Paediatric Cushing’s disease — a literature review of epidemiology, pathogenesis, clinical symptoms, and diagnostics

Abstract

Cushing's disease (CD) is characterised by excess production of adrenocorticotropic hormone (ACTH) by a pituitary corticotroph adenoma, which results in hypercortisolaemia. CD is extremely rare in the paediatric population, and few paediatric endocrinology centres have experience in diagnosing and treating this disease. The clinical presentation of hypercortisolaemia is variable, so proper and rapid diagnosis of CD is often challenging. The molecular pathogenesis of CD was largely unknown until recently. The latest research has revealed somatic mutations in the USP8 gene as the most common pathogenic molecular variants of this disease. Herein, we describe the current state of knowledge of paediatric CD epidemiology, molecular pathogenesis, clinical symptoms, and diagnostics. (Endokrynol Pol 2020; 71 (1): 87-95)

Paediatric Cushing’s disease: Epidemiology, pathogenesis, clinical management and outcome

“…In children aged less than 5 years, CD is extremely rare — the most common causes of CS in this age group are adrenocortical adenoma or carcinoma and bilateral adrenal hyperplasia [ 12 ]. The mean age of CD presentation, in several large paediatric series comprising 41–182 children, was 12.3–14.1 years [ 14 ].…”

Cushing disease in pediatrics: an update

“…1,10,12,13) Several genetic mutations are responsible for syndromes associated with pituitary adenomas, including MEN1, which causes multiple endocrine neoplasia type 1; cyclin-dependent kinase inhibitor 1B; Guanine nucleotide-binding protein, α stimulating, which causes McCune-Albright syndrome; Aryl hydrocarbon receptor-interacting protein, which causes familial isolated pituitary adenoma; and ubiquitin-specific protease 8 (USP8), which is the most common mutation found in patients with CD and prevents lysosomal degradation of the epidermal growth factor receptor, increasing its deubiquitination, proopiomelanocortin transcription, and ACTH secretion. 6) In pediatric CD patients, the USP8 gene is mutated in 31%-63% of corticotroph adenomas, and these patients are more likely to experience recurrence after surgery. 6) However, the major driver mutations in USP8 wild-type tumors remain unknown.…”

“…3,4) Cushing disease (CD), which is caused by an ACTH-producing pituitary adenoma, is responsible for 75%-80% of cases of endogenous CS 5) and is more common in children older than 5 years and more frequent in boys, with a prevalence of 63%. 6,7) Its rarity in childhood and adolescence (annual incidence of 0.89-1 per million pediatric patients) 8) has led pediatricians and pediatric endocrinologists to have limited experience in its diagnosis and treatment. 3,9) Growth and development are transcendental processes during childhood.…”

Pituitary transcription factors in the immunohistochemical and molecular diagnosis of pituitary tumours — a systematic review

“…The prevalence of PAs increases with age, the peak age for diagnosis being 30-60 years, and some are associated with sex: female patients account for the majority of somatotroph and corticotroph PAs, while males for the majority of gonadotroph PAs, as found in a cohort of 250 pituitary tumours [12]. Also, regarding the paediatric population, boys have a more aggressive forms of Cushing's disease than girls [13]. In the above-mentioned cohort, the proportion of invasive high-risk adenomas was 28.8%, having a recurrence rate of 17.8% and for apoplexy of 8.2% [12].…”