Natural History of Hyperphagia in Patients with Pseudohypoparathyroidism

Background/Objectives: Pseudohypoparathyroidism (PHP) is a group of genetic disorders characterized by end-organ resistance to multiple hormones, short stature, brachydactyly, subcutaneous ossifications, obesity, and developmental delays. The tissue specific imprinting of GNAS in the hypothalamus may lead to different eating behavior phenotypes in maternally inherited (PHP1A, PHP1B) vs. paternally inherited (PPHP) variants. In this exploratory study, we aimed to evaluate differences in eating behaviors in a cohort of patients with PHP1A, PPHP and PHP1B. Methods: Assessments included caregiver-reported measures (hyperphagia questionnaire, children's eating behavior questionnaire, child feeding questionnaire) and self-reported measures (three factor eating behavior questionnaire). Results: A total of 58 patients with PHP1A, 13 patients with PPHP and 10 patients with PHP1B contributed data, along with 124 obese pediatric controls. An increased risk of obesity was found in PHP1A vs. PPHP (adult body mass index (BMI) 39.8 ± 8.7 vs. 30.2 ± 7.4 kg/m², p = 0.03). Parents reported significantly earlier onset of interest in food in children with PHP1A (2.0 ± 2.3 years) and PHP1B (1.1 ± 1.3 years) compared with controls (5.2 ± 3.2 years, p < 0.001). Measures of hyperphagia, satiety and other feeding behaviors were all similar to controls. The highest hyperphagia questionnaire scores were seen prior to adolescence. In a multi-year, longitudinal assessment of 11 pediatric patients with PHP1A, hyperphagia scores were stable and 25% showed an improvement in symptoms. Conclusion: Patients with PHP1A/1B may have hyperphagia symptoms from a young age but they do not worsen over time. Patients may overeat when allowed access to food, but do not usually have disruptive food seeking behaviors. Early diagnosis can give clinicians the opportunity to provide anticipatory diagnosis on the increased risk of obesity in PHP1A/1B and need for scheduled meals and controlled portions. Further studies with larger cohorts are needed to confirm these findings.