Introduction: We present two cases of Carney and Carney-like Complex due to genetic aberrations with the cAMP/PKA pathway presenting with ACTH-independent Cushing Syndrome (CS) and extra-adrenal features.
Case report: Case 1 was referred aged 4 years with a 15 month history of cyclical CS (periodic weight gain, facial roundness, hirsutism). Neuroimaging did not identify a pituitary abnormality. Biochemistry confirmed ACTH-independent hypercortisolism, with a low ACTH and loss of the cortisol circadian rhythm. She was commenced on metyrapone at a dose tailored to cortisol production. Initial hypertension improved. Adrenal imaging was inconclusive. Tumour markers were negative. Genetic analysis demonstrated a heterozygous pathogenic PRKAR1A variant (c.491_492del) confirming a diagnosis of Carney Complex type 1. She proceeded to undergo a laparoscopic bilateral adrenalectomy, and commenced lifelong adrenal hormone replacement. Extra-adrenal manifestations of Carney Complex included cutaneous pigmentation, eye lesions and thyroid cysts. Case 2 was referred aged 3 months with unusual non-tender, non-pigmented firm lumps on his hands and feet. A month later, he developed rapid-onset hyperphagia and hypertension. Examination revealed a Cushingoid, obese (98th centile), and short (<0.4th centile) infant. ACTH-independent CS was confirmed biochemically. Adrenal imaging did not reveal any adrenal abnormalities. The CS was refractory to medical management and a laparoscopic bilateral adrenalectomy was performed, followed by adrenal hormone replacement. Histopathological examination of the adrenal tissue and the peripheral dermatological lesions revealed bilateral non-pigmented micronodular cortical hyperplasia and cutaneous mucinosis, respectively. CGH analysis of these affected tissues demonstrated a mosaic PRKACA duplication not present in the peripheral blood.
Discussion: We describe two cases of Carney and Carney-like complex secondary to genetic alterations within the cAMP/PKA pathway. Case 2 is the first time somatic, rather than germline, PRKACA mosaicism has been associated with micronodular hyperplasia, with cutaneous mucinosis being a novel finding. Delays in the diagnosis of paediatric CS can occur due to the rarity of the condition, its occasionally cyclical nature, and the often equivocal findings on adrenal imaging. A clinical diagnosis might only be confirmed following genetic testing. Whilst bilateral adrenalectomy treats CS, Carney and Carney-like Complex are rare multiple neoplasia syndromes, necessitating ongoing tumour surveillance.
02 Nov 2022 - 04 Nov 2022