Acta Pzdiatr 81: 91-2, 1992
C A S E REPORT
Cushing's syndrome due to primary pigmented nodular adrenocortical disease with cardiac myxomas and mucocutaneous lentigines Y Ichiba', Y Nishizaki2 and M Tanizaki3 Depurrments of Paediatrics' , Curdiolog.?, and Cardiovascular Surgery', Okuyamu National Hospilal, Okayama. Japan
Ichiba Y, Nishizaki Y, Tanizaki M. Cushing's syndrome due to primary pigmented nodular adrenocortical disease with cardiac myxomas and mucocutaneous lentigines. Acta Prediatr 1992;81:91-2. Stockholm. ISSN 0803-5253 A young Japanese female demonstrated unusual features of Cushing's syndrome, cardiac myxomas and mucocutaneous lentigines. At the age of 12 years she presented with growth failure and obesity. The dexamethasone suppression test, the metyrapone test and low corticotropin concentrations indicated a primary adrenal disorder. At surgery, the adrenal glands were not enlarged (the right, 4.0 g; the left; 4.5 g) but had numerous small dark brown nodules. The pathological findings showed multiple small black cortical nodules containing large cells with eosinophilic cytoplasm and lipofuscin, and internodular cortical atrophy. These abnormalities were consistent with primary pigmented nodular adrenocortical disease. At age 22 years she complained of fatigue and palpitations associated with midchest pain. Four cardiac myxomas, suspected from the echocardiogram, were surgically removed. Because Cushing's syndrome and cardiac myxomas are life-threatening conditions, an awareness of the complex is important. 0 primary pigmented nodular adrenocortical disease, Cardiac myxoma. mucocutaneous lentigines
Y Ichiba, Department of Pediatrics, Okayama National Hospital, 2-13-1, Minamigata, Okayama 700, Japan
A complex of primary pigmented nodular adrenocortical disease (PPNAD) associated with cardiac myxoma and pigmented lesions of the skin was recently described by Carney (1). Although this complex occurs primarily in children and young adults, it has only rarely been mentioned in the pediatric literature. We describe a girl with typical Carney's complex seen in our hospital. She presented with Cushing's syndrome and atrial myxoma.
morning were increased (31 pg/dl) and a lack of diurnal variation of cortisol levels was observed. The plasma corticotrophin level at 09:OO was undetectable ( < 20 pg/ ml). There was no suppression of urinary levels of 17hydroxycorticosteroids and 17-ketosteroids with either low-dose or high-dose dexamethasone administration. After metyrapone administration, only a small increase in I I-deoxycortisol was observed. An '3'I-19-idocholesterol scintiscan demonstrated bilateral increased adrenal uptake. A diagnosis of primary adrenocortical hyperplasia was made. The patient underwent bilateral Case report total adrenalectomy by the posterior approach in July In July 1974, a 12-year-old Japanese girl was admitted to 1974. The right and left adrenal glands weighed 4.0 g Okayama National Children's Hospital, Okayama, and 4.5 g, respectively. Both adrenal glands had numerJapan, for investigation of growth failure and obesity. ous small dark brown nodules (Fig. 1). The pathological She had been in good health until aged 10 years, when findings showed multiple small black cortical nodules weight and stunted growth were first noted. Subse- containing large cells with eosinophilic cytoplasm and quently, occasional headaches, weakness, and the lipofuscin, and internodular cortical atrophy. The postappearance of striae of the abdominal skin were operative course was uneventful and 20 mg of hydrocorobserved. On physical examination, her height was 125 tisone and 0.1 mg of fludrocortisone was administered cm (SD-3.3) and weight 40 kg (SD+O.l). Vital signs daily. She was well for the next 10 years. were normal except for a blood pressure reading of 145/ In August 1984, when she was aged 22 years, she 95 mmHg. She had moon facies, acne and truncal complained of fatigue and palpitation associated with obesity. No abdominal masses were palpable. She had mid-chest pain. Examination revealed cardiomegaly pigmented spots o n the forehead, cheeks, nose and and systolic murmur. An echocardiogram demonvermilion borders of the lips. Basal concentrations of strated a mass in the right ventricle. On cardiac urinary 17-hydroxycorticosteroids and 17-ketosteroids exploration, two large and two small tumors were found were increased. Plasma cortisol concentrations in early in the right atrium and venticle; they were excised and
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found to be myxomas (Fig. 2). At age 26 years, she had a healthy son and is doing well at age 28 in April 1990. Her mother, aged 55 years, has intense spotty pigmentation (lentigines and freckles) on her face, including the vermilion border of the lips. Her physical and laboratory examinations has revealed no features of Cushing’s syndrome. The results of two-dimensional echocardiography were normal. The patient’s son, aged 2 years, has no clinical manifestations.
