MON-719 - White-Sutton Syndrome Presenting as Early-Onset Obesity Mimicking Prader–Willi Syndrome: Expanding the Metabolic Phenotype of POGZ-Related Disorder

Background:
White-Sutton syndrome (WHSUS) is a rare neurodevelopmental disorder caused by pathogenic variants in the POGZ (Pogo Transposable Element Derived with ZNF Domain) gene, characterized by intellectual disability, developmental delay, and dysmorphic features. Recent literature increasingly recognizes obesity as a recurrent but undercharacterized component of its phenotypic spectrum. However, the clinical presentation may overlap with syndromic obesity disorders such as Prader–Willi syndrome (PWS), posing significant diagnostic challenges.

Objective:
To describe a child with early-onset obesity and neurodevelopmental impairment initially suspected of PWS, and to propose obesity as an underrecognized metabolic feature of POGZ-related disorder by contextualizing the findings within the current literature on WHSUS.

Case Presentation:
An 11-year-old boy presented with progressive obesity beginning in early infancy, mild intellectual disability, and learning difficulties requiring long-term special education. Developmental milestones were mildly delayed (independent walking at 18 months), with no history of neonatal hypotonia or hyperphagia. Physical examination revealed obesity (BMI SDS +2.68) with subtle dysmorphic features, including almond-shaped eyes and a downturned mouth. Endocrine evaluation demonstrated insulin resistance (32mIU(ml) and prediabetes (Hba1c:6%). Neurological, cardiac, ophthalmologic, and radiological assessments were unremarkable. Standard chromosomal analysis, chromosomal microarray, Fragile X testing, and methylation analysis for PWS were all normal. Whole exome sequencing identified a heterozygous likely pathogenic variant [c.2987dup (p.Arg997Profs*30)] in the POGZ , consistent with a diagnosis of White-Sutton syndrome.
A systematic review of the literature indicates that obesity or elevated BMI is a recurrent feature across reported WHSUS cohorts, with approximately 140 individuals described to date. Multiple independent studies consistently describe an increased risk of obesity, frequently co-occurring with feeding difficulties and sleep disturbances. Proposed mechanisms include POGZ-related chromatin dysregulation affecting neuroendocrine and circadian pathways, potentially contributing to metabolic imbalance through appetite-independent routes. Notably, our patient developed marked obesity in the absence of hyperphagia, suggesting that metabolic dysregulation in WHSUS may arise independently of appetite-driven mechanisms — a distinction with important implications for clinical monitoring and management.

Conclusion:
This case highlights WHSUS as an important differential diagnosis in children presenting with early-onset obesity and neurodevelopmental delay, particularly when classical features of PWS are absent.

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