A Rare Case of Monogenic Obesity Due to a Novel Variant in the ADCY3 Gene: Challenges in Follow-up and Treatment

Abstract

Adenylate cyclase 3 (ADCY3) gene alterations have been reported to be associated with obesity. However, few patients with homozygous mutations have been described to date and the follow-up procedure and treatment options are unclear. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, and head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 μIU/mL, and homeostatic model assessment for insulin resistance value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A (p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient’s weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount disease and acanthosis nigricans were evident, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur, even at young ages. More data in terms of the optimal treatment and follow-up process of these patients are needed.