Discussion This Japanese girl had florid Cushing’s syndrome manifested by hypertension, central obesity, moon facies, and striae cutis of the skin at age 10 years. Urinary 17-hydroxycorticosteroid concentrations were not suppressed by high-dose dexamethasone. Plasma corticotropin levels were undetectable. Bilateral total adrenalectomy was performed. Both adrenal glands had multiple, small, black nodules. These unusual abnormalities were given the name “primary adrenocortical nodular dysplasia” by Meador et al. in 1967 (2). Several patients with similar clinical and pathological manifestations have since been reported. In 1982, the association of cardiac myxomas with PPNAD was described (3). In 1985, a complex of PPNAD associated with myxomatous masses and pigmented lesions of the skin was described by Carney et al. (1) Our patient had a typical Carney’s complex of PPNAD, cardiac myxomas, and pigmented lesions of the face. The hypercortisolism in patients with PPNAD is characterized by presentation at a young age, increased plasma and urinary glucocorticoid concentrations that are not suppressed by high doses of dexamethasone, low-to-undetectable plasma ACTH levels and a lack of plasma 11deoxycortisol response to metyrapone. Biochemical data support autonomous adrenal hyperfunction. Adrenal glands appear normal or nodular on computed imaging. PPNAD occurs before the patient is aged 10 years, nodules are generally 0.5-3 mm in size and may not be detectable with CT or MR imaging (4). ‘3’I-iodocholesterolscintigram is the most useful imaging technique demonstrating bilateral disease. Pathological findings show small-to-normal-sized adrenal glands, multiple small black cortical nodules containing large cells with eosinophilic cytoplasm and lipofuscin, and internodular cortical atrophy (5). Surgery is the usual treatment of patients with PPNAD (5). Bilateral adrenalectomy has affected either a cure or amelioration of Cushing’s syndrome without the subsequent development of Nelson’s syndrome.
ACTA PRDIATR 81 (1992)
The pathogenesis of PPNAD remains unknown. Recent work has identified the presence of adrenocortical-stimulating antibodies in the serum of patients, similar to the thyroid-stimulating antibodies that have been identified in patients with Graves disease (6). Ten years after adrenalectomy the patient had cardiac myxomas which were successfully excised. In Carney’s review, cardiac myxomas were the direct cause of death in nine of 12 patients ( I ) . Cardiac myxomas may occur at an early age, the discovery of a myxoma in a child or young adult should alert the physician to the likely possibility of this complex. Cutaneous manifestations of Carney’s complex is spotty mucocutaneous pigmentation, including lentigines and blue nevi. Both our patient and her mother had pigmented spots on the forehad, cheeks, nose and vermilion borders of the lips. According to Carney’s criteria, the condition is diagnosed by the presence of two of the three criteria. Our patient had three. An awareness of Carney’s complex is important because Cushing’s syndrome and cardiac myxomas are life-threatening diseases. In the family we mentioned, spotty facial pigmentation was present in the index case and her mother. Some familial cases with Carney’s complex have been reported and autosomal dominant inheritance has been proposed. First-degree relatives of affected persons should be examined for endocrinological and cardiovascular procedures.
