Diagnostic Journey with an 80-gene Panel in Non-syndromic Early-Onset Severe Obesity: Association of Outcomes with Metabolic Status and Hyperphagia

Tercan U., Yıldız M., Aslanger A. D., Kardelen Al A. D., Poyrazoğlu Ş., Baş F., ...More

61st Annual ESPE (ESPE 2023), The Hague, Netherlands, 21 - 23 September 2023, pp.243-244

  • Publication Type: Conference Paper / Full Text
  • City: The Hague
  • Country: Netherlands
  • Page Numbers: pp.243-244
  • Istanbul University Affiliated: Yes


Background: Monogenic defects are among the significant causes of early-onset non-syndromic severe obesity in childhood. Identifying the genetic cause of obesity can guide for treatment. The aim of our study is to investigate the clinical and biochemical features of patients with early-onset severe obesity and evaluate the underlying molecular diagnosis.

Materials and Methods: A total of 39 patients (M/F: 22/17) with non-syndromic, early-onset (<5 years) and morbid obesity (body mass index (BMI)/95th percentile BMI ratio >120%) were included in the study. Demographic data, clinical findings, and biochemical results of the cases were recorded. Hyperphagia was evaluated using the Dykens hyperphagia questionnaire. Genetic analyses were conducted within the ROAD (Rare Obesity Advanced Diagnosis) project. 80 genes were examined using the next-generation sequencing method.

Results: The median age of the cases was 12.1 (2.1-20.1) years. The consanguinity rate was 30.8%, while the obesity rate among first-degree relatives was 66.7%. Based on birth weight according to gestational week; 2.9% were SGA, 22.9% were LGA. Bariatric surgery was performed on 7.7% of patients (n=3), and 17.9% (n=7) had a family history of bariatric surgery. The mean height SDS was 1.2±1.4; BMI SDS was 3.4±0.7; the ratio of BMI value to the 95th percentile BMI value was 146±27, the rate of acanthosis nigricans was 30.8%, the prepubertal patient rate was 33.3%. Except for one patient diagnosed with type 2 diabetes mellitus, 32% of 25 patients who underwent OGTT (n=8) had impaired glucose tolerance and hyperinsulinemia, and 48% (n=12) had hyperinsulinemia. Dyslipidemia was present in 35.9% of patients, and hepatosteatosis was present in 60.7%. The frequency of metabolic syndrome in patients >10 years (n=23) was 39.1%. In 30.8% of patients (n=12), at least one variant was detected in obesity-related genes. Homozygous variants were detected in 3 patients in the LEPR gene, and heterozygous variants were detected in 4 in PCSK1, 2 in MC4R, 2 in UCP3, 1 in NTRK2, 1 in PPARG, and 1 in DYRK1B. There was no difference in metabolic parameters, hyperphagia score, severity, and onset of hyperphagia between those with and without documented monogenic obesity (P>0.05). The median age at onset of hyperphagia was 4(0.3-15) years.

Conclusion: The genetic cause of early-onset non-syndromic severe obesity can be determined with extensive gene panels, thus enabling a rapid and cost-effective diagnosis and offering treatment options. If the cause can be identified, genetic counseling can be provided to the patient.