Monogenic Obesity Diagnosis

---
name: monogenic-obesity-diagnosis
description: >
  Diagnose monogenic and syndromic obesity in children and adolescents using a structured step-by-step algorithm.
  Use this skill whenever a clinician suspects a genetic cause of obesity, asks about leptin deficiency, MC4R mutation,
  POMC deficiency, PCSK1 deficiency, leptin receptor deficiency, Bardet-Biedl syndrome, Prader-Willi syndrome,
  Alström syndrome, or any case of early-onset severe obesity with hyperphagia. Also trigger for questions about
  targeted pharmacotherapy including setmelanotide or metreleptin, or when to order a genomic obesity panel.
  Cross-references the NHS Genomic Test Finder skill to surface the relevant R-code once a diagnosis is reached.
---

# Monogenic & Syndromic Obesity — Diagnostic Pathway

Structured diagnosis for children and adolescents with suspected genetically-driven obesity. Uses the leptin-melanocortin pathway framework and key clinical features to reach a specific genetic diagnosis and matched pharmacotherapy.

**Sources:** Kalinderi et al., Children 2024; Fitch et al., Obesity Pillars 2024.

---

## Step 1 — Entry Criteria: Is This Case Atypical Enough to Pursue?

Proceed with this pathway if **≥1** of the following:

- Obesity onset **before age 5** (especially before age 2)
- **Severe, insatiable hyperphagia** — child cannot feel full, food-seeking behaviour
- **BMI z-score ≥ +3** early in life
- Positive **family history** of severe early-onset obesity (autosomal recessive or dominant pattern)
- Prior red flag screen (etiology screener) flagged a monogenic or syndromic cause
- Failed standard behavioural intervention with no plausible exogenous explanation

> If you haven't run the etiology screener yet, consider doing so first.

---

## Step 2 — Primary Branch: Is Developmental Delay or Intellectual Disability Present?

This is the single most important fork in the diagnostic algorithm.

### ➤ YES — Developmental delay, intellectual disability, or learning difficulties present

→ Suspect **Syndromic obesity**. Continue to **Step 3A**.

### ➤ NO — Normal development and cognition

→ Suspect **Monogenic (non-syndromic) obesity**. Continue to **Step 3B**.

---

## Step 3A — Syndromic Obesity: Identify the Syndrome

Collect: dysmorphic features, vision/hearing, organ anomalies, hypotonia history, polydactyly, behaviour pattern.

| Syndrome | Key Distinguishing Features | Inheritance |
|---|---|---|
| **Prader-Willi (PWS)** | Neonatal hypotonia, poor feeding → hyperphagia age 2–5; short stature; hypogonadism; almond-shaped eyes; skin picking; no polydactyly | Chromosome 15q11-q13 (imprinting) |
| **Bardet-Biedl (BBS)** | Rod-cone dystrophy (night blindness, visual field loss); polydactyly (pre- or post-axial); renal anomalies; hypogonadism; mild-moderate cognitive impairment | AR — BBS1–BBS21 genes |
| **Albright's Hereditary Osteodystrophy (AHO/GNAS)** | Short stature; round facies; brachydactyly; ectopic ossification; hormone resistance (PTH, TSH) | AD — GNAS (maternally inherited → pseudohypoparathyroidism type 1A) |
| **Smith-Magenis (SMS)** | Severe behavioural problems; inverted sleep-wake cycle; self-injurious behaviour; hugging behaviour | AD (usually de novo) — RAI1 deletion 17p11.2 |
| **SIM1 haploinsufficiency** | PWS-like phenotype but NO neonatal hypotonia; severe hyperphagia; developmental delay variable | AD |
| **SH2B1 deletion (16p11.2)** | Hyperphagia; severe insulin resistance; developmental and language delay | AD — 16p11.2 chromosomal deletion |

**If PWS is suspected →** confirm with methylation testing (not standard sequencing).

**If BBS is suspected →** retinal assessment + renal ultrasound before genetics.

**→ Once syndrome identified, go to Step 5 for genomic test and Step 6 for pharmacotherapy.**

---

## Step 3B — Monogenic Obesity: Work Through the Leptin-Melanocortin Pathway

All monogenic non-syndromic obesity disrupts the hypothalamic satiety axis. Ask about: onset age, severity of hyperphagia, immune phenotype, adrenal/gonadal function, GI symptoms.

