Prader-Willi syndrome is a genetic disorder caused by loss of function of genes on chromosome 15q11-q13 (paternal deletion), presenting in infancy with hypotonia and feeding difficulties, followed in early childhood by hyperphagia, obesity, intellectual disability, short stature, and hypogonadism.

Exam domain	One-glance essentials
Definition / diagnosis	Multisystem disorder from loss of paternal gene expression at 15q11-q13 ^[1] Deletion, maternal UPD and imprinting defects are main mechanisms ^[1]
Epidemiology / risks	Usually sporadic; recurrence depends on molecular mechanism ^[1] Maternal-age-related UPD is increasingly recognised ^[1]
Core mechanism	Hypothalamic dysfunction causes hypotonia, endocrine deficits and hyperphagia ^[1] Abnormal satiety produces severe obesity without environmental control ^[1]
Clinical picture	Neonatal hypotonia and poor feeding evolve into hyperphagia and obesity ^[1] Short stature, hypogonadism, learning difficulty and behavioural rigidity ^[1]
Investigations	DNA methylation confirms the diagnosis in almost all cases ^[2] Assess endocrine axes, sleep-disordered breathing, scoliosis and metabolic risk ^[2]
Management	Strict food security plus diet and exercise supervision ^[3] Growth hormone and replacement of endocrine deficiencies improve health ^[3]
Complications	Morbid obesity, diabetes, OSA and right-heart strain ^[4] Gastric dilatation, aspiration and scoliosis may be life-threatening ^[4]
Prevention / follow-up	Lock food access and establish structured routines early ^[3] Monitor weight, sleep, glucose, thyroid and adrenal risk ^[3]
Exam traps	*Prader-Willi is paternal loss; Angelman is maternal loss* ^[2] Reduced vomiting can mask serious gastric pathology ^[3]

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome)

^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome)

^[3] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome clinical features)

^[4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome: "Hyperphagia ± obesity can cause cardiac insufficiency, OSA, DM")

Prader-Willi Syndrome (PWS) — Paediatrics

Prader-Willi syndrome (PWS) is a complex genomic imprinting disorder caused by the absence of expression of paternally-derived genes on chromosome 15q11.2-q13. It is the first confirmed human imprinting disorder ^[1].

Breaking down the name: "Prader" and "Willi" refer to the Swiss physicians Andrea Prader and Heinrich Willi who first described the condition in 1956.

The key concept here is genomic imprinting — a form of epigenetic regulation where certain genes are expressed from only ONE parental allele (the other is silenced/imprinted). In PWS, the genes in the 15q11-q13 region that are normally expressed from the paternal copy are lost or silenced. Since the maternal copies of these same genes are normally imprinted (switched off), losing the paternal copy means there is zero functional expression of these critical genes.

PWS is the MOST common syndromic form of obesity ^[2] — this is extremely high yield for exams.

Core Concept: Imprinting at 15q11-q13

Both paternal and maternal copies of 15q11-13 must function for normal development (the region is involved in hypothalamus function and hence hormone control) ^[1]. Some genes are maternally imprinted (silenced on the maternal copy) → absence of a functioning paternal copy results in Prader-Willi syndrome. The UBE3A gene is paternally imprinted (silenced on the paternal copy) → absence of a functioning maternal copy results in Angelman syndrome ^[1]. Same chromosomal region, opposite parent-of-origin → completely different phenotypes. This is the classic exam comparison.

Incidence: approximately 1 in 10,000–30,000 live births ^[1]
Males and females are equally affected (M = F) ^[1]^[2]
Majority of cases occur sporadically (i.e., most are de novo events, not inherited) ^[2]
No significant racial or ethnic predilection
PWS is recognised worldwide; in Hong Kong, given the population of ~7.5 million and birth rate of approximately 30,000–40,000 per year, one would expect roughly 1–4 new cases per year, making it rare but consistently encountered in tertiary paediatric genetics clinics

Because the majority of PWS arises from de novo deletions or sporadic UPD events, there are few modifiable risk factors. However:

Risk Factor	Mechanism
Advanced maternal age	Increases risk of meiotic non-disjunction → trisomy 15 rescue → maternal UPD (accounts for ~25–35% of cases)
Family history of chromosomal rearrangements	Balanced translocations involving 15q in a parent increase risk of unbalanced offspring
Imprinting centre defects (rare)	Microdeletions of the imprinting centre → can be inherited (autosomal dominant with parent-of-origin effect) with up to 50% recurrence if the father carries it
Paternal age	Less clearly established than maternal age, but de novo deletions may have a paternal age effect

Recurrence Risk — Exam Must-Know

De novo deletion (~60%): recurrence risk < 1%
Maternal UPD (~35%): recurrence risk < 1% (sporadic meiotic error)
Imprinting centre defect (< 5%): if inherited → up to 50% recurrence if transmitted by father (because only paternal transmission causes disease)
Chromosomal translocation: variable, depends on carrier status of parents

Always offer genetic counselling to the family.

4. Anatomy & Function of the 15q11.2-q13 Region

The 15q11.2-q13 region spans approximately 6 Mb and contains multiple genes under imprinting control. The key functional genes that are paternally expressed (maternally imprinted/silenced) include:

Gene	Function	Relevance to PWS Phenotype
SNRPN (Small Nuclear Ribonucleoprotein Polypeptide N)	mRNA processing; also contains the imprinting centre (IC) within its promoter	Central regulatory gene; loss disrupts expression of the entire paternal gene cluster
MAGEL2	Expressed in hypothalamus; involved in circadian rhythm, endocrine function	Hypothalamic dysfunction → appetite dysregulation, growth hormone deficiency
NECDIN (NDN)	Neuronal differentiation, anti-apoptotic in neurons	Neurodevelopmental features, intellectual disability
MKRN3	Regulates onset of puberty (acts as a brake on GnRH pulsatility)	Loss → can contribute to premature central puberty in some genomic disorders (though PWS usually shows delayed/incomplete puberty)
snoRNA cluster (SNORD116)	Small nucleolar RNAs; post-transcriptional modification of ribosomal RNA	Deletion of SNORD116 alone is sufficient to cause the core PWS phenotype — this is the critical minimal deletion region
SNORD115 (HBII-52)	Regulates alternative splicing of serotonin 2C receptor (5-HT2C)	May contribute to hyperphagia (5-HT2C receptor is involved in satiety signalling)

