders of her lips (Fig. 2 Q . A streak of black pigmentation (2.2 by 1.0 cm) was noted over her right scapula. A tiny black pigmented spot was present on the lateral wall of her left axilla; a similar lesion was present on the back of her left thigh, and two more such spots were visible on the lateral aspect of her left knee. A 26-year-old brother (III.7) had extensive lentig inosis (Fig. 2 B); he had had several cutaneous myxomas excised, and he had had acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. His clinical findings are re corded in detail in the subsequent case reports (case 2). We examined his 9-day-old daughter (IV.6). She did not have lentiginosis but had a taillike appendage in the sacral area; no underly ing bony abnormality was noted on x-ray exami nation. Microscopic examination of the append age showed a fibrofatty core covered by normal epidermis. A 25-year-old sister (III.8) was mildly subnor mal mentally. She had a few common freckles on the bridge of her nose but no lentigines. A large (4.5-cm), round cafe au lait spot was present on the
Fig. 2. Photographs of some affected members of the family. A, Index patient (III.3) has spotty pigmentation below eye, on lacrimal caruncle, and on cheek, nose, and vermilion border of upper lip. B, Her brother (III.7) has pigmented spots on forehead, cheek, nose, and vermilion borders of lips. A single spot of pigmentation was present on right conjunctival semilunar fold. C, A niece (IV.5) has butterfly distribution of spotty pigmentation around eyes, across nose, and on the skin of the upper lip.
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anterior aspect of her left thigh; no other dyspigm e n t a t i o n w a s visible in n a t u r a l or ultraviolet light. Her only somatic developmental a n o m a l y w a s a slightly short left fourth toe. She h a d a n o r m a l female karyotype. A 23-year-old brother (ΙΠ.9) w a s h e a l t h y . He h a d no manifestation of t h e complex. Siblings III.10 a n d III.11 were s p o n t a n e o u s miscarriages during the first trimester of pregnancy.
REPORT OF CASES Case I.—The index patient (III.3), a 34-year-old woman, had come to our medical center in 1984 because of persistent headaches. She had had pigmented spots on her face and lips since birth. At age 14 years, she had undergone removal of a lesion from her right upper eyelid; microscopically, it was a "papilloma having a core of fibrovascular tissue." Recurrence of the eyelid lesion 3 years later necessitated another excision. At age 16 years, she had had pigmented lesions excised from her cheeks, upper lip, and left shoulder. The lesions on her cheeks were blue nevi; the others were lentigines. At age 19 years, two dark brown lesions had been removed from her lower lip. (Histologie slides of these lesions were not available.) She had begun to wear glasses for mild myopia at age 9 years. Her menarche was at age 12 years, and she had always menstruated normally. When the patient was 24 years old, a heart murmur had been detected during the course of a physical examination. 7 An echocardiogram demonstrated a mass in the left ventricle. On cardiac exploration, a smaller left atrial mass was found in addition to the left ventricular tumor; both tumors proved to be myxomas. At age 25 years, she had undergone removal of an asymptomatic lump from her left breast; histologically, the lesion was multicentric myxoid fibroadenoma. Dur ing the following year, two nodules had been excised from the skin on her back; microscopically, they were myxomas. At age 27 years, she had had lentigines excised from her perianal skin and vulva. In the same year, she had undergone a right thyroid lobectomy for a 1.5-cm follicular adenoma. When she was 32 years old, impaired hearing in her right ear had led to the discov ery of a pedunculated mass in the external auditory canal; histologically, this lesion was a myxoma with an epithelial component that resembled trichofolliculoma. At age 34 years, she had undergone excision of addi tional regions of myxoid fibroadenomatosis from both breasts. When she was examined at our institution, her heart and nervous system were normal. Two-dimensional echocardiography, high-resolution computed tomographic scanning of the thorax and head (including coro nal views through the pituitary area with use of a contrast medium), and electroencephalography showed normal findings; no recurrence of the cardiac myxomas
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was detected. Results of biochemical investigation of her pituitary-adrenal function were normal; specifi cally, the plasma cortisol levels were 8.2 /ug/dl in the morning (normal range, 7 to 25 //g/dl) and 8.5 //g/dl in the afternoon (normal range, 2 to 14 //g/dl). She had a normal female karyotype. Her headaches had been caused by an abscessed tooth. During the course of the examination, various mucocutaneous lesions were observed. Numerous small, dark brown pigmented spots were present on the central part of her face, especially on the cheeks, nose, and upper lip including the vermilion border (Fig. 2 A). Similar single spots of dark pigmentation were present on the conjunc tiva of the right medial canthus, on the inside of the right cheek, and on the right areola. Multiple spots were present on the labia minora and buttocks. A 2-mm, darkly