### Key Pathway: LEP → LEPR → POMC/PCSK1 → MC4R

---

### Leptin Deficiency (LEP mutation)
- **Clinical hallmarks:** Profound hyperphagia from birth; normal birth weight then rapid weight gain; **recurrent infections** (impaired immune function); hypogonadotropic hypogonadism; low/undetectable serum leptin; AR
- **Distinguishing feature:** Very low leptin level despite severe obesity (leptin is normally elevated in obesity)
- **Lab:** Serum leptin (undetectable or extremely low)
- **→ Pharmacotherapy:** Metreleptin (recombinant leptin) — **0.03–0.06 mg/kg/day SC** — highly effective

---

### Leptin Receptor Deficiency (LEPR mutation)
- **Clinical hallmarks:** Similar to leptin deficiency — severe early-onset hyperphagia, rapid weight gain; **normal or elevated** serum leptin (receptor non-functional); hypogonadotropic hypogonadism; growth hormone deficiency; AR
- **Distinguishing feature:** High leptin but same phenotype as leptin deficiency
- **Lab:** Serum leptin (elevated), LEPR sequencing
- **→ Pharmacotherapy:** Setmelanotide — **up to 3 mg SC daily** — targets downstream MC4R axis

---

### POMC Deficiency
- **Clinical hallmarks:** Early-onset hyperphagia + severe obesity; **adrenal insufficiency** (ACTH deficiency — POMC is precursor); **red/fair hair** in European populations (MSH derived from POMC); pale skin; AR
- **Distinguishing feature:** Adrenal insufficiency + red hair + hyperphagia triad
- **Lab:** Low cortisol/ACTH, POMC sequencing
- **→ Pharmacotherapy:** Setmelanotide — **up to 3 mg SC daily** (targets MC4R directly below POMC)

---

### PCSK1 Deficiency (PC1/3)
- **Clinical hallmarks:** Severe early-onset obesity; **malabsorptive diarrhoea in infancy** (impaired proinsulin processing → GI dysmotility); hypoglycaemia; hypogonadotropic hypogonadism; central diabetes insipidus possible; AR
- **Distinguishing feature:** Neonatal diarrhoea + hypoglycaemia + obesity
- **Lab:** Proinsulin:insulin ratio elevated, PCSK1 sequencing
- **→ Pharmacotherapy:** Setmelanotide — **up to 3 mg SC daily**

---

### MC4R Mutation
- **Clinical hallmarks:** Most **common** monogenic cause (2–5% of severe childhood obesity); hyperphagia; tall stature (linear growth acceleration); **increased lean mass and bone density** (distinguishes from other causes); hyperinsulinaemia; AD (heterozygous = incomplete penetrance)
- **Distinguishing feature:** Tall for age + increased muscle mass + hyperphagia — NOT short or dysmorphic
- **Lab:** MC4R sequencing
- **→ Pharmacotherapy:** Setmelanotide shows benefit (especially homozygous/compound het). Also consider GLP-1 agonists (semaglutide/liraglutide) for general obesity component.

---

### Alström Syndrome (ALMS1)
- **Clinical hallmarks:** Resembles BBS but **NO polydactyly, NO intellectual disability**; cone-rod dystrophy (nystagmus, photophobia early); cardiomyopathy (dilated, often presenting in infancy); sensorineural hearing loss; type 2 diabetes early; AR
- **Distinguishing feature:** BBS-like but cognitively normal + cardiomyopathy
- **Lab:** ALMS1 sequencing, echocardiogram, audiology

---

### SRC1 (NCOA1) Deficiency
- **Clinical hallmarks:** Severe hyperphagia; cognitive impairment variable; reduced physical activity; AR
- **Lab:** NCOA1 sequencing (rare — often identified via research panels)

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## Step 4 — Confirm with Genetic Testing

Once a likely diagnosis is identified, order the appropriate NHS genomic test.