The paternally-expressed genes at 15q11-q13 are highly expressed in the hypothalamus. The hypothalamus controls:

Appetite regulation (arcuate nucleus → POMC/AgRP pathways) — loss → hyperphagia
Growth hormone (GH) secretion (GHRH from arcuate/ventromedial nuclei) — loss → GH deficiency, short stature
Gonadotropin regulation (GnRH from preoptic area) — loss → hypogonadism
Temperature regulation — dysfunction → temperature instability in neonates
Sleep-wake cycle — dysfunction → excessive daytime sleepiness, sleep-disordered breathing
Pain threshold — hypothalamic dysfunction → high pain threshold (children may not report injuries)

This explains why PWS is fundamentally a hypothalamic disorder despite being caused by a chromosomal/epigenetic defect.

5. Aetiology & Pathophysiology

5.1 Genetic Mechanisms

There are three main mechanisms ^[1]:

A microdeletion on the paternally-inherited chromosome 15 removes the 15q11-q13 region
Two common breakpoints:
- Type I deletion (BP1–BP3): larger (~6 Mb), may have slightly more severe phenotype
- Type II deletion (BP2–BP3): smaller (~5.3 Mb), more common
Since the maternal copy is already imprinted (silenced), deleting the paternal copy leaves no functioning copy

The child inherits two copies of chromosome 15 from the mother and none from the father
Both maternal copies are imprinted → no expression of the paternally-active genes
Mechanism: usually trisomy rescue — conception with trisomy 15 (two maternal + one paternal) → post-zygotic loss of the paternal chromosome 15 to restore disomy → both remaining copies are maternal
Associated with advanced maternal age (meiotic non-disjunction → trisomy)

The imprinting centre (located within the SNRPN promoter) normally directs the paternal allele to be expressed
IC defects (microdeletions or epimutations) cause the paternal allele to carry a maternal imprint → silenced despite being paternally inherited
Epimutations are sporadic (low recurrence); IC microdeletions can be inherited (up to 50% recurrence)

Exam Comparison: PWS vs Angelman Syndrome

Feature	Prader-Willi	Angelman
Chromosome	Same: 15q11-q13	Same: 15q11-q13
Parent-of-origin	Paternal genes lost	Maternal genes (UBE3A) lost
Mechanism	Paternal deletion/maternal UPD/IC defect	Maternal deletion/paternal UPD/UBE3A mutation/IC defect
Obesity	Yes (hyperphagia)	No
Intellectual disability	Mild–moderate	Severe
Movement	Hypotonia	Ataxia, jerky movements ("puppet-like")
Characteristic behaviour	Food-seeking, tantrums	Happy demeanour, frequent laughing
Seizures	Uncommon	Very common

The loss of paternally-expressed genes at 15q11-q13 causes a cascade of hypothalamic and neurodevelopmental dysfunction:

Key pathophysiological points:

Neonatal hypotonia: The profound central hypotonia in PWS neonates is due to neuronal dysfunction (loss of NECDIN and other neuronal genes), NOT a primary muscle disease. This is why nerve conduction and EMG are normal — the problem is central, not peripheral.
Biphasic feeding pattern:
- Phase 1 (Infancy): Poor feeding, weak suck, failure to thrive — due to severe hypotonia affecting the oropharyngeal muscles and reduced drive to feed
- Phase 2 (Early childhood, typically ages 2–6): Hyperphagia begins — due to hypothalamic satiety signalling failure (loss of SNORD116 → abnormal 5-HT2C receptor processing → impaired melanocortin pathway signalling). The child develops an insatiable appetite. Without environmental food restriction, morbid obesity ensues.
GH deficiency: The hypothalamus fails to produce adequate GHRH → reduced GH secretion from the anterior pituitary → low IGF-1 → short stature, increased body fat percentage, decreased lean muscle mass, reduced bone mineral density.
Hypogonadism: Combination of hypothalamic (central) and primary gonadal dysfunction:
- Central: reduced GnRH pulsatility → low LH/FSH
- Primary: intrinsic gonadal dysfunction (especially in males → cryptorchidism, micropenis)
- Results in delayed/incomplete puberty in both sexes
Behavioural phenotype: Loss of serotonergic regulation (SNORD115 → 5-HT2C receptor dysfunction) and other neuronal gene loss → characteristic behavioural profile including temper tantrums, obsessive-compulsive features, skin picking, stubbornness, and food-seeking behaviour.

6. Classification

Class	Proportion	Genetic Defect	Recurrence Risk
Ia	~55–60%	Type I or II paternal deletion	< 1%
Ib	~2–3%	Unbalanced translocation/other rearrangement	Variable (check parental karyotypes)
II	~25–35%	Maternal UPD 15	< 1%
IIIa	~2–3%	IC epimutation (no deletion)	< 1%
IIIb	~1%	IC microdeletion	Up to 50% if paternal

Miller et al. described 7 nutritional phases that are clinically useful:

Phase	Age	Features
0	Prenatal	Decreased fetal movement, polyhydramnios
1a	Birth to 9 months	Hypotonia, poor feeding, FTT; requires assisted feeding (NGT/gavage)
1b	9–25 months	Improved feeding, growing along a centile; no excessive weight gain
2a	2.1–4.5 years	Weight gain without increased appetite or calories
2b	4.5–8 years	Increased appetite with some ability to feel full
3	8 years–adulthood	Hyperphagic, rarely feels full — classic insatiable appetite; major risk for obesity
4	Adulthood (some)	Appetite may decrease; not universal

