# Monogenic Obesity Diagnosis > 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. - Skill: `dromlakhani/monogenic-obesity-diagnosis` (Agent Skill) - Install (CLI): `npx skillmds add dromlakhani/monogenic-obesity-diagnosis` - Raw SKILL.md: https://api.skillmd.com/api/skills/dromlakhani/monogenic-obesity-diagnosis/raw - Safety review: pending (external: skill-scanner PASS, skillspector PASS) - Works with: Claude Code, Claude.ai, OpenAI Codex - Category: Coding & Dev Tools - Author: dromlakhani (https://skillmd.com/u/dromlakhani) - Updated: 2026-08-19 - Page: https://skillmd.com/skills/dromlakhani/monogenic-obesity-diagnosis --- # 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) --- ## 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. --- ## 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. --- ## 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. --- ## 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.