pigmented, nontender, cystic nodule was noted on the anthelix of the left ear, and a small thickening was felt in the middle of the right lower eyelid, just below the eyelashes; these lesions were probably myxomas. Approximately 6 months later, the patient began to feel excessively tired; in addition, she became emotion ally labile, her menstruation was prolonged, a slight growth of hair appeared on her face, and she rapidly gained weight—from 78.0 kg to 89.5 kg. She had no other signs of the Cushing syndrome, and her blood pressure remained normal. Her optic fundi and visual fields were normal. Her urinary excretion of free cortisol was moderately elevated to 186//g/24 h (normal range, 24 to 108 /ug/24 h). The plasma cortisol levels were elevated in the afternoon (20 and 22 //g/dl), but the morning levels were normal (17 and 20 //g/dl). The serum concentrations of thyroid-stimulating hormone, thyroxine, triiodothyronine, testosterone, prolactin, and somatomedin C were normal, as were results of the glucose tolerance test and the serum levels of growth hormone in response to insulin and glucose. Thinsection imaging of the adrenal glands by computed tomography showed slight globular enlargement in the posterior limb of the left adrenal gland to a maximal diameter of approximately 5 mm, but the adrenal glands were not diffusely enlarged and otherwise ap peared normal. Repeat computed tomography of the head, with use of a contrast agent and including coronal sections of the pituitary fossa, revealed, in the right side of the pituitary fossa, a 5-mm zone of decreased density that rapidly equilibrated with the contrast medium; the appearance was suggestive of a microadenoma of the pituitary. Further investigations, however, indicated that the increased production of cortisol was not caused by hyperpituitarism. The plasma corticotropin level was 39 pg/ml, which is in the low-normal range for our laboratory (0 to 120 pg/ml). The production of cortisol was not suppressed by the administration of a large dose (16 mg) of dexamethasone, and the administration of metyrapone produced only a small increase in the plasma levels of 11-deoxycorticosteroids—from 2.2 to 5.2 //g/dl (normal range, 0 to 5 //g/dl). Therefore, although the patient probably had a microadenoma of the pituitary gland, we concluded that her hypercortisol-
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ism was of adrenal origin and was not dependent on production of corticotropin in the pituitary. In September 1985, bilateral adrenalectomy was per formed. The right and left adrenal glands weighed 3.5 and 4.7 g, respectively, and they had the characteristic gross and microscopic appearances of primary pigmented nodular adrenocortical disease. Case 2 . ^ A brother (III.7) of the index patient was 26 years old at the time of our examination. For as long as he could remember, he had had dark spots on his face and lips. When he was 16 years old, a "cyst" had been removed from his left shoulder. At 20 years of age, he had undergone excision of two lesions, one (which was pedunculated, fingerlike, and 5 cm long and 1 cm wide) from the skin of his perineum and another (a 7-mm nodule) from his left buttock. Histologically, both were myxomas; the perineal lesion had an epithelial compo nent that resembled trichofolliculoma. At age 18 or 19 years, he had become aware of an enlargement of his hands and feet and then of his head and face. On examination at another institution at age 21 years, he had been told that he had acromegaly. His plasma growth hormone level was increased, and tomograms of the sella turcica showed asymmetric enlarge ment and a thin floor. A pituitary tumor, removed by transsphenoidal hypophysectomy, proved to be an ade noma composed of growth hormone-producing cells. The signs of acromegaly subsequently subsided. At age 24 years, he had undergone excision of a lobulated myxoma from the skin of his right thigh. When we examined this patient, his general health was good, and no signs of acromegaly were evident. Physical examination of his heart disclosed normal findings, and chest roentgenography and twodimensional echocardiography confirmed these results. His entire face, but especially the infraorbital areas, had numerous dark brown and black lentigines (Fig. 2 B). Several black lentigines were present on his lips, including their vermilion borders. In each eye, a tiny lentigo was present on the bulbar conjunctiva near the medial canthus (on the conjunctival semilunar fold). A small, dusky pink swelling (presumably a myxoma) was noted on the posterior surface of the helix of the right ear. A small cluster of lentigines was present on the anterior chest wall, and others were present on the thighs and forearms. A small horizontal streak of pigmentation extended from the lateral angle of the left palpebral opening, and a similar streak of dark pigmen tation was noted on the top of his right shoulder. A small spot of dark pigmentation was also present on the dorsal surface of the glans penis. He had a normal male karyotype. DISCUSSION In t h i s family, lentigines were present in the index patient, in three of her seven siblings, in their mother, a n d in a niece (the d a u g h t e r of a n affected sister). Cutaneous m y x o m a s were present in t h e index patient, in two of her brothers, a n d probably in their mother. I n addition, t h e index p a t i e n t h a d
