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Developmental Endocrinology Branch, National Institute of Child Health and Human Development (G.P.C., C.A.S.); Laboratory of Molecular and Cellular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (N.J.S.); and the Department of Radiology, Warren G. Magnuson Clinical Center (J.L.D.), National Institutes of Health, Bethesda, Maryland 20892; and the Department of Laboratory Medicine and Pathology, Mayo Clinic (J.A.C.), Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Section on Pediatric Endocrinology/Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov
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Case Report |
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This patient’s early growth and development were normal. In 1958, at the age of 7 yr, he was referred for investigation of isosexual precocious puberty. No specific cause was identified, although his bone age was advanced. The patient reached his final height of 152 cm at age 10 yr. In 1967 (age 19 yr), the patient developed back pain; radiographic evaluation revealed partial collapse of T12, a biconcave L5, and severe osteopenia. Urinary 17-ketosteroid excretion was 184 µmol/g creatinine·24 h (normal range, 17–63 µmol/g creatinine·24 h). He was then evaluated at the NIH. His weight was 49.3 kg, and his body mass index was 21.9. Both his height and weight were below the fifth percentile. Blood pressure varied between 105/75 and 140/90 mm Hg. He had gained weight, although he was not grossly obese or acutely ill; he had moon facies and thin, weak extremities. Numerous darkly pigmented lesions were noted on the skin of his face and lips and both conjuctivae. His height was 150 cm, 2 cm below his earlier defined final height.
Mild hypokalemia and glucose intolerance were present. Thyroid function
tests were normal. Roentgenographic examination of the skeleton showed
anterior wedging of all thoracic and the first four lumbar vertebrae
and severe generalized loss of bone density of all vertebrae, ribs, and
the skull. The biochemical diagnosis of CS was then established. The
patient had lost the normal diurnal variation in plasma cortisol
levels, and his baseline values of urinary adrenal function indexes
were elevated. The latter were as follows: urinary 17-hydroxysteroids
(17-OHS), 53.3 µmol/24 h (normal range, 5.4–27.6 µmol/24 h);
17-ketosteroids, 41.8 µmol/24 h (normal range, 25–88 µmol/24 h);
and UFC, 585 nmol/24 h (normal range, 55–276 nmol/24 h). A Liddle test
demonstrated a paradoxical increase in daily excretion rates of urinary
17-OHS on days 4, 5, and 6 of the test (Fig. 1
). A similar response was
observed after the 8-mg single dose, overnight dexamethasone
suppression test (Table 1).
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Postoperatively, urinary 17-OHS and UFC levels decreased to the
normal range, and the patient required no glucocorticoid replacement
(Table 1
and Fig. 2). The patient was considered cured;
however, repeated dexamethasone suppression tests at regular intervals
demonstrated lack of suppression of urinary 17-OHS and persistent
absence of cortisol diurnal variation, whereas in one instance (in
1977) levels of 17-OHS increased paradoxically from 8.9 to 33.6
µmol/24 h postdexamethasone administration (Table 1 and Fig. 2). By
1984, it was recognized that the patient met diagnostic criteria for
the syndrome of myxomas, spotty skin pigmentation, and endocrine
hyperactivity (Carney complex) (2). A specimen from the left adrenal
gland was reviewed by one of the authors (J.A.C.) and was found to have
changes typical of PPNAD. Several of the patient’s skin lesions were
biopsied and were shown to be lentigines and myxomas. A testicular
ultrasound revealed dense echogenic lesions (calcifications) in the
posterior parts of both testes consistent with large cell calcifying
Sertoli cell tumors (LCCSCT) (3).
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) led to
reevaluation of the patient at the NIH Clinical Center at age 45 yr. On
admission, the patient was an extremely short adult with an asthenic
appearance. His height was 147 cm, his weight was 52.3 kg, his body
mass index was 24.2, and his arm span was 156 cm. Blood pressure varied
between 129/76 and 148/94 mm Hg. Lentigines on the skin of the
periorbital, perioral, and palpebral areas of the face and cheeks as
well as on the conjuctivae and intraorally were noted on examination
(Fig. 3A). Abdominal thin purplish striae were evident,
along with several nevi and cystic acne in the back. There was extreme
kyphosis. Numerous bilateral small (5-mm) hard testicular masses were
palpable. Atrophy and severe proximal muscle weakness of the
extremities were present (Fig. 3B).
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Investigation of the hypothalamic-pituitary-adrenal function gave the
following results: 1) baseline plasma cortisol concentrations without
any diurnal variation (Table 1), confirmed by salivary cortisol levels;
the latter were 11.5 nmol/L in the morning (normal range, 16.5–38.6
nmol/L) and 11.1 nmol/L (normal range, 2.8–5.5 nmol/L) in the evening
(4); 2) low normal baseline plasma ACTH of 6.75 pmol/L (normal range,
<1.1–20 pmol/L); and 3) failure of plasma cortisol and ACTH to
increase after iv administration of 1 µg/kg ovine (o) CRH (peak
plasma cortisol value of 221 nmol/L 45 min post-oCRH, and peak plasma
ACTH value of 10.2 pmol/L 30 min post-oCRH). An adrenal computed
tomography (CT) scan showed a 1.5-cm nodule involving the medial limb
of the right adrenal gland. The left adrenal gland was absent
(previously removed surgically; Fig. 4). The patient
refused further treatment.
