pediatric-obesity-etiology-screener

Pediatric Obesity: Atypical Etiology Screener

Distinguish typical exogenous obesity from monogenic, syndromic, or secondary endocrine causes using a structured red flag screen.

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Step 1 — Establish the Typical Baseline

Typical exogenous obesity looks like this — if ALL present, atypical cause is less likely:

Feature	Typical Exogenous Obesity
Onset	Gradual, often after age 5
Height	Normal to tall for age (advanced skeletal maturation)
Development	Normal milestones
Appetite	Increased but not insatiable
Dysmorphic features	Absent
Family history	Usually positive for obesity

⚠️ If any feature deviates from the above, proceed through the red flag screen below.

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Step 2 — Red Flag Screen

Work through each domain. One or more flags = investigate further.

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🔴 Domain 1: Age and Onset of Obesity

Red Flag	Suspect
Obesity onset before age 2–5 years, especially severe	Monogenic obesity: leptin deficiency, leptin receptor deficiency, POMC deficiency, MC4R mutation
Abrupt, rapid weight gain at any age	Hypothalamic lesion (craniopharyngioma), ROHHAD/ROHHADNET syndrome, new-onset endocrine disorder

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🔴 Domain 2: Growth Pattern

Red Flag	Suspect
Short stature in a child with obesity	Endocrine cause (Cushing disease, hypothyroidism, GH deficiency) or genetic syndrome
Declining height velocity despite obesity	Endocrine disorder — especially Cushing or hypothyroidism

📏 Key rule: Exogenous obesity accelerates growth. A child with obesity who is short or growing slowly almost certainly has a non-exogenous cause. This is one of the most important red flags in paediatric practice.

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🔴 Domain 3: Appetite

Red Flag	Suspect
Marked, uncontrollable hyperphagia — insatiable hunger, food-seeking behaviour, food obsession	Monogenic obesity (leptin deficiency, POMC deficiency, MC4R), Prader-Willi syndrome, hypothalamic obesity

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🔴 Domain 4: Development and Neurology

Red Flag	Suspect
Developmental delay or intellectual disability	Syndromic causes: Prader-Willi, Bardet-Biedl, Cohen syndrome
Hypotonia in infancy followed by hyperphagia and rapid weight gain in early childhood	Prader-Willi syndrome (classic presentation)
Headaches, nausea, vision changes, nystagmus	Craniopharyngioma or other hypothalamic-pituitary tumour
Autonomic dysregulation, hypoventilation	ROHHAD/ROHHADNET syndrome

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🔴 Domain 5: Physical and Genitourinary Findings

Red Flag	Suspect
Dysmorphic features — unusual facies, small hands/feet, polydactyly	Bardet-Biedl syndrome (polydactyly), Prader-Willi syndrome, other chromosomal syndromes
Delayed or absent puberty, undescended testes, micropenis, small testes	Prader-Willi syndrome, Bardet-Biedl syndrome, leptin deficiency, endocrine cause
Precocious puberty	CNS lesion, ROHHAD syndrome
Pale skin with red hair (in White individuals)	POMC deficiency (classic triad: early-onset obesity + red hair + adrenal insufficiency)
Retinal pigmentation, visual impairment, or deafness	Bardet-Biedl syndrome, Alström syndrome
Dry/coarse hair, constipation, cold intolerance, bradycardia	Hypothyroidism
Violaceous striae, interscapular fat pad (buffalo hump), moon facies, proximal myopathy, hypertension	Cushing syndrome / Cushing disease
Polydipsia, polyuria	Diabetes insipidus (hypothalamic cause), or new-onset T1DM masking with insulin-driven weight gain

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Step 3 — Triage by Flag Pattern

Flags Present	Most Likely Cause	Urgency
Onset < 2 yrs + severe hyperphagia, no dysmorphia	Monogenic obesity (leptin, POMC, MC4R)	Elective referral to paediatric endocrinology/genetics
Neonatal hypotonia + later hyperphagia + developmental delay + hypogonadism + small hands/feet	Prader-Willi syndrome	Genetic testing (methylation studies) — confirm urgently
Polydactyly + retinal dystrophy + intellectual disability + hypogonadism	Bardet-Biedl syndrome	Genetics + ophthalmology referral
Short stature + obesity + violaceous striae + buffalo hump	Cushing syndrome	Endocrine workup (24h UFC, midnight salivary cortisol, low-dose DST)
Short stature + obesity + dry skin + constipation + bradycardia	Hypothyroidism	TSH + Free T4 — urgent
GH deficiency signs + short stature + obesity	GH deficiency	IGF-1, IGFBP-3, GH stimulation testing
Rapid-onset obesity + autonomic dysfunction + hypoventilation	ROHHAD/ROHHADNET	Urgent paediatric neurology/respirology
Headaches + visual changes + rapid weight gain	Craniopharyngioma	Urgent MRI brain/pituitary
Red hair + early-onset obesity + adrenal insufficiency signs	POMC deficiency	Urgent cortisol, ACTH, genetics
Visual impairment + sensorineural deafness + obesity	Alström syndrome	Genetics + ophthalmology

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Step 4 — Initial Investigations to Order

Based on red flags identified, order as indicated:

Endocrine screen (if short stature, striae, or growth deceleration):

• TSH, Free T4
• 24-hour urinary free cortisol or midnight salivary cortisol
• Morning cortisol + ACTH
• IGF-1, IGFBP-3

Genetic/syndromic workup:

• Chromosomal microarray (for dysmorphic features or intellectual disability)
• Prader-Willi methylation studies (if clinical features present)
• Specific gene panel (leptin, leptin receptor, POMC, MC4R, BBS genes) via genetics referral

Neuroimaging:

• MRI brain and pituitary (if headaches, visual symptoms, rapid-onset hypothalamic obesity, or ROHHAD suspected)

Ophthalmology:

• Fundoscopy / ERG (if Bardet-Biedl or Alström suspected)

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Clinical Guardrails

• Short stature + obesity = endocrine cause until proven otherwise. Do not attribute growth failure to obesity alone.
• POMC deficiency is rare but treatable — setmelanotide (MC4R agonist) is approved; early identification matters.
• Leptin deficiency is also treatable with recombinant leptin — do not miss it in severe early-onset obesity.
• Prader-Willi: Genetic confirmation should precede growth hormone therapy (standard of care in PWS); confirm before starting.
• Cushing in children is almost always ACTH-dependent (Cushing disease) — screen carefully; obesity + hypertension + poor linear growth is the triad.
• ROHHAD is life-threatening — hypoventilation can cause sudden death; refer urgently if suspected.
• Monogenic obesity does not exclude pharmacotherapy — GLP-1RAs and setmelanotide may still be appropriate after diagnosis.

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Source

Clinical content synthesised from:

• CMAJ 2025 Clinical Practice Guideline: Managing obesity in children. Ball GDC et al. doi: 10.1503/cmaj.241456
• Choquet H, Meyre D. Genetics of Obesity: What have we Learned? Curr Genomics. 2011.
• Forsythe E, Beales PL. Bardet-Biedl Syndrome. Eur J Hum Genet. 2013.
• Styne DM et al. Pediatric Obesity — Assessment, Treatment, and Prevention. JCEM 2017.