**Invoke the `nhs-genomic-test-finder` skill** and search for the relevant R-code. Key tests to look up:

| Suspected Diagnosis | Search Term for NHS Finder |
|---|---|
| Leptin/LEPR/POMC/MC4R/PCSK1 deficiency | "monogenic obesity" or "R191" |
| Bardet-Biedl syndrome | "Bardet-Biedl" |
| Prader-Willi syndrome | "Prader-Willi" |
| Alström syndrome | "Alström" or "ALMS1" |
| Syndromic obesity panel (broad) | "obesity panel" or "R190" |

> The NHS Genomic Test Finder will surface: Test ID (R-code), target genes, test method, commissioning category, and referral pathway.

**Commissioning reminder:** Monogenic obesity panels are typically **Specialised or Highly Specialised** — referral to a paediatric genetics or obesity medicine centre is usually required before testing.

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## Step 5 — Targeted Pharmacotherapy Summary

| Diagnosis | Drug | Dose | Route | Notes |
|---|---|---|---|---|
| **LEP deficiency** | Metreleptin | 0.03–0.06 mg/kg/day | SC daily | Highly effective; restores satiety and immune function; requires specialist prescribing |
| **LEPR deficiency** | Setmelanotide | Start 0.5 mg → titrate to **max 3 mg/day** | SC daily | EU/US approved; LEPR indication |
| **POMC deficiency** | Setmelanotide | Start 0.5 mg → titrate to **max 3 mg/day** | SC daily | Licensed in EU/US for POMC deficiency |
| **PCSK1 deficiency** | Setmelanotide | Start 0.5 mg → titrate to **max 3 mg/day** | SC daily | Licensed in EU/US |
| **BBS** | Setmelanotide | Start 0.5 mg → titrate to **max 3 mg/day** | SC daily | Licensed for BBS specifically |
| **MC4R mutation** | Setmelanotide | As above | SC daily | Consider + GLP-1 agonist for insulin resistance |
| **General severe obesity (≥12 years)** | Semaglutide | Up to **2.4 mg/week** | SC weekly | STEP TEENS data; NICE approved in UK ≥12 |
| **General severe obesity (≥12 years)** | Liraglutide | Up to **3 mg/day** | SC daily | SCALE TEENS data |

> ⚠️ **Setmelanotide (Imcivree) and Metreleptin (Myalepta)** are specialist medications — prescribe only through a centre experienced in monogenic obesity. Check current NHS England commissioning for access criteria.

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## Step 6 — Clinical Guardrails

**Don't miss LEP deficiency because leptin wasn't checked.** Serum leptin is cheap, fast, and diagnostic — order it in any child with severe early-onset obesity + recurrent infections.

**Elevated leptin ≠ no monogenic cause.** LEPR deficiency has high leptin; interpret in clinical context.

**MC4R is heterozygous and common.** Finding one pathogenic MC4R variant doesn't mean you've found the whole picture — check for comorbid contributors. Incomplete penetrance is real.

**PWS methylation testing, not sequencing.** Standard sequencing misses PWS (imprinting defect). Request methylation-specific testing.

**BBS needs eyes and kidneys assessed before genetics.** Retinal dystrophy and renal anomalies are the dangerous comorbidities — don't let the genetics delay urgent organ assessment.

**Adrenal insufficiency in POMC deficiency is life-threatening.** Check cortisol before starting setmelanotide — ACTH deficiency requires hydrocortisone replacement first.

**Setmelanotide in BBS:** Works even without POMC/LEPR deficiency — MC4R pathway activation is the mechanism. Approved for BBS as a class, not gene-by-gene.

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## Sources

- Kalinderi K et al. "Monogenic and Syndromic Forms of Childhood Obesity: An Update." *Children* 2024;11:153. https://doi.org/10.3390/children11020153
- Fitch AK et al. "Differentiating Monogenic and Syndromic Causes of Obesity from Common Polygenic Obesity." *Obesity Pillars* 2024. https://doi.org/10.1016/j.obpill.2024.100120
- NHS England National Genomic Test Directory for Rare and Inherited Disease, v9.0, April 2026.