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Discussion |
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Carney complex describes the association of PPNAD, an ACTH-independent, primary adrenal form of hypercortisolism, spotty skin pigmentation, and blue nevi of the skin and mucosae together with a variety of tumors (2). The latter include cardiac and cutaneous myxomas, mammary myxoid fibroadenomas, LCCSCT of the testes, GH-secreting pituitary adenomas, psammomatous melanotic schwannomas, and possibly other neoplasms, including adrenocortical and thyroid follicular carcinomas and ovarian cysts (5, 6, 7, 8, 9). Like other syndromes associated with multiple endocrine neoplasias, Carney complex is an autosomal dominant disorder (10). The causative gene (Mendelian inheritance in man 160980) was recently mapped on chromosome 2p16 by linkage analysis (11) and appears to be associated with a gain of function mutation (12).
PPNAD in Carney complex
Diagnosis. PPNAD represents a rare, pituitary-independent, primary adrenal form of CS, which is present in 32% of patients with Carney complex (2, 11, 13). Pathologically, both adrenal glands are involved in the disease process and feature small brown-black nodules separated by atrophic adrenal cortex (2, 8, 14). Microscopically, the nodules consist of large cortical cells with eosinophilic cytoplasm and large hyperchromatic nuclei with prominent nucleoli. The cytoplasm is rich in lipofuscin pigment and, possibly, neuromelanin (2, 6).
Clinically evident CS exists in 84% of patients with PPNAD (overt PPNAD) (2, 6, 11). Six percent of patients with PPNAD have only biochemical evidence of adrenocortical hyperfunction or autonomy (subclinical PPNAD), and 10% of patients may remain undiagnosed due to paucity of symptoms (latent PPNAD) (6). Symptomatic patients present with most of the typical manifestations of CS by the second decade of life. Osteoporosis is remarkably prevalent in CS due to PPNAD (39% of cases) (1, 11, 14). Due to the existence of hypercortisolism early in life, short stature due to stunted growth has been described in 29% of PPNAD patients with CS (2, 6, 10, 14). Precocious puberty (occasionally associated with coexistence of LCCSCT of the testes) and hypokalemia are also seen much more frequently (9% and 8%, respectively) in PPNAD patients with CS than in patients with CS due to more common causes (11). The symptoms and signs of CS in PPNAD are insidious, albeit progressive, and most patients come to medical attention several years after their onset (10), not unlike other patients with atypical CS (15). In patients with PPNAD, CS may be periodic (16), whereas hypercortisolemia may resolve spontaneously (13).
The biochemical and radiological evaluation of patients with CS caused by PPNAD reveals the ACTH-independent nature of this disorder; plasma levels of ACTH are low normal or undetectable. Adrenal steroid production is not suppressible by high dose dexamethasone and responds poorly to stimulation with metyrapone and/or CRH (9, 10, 13). Moreover, most patients have a paradoxical increase in urinary 17-OHS and/or UFC excretion after the administration of high dose dexamethasone (6, 13). CT examination shows adrenal glands of normal size in half of the cases (10, 17). The presence of multiple small adrenal nodules with intervening segments of atrophic adrenal cortex gives a "string of beads" appearance that is characteristic of PPNAD, especially in the 12–18 yr age group (17). Beyond the age of 18 yr, unilateral 2- to 3-cm adrenal macronodules are common in PPNAD, making it impossible to distinguish CS due to PPNAD from the much more common ACTH-dependent adrenal adenomatous hyperplasia based on radiological criteria only (17). [6ß-131I]Iodomethyl-19-norcholesterol scintigraphy may show bilateral nuclide adrenal uptake and may be of significant aid in diagnosis, especially for patients younger than 12 yr (6, 17, 18).
Treatment. The hypercortisolism due to PPNAD resolves after bilateral adrenalectomy. It is noteworthy that Nelson’s syndrome has not been reported after this treatment in patients with Carney complex (6, 10, 18). In the extensive series published by Carney and Young (6), bilateral adrenalectomy was performed in 48 patients (65% of the total number of reviewed cases) and led to cure of CS. Subtotal adrenalectomy was performed in 6 patients (8%). Among these patients, 4 were considered successfully treated, and 2 experienced recurrence of CS. Unilateral adrenalectomy was performed in 17 patients (23%). Among these, 6 were considered successfully treated, 7 had persistence of CS, 2 died postoperatively, and 2 were lost to follow-up. The patients that experienced persistence or recurrence of CS after an initial improvement with subtotal or unilateral adrenalectomy (35% of these cases) required completion of total adrenalectomy (6). It should be noted, however, that in the above series, successful treatment only meant remission of the clinical features of CS despite the persistence of autonomous adrenocortical function observed in those patients who were tested. Thus, our patient would have been classified as successfully treated. However, as is evident, the persistent loss of diurnal rhythmicity in plasma cortisol levels and the adrenal autonomous hyperfunction (as demonstrated by a flat plasma cortisol response to oCRH), despite the lack of biochemical hypercortisolism may lead to significant morbidity over the course of one or more decades.
Our patient is one of the longest followed-up patients with Carney complex (2). His case illustrates 1) the need for bilateral adrenalectomy in patients with CS due to PPNAD, and 2) the unique clinical and biochemical presentation of CS in the context of PPNAD. Indeed, in this condition, there is a paucity or underrepresentation of certain usual variety CS common cardinal stigmata (moon facies, central obesity, and diabetes) and overrepresentation of other less common features (severe osteoporosis and myasthenia). The devastating effects of abnormal diurnal cortisol variation despite mostly normal total daily UFC excretion are an intriguing finding, with implications for a number of other conditions associated with disruption of diurnal cortisol rhythm and/or mild hypercortisolism, including major depression, chronic excessive exercise, chronic active alcoholism, and eating disorders as well as atypical eucortisolemic adrenal adenomas (15, 19). The recent report of marked low bone turnover osteoporosis in young women with major depression clearly makes this point (20).
Received August 20, 1996.
Revised December 6, 1996.
Accepted December 16, 1996.
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