ESPE Abstracts

Background: We have identified a novel tandem duplication leading to ubiquitous expression of the agouti-signaling protein (ASIP) in a female patient with severe early onset obesity, red hair, tall stature, and insulin resistance (Kempf, E. et al, 2022). Due to the ectopic expression, ASIP - which normally is only expressed in the skin - can interact with the Melanocortin-4-Receptor receptor in the hypothalamus thereby causing the obesity phenotype.

Objective: To characterize the clinical presentation of patients with an ASIP mutation.

Methods: In a unselected cohort of n = 1,745 children of the Leipzig Childhood Obesity cohort we screened for the genomic ASIP tandem duplication. Additionally, parents of affected patients and patients with matching phenotype from our outpatient clinic were analyzed. Identified patients were invited for clinical examination, medical history and phenotypical description as well as laboratory assessment. Auxologic measurements were taken, hyperphagia was assessed according to the parents' judgement.

Results: In total, clinical data from 7 children harboring the ASIP -tandem-duplication was collected. Of these patients, four were identified by unselected cohort screening, two patients by phenotypically driven analysis, one was the index. Additionally, the same mutation was found in four of their parents. The identified patients consistently exhibit severe obesity (BMI-SDS: range 2.4-4.97; median 2,89) with onset within the first three years of life. All had a body height SDS above the obesity specific 50^th percentile (Kempf, E. et al, 2022). Red hair is common (6 of 7 children). Hyperphagia symptoms are not reported consistently (5 of 7 patients). Hyperinsulinemia was only present in three of the patients. Interestingly, one of the affected patients had an unaffected twin brother. Their weight differed by 30 kg, their height by 9cm. Assessment was performed in three of the affected parents. All suffered from obesity (BMI 33.3; 39.6 and 47.7 kg/m²), two of them had red hair. One parent suffered from hyperinsulinemia; another from type 2 diabetes.

Discussion and Conclusion: The study reinforces initial findings that ectopic ASIP expression is associated with severe, early-onset obesity, tall stature, and red hair by assessing a larger group of affected individuals. Surprisingly, compared to other causes of monogenic obesity, the proportion of patients with confirmed ASIP-tandem duplication within the Childhood Obesity Cohorts was relatively high, at 0.28%. In conclusion, we need to rethink our diagnostic algorithms, as none of these patients with monogenic obesity were detected by standard genetic diagnostic procedures.