Prepubertal Cushing's disease: diagnosis and therapeutic outcome
A Kumaran1, LF Chan1, L Martin1, F Afshar2, M Matson3, PN Plowman4, JP Monsoon1, GM Besser1, AB Grossman1, MO Savage1 & HL Storr1
Cushings disease (CD) is very rare in prepubertal children, and remains a challenge to diagnose and manage. We review the diagnostic features and therapeutic outcome of prepubertal (defined as testicular volume <4 ml (M) and breast stage <2 (F)) CD patients treated in a single centre. Fifteen prepubertal patients (median age 9.4 years; range 5.813.7) fulfilled standard diagnostic criteria for CD and there was male preponderance (12 M (80%), median age 9.1 years; 3F (20%), median age 10.6 years). Serum cortisol failed to suppress to <50 nmol/l during LDDST (0.5 mg, 6 h or 30 μg/kg per day, for 48 h) in all patients. Suppression of serum cortisol to <50% of baseline during a HDDST (2 mg, 6 h or 120 μg/kg per day for 48 h) occurred in 85% (11/13) of patients. A CRH test (1 μg/kg i.v.) induced a ≥20% increase of serum cortisol from baseline in all patients (mean change 222%). Pituitary MR imaging revealed a macroadenoma in one patient and corticotroph microadenomas in 60% (9/15) of patients. The concordance of pituitary imaging with findings at transsphenoidal surgery (TSS) in the patients with microadenomas was poor (29%, 4/14). In 9 patients, bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) was performed and there was lateralisation of ACTH (an inter-petrosal sinus gradient ≥1.4 after 100 μg i.v. CRH) in 89% (8/9). Concordance of BSIPSS with the findings at TSS occurred in 78% (7/9) patients. Post TSS, the corticotroph adenoma was confirmed histologically in 43% (6/14). Bilateral adrenalectomy was performed in one patient because of extreme illness with respiratory failure. TSS alone achieved cure (serum cortisol <50 nmol/l) in 43% (6/14) of patients. Of these, 83% (5/6) underwent BSIPSS and there was 100% concordance of the site of ACTH secretion with the surgical findings. The remaining patients underwent post-TSS pituitary irradiation (45 Gy) and 89% (8/9) are cured. BSIPSS improved the cure rate by TSS alone to 56% (5/9). GH deficiency was common (77%, 10/13) especially after pituitary irradiation (89%, 8/9). Characteristic features of prepubertal CD include: an exuberant response of serum cortisol after iv CRH which is often diagnostic and frequent absence of the adenoma on MR imaging. Pre-operative BSIPSS was strongly predictive of the site of the adenoma and leads to a good prognosis for cure by TSS.