Prader-Willi and Genetic Obesity Syndromes
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Direct answer
Prader-Willi syndrome is a leading syndromic cause of obesity, caused by loss of paternally expressed genes at chromosome 15q11-q13, most often through a paternal deletion. It presents with neonatal hypotonia and feeding difficulty, followed by insatiable hyperphagia, hypogonadism, short stature and learning difficulty. Methylation testing confirms it, whereas Bardet-Biedl syndrome and leptin pathway defects cause obesity through different genes.
What you must remember
- Imprinting: the parent of origin decides the phenotype, because Prader-Willi needs paternal loss at 15q11-q13 while Angelman syndrome needs maternal loss at the same locus.
- Genetic mechanisms: paternal deletion in most cases, maternal uniparental disomy in about a quarter, and imprinting defects in a small minority.
- Diagnosis: DNA methylation analysis of the imprinted region is the first-line test, with FISH, microarray and uniparental disomy testing refining the subtype.
- Feeding phases: neonatal hypotonia and poor feeding, then insatiable appetite and obesity from early childhood unless food access is controlled.
- Endocrine features: hypogonadism, growth hormone deficiency and short stature, with growth hormone therapy improving growth and body composition.
- Bardet-Biedl syndrome: an autosomal recessive ciliopathy with rod-cone retinal dystrophy, postaxial polydactyly, obesity, learning difficulty, hypogonadism and renal anomalies.
- Leptin pathway: MC4R mutations are the commonest monogenic cause of severe early-onset obesity, while leptin, leptin receptor and POMC deficiencies are rarer.
Telling the genetic obesity syndromes apart
A 6-year-old boy has had hypotonia since birth and hyperphagia since age 3, with small genitalia on examination. Obesity with developmental delay points to a syndrome rather than simple overeating, so the mechanism matters. The table separates the common syndromes by mechanism and clinical clue.
| Syndrome | Mechanism | Distinguishing feature |
|---|---|---|
| Prader-Willi | Loss of paternal 15q11-q13 expression | Neonatal hypotonia, hyperphagia, hypogonadism |
| Angelman | Loss of maternal UBE3A at 15q11-q13 | Ataxia, seizures, happy demeanour, no obesity |
| Bardet-Biedl | Autosomal recessive ciliopathy | Retinal dystrophy with polydactyly |
| MC4R deficiency | Melanocortin receptor mutation | Early, severe obesity without syndromic features |
| Leptin deficiency | Rare LEP mutation | Severe obesity with hypogonadism |
Prader-Willi and Angelman syndromes share a region, so the parent of origin is the decisive clue. Monogenic obesity from MC4R or leptin pathway defects usually lacks the dysmorphic and developmental features that make the syndromic forms recognisable.
In practice, the clinician should first take a developmental and feeding history, then examine for dysmorphism, eye findings and extra digits. Those features narrow the molecular test that is worth ordering.
Where the exam tries to catch you
Most errors come from forgetting imprinting or missing the clinical clue that points to a syndrome.
- Trap: labelling a hypotonic infant with later obesity as Angelman syndrome Correct: Angelman lacks hyperphagia and is marked by ataxia, seizures and a happy demeanour, whereas Prader-Willi has paternal loss and hyperphagia.
- Trap: ordering only a karyotype Correct: karyotype misses imprinting defects and uniparental disomy, so methylation testing is the first-line investigation.
- Trap: attributing Bardet-Biedl obesity to overeating alone Correct: polydactyly and retinal dystrophy are the clues, and they point to a ciliopathy.
Frequently asked questions
Which test confirms Prader-Willi syndrome?
DNA methylation analysis of the 15q11-q13 imprinted region confirms Prader-Willi syndrome and detects most underlying mechanisms in one test. Fluorescence in situ hybridisation or microarray then identifies deletions, while SNP-based analysis detects uniparental disomy. A standard karyotype alone misses many cases.
Why does Prader-Willi syndrome differ from Angelman syndrome?
Prader-Willi syndrome results from loss of paternally expressed genes at chromosome 15q11-q13, whereas Angelman syndrome results from loss of the maternally expressed UBE3A gene in the same region. The parent of origin therefore determines which syndrome develops. Angelman syndrome features ataxia, seizures and a happy demeanour rather than hyperphagia.
What causes hyperphagia in Prader-Willi syndrome?
Hyperphagia in Prader-Willi syndrome is thought to arise from hypothalamic dysfunction, not from a simple lack of willpower. Patients develop an insatiable drive to eat from early childhood, so food security and environmental controls are needed. Managing this drive is a central part of long-term care.
Which obesity syndrome is associated with polydactyly and retinal dystrophy?
Bardet-Biedl syndrome is the genetic obesity syndrome associated with polydactyly and retinal dystrophy. It is an autosomal recessive ciliopathy that also causes learning difficulty, hypogonadism and renal anomalies. Rod-cone retinal degeneration is often an early clue and should prompt suspicion of this diagnosis.
Is growth hormone therapy used in Prader-Willi syndrome?
Growth hormone therapy is used in Prader-Willi syndrome to improve height, body composition and muscle mass. It is started in childhood after the diagnosis is confirmed, with close monitoring during treatment. Growth hormone is part of multidisciplinary care and does not treat the underlying hyperphagia.