References 1 . Carney JA, Gordon H, Carpenter PC, Shenoy BV, G o VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270-83 2. Meador CK, Bowdoin 9, Owen WC, Farmer TA. Primary adrenocortical nodular dysplasia: A rare cause of Cushing’s syndrome. J Clin Endocrinol Metab 1967;27:1255-63 3. Schwezer-Cagianut M, Salomon R, Hedinger CE. Primary adrenocortical nodular dysplasia with Cushing’s syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch [A] 1982;397:183-92 4. Doppman JL, Travis WD, Nieman L, et al. Cushing syndrome due to primary pigmented nodular adrenocortical disease: Findings at CT and MR imaging. Radiology 1989;172:415-20 5. Grant CS, Carney JA, Carpenter PC, Heerden JA. Primary pigmented nodular adrenocortical disease: diagnosis and management. Surgery 1986;100:1178-84 6. Young WF, Carney JA, Musa BU, et al. Familial Cushing’s syndrome due to primary pigmented nodular adrenocortical disease. New Engl J Med 1989;321:1659-64
Submitted June 19, 1990. Accepted Feb. 4, 1991
C A S E REPORT
Cushing's syndrome due to primary pigmented nodular adrenocortical disease with cardiac myxomas and mucocutaneous lentigines Y Ichiba', Y Nishizaki2 and M Tanizaki3 Depurrments of Paediatrics' , Curdiolog.?, and Cardiovascular Surgery', Okuyamu National Hospilal, Okayama. Japan
Ichiba Y, Nishizaki Y, Tanizaki M. Cushing's syndrome due to primary pigmented nodular adrenocortical disease with cardiac myxomas and mucocutaneous lentigines. Acta Prediatr 1992;81:91-2. Stockholm. ISSN 0803-5253 A young Japanese female demonstrated unusual features of Cushing's syndrome, cardiac myxomas and mucocutaneous lentigines. At the age of 12 years she presented with growth failure and obesity. The dexamethasone suppression test, the metyrapone test and low corticotropin concentrations indicated a primary adrenal disorder. At surgery, the adrenal glands were not enlarged (the right, 4.0 g; the left; 4.5 g) but had numerous small dark brown nodules. The pathological findings showed multiple small black cortical nodules containing large cells with eosinophilic cytoplasm and lipofuscin, and internodular cortical atrophy. These abnormalities were consistent with primary pigmented nodular adrenocortical disease. At age 22 years she complained of fatigue and palpitations associated with midchest pain. Four cardiac myxomas, suspected from the echocardiogram, were surgically removed. Because Cushing's syndrome and cardiac myxomas are life-threatening conditions, an awareness of the complex is important. 0 primary pigmented nodular adrenocortical disease, Cardiac myxoma. mucocutaneous lentigines
Y Ichiba, Department of Pediatrics, Okayama National Hospital, 2-13-1, Minamigata, Okayama 700, Japan
A complex of primary pigmented nodular adrenocortical disease (PPNAD) associated with cardiac myxoma and pigmented lesions of the skin was recently described by Carney (1). Although this complex occurs primarily in children and young adults, it has only rarely been mentioned in the pediatric literature. We describe a girl with typical Carney's complex seen in our hospital. She presented with Cushing's syndrome and atrial myxoma.
morning were increased (31 pg/dl) and a lack of diurnal variation of cortisol levels was observed. The plasma corticotrophin level at 09:OO was undetectable ( < 20 pg/ ml). There was no suppression of urinary levels of 17hydroxycorticosteroids and 17-ketosteroids with either low-dose or high-dose dexamethasone administration. After metyrapone administration, only a small increase in I I-deoxycortisol was observed. An '3'I-19-idocholesterol scintiscan demonstrated bilateral increased adrenal uptake. A diagnosis of primary adrenocortical hyperplasia was made. The patient underwent bilateral Case report total adrenalectomy by the posterior approach in July In July 1974, a 12-year-old Japanese girl was admitted to 1974. The right and left adrenal glands weighed 4.0 g Okayama National Children's Hospital, Okayama, and 4.5 g, respectively. Both adrenal glands had numerJapan, for investigation of growth failure and obesity. ous small dark brown nodules (Fig. 1). The pathological She had been in good health until aged 10 years, when findings showed multiple small black cortical nodules weight and stunted growth were first noted. Subse- containing large cells with eosinophilic cytoplasm and quently, occasional headaches, weakness, and the lipofuscin, and internodular cortical atrophy. The postappearance of striae of the abdominal skin were operative course was uneventful and 20 mg of hydrocorobserved. On physical examination, her height was 125 tisone and 0.1 mg of fludrocortisone was administered cm (SD-3.3) and weight 40 kg (SD+O.l). Vital signs daily. She was well for the next 10 years. were normal except for a blood pressure reading of 145/ In August 1984, when she was aged 22 years, she 95 mmHg. She had moon facies, acne and truncal complained of fatigue and palpitation associated with obesity. No abdominal masses were palpable. She had mid-chest pain. Examination revealed cardiomegaly pigmented spots o n the forehead, cheeks, nose and and systolic murmur. An echocardiogram demonvermilion borders of the lips. Basal concentrations of strated a mass in the right ventricle. On cardiac urinary 17-hydroxycorticosteroids and 17-ketosteroids exploration, two large and two small tumors were found were increased. Plasma cortisol concentrations in early in the right atrium and venticle; they were excised and
92
Y Ichiha et al.
found to be myxomas (Fig. 2). At age 26 years, she had a healthy son and is doing well at age 28 in April 1990. Her mother, aged 55 years, has intense spotty pigmentation (lentigines and freckles) on her face, including the vermilion border of the lips. Her physical and laboratory examinations has revealed no features of Cushing’s syndrome. The results of two-dimensional echocardiography were normal. The patient’s son, aged 2 years, has no clinical manifestations.