7. Clinical Features

7.1 Symptoms (What the Caregivers Report)

Decreased fetal movements — due to fetal hypotonia (reduced muscle bulk and tone means less vigorous movement)
Polyhydramnios — the hypotonic fetus swallows less amniotic fluid than normal → fluid accumulates

Neonatal feeding difficulties, followed by FTT in infancy ^[1] — weak suck reflex due to central hypotonia; many require nasogastric tube (NGT) feeding or gavage feeding
Weak cry ^[1] — hypotonia of the laryngeal and respiratory muscles → feeble, mewing cry
Lethargy / reduced spontaneous movement — central hypotonia reduces the drive to move
Temperature instability — hypothalamic thermoregulatory dysfunction; parents may report the baby feels cold or has episodes of unexplained fever

Delayed milestones — motor milestones delayed (average sitting at 12 months, walking at 24 months); speech delay is common
Global developmental delay and intellectual disability: usually mild–moderate ^[1]
Learning difficulties: ASD features ^[1] — some children meet criteria for autism spectrum disorder; rigidity of thinking, difficulty with social cues

Hyperphagia ± obesity ^[1] — caregivers report the child is "always hungry," food-seeking behaviour (hiding food, stealing food, eating from rubbish bins). This typically emerges between ages 2–6 and escalates. Without strict environmental control, morbid obesity develops rapidly.
Behavioural disturbances:
- Temper tantrums — often triggered by food restriction or changes in routine; disproportionately severe
- Obsessive-compulsive behaviours — hoarding, insistence on routine, repetitive questioning
- Skin picking — compulsive excoriation, especially of the extremities; can lead to chronic wounds and secondary infection. Mechanism: possibly related to altered pain perception (high pain threshold) and OCD-like compulsions
- Stubbornness / argumentativeness — characteristic behavioural phenotype
Excessive daytime sleepiness — hypothalamic sleep-wake dysregulation + obesity → obstructive sleep apnoea (OSA)
Delayed or incomplete puberty — parents notice absent or minimal secondary sexual characteristics compared to peers

Psychiatric symptoms: increased risk of mood disorders, psychosis (especially in UPD subtype), anxiety
Scoliosis symptoms — back pain, asymmetric posture

7.2 Signs (What You Find on Examination)

Short stature ^[1] — due to GH deficiency; typically below 3rd centile without GH treatment
Obesity — central obesity pattern in older children; truncal fat distribution
Hypopigmentation: fair skin/hair compared to family ^[1] — the OCA2 gene (involved in melanin synthesis) is located within the commonly deleted 15q11-q13 region; deletion removes one copy → reduced pigmentation relative to family members (most apparent in deletion subtype)

Clinical features of craniofacial appearance ^[1]:

Long, narrow head (dolichocephaly) with narrow bitemporal diameter — "dolicho" = long, "cephaly" = head
Narrow forehead
Almond-shaped eyes — characteristic palpebral fissure shape
Downturned mouth — contributes to the "sad" facial appearance
Thin upper lip
Narrow nasal bridge

Small hands and feet ^[1] — "acromicria" ("acro" = extremity, "micria" = small); typically below the 25th centile for age; hands are characteristically narrow with tapering fingers and a straight ulnar border

Hypotonia with poor suck ^[1] — CENTRAL hypotonia (not peripheral); reflexes are present but may be diminished; the hypotonia improves with age but never fully normalises
High pain threshold — the child may not react appropriately to painful stimuli (e.g., fractures, burns may go unnoticed)

Males: Cryptorchidism (undescended testes, often bilateral), micropenis, hypoplastic scrotal skin (scrotal hypoplasia — the scrotum appears small, smooth, and poorly rugated)
Females: Hypoplastic labia minora, clitoral hypoplasia — less obvious than male findings, can be missed on cursory examination

Thick, viscous saliva — altered salivary composition; contributes to dental caries
Strabismus — ocular misalignment, present in ~50–60% of patients; related to hypotonia of extraocular muscles and/or central oculomotor dysfunction
Scoliosis — present in up to 80% of patients by adolescence; combination of hypotonia, obesity, and potential vertebral anomalies
Dental crowding / enamel hypoplasia — small jaw + thick saliva → dental problems

Red Flag Features That Should Prompt DNA Testing for PWS

The following clinical features (marked red in the source) should prompt DNA methylation testing ^[1]:

Neonatal hypotonia with poor suck — unexplained, central-pattern hypotonia in a neonate
Feeding difficulties requiring tube feeding in infancy
Hyperphagia with progressive obesity in early childhood — especially if combined with characteristic facies

If a neonate presents with severe, unexplained central hypotonia + poor feeding + weak cry → think PWS and send methylation analysis of 15q11-q13. Early diagnosis changes management trajectory dramatically (early GH, feeding support, anticipatory obesity prevention).

Age Group	Key Clinical Features	Pathophysiological Basis
Prenatal	↓ Fetal movements, polyhydramnios, breech presentation	Fetal hypotonia → reduced swallowing, reduced movement
Neonate	Severe hypotonia, poor suck, weak cry, FTT, cryptorchidism (males), temperature instability	Central neuronal dysfunction, hypothalamic immaturity
Infant (0–2 yr)	Continued hypotonia, feeding difficulties → FTT, motor delay	Persistent central hypotonia, global developmental delay
Early childhood (2–6 yr)	Weight gain begins, transition to hyperphagia, emerging behavioural features, short stature becomes apparent	Hypothalamic appetite dysregulation emerges; GH deficiency manifests
Late childhood (6–12 yr)	Hyperphagia → obesity, skin picking, OCD features, scoliosis, strabismus	Full hypothalamic phenotype; behavioural circuits mature with aberrant serotonergic signalling
Adolescence	Delayed/incomplete puberty, worsening obesity, OSA, insulin resistance, psychiatric features	Hypogonadism (central + primary), metabolic consequences of obesity
Adulthood	T2DM, cardiovascular disease, osteoporosis, psychiatric illness (psychosis in UPD subtype), reduced life expectancy	Cumulative metabolic burden; ongoing endocrine deficiencies

