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Cyclical Cushing Syndrome Presenting in Infancy: An Early Form of Primary Pigmented Nodular Adrenocortical Disease, or a New Entity?

Pediatric Endocrinology (D.F.G.), Children’s Hospital and Regional Medical Center, University of Washington, Seattle, Washington 98105; Developmental Endocrinology Branch (I.B., L.M., K.G., N.C., M.K., C.A.S.), National Institute of Child Health and Human Development, Laboratory of Pathology (D.C., D.E.K.), National Cancer Institute, Department of Diagnostic Radiology (N.C.), Warren Magnuson Clinical Center, Electron Microscopy, Laboratory of Pathology (M.A.-A., M.T.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; and Department of Laboratory Medicine and Pathology (emeritus member) (J.A.C.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. Constantine A. Stratakis, Section on Endocrinology and Genetics, 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}mail.nih.gov; or Dr. Daniel F. Gunther, Associate Professor of Pediatrics, Children’s Hospital and Regional Medical Center, 1800 Sand Point Way NE M1-3, Seattle, Washington 98105. E-mail: dan.gunther{at}seattlechildrens.org.

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.

Abbreviations: CT, Computed tomography; oCRH, ovine CRH; 17OHCS, 17-hydroxycorticosteroid; PPNAD, primary pigmented nodular adrenocortical disease; UFC, urine free cortisol.

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