Detection of adrenocorticotropin-secreting pituitary adenomas by magnetic resonance imaging in children and adolescents with cushing disease.

CONTEXT: We recently showed that pre- and postcontrast spoiled gradient-recalled acquisition in the steady-state (SPGR) was superior to conventional pre- and postcontrast T-1 weighted spin echo (SE) acquisition magnetic resonance imaging (MRI) for the diagnostic evaluation of pituitary tumors in adult patients. OBJECTIVE: The present investigation assessed the use of SPGR vs. SE-MRI in the diagnostic evaluation of ACTH-secreting tumors in children and adolescents with Cushing disease. DESIGN: Data were analyzed retrospectively from a series of patients seen over 7 yr (1997-2004). SETTING: The setting for this study was a tertiary care referral center. PATIENTS: Thirty children with Cushing disease (13 females and 17 males with a mean age of 12 +/- 3 yr) were studied. INTERVENTIONS AND OUTCOME MEASURES: Imaging results were compared with surgical and pathological findings and the clinical outcome. RESULTS: Twenty-eight patients had microadenomas, and two had macroadenomas; the latter were identified by both MRI techniques. Precontrast SE and SPGR-MRI identified four and six of the microadenomas, respectively. Postcontrast SPGR-MRI identified the location of the tumor in 18 of 28 patients, whereas postcontrast SE-MRI identified the location and accurately estimated the size of the tumor in only five patients (P < 0.001). CONCLUSIONS: We conclude that conventional MRI, even with contrast enhancement, mostly failed to identify ACTH-secreting microadenomas in children and adolescents with Cushing disease. Postcontrast SPGR-MRI was superior to SE-MRI and should be used in addition to conventional SE-MRI in the pituitary evaluation of children and adolescents with suspected Cushing disease.

Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity?

Cushing syndrome is uncommon in childhood and rare in infancy. We report the case of a 3-yr-old child who presented with symptoms of Cushing syndrome beginning shortly after birth. Her hypercortisolemia was cyclical, causing relapsing and remitting symptoms, which eventually led to suspicions of possible Munchausen syndrome by proxy. Investigation at the National Institutes of Health excluded exogenous administration of glucocorticoids and indicated ACTH-independent Cushing syndrome. Paradoxical response to dexamethasone stimulation (Liddle's test) suggested a diagnosis of primary pigmented nodular adrenocortical disease (PPNAD). After bilateral adrenalectomy, both glands showed micronodular adrenocortical hyperplasia, but histology was not consistent with typical PPNAD. DNA analysis of the coding sequences of the PRKAR1A gene (associated with PPNAD and Carney complex) and the GNAS gene (associated with McCune-Albright syndrome) showed no mutations. We conclude that hypercortisolemia in infancy may be caused by micronodular adrenocortical hyperplasia, which can be cyclical and confused with exogenous Cushing syndrome. A paradoxical rise of glucocorticoid excretion during Liddle's test may delineate these patients. Infantile micronodular disease has some features of PPNAD and may represent its early form; however, at least in the case of the patient reported here, micronodular hyperplasia was not caused by coding mutations of the PRKAR1A or GNAS genes or associated with typical histology or any other features of Carney complex or McCune-Albright syndrome and may represent a distinct entity.

Pathology and molecular genetics of the pituitary gland in patients with the 'complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas' (Carney complex).

Carney complex (CNC) is a familial multiple neoplasia and lentiginosis syndrome with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; all have been growth hormone (GH) and prolactin (PRL)-producing. In at least some patients, pituitary gland involvement is manifested by hyperplastic areas; hyperplasia appears to involve somatomammotrophs only and to precede GH-producing tumor formation, in a pathway similar to that seen in MAS-related pituitary tumors (and in oncogenesis in other CNC tissues). One patient with CNC and advanced acromegaly had a GH-producing macroadenoma that showed extensive genetic changes at the chromosomal level. These changes appeared to represent secondary or tertiary genetic 'hits' involved in pituitary oncogenesis and were confirmed at the molecular level. So far, almost half of the patients with CNC have germline-inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost. Loss of heterozygosity suggests that PRKAR1A, which codes for the regulatory subunit type 1alpha of the cAMP-dependent protein kinase A (PKA), may act as a tumor-suppressor gene in pituitary tissue. These data provide evidence for a PKA-induced somatomammotroph hyperplasia in the pituitary tissue of CNC patients; hyperplasia leads to additional genetic changes at the somatic level, which in turn cause the formation of adenomas in some, but not all, patients.