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two cardiac m y x o m a s , multiple myxoid m a m m a r y fibroadenomas, a n d t h e C u s h i n g syndrome, a n d a n affected brother h a d acromegaly caused by a growth hormone-secreting tumor of the pituitary gland. T h u s , a t least one manifestation of t h e complex of m y x o m a s , spotty pigmentation, a n d endocrine overactivity h a s occurred in three suc cessive generations of t h e family we describe. Both m a l e a n d female family m e m b e r s were af fected, a n d 5 of the 11 children of affected persons h a d the disorder. The karyotypes of two affected persons were n o r m a l . These observations are con sistent with d o m i n a n t , probably autosomal, in heritance, but in the absence of male-to-male t r a n s m i s s i o n , the mode of inheritance is not yet certain. We are a w a r e of two other families (Table 1, families III a n d V) in which the mothers a n d one or two of their sons are affected, but we h a v e not yet encountered a family with a n affected father a n d son. If the mode of inheritance is Xlinked d o m i n a n t , the niece (IV.6) who is the d a u g h t e r of a n affected brother (III.7) of our index case should also be affected—but she is not. She is still a n infant, however; t h u s , signs of the syn drome m a y subsequently appear. When more fam ilies with this s y n d r o m e h a v e been investigated, this question should be resolved; currently, the autosomal d o m i n a n t mode of inheritance seems most likely. T h e phenotypes of the affected persons in this family were variable. Only t h e index p a t i e n t h a d five of t h e seven known components of the syn drome. T h u s far, in this family, only s h e h a s h a d cardiac m y x o m a , a n d only s h e a n d one brother (III.7) h a v e h a d endocrine overactivity. Such vari ability is a characteristic feature of the other familial cases we h a v e reviewed (Table 1). For instance, in family I, only one of t h e affected siblings h a d a cardiac m y x o m a ; a n d in family II, two sisters h a d cardiac m y x o m a s a n d pigmented nodular adrenocortical disease, but only one of these sisters h a d pigmented a n d m y x o m a t o u s cutaneous lesions. There is little doubt t h a t these different condi tions are associated pathogenically. T h e associa tion, albeit variable, of conditions a s u n c o m m o n a s cardiac m y x o m a s , pigmented nodular adreno cortical disease, a n d large-cell calcifying Sertoli cell t u m o r s of the testis in individual p a t i e n t s a n d in families surely c a n n o t be due to chance. In the family we describe, the fact t h a t the index patient h a d c a r d i a c m y x o m a s a n d one of her brothers h a d
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a growth hormone-secreting tumor of the pituitary is not likely to be coincidental because we have recently learned of another person, unrelated to this family, with cutaneous and mucocutaneous pigmentation, cutaneous myxomas, and a growth hormone-secreting pituitary adenoma (Edis AJ: Personal communication). Thus, in the terminol ogy introduced in the United States by Opitz and associates, 8 the associations that have been ob served in this family (and in others) can be regarded as a "formal-genesis syndrome," mean ing that the various conditions have a common pathogenesis. Because we do not know the basic mechanism responsible for these diverse manifes tations, we cannot yet regard them as constituting a "causal-genesis syndrome." The complex we have described 3 must be distin guished from two other syndromes in which lentigines are associated with other developmental anomalies and in which autosomal dominant inheritance has been demonstrated. It is ob viously not the same as the one described by Forney and colleagues, 9 in which the affected persons had pigmented skin lesions similar to those in our patients but had different cardiac lesions. Three affected members in that family had congenital mitral insufficiency (probably mi tral valve prolapse), not cardiac myxomas. More over, they had conductive deafness and skeletal anomalies, neither of which was observed in the current family or in the cases that we previously reviewed. The complex that we report also differs from the syndrome of lentiginosis and hypertrophic cardiomyopathy, 10 because cardiac and cu taneous myxomas are not components of that syndrome. Some persons with that syndrome may also have variable combinations of short stature, hypogonadism, and sensorineural deafness, none of which was observed in the syndrome that we are reporting. Two other recently described cases, however, are probably partial forms of the syndrome that we are reporting. In 1980, Atherton and asso ciates 1 described a 10-year-old boy with spotty lesions of the skin, subcutaneous myxoid neurofibromas, and a left atrial myxoma. They suggested that this disorder be referred to as the NAME syndrome (for nevi, atrial myxoma, myxoid neurofibroma, and ephelides). The boy's parents and his two older brothers were said to be "freckled," but presumably they were regarded as normal. In
