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- What are the peculiarities of Cushing ’ s syndrome associated with McCune –
Albright syndrome?
Cushing’s syndrome is rare in McCune–Albright syndrome (MAS) and occurs
only in 5–7 % of patients. CS associated with MAS may even manifest at birth
(due to intrauterine hypercortisolemia), but majority of children present before
5 years of age. CS associated with MAS is due to ACTH-independent diffuse/
nodular adrenal hyperplasia. Cushingoid facies, low birth weight, and failure to
thrive are the common presenting features. Hypercortisolemia associated with
MAS may resolve spontaneously as fetal zone of adrenal cortex (which over
expresses Gs-α) regresses by 1 year of age and is replaced by the defi nitive adult
zone. Children who have spontaneous resolution of CS may develop adrenal insuf-
fi ciency subsequently. The presence of café-au-lait macules, fi brous dysplasia, and
other endocrinopathies helps in the diagnosis of MAS. The defi nitive therapy of
CS associated with MAS is bilateral adrenalectomy. Medical therapy with keto-
conazole is not preferred as many children with MAS have coexisting liver dis-
ease; however, metyrapone may be used in critically ill infants awaiting surgery. - What is primary pigmented nodular adrenocortical disease?
Primary pigmented nodular adrenocortical disease (PPNAD) is an ACTH-
independent cause of Cushing’s syndrome. Approximately 70 % patients with
PPNAD have overt Cushing’s syndrome and the rest have subclinical
CS. PPNAD commonly presents in second/third decade of life and has a female
preponderance. Multiple pigmented nodules (<5 mm) with internodular atro-
phy is the characteristic histological feature of PPNAD. Pigmentation is due to
accumulation of lipofuscin pigment, whereas internodular atrophy due to sup-
pression of ACTH by hypercortisolemia as a result of autonomously function-
ing nodules. PPNAD is commonly (>90 %) associated with Carney’s complex.
The genes implicated in pathogenesis of PPNAD are PRKAR1A, PDE11A,
PDE8B, and MYH8 and are involved in increased cyclic adenosine monophos-
phate (cAMP) generation, thereby facilitating tumorigenesis.- What are the distinctive features of childhood Cushing ’ s syndrome associated
with PPNAD?
The distinctive features of childhood Cushing’s syndrome associated with
PPNAD include young age of onset (usually <15 years), subtle features of pro-
tein catabolism, normal growth velocity (due to insidious onset and mild hyper-
cortisolemia), and osteoporosis. Biochemical characteristics include mild
hypercortisolemia and paradoxical increase in serum cortisol/UFC following
high-dose dexamethasone suppression test. Adrenal imaging is normal; occa-
sionally, CT adrenal may demonstrate characteristic “beads on a string appear-
ance.” Bilateral adrenalectomy is curative (Fig. 4.6 ).
4 Childhood Cushing’s Syndrome