Severe obesity is increasing in prevalence worldwide. Obtaining a detailed history, particularly the pattern and timing of weight gain, can provide clues to an underlying genetic cause of obesity. Proprotein convertase subtilisin/kexin type 1 (PCSK1) plays an important role in the appetite regulation. Furthermore, PCSK1 also functions in the pancreas and is associated with severe insulin resistance and multiple comorbidities when deficient. However, genetic testing may return a result of a variant of uncertain significance (VUS), which could lead to the discovery of a novel mutation that explains the same clinical syndrome. A prior cohort reported that 34.9% of heterozygous VUS associated with a recessive condition in patients with early childhood obesity.

Herein, we present the case of a 14-year-old girl with severe obesity and insulin resistance associated with a heterozygous PCSK1 variant.

A 14-year-old Thai female presented with hyperpigmented plaques around her neck and axillary areas. She had experienced significant weight gain since her second year of life. Her father’s and mother’s BMIs are 24.2 and 37.1 kg/m², respectively. She has one younger sister with a normal body weight. She has had normal developmental milestones and no problems with bowel function. However, she reports persistent hunger and frequently eats during the night. Her height was 173 cm, and her weight was 134.2 kg, resulting in a BMI of 44.8 kg/m². Physical examination revealed severe acanthosis nigricans. Laboratory investigations showed normal fasting blood glucose but a HbA1c of 5.8%. Her fasting insulin level was 111.5 μIU/mL (reference range: 2.6–24.9 μIU/mL), with a HOMA-IR of 26.9. Liver, kidney, and thyroid function tests were within normal limits. Due to her early-onset obesity and severe insulin resistance, genetic testing was performed. A heterozygous variant in PCSK1, c.1628C > G p.(Thr543Arg), was identified but classified as VUS. After discussing treatment options, semaglutide along with metformin and dietary counseling were initiated. The patient’s weight decreased slightly from 135 kg to 132 kg over three-months of treatment. Bariatric surgery was also discussed, but her parents declined. The patient was lost to follow-up and returned with erythematous plaque over an area of acanthosis nigricans. Her weight had increased from 132 kg to 155 kg during the three-year period.

Childhood-onset severe obesity and insulin resistance should raise the suspicion monogenic obesity, even if the variant is classified as VUS.