Hyperphagia ± obesity can cause: ^[1]

Cardiac insufficiency — morbid obesity → increased cardiac workload → dilated cardiomyopathy
Obstructive sleep apnoea (OSA) — obesity + hypotonia → upper airway obstruction during sleep
Type 2 diabetes mellitus (T2DM) — obesity → insulin resistance → β-cell failure

8. Growth and Development Considerations (Paediatric-Specific)

Birth weight is usually normal or slightly low
Length/height progressively falls behind → typically below 3rd centile by mid-childhood without GH therapy
GH treatment (approved for PWS in most countries regardless of GH stimulation test results) improves height velocity, body composition (↑ lean mass, ↓ fat mass), and possibly cognitive outcomes
Plot on standard growth charts (no PWS-specific growth charts in routine use, though they exist for research)

Motor: Gross motor milestones delayed by approximately 1–2 years (sit ~12 months, walk ~24 months)
Speech/language: Delayed; articulation difficulties due to hypotonia of orofacial muscles
Cognitive: Mild to moderate intellectual disability ^[1]; mean IQ ~60–70 (range 40–105); relative strength in reading/visual processing, weakness in maths/abstract reasoning
Social/behavioural: Rigid thinking, difficulty with transitions, food-related behavioural challenges; some meet criteria for ASD

PWS profoundly affects the entire family; parents become "food police" — controlling the environment to prevent hyperphagia
Family support groups (e.g., Prader-Willi Syndrome Association of Hong Kong) are essential
Sibling support should be offered — siblings may feel neglected due to the intense care needs
Transition planning to adult services should begin in early adolescence

Children with PWS may have capacity for assent (agreement to participate in care) depending on cognitive level
Consent is provided by parents/guardians; as the child matures, involve them in discussions at an age-appropriate level
Communication should be concrete, visual where possible, and with clear routines (children with PWS respond well to structure)

9. Paediatric-Specific Considerations

Issue	Paediatric Approach	Adult Approach
Diagnosis	Often diagnosed in neonatal period or infancy via DNA methylation	May present late if undiagnosed in childhood (rare now)
GH therapy	Started early (often < 2 years); FDA/EMA approved for PWS specifically	May be continued or initiated; less evidence for adult-onset GH in PWS
Obesity prevention	Environmental food control is paramount; lock cupboards	Less emphasis on prevention; more on weight management
Puberty	Monitor for precocious or delayed puberty; sex hormone replacement may be needed	Ongoing sex hormone replacement
Behaviour	Parent-mediated behavioural strategies; structured environment	Supported living; vocational training
Formulations	Liquid GH (injection); doses are weight-based (mg/kg/day)	Same formulations; doses may differ

Parameter	Relevance	Key Point
BMI	Use age- and sex-specific BMI percentiles in children	PWS children may have "normal" BMI but abnormally high body fat percentage
IGF-1	Age-specific reference ranges	Often low in PWS even before GH treatment
Glucose/HbA1c	Paediatric diabetes screening	Regular monitoring given obesity risk; fasting glucose ≥ 7.0 mmol/L or HbA1c ≥ 48 mmol/mol (6.5%) diagnostic
TSH/fT4	Central hypothyroidism possible	Check fT4 (not just TSH, as central hypothyroidism shows low fT4 with inappropriately normal/low TSH)
Cortisol	Central adrenal insufficiency reported (controversial)	Morning cortisol + consider ACTH stimulation test if symptomatic
Bone age	Delayed in GH deficiency	Wrist X-ray for bone age assessment

High Yield Summary

PWS is the most common syndromic form of obesity and the first confirmed human imprinting disorder ^[1]^[2]
Caused by loss of paternally-expressed genes at 15q11-q13 — three mechanisms: paternal deletion (~60%), maternal UPD (~35%), imprinting centre defect (< 5%) ^[1]
Core pathophysiology = hypothalamic dysfunction → appetite dysregulation, GH deficiency, hypogonadism, temperature instability, sleep disturbance, high pain threshold
Biphasic nutritional phenotype: neonatal hypotonia/poor feeding/FTT → childhood hyperphagia/obesity
Craniofacial features: dolichocephaly, narrow bitemporal diameter, almond-shaped eyes, thin upper lip, downturned mouth, narrow nasal bridge ^[1]
Other features: short stature, small hands and feet, hypopigmentation relative to family, cryptorchidism/micropenis in males, mild–moderate ID, behavioural disturbances (skin picking, OCD, tantrums) ^[1]
Neonatal hypotonia with poor suck and weak cry should prompt DNA methylation testing ^[1]
Comparison with Angelman syndrome: same region (15q11-q13), but Angelman = loss of maternal UBE3A → severe ID, ataxia, happy demeanour, seizures
Recurrence risk depends on mechanism: < 1% for deletion/UPD; up to 50% for inherited IC microdeletions
Paediatric-specific: GH therapy started early; environmental food control; monitor for T2DM, OSA, scoliosis; family-centred, multidisciplinary care essential

Active Recall - Prader-Willi Syndrome (Definition, Epidemiology, Aetiology, Pathophysiology, Clinical Features)

Differential Diagnosis of Prader-Willi Syndrome

The differential diagnosis of PWS depends on the presenting age and dominant clinical feature. In practice, a child with PWS may present at different time points with different lead problems — neonatal hypotonia, childhood obesity, short stature, intellectual disability, or hypogonadism — and the differential list shifts accordingly. Let's work through this systematically.

PWS is a "great mimic" because it spans multiple organ systems. The most common clinical scenarios prompting the differential are:

Neonatal / infantile hypotonia (the earliest and most common presentation)
Childhood obesity with hyperphagia
Short stature with GH deficiency
Hypogonadism / cryptorchidism
Intellectual disability with behavioural phenotype

We will address each scenario, then bring them together.

