Peer-reviewed article
A Novel Variant of the SH2B1 Gene in an Obese Child With Type 2 Diabetes
Morillo M, Ukarapong S, Seeherunvong T ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a medical case report describing a single child with severe obesity, type 2 diabetes, and behavioral problems who was found to carry a novel genetic mutation in the SH2B1 gene. The report documents the child's clinical presentation, including elevated insulin and leptin levels, and discusses how the genetic variant may contribute to obesity and insulin resistance. While the work contributes to understanding rare genetic forms of childhood obesity, it is primarily a clinical genetics study rather than a child well-being or intervention evaluation.
Key points
- A 13-year-old child presented with severe obesity (BMI 66% above 95th percentile), type 2 diabetes, polyphagia, and behavioral problems
- Genetic testing revealed a novel heterozygous mutation in SH2B1 gene predicted to be pathogenic
- The child showed marked leptin resistance with fasting leptin level of 41.5 ng/mL
- SH2B1 variants have been associated with obesity, insulin resistance, and maladaptive behavior
- The report emphasizes the importance of investigating monogenic causes in cases of severe childhood obesity with diabetes and behavioral problems
Limitations
This is a single case report with no comparison group or intervention evaluation, so it cannot establish causation or generalizability. It describes clinical observations and genetic findings but provides no evidence about treatment effectiveness or outcomes for children with similar presentations.
Abstract
Abstract Obesity in children and adolescents is at epidemic levels in the United States and creates high risk for comorbidities later in life. Childhood obesity is thought to be the result of behavioral and nutritional problems. Although genetic factors may play a role in the etiology of obesity, monogenic forms of obesity are rare. We present a child with obesity, behavioral problems, leptin resistance, and type 2 diabetes who also carries a mutation of Sarcoma Homologous 2B adapter protein 1 (SH2B1). The subject was evaluated at 13 7/12 years old. He had polyphagia, learning disability, aggressive behavior and marked obesity. At ages 9,11, and 13 years respectively, his BMI was 9%, 16%, and 52% above the 95th percentile. At 13 7/12 years old, his height was at the 80th percentile and BMI was 66% above the 95th percentile. He had marked acanthosis nigricans and he was prepubertal. Fasting blood glucose and insulin levels were 116 mg/dl and 592 mIU/L, respectively. Hemoglobin A1c was 6.5% and metformin therapy was initiated for type 2 diabetes. Fasting leptin level (41.5 ng/mL) was markedly elevated indicating leptin resistance. DNA methylation study excluded Prader-Willi syndrome. DNA sequencing indicated a novel heterozygous c.1555G>T variant of SH2B1 gene, which is predicted to result in the amino acid substitution p. Asp519Tyr. The analysis by PolyPhen-2 and MutationTaster predicts that the variant is a pathogenic mutation affecting protein functions. SH2B1 interacts with JAK2 and may play a role in insulin signaling. Pathogenic heterozygous variants in SH2B1 have been associated with obesity, insulin resistance and maladaptive behavior phenotypes (Pearce et al, 2014). Sh2b1-null mice develop severe leptin resistance, obesity, and type 2 diabetes. Our report underscores the importance of investigating monogenic causes of obesity in subjects who present severe obesity, diabetes, and behavioral problems. Additional studies are needed to determine the association between this novel mutation and the clinical features of this patient.