Discussion This Japanese girl had florid Cushing’s syndrome manifested by hypertension, central obesity, moon facies, and striae cutis of the skin at age 10 years. Urinary 17-hydroxycorticosteroid concentrations were not suppressed by high-dose dexamethasone. Plasma corticotropin levels were undetectable. Bilateral total adrenalectomy was performed. Both adrenal glands had multiple, small, black nodules. These unusual abnormalities were given the name “primary adrenocortical nodular dysplasia” by Meador et al. in 1967 (2). Several patients with similar clinical and pathological manifestations have since been reported. In 1982, the association of cardiac myxomas with PPNAD was described (3). In 1985, a complex of PPNAD associated with myxomatous masses and pigmented lesions of the skin was described by Carney et al. (1) Our patient had a typical Carney’s complex of PPNAD, cardiac myxomas, and pigmented lesions of the face. The hypercortisolism in patients with PPNAD is characterized by presentation at a young age, increased plasma and urinary glucocorticoid concentrations that are not suppressed by high doses of dexamethasone, low-to-undetectable plasma ACTH levels and a lack of plasma 11deoxycortisol response to metyrapone. Biochemical data support autonomous adrenal hyperfunction. Adrenal glands appear normal or nodular on computed imaging. PPNAD occurs before the patient is aged 10 years, nodules are generally 0.5-3 mm in size and may not be detectable with CT or MR imaging (4). ‘3’I-iodocholesterolscintigram is the most useful imaging technique demonstrating bilateral disease. Pathological findings show small-to-normal-sized adrenal glands, multiple small black cortical nodules containing large cells with eosinophilic cytoplasm and lipofuscin, and internodular cortical atrophy (5). Surgery is the usual treatment of patients with PPNAD (5). Bilateral adrenalectomy has affected either a cure or amelioration of Cushing’s syndrome without the subsequent development of Nelson’s syndrome.
ACTA PRDIATR 81 (1992)
The pathogenesis of PPNAD remains unknown. Recent work has identified the presence of adrenocortical-stimulating antibodies in the serum of patients, similar to the thyroid-stimulating antibodies that have been identified in patients with Graves disease (6). Ten years after adrenalectomy the patient had cardiac myxomas which were successfully excised. In Carney’s review, cardiac myxomas were the direct cause of death in nine of 12 patients ( I ) . Cardiac myxomas may occur at an early age, the discovery of a myxoma in a child or young adult should alert the physician to the likely possibility of this complex. Cutaneous manifestations of Carney’s complex is spotty mucocutaneous pigmentation, including lentigines and blue nevi. Both our patient and her mother had pigmented spots on the forehad, cheeks, nose and vermilion borders of the lips. According to Carney’s criteria, the condition is diagnosed by the presence of two of the three criteria. Our patient had three. An awareness of Carney’s complex is important because Cushing’s syndrome and cardiac myxomas are life-threatening diseases. In the family we mentioned, spotty facial pigmentation was present in the index case and her mother. Some familial cases with Carney’s complex have been reported and autosomal dominant inheritance has been proposed. First-degree relatives of affected persons should be examined for endocrinological and cardiovascular procedures.
References 1 . Carney JA, Gordon H, Carpenter PC, Shenoy BV, G o VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270-83 2. Meador CK, Bowdoin 9, Owen WC, Farmer TA. Primary adrenocortical nodular dysplasia: A rare cause of Cushing’s syndrome. J Clin Endocrinol Metab 1967;27:1255-63 3. Schwezer-Cagianut M, Salomon R, Hedinger CE. Primary adrenocortical nodular dysplasia with Cushing’s syndrome and cardiac myxomas: a peculiar familial disease. Virchows Arch [A] 1982;397:183-92 4. Doppman JL, Travis WD, Nieman L, et al. Cushing syndrome due to primary pigmented nodular adrenocortical disease: Findings at CT and MR imaging. Radiology 1989;172:415-20 5. Grant CS, Carney JA, Carpenter PC, Heerden JA. Primary pigmented nodular adrenocortical disease: diagnosis and management. Surgery 1986;100:1178-84 6. Young WF, Carney JA, Musa BU, et al. Familial Cushing’s syndrome due to primary pigmented nodular adrenocortical disease. New Engl J Med 1989;321:1659-64
Submitted June 19, 1990. Accepted Feb. 4, 1991