2. Differential Diagnosis by Presenting Feature

This is the most critical differential in clinical practice because PWS is diagnosed earliest via this presentation. Neonatal hypotonia is divided into central (brain/spinal cord) vs peripheral (anterior horn cell, nerve, NMJ, muscle) causes.

Why does PWS cause central hypotonia? Loss of paternally-expressed neuronal genes (NECDIN, MAGEL2) at 15q11-q13 leads to abnormal neuronal development and function → profound axial and appendicular hypotonia with preserved deep tendon reflexes (unlike peripheral causes where reflexes are absent/diminished) ^[1].

Differential	Key Distinguishing Features from PWS	Investigation
Prader-Willi syndrome	Hypotonia with poor suck and weak cry ^[1]; characteristic facies (almond eyes, narrow bitemporal diameter); cryptorchidism in males; FTT in infancy → hyperphagia later	DNA methylation analysis of 15q11-q13
Spinal Muscular Atrophy Type 1 ("Werdnig-Hoffmann")	Severe progressive weakness; tongue fasciculations; areflexia; alert face ("bright eyes"); no feeding difficulty initially but progresses; no dysmorphic features	SMN1 gene deletion (homozygous exon 7 deletion); EMG: denervation
Congenital Myotonic Dystrophy (DM1)	Mother usually affected (AD, anticipation); facial diplegia ("tented mouth"); talipes; may have respiratory failure; myotonia in mother on handshake	CTG trinucleotide repeat expansion in DMPK gene (maternal); EMG in mother
Down Syndrome (Trisomy 21)	Hypotonia + characteristic facies (upslanting palpebral fissures, flat nasal bridge, protruding tongue, single palmar crease); congenital heart disease (AVSD) ^[3]	Karyotype / chromosomal microarray
Hypoxic-Ischaemic Encephalopathy	History of perinatal asphyxia; encephalopathy (seizures, altered consciousness); no dysmorphic features; MRI brain abnormalities	MRI brain; clinical history
Congenital myopathy (e.g., nemaline, central core, centronuclear)	Usually NOT dysmorphic; may have facial weakness; relatively stable course; CK may be normal or mildly elevated; muscle biopsy shows specific structural changes	Muscle biopsy; genetic testing
Congenital myasthenic syndromes	Fatigable weakness (fluctuates with activity); ptosis; bulbar weakness; normal cognition; may improve with anticholinesterases	Repetitive nerve stimulation; genetic panel for CMS genes
Zellweger syndrome (peroxisomal biogenesis disorder)	Severe hypotonia + seizures + hepatomegaly + characteristic facies (large fontanelle, high forehead); elevated VLCFA	Very long-chain fatty acids (VLCFA); peroxisomal enzyme assays

Central vs Peripheral Hypotonia — The Key Bedside Distinction

Feature	Central (e.g., PWS)	Peripheral (e.g., SMA)
Deep tendon reflexes	Present (may be ↓)	Absent or markedly ↓
Alertness/Cognition	Often reduced	Often preserved ("bright eyes" in SMA)
Fisting of hands	May be present	Usually absent
Seizures	May occur	Rare
Fasciculations	Absent	Present (tongue in SMA)
Dysmorphic features	Often present	Usually absent
Antigravity movements	Present but reduced	Absent or very weak

In PWS, the hypotonia is central — the brain is the problem, not the muscle or nerve. Reflexes are present, there are no fasciculations, and there ARE dysmorphic features.

PWS is the MOST common syndromic form of obesity ^[2]. This is the hallmark that separates PWS from most other causes of paediatric obesity. The differential for a child with obesity + other features (short stature, ID, dysmorphism) is the group of syndromic obesity disorders.

Why does PWS cause hyperphagia? Loss of SNORD116 snoRNAs → aberrant processing of the serotonin 5-HT2C receptor → impaired melanocortin-4 pathway satiety signalling in the arcuate nucleus of the hypothalamus → absent sensation of fullness.

Differential	Key Features	Gene / Locus	How to Distinguish from PWS
Prader-Willi syndrome	Hyperphagia ± obesity; short stature; small hands/feet; almond eyes; neonatal hypotonia → FTT → hyperphagia ^[1]	15q11-q13 (paternal)	DNA methylation analysis
Bardet-Biedl syndrome (BBS)	Obesity + retinitis pigmentosa (progressive visual loss, night blindness) + polydactyly + renal anomalies + hypogonadism + ID	BBS1-21 genes (AR)	Eye examination (retinal dystrophy); renal USS; polydactyly on exam
Alström syndrome	Obesity + cone-rod dystrophy (early visual loss) + sensorineural hearing loss + cardiomyopathy + T2DM; NO polydactyly, NO ID	ALMS1 gene (AR)	Early-onset visual loss + hearing loss + cardiomyopathy; normal intelligence
Cohen syndrome	Truncal obesity (but NOT hyperphagia typically) + progressive retinal dystrophy + characteristic facies (prominent central incisors, open mouth) + neutropenia + friendly personality	VPS13B / COH1 (AR)	Intermittent neutropenia; prominent central incisors; NO neonatal hypotonia
Beckwith-Wiedemann syndrome	Macrosomia (overgrowth, NOT short stature) + macroglossia + omphalocele + neonatal hypoglycaemia + hemihypertrophy; risk of Wilms tumour	11p15.5 imprinting	Overgrowth (opposite of PWS — these children are too BIG); organomegaly
Melanocortin-4 receptor (MC4R) deficiency	Most common monogenic cause of obesity; hyperphagia + tall stature (NOT short) + increased linear growth + hyperinsulinaemia; NO ID, NO dysmorphism	MC4R (AD)	TALL with increased growth velocity — the opposite of PWS
Hypothyroidism ^[4]	Weight gain + decreased linear growth velocity + constipation + cold intolerance + delayed relaxation of reflexes + goitre; NO hyperphagia per se	TSH, fT4	TFT: elevated TSH, low fT4; no dysmorphic features
Cushing syndrome ^[4]	Central obesity + moon facies + striae + proximal myopathy + hypertension + growth arrest; may be iatrogenic (steroids)	24h UFC, late-night salivary cortisol, 1mg overnight DST ^[5]	Cushingoid habitus; growth arrest with weight gain is characteristic; check drug history for exogenous steroids
Growth hormone deficiency (isolated) ^[4]	Short stature + increased truncal fat + reduced lean mass + delayed bone age; NO hyperphagia, NO ID, NO dysmorphism	GH stimulation tests; IGF-1	Normal cognitive function; no dysmorphic features; responds well to GH alone
Hypothalamic tumours (e.g., craniopharyngioma) ^[4]	Obesity + visual field defects + headaches + growth failure ± DI; acquired onset	MRI brain; visual field assessment	Acquired onset (not congenital); headache/visual symptoms; MRI shows mass
Simple (exogenous) obesity	Tall for age (excess nutrition → advanced bone age → tall); no dysmorphic features; NO ID; normal or accelerated puberty	Clinical diagnosis; exclude secondary causes	TALL stature is the key — simple obesity in children causes TALL stature, whereas syndromic obesity causes SHORT stature

