Paediatric Cushing syndrome: a prospective, multisite, observational cohort study

Background Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management.Methods In this prospective, multisite cohort study, we studied children and adolescents (<= 18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants' clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment.Findings Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1<middle dot>0-3<middle dot>0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10<middle dot>4 years [IQR 7<middle dot>4-13<middle dot>6] vs 13<middle dot>0 years [10<middle dot>5-15<middle dot>3] for Cushing disease vs 13<middle dot>4 years [11<middle dot>0-13<middle dot>7] for ectopic Cushing syndrome; p<0<middle dot>0001). Body-mass index z-scores did not differ between the diagnostic groups (1<middle dot>90 [1<middle dot>19-2<middle dot>34] for adrenal-associated Cushing syndrome vs 2<middle dot>18 [1<middle dot>60-2<middle dot>56] for Cushing disease vs 2<middle dot>22 [1<middle dot>42-2<middle dot>35] for ectopic Cushing syndrome; p=0<middle dot>26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15<middle dot>5 [IQR 12<middle dot>7-18<middle dot>0]) than patients with adrenal-associated Cushing syndrome (1<middle dot>5 [0<middle dot>6-5<middle dot>7]) or Cushing disease (3<middle dot>9 [2<middle dot>3-6<middle dot>9]; p<0<middle dot>0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease.Interpretation This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition.