What causes hyperphagia in children?

Causes of Hyperphagia in Children

Prader-Willi syndrome (PWS) is the most important genetic cause of hyperphagia in children and should be the primary diagnostic consideration when evaluating a child with excessive appetite, particularly when accompanied by early hypotonia, developmental delay, and rapid weight gain. 1

Primary Genetic Cause: Prader-Willi Syndrome

PWS accounts for the most common syndromic cause of childhood hyperphagia, occurring in approximately 1 in 15,000 to 1 in 25,000 live births and affecting both genders equally across all geographic regions. 1 The syndrome results from lack of expression of genes from the paternally inherited chromosome 15q11-q13 region, specifically involving the SNORD116 gene. 1

Molecular Mechanisms in PWS

The genetic basis involves three primary mechanisms:

• Paternal deletion (approximately 70% of cases): microdeletion of 3-4 megabases spanning the PWS region on the paternally inherited chromosome 15 1
• Maternal uniparental disomy (approximately 20% of cases): inheritance of both chromosome 15 copies from the mother with no paternal contribution 1
• Imprinting defects (rare but important): full methylation of the PWS region on both chromosome 15 copies, which can carry up to 50% recurrence risk if inherited 1

Pathophysiology of Hyperphagia in PWS

The hyperphagia in PWS results from hypothalamic dysfunction affecting the orexin-hormone system and impaired neural response to food intake, leading to inability to regulate food consumption in line with energy needs. 1, 2 Research demonstrates that SNORD116 plays a critical role in the orexin system within the lateral hypothalamus, which controls both feeding modulation and wakefulness. 1

Hyperinsulinemia appears to be a probable trigger for weight gain and subsequent hyperphagia development in PWS. 3 Children with PWS show significant increases in plasma insulin levels during the transition from early feeding difficulties (phases 1a-1b) to weight gain and hyperphagia (phases 2-3), coinciding with the onset of obesity and insatiable appetite. 3

Clinical Presentation by Age

Birth to 2 Years

• Significant hypotonia with poor suck and difficulty with weight gain (paradoxically, these infants do NOT have hyperphagia initially) 1
• Excessive sleepiness with failure to awaken for feeding 1
• Hypogonadism (undescended testes, small phallus, or small clitoris) 1

Ages 2-6 Years

• Congenital hypotonia with history of poor suck persists 1
• Global developmental delay becomes apparent 1
• Transition to hyperphagia begins during this period 1

Ages 6-12 Years

• Excessive eating (hyperphagia) with obsession with food becomes the dominant feature 1
• Central obesity develops if food intake is uncontrolled 1
• Impaired satiety for food with rapid weight gain 1
• Poor linear growth despite excessive caloric intake 1

Age 13 Years Through Adulthood

• Cognitive impairment (usually mild intellectual disability) 1
• Persistent excessive eating with food obsession and central obesity 1
• Hypothalamic hypogonadism 1
• Characteristic behavior problems including temper tantrums and obsessive-compulsive features 1

Hormonal Abnormalities Contributing to Hyperphagia

Beyond PWS, hormonal dysregulation can contribute to hyperphagia:

• Elevated ghrelin levels from infancy to adulthood in PWS 4
• Leptin abnormalities with increased levels that fail to suppress appetite appropriately 4
• Low thyroid hormone, insulin dysregulation, and peptide YY deficiency at certain developmental stages 4
• Orexin A abnormalities with associated brain structure alterations documented between ages 4-30 years 4

Diagnostic Approach

When hyperphagia is identified in a child, immediately consider PWS and proceed with methylation analysis of chromosome 15q11-q13 as the first-line diagnostic test. 1 This is particularly urgent when hyperphagia occurs with:

• History of neonatal hypotonia and feeding difficulties 1
• Global developmental delay 1
• Rapid weight gain with central obesity 1
• Poor linear growth despite excessive food intake 1
• Hypogonadism 1

Do not wait for all features to be present—the constellation of early hypotonia followed by later hyperphagia is sufficient to warrant immediate genetic testing. 1

Clinical Consequences and Mortality Risk

Hyperphagia in PWS directly causes life-threatening complications independent of obesity, including choking, gastric rupture, and respiratory illness. 2 Without adequate weight control and management of eating behaviors, complications include:

• Massive obesity with associated diabetes 1
• Obstructive sleep apnea 1
• Right-sided heart failure 1
• Death typically occurs in the fourth decade without intervention 1

However, with meticulous weight control, individuals with PWS can remain healthy into their seventh decade. 1

Critical Management Pitfall

The most dangerous error is failing to recognize that hyperphagia in PWS represents a neurological inability to feel satiety, not a behavioral choice. 1, 2 Food-seeking behaviors can include eating nonfood items, spoiled food, stealing money for food, and even running away from home to obtain food. 1 These behaviors require environmental controls (locks on cabinets and refrigerators) rather than behavioral punishment alone. 1