The Cardinal Rule: Tall vs Short Obese Child

An obese child who is TALL for age → likely simple (exogenous) obesity (excess caloric intake promotes growth; advanced bone age).

An obese child who is SHORT for age → must exclude syndromic/endocrine causes — PWS, hypothyroidism, Cushing syndrome, GH deficiency, craniopharyngioma, Bardet-Biedl, etc.

This is one of the most commonly tested distinctions in paediatric endocrinology. Never dismiss a short, obese child as "just overweight" — always investigate.

PWS causes short stature due to GH deficiency (hypothalamic GHRH insufficiency → reduced GH → reduced IGF-1 → poor linear growth + increased adiposity + reduced lean mass + decreased bone mineral density).

Differential	Distinguishing Features	Key Investigations
Turner syndrome (45,X)	Short stature; webbing of neck; low hairline; cubitus valgus; broad chest with widely spaced nipples; left-sided cardiac lesions (coarctation, bicuspid AoV) ^[3]; affects FEMALES only	Karyotype
Noonan syndrome	Turner-like features in BOTH sexes; ptosis; downslanting palpebral fissures; low-set ears; right-sided cardiac lesions (valvular PS, HCM); cryptorchidism in males ^[3]	RAS-MAPK gene panel (PTPN11 most common)
Silver-Russell syndrome	Severe IUGR → small at birth; relative macrocephaly; body asymmetry (hemihypertrophy); triangular face; feeding difficulties; NO obesity	Methylation analysis at 11p15 / UPD7
Constitutional delay of growth and puberty	Short for age but normal growth velocity; delayed bone age; delayed puberty; family history of "late bloomers"; eventually catches up	Bone age (delayed); growth velocity (normal); often a diagnosis of exclusion
Skeletal dysplasias (e.g., achondroplasia)	Disproportionate short stature (short limbs vs trunk); characteristic facies and body habitus	Skeletal survey; FGFR3 gene
Chronic illness (coeliac disease, IBD, CKD)	Growth failure + symptoms of underlying disease; may be subtle	Tissue transglutaminase Ab; inflammatory markers; renal function

PWS involves combined central and primary hypogonadism:

Central: reduced hypothalamic GnRH → low LH (± low FSH)
Primary: intrinsic gonadal dysfunction → low LH but high FSH ^[6] (in some patients; the pattern may evolve with age)

Differential	Distinguishing Features
Isolated cryptorchidism (common, ~3% of term males)	Unilateral or bilateral undescended testes; otherwise normal; no other dysmorphic features; normal growth and development
Kallmann syndrome	Hypogonadotropic hypogonadism + anosmia/hyposmia; delayed puberty; may have renal agenesis, synkinesia (mirror movements); normal cognition
Klinefelter syndrome (47,XXY)	Tall stature (NOT short); small firm testes; gynaecomastia; mild cognitive difficulties; increased risk of metabolic syndrome
Noonan syndrome	Short stature + cryptorchidism + right-sided cardiac lesions + dysmorphic facies ^[3]
Congenital adrenal hypoplasia (DAX1/NR0B1 mutation)	X-linked; adrenal insufficiency in infancy + hypogonadotropic hypogonadism at puberty

PWS is associated with mild to moderate ID, learning difficulties, and ASD features ^[1]. The behavioural phenotype (skin picking, tantrums, OCD, food-seeking) is quite characteristic, but other conditions can overlap.

Differential	Key Distinguishing Features
Angelman syndrome	Loss of maternal UBE3A at 15q11-q13 ^[1]; severe ID; ataxic gait; frequent laughter/happy demeanour; seizures; NO obesity; microcephaly
Fragile X syndrome	Most common inherited cause of ID; long face, prominent ears, macroorchidism (post-pubertal); CGG trinucleotide repeat in FMR1 gene; X-linked
Down syndrome (Trisomy 21)	Characteristic facies; hypotonia; congenital heart disease; ID (variable); Alzheimer-type dementia in adulthood ^[3]
Smith-Magenis syndrome	17p11.2 deletion (RAI1); self-hugging behaviour; sleep disturbance (inverted melatonin rhythm); self-injurious behaviour; brachycephaly; broad face
Fetal alcohol spectrum disorder	Maternal alcohol exposure; smooth philtrum, thin upper lip, short palpebral fissures; growth restriction; microcephaly; ID; NO obesity
Autism spectrum disorder (non-syndromic)	Social communication difficulties + restricted/repetitive behaviours; NO dysmorphic features; variable cognitive ability; no obesity or endocrine features

The combination of the following is virtually pathognomonic for PWS and is unlikely to occur together in any other condition:

1. Neonatal hypotonia with poor suck → FTT in infancy → hyperphagia and obesity in childhood (biphasic feeding pattern) 2. Short stature with small hands and feet 3. Characteristic facies: dolichocephaly, almond-shaped eyes, thin upper lip, downturned mouth ^[1] 4. Hypogonadism (cryptorchidism/micropenis in males) 5. Mild–moderate intellectual disability with behavioural disturbance (skin picking, OCD, tantrums) 6. Hypopigmentation relative to family ^[1]

No single feature alone makes the diagnosis — it is the pattern recognition across multiple systems, anchored in the biphasic feeding phenotype, that should trigger DNA methylation testing.

