Genetic Obesity Case with 2 Heterozygote Variants: MKS1 and MC4R in Which Weight Loss Managed with Tirzepatide

Introduction:
Multiple environmental and genetic factors contribute to the pathogenesis of obesity. Pathogenic variants of Genes involved in metabolism and satiety could result in obesity. Monogenic forms of obesity are more common than polygenic forms. We are describing a patient with obesity and heterozygosity for Meckel Syndrome Type 1 protein (MKS1) and melanocortin-4 receptor (MC4R) variants who was treated with novel dual incretin mimetic tirzepatide.

Case Description:
33 y. o. female with polycystic ovarian syndrome, history of gestational diabetes and class 3 obesity presented for medical weight management. She was diagnosed with obesity since childhood and continued to gain weight later. With lifestyle modification and implementing nutritional ketosis via diet, she had lost 60 lbs over 5 years. However, after stopping the diet, she slowly regained the weight. She was prescribed phentermine that caused adverse effects leading to discontinuation. Her medications included metformin and an oral contraceptive. On exam vital signs were normal, weight was 137 Kg (302 lbs.) BMI of 48.7kg/m2. There were no signs of Cushing syndrome. Thyroid function, lipid profile, electrolytes, and hemoglobin A1C were normal. Cortisol adequately suppressed with overnight dexamethasone test. Insulin was elevated at 23.6 and Glucose 91 mg/dl. Genetic testing was performed and was positive for MKS1 and MC4R variant. She was started on tirzepatide for weight loss and lost 20% of excess body weight (28 kgs/62 lbs) in 3 months.

Discussion:
The most common form of monogenic Obesity is due to MC4R deficiency. MC4R is widely expressed in the hypothalamus and regulates feeding behavior and energy homeostasis. Loss-of-function of MC4R gene causes hyperphagia and early onset obesity. Our patient had a MCR4 sequence variant C.892G. >A, which is never been reported in literature and its clinical significance is unknown. Our patient was also heterozygous for MKS1 variant c.184_190del and is predicted to result in frameshift and premature protein termination. MKS1 mutations normally lead to Meckel syndrome and homozygous mutation can cause Bardet Biedl syndrome 13 associated with polydactyly, obesity, and retinitis pigmentosa. Only one allele was detected, and it is possible that a second pathogenic variant was not detected by the sequencing test. Regarding therapy, setmelanotide, a new MC4R agonist is the only medication approved for genetic obesity in patients with specific genetic mutations (POMC, PCSK1, or LEPR deficiency). There are other pharmacotherapies that can be used for weight loss in individuals with genetic obesity with good results such as the Glucagon like peptide 1 (GLP1) receptor agonists semaglutide and liraglutide. Recently, a new class of dual incretin GLP1 and glucose-dependent insulinotropic peptide (GIP) receptor agonist tirzepatide has been approved for the treatment of diabetes and has been used off label for treating obesity. Our patient had insulin resistance and history of gestational diabetes with chronic obesity making her a suitable candidate for tirzepatide with desired results.