MON-700 - Tirzepatide Response in A Patient with Chung-Jansen Syndrome and Coexisting MC4R and VPS13B Mutations

Background:
Chung-Jansen syndrome, caused by pathogenic variants in PHIP, is a rare neurodevelopmental condition characterized by developmental delay, hypotonia, hyperphagia, and severe early-onset obesity. PHIP is a transcription factor regulating POMC-associated satiety signalling. No published data exist on the use of tirzepatide in Chung-Jansen syndrome. We present a patient with a PHIP loss-of-function variant and coexisting MC4R and VPS13B variants who achieved significant improvement in adiposity with tirzepatide.

Case Presentation:
31 y/o fraternal twin male exhibited hyperphagia, hypotonia, constipation, delayed milestones, and motor impairment since infancy. Weight escalated rapidly throughout childhood, reaching 300 lb by age 18, peaking at ~550 lb in early adulthood during periods of severe depression and compulsive food-seeking behaviour. Comorbidities included severe obstructive sleep apnea, major depression and anxiety, and hypogonadotropic hypogonadism. He had no diabetes, dyslipidemia, or HTN.
At age 30, genetic testing revealed a de novo heterozygous PHIP c.2161C>T (p.Arg721)* premature termination variant, likely autosomal dominant and pathogenic based on in silico analysis. He also harbored MC4R and VPS13B variants inherited from his father and mother respectively both associated with milder cases of obesity indicating a possibly multilocus, compounded genetic effect on appetite regulation and energy balance.
Interventions prior to his genetic diagnosis included stimulants (Vyvanse), SSRIs, atypical antipsychotics, topiramate, structured residential programs, and transcranial magnetic stimulation, all without meaningful or sustained benefit. Bariatric surgery had been deferred due to uncontrolled hyperphagia and psychiatric instability.
At 31 y/o 2.5 mg weekly tirzepatide was started, slowly titrated to 7.5 mg weekly, with concurrent metformin, CPAP treatment and lifestyle changes. No significant side effects noted. Within approximately 1.5 years his BMI decreased from >73.8 to 60.4 kg/m2. Appetite, compulsive food-seeking behaviors, energy levels, and GI symptoms are continuing to improve.

Conclusion:
This case highlights a novel PHIP pathogenic variant causing Chung-Jansen syndrome, compounded by inherited MC4R and VPS13B mutations, resulting in extreme early-onset obesity with neurodevelopmental implications and severe hyperphagia. Tirzepatide treatment has been well tolerated and associated with a significant reduction in adiposity in this patient. Further follow-up will clarify its long-term weight trajectory. Incretin-based therapies may represent an important therapeutic option in PHIP-related and other types of rare obesity.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*