In clinical practice, when you suspect PWS, the following approach helps narrow the differential:

Step	Action	Rationale
1. History	Pregnancy (fetal movements, polyhydramnios), neonatal period (feeding, tone, cry), feeding pattern evolution, behavioural features, family history	Biphasic feeding pattern is almost unique to PWS
2. Examination	Growth parameters (height, weight, head circumference); dysmorphology assessment; genital examination; neurological examination (tone, reflexes)	Short + obese + dysmorphic + hypotonic → think PWS; tall + obese → think exogenous obesity or MC4R
3. First-line investigation	DNA methylation analysis of 15q11-q13 ^[6] — this is the single best screening test	Detects ALL three genetic mechanisms (deletion, UPD, IC defect); 99% sensitivity for PWS
4. Endocrine workup	IGF-1, GH stimulation test, LH/FSH, TFT, fasting glucose/OGTT, cortisol	To confirm and manage endocrine complications; also helps exclude other endocrine causes of obesity/short stature
5. Exclude mimics	If methylation is normal → reconsider differential; consider Bardet-Biedl, Alström, Smith-Magenis, Temple syndrome (14q32 maternal UPD — "PWS-like" phenotype), Schaaf-Yang syndrome (MAGEL2 mutations)	Methylation-negative cases need further genetic evaluation

Temple Syndrome and Schaaf-Yang Syndrome — The PWS Mimics

Temple syndrome (maternal UPD of chromosome 14 / 14q32 imprinting disorder) can present with neonatal hypotonia, feeding difficulties, short stature, obesity, and early puberty — very similar to PWS. DNA methylation at 15q11-q13 will be NORMAL; methylation at 14q32 will be abnormal. Always consider if PWS methylation testing is negative but clinical suspicion remains high.

Schaaf-Yang syndrome (truncating mutations in MAGEL2, a gene within the PWS region) causes a PWS-like phenotype with neonatal hypotonia, feeding difficulties, ID, and joint contractures (arthrogryposis) — but may NOT be detected by standard PWS methylation analysis because the MAGEL2 gene itself is intact on the paternal allele; the mutation is a point/truncating variant within the gene. Requires specific MAGEL2 sequencing.

Feature	PWS	Bardet-Biedl	Alström	Cohen	MC4R Deficiency
Inheritance	Imprinting (15q11-q13)	AR	AR	AR	AD
Neonatal hypotonia	+++	−	−	−	−
Hyperphagia	+++	++	++	−	+++
Stature	Short	Variable	Variable (may be tall early)	Short	Tall
Retinal dystrophy	−	+++	+++	+++	−
Polydactyly	−	+++	−	−	−
Hearing loss	−	−	+++	−	−
Cardiomyopathy	−	−	+++	−	−
Renal anomalies	−	+++	+	−	−
Neutropenia	−	−	−	+++	−
Intellectual disability	Mild–moderate	Variable	Absent	Mild–moderate	Absent
Hands/feet	Small	Polydactyly/brachydactyly	Normal	Narrow/slender	Normal

High Yield Summary — Differential Diagnosis of PWS

The differential depends on the presenting feature: neonatal hypotonia, childhood obesity, short stature, hypogonadism, or intellectual disability each generates a different DDx list.
For neonatal hypotonia: distinguish CENTRAL (PWS, Down, HIE, congenital myotonic dystrophy) from PERIPHERAL (SMA, congenital myopathy, CMS) causes — reflexes present + dysmorphic = central.
PWS is the most common syndromic form of obesity ^[2] — the main syndromic obesity differentials are Bardet-Biedl (retinitis pigmentosa + polydactyly), Alström (visual/hearing loss + cardiomyopathy), Cohen (neutropenia + prominent incisors).
Short + obese child → always exclude secondary/syndromic causes; tall + obese child → likely exogenous obesity.
DNA methylation analysis of 15q11-q13 is the first-line diagnostic test ^[6] — 99% sensitive for all PWS mechanisms.
If methylation is negative but clinical suspicion high → consider Temple syndrome (14q32), Schaaf-Yang syndrome (MAGEL2 mutation), or other syndromic obesity conditions.
Angelman syndrome is the mirror-image condition: same locus, maternal allele loss, severe ID + seizures + happy demeanour + NO obesity ^[1].
Endocrine causes of secondary obesity (hypothyroidism, Cushing syndrome, GH deficiency, hypothalamic tumours) ^[4] should always be excluded alongside syndromic causes.

Active Recall - Differential Diagnosis of Prader-Willi Syndrome

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome) ^[2] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 857, Prader-Willi Syndrome — Overview) ^[3] Senior notes: Ryan Ho Cardiology.pdf (p. 185, Common syndromes associated with congenital heart diseases) ^[4] Senior notes: Block A - I am overweight, doctor_ obesity; Hyperlipidaemia.pdf (p. 8, Conditions associated with obesity — endocrine diseases causing secondary obesity) ^[5] Senior notes: Ryan Ho Chemical Path.pdf (p. 29, Diagnosis of Cushing Syndrome) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 861, Diagnosis — DNA methylation and biochemical tests)

Diagnostic Criteria, Algorithm & Investigations for Prader-Willi Syndrome

Unlike many conditions with formal "criteria" (e.g., Jones criteria for rheumatic fever), PWS does not have a single universally mandated diagnostic scoring system in current practice. Historically, the Holm criteria (1993) were used as a clinical scoring system to decide whom to test genetically. Today, with easy access to DNA methylation analysis, the approach has shifted: if clinical suspicion exists, go straight to genetic testing — the Holm criteria are now used more as a clinical trigger for testing rather than a definitive diagnostic tool.

