Paeds · genetics-dysmorphology-and-metabolism
Prader-Willi and Angelman syndromes
Also known as 15q11-q13 imprinting disorders · PWS · Angelman syndrome · Happy puppet syndrome · Genomic imprinting disorders of chromosome 15
A fellowship approach to Prader-Willi and Angelman syndromes: recognise the reciprocal imprinting errors at 15q11-q13, confirm the diagnosis with methylation analysis, and build syndrome-specific multidisciplinary management — growth hormone and behavioural support for PWS, anticonvulsant and communication strategies for AS — combined with imprinting-aware cascade genetic counselling.
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Red flags
- Neonatal hypotonia, poor feeding, weak cry, and failure to thrive — Prader-Willi syndrome is a top differential of the floppy infant
- A child with severe intellectual disability, ataxic gait, happy demeanour with frequent laughter, and seizures — Angelman syndrome until proven otherwise
- Sudden onset of severe hyperphagia with rapid weight gain in a previously hypotonic, failure-to-thrive infant — the transition to the PWS phenotype
- Microcephaly, fair skin and hair with deletion, and seizures that are resistant to multiple anticonvulsants in a developmentally delayed child
- An imprinting-centre-defect family — recurrence risk can approach 50 per cent, requiring prenatal testing for subsequent pregnancies
- Normal methylation in a child with classic Angelman features — order UBE3A sequencing, as the mutation form is methylation-normal
- Gastric dilation or rupture in a PWS patient with binge eating — a life-threatening complication of uncontrolled hyperphagia
Life stages
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Board mappings
- Genomic imprinting and 15q11-q13 disorders
- Neonatal hypotonia and the floppy infant differential
- Methylation analysis as a diagnostic test
- Molecular subtypes and recurrence risk of PWS and AS
- Growth hormone therapy in PWS
- Anticonvulsant management in Angelman syndrome
- Recognising PWS in the neonate
- Recognising Angelman syndrome in the toddler
- Counselling imprinting-aware recurrence risk
- Long case of a child with PWS and obesity
- Discussing the UBE3A mutation result with an AS family
- Genetic causes of neurodevelopmental disability
- Genomic imprinting in clinical practice
- Communication in complex chronic disability
- Molecular genetics of PWS and AS
- Methylation testing strategy
- Management of the floppy infant
- Developmental assessment of the child with PWS or AS
- Counselling on imprinting genetic results
- Genomic imprinting disorders
- Prader-Willi and Angelman syndromes
- Evaluation of neonatal hypotonia
- Genetic causes of intellectual disability
- Genomic imprinting and counselling
- PWS and AS as reciprocal imprinting disorders
- Molecular diagnosis and subtype classification
- Multidisciplinary care of imprinting syndromes
The fellowship mark goes to the candidate who thinks in three layers at once. The first layer is the child in front of you: the hypotonic neonate failing to feed (PWS) or the ataxic toddler with seizures and a happy demeanour (AS). The second is the molecular mechanism: a parent-of-origin-specific imprinting error at 15q11-q13 that silences one parental allele and leaves the other unable to compensate. The third is the family: the subtype (deletion, uniparental disomy, imprinting defect, or UBE3A mutation) sets the recurrence risk, and counselling must be imprinting-aware — because imprinting-centre defects and UBE3A mutations carry up to 50 per cent recurrence, while typical deletions and UPD are sporadic. [1] [2] [4]
Overview & Definition
Prader-Willi syndrome and Angelman syndrome are the prototypical disorders of genomic imprinting in humans, and they arise from reciprocal errors at the same chromosomal locus — 15q11-q13. Genomic imprinting is the parent-of-origin-specific expression of certain genes, where only the maternal or paternal copy is active in specific tissues. In the 15q11-q13 region, paternally expressed genes (including SNRPN, MAGEL2, NDN, and the SNORD116 snoRNA cluster) are active on the paternal chromosome, while UBE3A, a ubiquitin-protein ligase, is active primarily on the maternal chromosome in the brain. [3] [5]
Loss of the paternal contribution produces Prader-Willi syndrome: the child has no functional paternally expressed genes, and the maternal copies are silenced by imprinting. The neonate presents with profound hypotonia, poor feeding, and failure to thrive, and the phenotype shifts after infancy to hyperphagia, obesity, intellectual disability, short stature, and hypogonadism. Loss of the maternal contribution at the same locus — specifically of UBE3A — produces Angelman syndrome: the child lacks functional UBE3A protein in the brain because the paternal allele is silenced in neurons, and the result is severe intellectual disability, ataxia, a characteristic happy demeanour, seizures, and microcephaly. [1] [2]
References10ShowHide
- [1]Driscoll DJ, Miller JL, Cassidy SB Prader-Willi Syndrome. GeneReviews, 1993.PMID 20301505
- [2]Dagli AI, Mathews J, Williams CA Angelman Syndrome. GeneReviews, 1993.PMID 20301323
- [3]Cassidy SB. Prader-Willi and Angelman syndromes. Disorders of genomic imprinting. Medicine, 1998.PMID 9556704
- [4]Beygo J, Buiting K, Ramsden SC, et al. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet, 2019.PMID 31235867
- [5]Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet, 2012.PMID 22237428
- [6]Duis J, Nespeca M, Summers J, et al. A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome. Mol Genet Genomic Med, 2022.PMID 35150089
- [7]Koch L. Growth hormone in health and disease: Consensus guidelines for GH therapy in Prader-Willi syndrome--this way forward? Nat Rev Endocrinol, 2013.PMID 23609333
- [8]Pellikaan K, Nguyen NQC, Rosenberg AGW, et al. Malignancies in Prader-Willi Syndrome: Results From a Large International Cohort and Literature Review. J Clin Endocrinol Metab, 2023.PMID 37267430
- [9]Manssen L, Krey I, Gburek-Augustat J, et al. Precision Medicine in Angelman Syndrome. Neuropediatrics, 2025.PMID 39168152
- [10]Roy B, Amemasor E, Hussain S, et al. UBE3A: The Role in Autism Spectrum Disorders (ASDs) and a Potential Candidate for Biomarker Studies and Designing Therapeutic Strategies. Diseases, 2023.PMID 38248358