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1984, Rhodes and colleagues 2 described a 13-yearold girl with lentigines, cutaneous and oral myxo mas, blue nevi, and a myxoma of the right atrium. They suggested that this combination be called the LAMB syndrome (for /entigines, atrial myx oma, mucocutaneous myxoma, and olue nevi). The physical findings in this patient's parents and siblings were essentially normal. These acronymic designations may be misleading. The char acteristic skin lesions are not ephelides or neurofibromas, and the cardiac myxomas may occur in the ventricles as well as in the atria. A statement about the genetics of the complex cannot be made confidently on the basis of the single family that we have examined and the other four families that have been described else where (Table 1). We cannot even speculate about whether the various manifestations of the com plex are the pleiotropic effects of a mutation at a single gene locus, with variable expression within and between families, or whether they are the effects of two or more closely linked genes. These issues can be resolved only after many more families have been investigated systematically. Nonetheless, at present, the heritable nature of the complex cannot be doubted. Therefore, should any patient be encountered with two or more compo nents of the syndrome, the first-degree relatives of the patient should immediately be investigated. The critical importance of this approach is exemplified by our recent experience with a family that was previously described by Proppe and Scully6 (family III in Table 1). In the original report of large-cell calcifying Sertoli cell tumor of the testis, these authors described two brothers who had this tumor and also had cardiac myxoma and nodular adrenocortical hyperplasia. Because we recognized that the adrenal disorder was pri mary pigmented nodular adrenocortical disease, we inquired further and learned that both young men had had cutaneous and mucocutaneous spotty pigmentation. We were able to locate their parents, and we recommended that they be investigated for the syndrome. The father had no mucocutaneous pigmentation, and his echocardiogram was nor mal. The mother, 58 years old, was asymptomatic but had the characteristic cutaneous and mucocu taneous pigmentation on her face, lips, conjunc tiva, labia minora, and clitoris. Tests of her adre nocortical function yielded normal results, but an echocardiogram showed a left atrial filling defect,
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which proved to be caused by a myxoma. The clinical and echocardiographic findings in the two maternal aunts and the maternal grandmother were normal; the paternal grandfather has died but had no obvious signs of the complex. This family indicates the heritable nature of the condi tion and also its variable expressivity. More im portant, it justifies our recommendation that the first-degree relatives of patients with this syn drome should be thoroughly investigated. At present, we recommend that first-degree rela tives (parents, siblings, and children) of affected persons have a complete physical examination, including examination of the cardiovascular sys tem, study of the skin in natural and ultraviolet light, and palpation of the testes. An echocardiogram should be done in all cases. Adrenal function should be tested by determining the 24-hour excre tion of free cortisol in the urine (in one report, a patient had massive intermittent hypercortisolemia but no Cushing syndrome 11 ). Until future experience teaches us differently, we recommend that these investigations be repeated every year. ACKNOWLEDGMENT We thank the following colleagues who provided clinical information, echocardiograms, or histologic slides for the study: J. L. Booth, L. R. Christie, J. D. Lott, G. A. Oliver, C. Siqueira, A. Starr, and G. Starr.
Mayo Clin Proc, March 1986, Vol 61
REFERENCES 1. Atherton DJ, Pitcher DW, Wells RS, MacDonald DM: A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syn drome. Br J Dermatol 103:421-429, 1980 2. Rhodes AR, Silverman RA, Harrist TJ, Perez-Atayde AR: Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the "LAMB" syndrome. J Am Acad Dermatol 10:72-82,1984 3. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW: The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 64:270283, 1985 4. Schweizer-Cagianut M, Salomon F, Hedinger CE: Pri mary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch [A] 397:183-192, 1982 5. Barlow JF, Abu-Gazeleh S, Tarn GE, Wirtz PS, Ofstein LC, O'Brien CP, Woods GL, Drymalski WG: Myxoid tumor of the uterus and right atrial myxomas. SD J Med 36:9-13, July 1983 6. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 74:607-619, 1980 7. Morgan DL, Palazola J, Reed W, Bell HH, Kindred LH, Beauchamp GD: Left heart myxomas. Am J Cardiol 40:611-614, 1977 8. Opitz JM, Herrmann J, Pettersen JC, Bersu ET, Colacino SC: Terminological, diagnostic, nosological, and anatomical-developmental aspects of developmental de fects in man. Adv Hum Genet 9:71-164, 1979 9. Forney WR, Robinson SJ, Pascoe DJ: Congenital heart disease, deafness, and skeletal malformations: a new syndrome? J Pediatr 68:14-26, 1966 10. Polani PE, Moynahan EJ: Progressive cardiomyopathic lentiginosis. Q J Med 41:205-239, 1972 11. Rosenzweig JL, Lawrence DA, Vogel DL, Costa J, Gorden P: Adrenocorticotropin-independent hypercortisolemia and testicular tumors in a patient with a pituitary tumor and gigantism. J Clin Endocrinol Metab 55:421-427,1982