ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2024;109(8):2053-2060. PMID: 38318871 doi: 10.1210/clinem/dgae073. https://pubmed.ncbi.nlm.nih.gov/38318871/

Brief summary: This retrospective study investigated the endocrine manifestations in 155 pre- and pubertal children and adolescents with adrenocortical tumors included in the German Paediatric Oncology Haematology-Malignant Endocrine Tumour (GPOH-MET) studies during 1997-2022.

Comment: Adrenocortical carcinomas are rare in children and most adrenocortical tumors (ACT) are functional (1-3). This study investigated the endocrine manifestations in 155 pre-and pubertal children and adolescents with ACT included in the GPOH-MET study (cases from Germany, Austria, Switzerland) during 1997-2022. Median age at diagnosis was 4.2 years with a female preponderance (71%) and the median time interval of symptoms prior to diagnosis was 4.2 months.

In prepubertal girls (n=63) the main symptoms were pubarche (68.3%), clitoral hypertrophy (49.2%) and weight gain (31.7%) while as many as 12.7% of the girls did not have any clinical signs or symptoms. In pubertal girls (n=47) the main manifestations were excessive pubic hair (46.8%), acne (36.2%) and hypertension (36.2). In addition, 25% of the pubertal females presented with abdominal/back pain. In prepubertal boys (n=34) the leading signs and symptoms were pubarche (55.9%), penile growth (47.1%) and acne (32.4%), while the pubertal boys (n=11) mostly presented with weight gain (45.5%), hypertension (36.4%) and excess pubic hair/Cushingoid features (27.3%). Half of the pubertal boys also complained of back pain.

The most frequent symptoms in patients of prepubertal age with adrenocortical adenoma (ACA) were pubarche (56.7%), weight gain/obesity (40.0%), and clitoral hypertrophy/penile growth (33.3%), whereas pubarche (72.5%), clitoral hypertrophy/penile growth (56.9%), and acne (31.4%) were most frequent in patients with adrenocortical carcinoma (ACC). In pubertal patients with ACA, the most frequent symptoms were excessive pubic hair (47.1%), weight gain/obesity (29.4%), and sweat odor or deep voice (23.6%), while in patients with ACC, the most frequent symptoms were hypertension (50.0%), excessive pubic hair (42.1%), and weight gain/obesity and tiredness (39.5%).

In metastatic disease, the most frequent sign was hypertension, while in those without metastasis the most common sign was clitoral hypertrophy. In addition, no differences were observed for endocrine manifestations in ACC patients with Ki67-index < 15% compared to Ki67-index ≥ 15%. The hormonal profiles were mostly in line with the endocrine manifestations, but Cushing’s syndrome was overlooked in several cases, especially in prepubertal children with androgen excess.

In conclusion, this is the first comprehensive analysis of the various endocrine manifestations in 155 children and adolescents with ACT. The latency from first endocrine symptoms to ACT diagnosis was 4.8 months, which concurs with previous reports. These data demonstrate that the endocrine phenotype is age- and sex-dependent, and it is not associated with tumor dignity. The most frequent overarching endocrine phenotype is mixed (virilization/peripheral precocity combined with Cushing syndrome; 53.8%), followed by virilization/peripheral precocity (27.9%), and Cushing syndrome (11.5%).

References: 1. Sandrini R, Ribeiro RC, DeLacerda L. Childhood adrenocortical tumors. J Clin Endocrinol Metab. 1997;82(7):2027-2031.2. Ribeiro RC, Pinto EM, Zambetti GP, Rodriguez-Galindo C. The international pediatric adrenocortical tumor registry initiative: contributions to clinical, biological, and treatment advances in pediatric adrenocortical tumors. MolCell Endocrinol. 2012;351(1):37-43.3. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, Ribeiro RC. Biology, clinical characteristics, and management of adrenocortical tumors in children. Pediatr Blood Cancer. 2005;45(3):265-273.