1.1 Holm Diagnostic Criteria (1993) — Still Referenced in Exams

The Holm criteria use a point-based system with major criteria (1 point each) and minor criteria (0.5 points each). The threshold for recommending genetic testing is:

Children ≤ 3 years: ≥ 5 points, with ≥ 4 from major criteria
Children > 3 years: ≥ 8 points, with ≥ 5 from major criteria

Major Criteria (1 point each)	Pathophysiological Basis
1. Neonatal/infantile central hypotonia with poor suck ^[1]	Loss of neuronal genes (NECDIN, MAGEL2) → central motor dysfunction
2. Feeding problems in infancy requiring special techniques ± FTT	Severe oropharyngeal hypotonia → poor coordination of suck-swallow-breathe
3. Rapid weight gain between ages 1–6 years (crossing centiles)	Hypothalamic satiety failure (SNORD116 loss → impaired 5-HT2C receptor → absent fullness signal)
4. Characteristic facial features (≥ 3 of: dolichocephaly, narrow bifrontal diameter, almond-shaped eyes, downturned mouth, thin upper lip) ^[1]	Likely neural crest / developmental field effect of absent 15q11-q13 gene products
5. Hypogonadism (genital hypoplasia: males — cryptorchidism, scrotal hypoplasia, micropenis; females — hypoplastic labia minora/clitoris; incomplete puberty)	Combined central (↓ GnRH) + primary gonadal dysfunction
6. Global developmental delay / mild–moderate ID ^[1]	Neuronal dysfunction from loss of NECDIN, MAGEL2 and other paternally-expressed neuronal genes
7. Hyperphagia / food foraging / obsession with food	Hypothalamic appetite dysregulation
8. Deletion of 15q11-q13 or other cytogenetic/molecular abnormality in the PWS region	The definitive genetic confirmation

Minor Criteria (0.5 points each)	Pathophysiological Basis
1. Decreased fetal movement / infantile lethargy	Fetal/neonatal hypotonia
2. Typical behavioural problems (temper tantrums, OCD, stubbornness, rigidity, skin picking)	Aberrant serotonergic signalling; altered central reward circuits
3. Sleep disturbance / sleep apnoea	Hypothalamic sleep-wake dysregulation + obesity + hypotonia
4. Short stature by age 15 (relative to family) ^[1]	GH deficiency (↓ GHRH → ↓ GH → ↓ IGF-1)
5. Hypopigmentation compared to family ^[1]	OCA2 gene within deleted region → reduced melanin synthesis
6. Small hands and/or feet for age ^[1]	Likely GH/IGF-1 deficiency effect on acral growth
7. Narrow hands with straight ulnar border	Developmental patterning
8. Esotropia / myopia	Hypotonia of extraocular muscles; central oculomotor dysfunction
9. Thick, viscous saliva	Altered salivary gland innervation / composition
10. Speech articulation defects	Orofacial hypotonia
11. Skin picking	OCD-spectrum behaviour + high pain threshold

Supportive Findings (not scored)
High pain threshold
Decreased vomiting (children with PWS rarely vomit — important because gastric distension can go unrecognised)
Scoliosis
Early adrenarche
Osteoporosis
Unusual skill with jigsaw puzzles
Normal neuromuscular investigations (EMG/NCS) — because the hypotonia is central

Modern Approach: Clinical Suspicion → DNA Methylation Testing

In current practice (2025–2026), you do NOT need to score the Holm criteria before ordering genetic testing. DNA methylation analysis is the ONLY technique that will identify all three mechanisms of PWS (paternal deletion, maternal UPD, imprinting centre defect) ^[6]. If a neonate has unexplained central hypotonia with poor feeding, or a toddler has emerging hyperphagia with short stature and dysmorphic features — send methylation analysis directly. The Holm criteria remain useful as a clinical framework to remind you which features to look for.

The diagnostic algorithm is structured in two phases: (A) clinical recognition → (B) genetic confirmation and subtyping.

3. Investigation Modalities — Detailed Breakdown

3.1 Genetic Testing (The Cornerstone)

DNA methylation is already sufficient for diagnosis but further evaluation is required to delineate the cause and risk of recurrence ^[6]

DNA methylation is the ONLY technique that can identify paternal deletion, maternal uniparental disomy or imprinting defects but cannot distinguish between them ^[6]

What is it? Methylation analysis exploits the fact that the PWS region on chromosome 15 has different methylation patterns on the maternal vs paternal alleles:

Paternal allele: UNmethylated at the SNRPN promoter/exon 1 → genes are EXPRESSED
Maternal allele: Methylated at the SNRPN promoter/exon 1 → genes are SILENCED

In a normal individual, you see BOTH methylation patterns (one methylated band from mother, one unmethylated band from father). In PWS, you see ONLY the maternal (methylated) pattern — because the paternal allele is either deleted, absent (UPD), or inappropriately methylated (IC defect).

Methods:

Methylation-specific PCR (MS-PCR): quick, inexpensive, widely available
Methylation-specific MLPA (MS-MLPA): can simultaneously detect methylation abnormality AND deletions — becoming the preferred single-step test in many centres
Southern blot with methylation-sensitive enzymes: the original method; less used now due to requiring large amounts of DNA

Interpretation:

Result	Meaning
Both maternal + paternal bands	Normal → PWS excluded (sensitivity ~99%)
Maternal band ONLY	PWS confirmed → proceed to subtyping

Sensitivity: ~99% for all PWS mechanisms. This is why it's the gold-standard screening test.

Limitation: Cannot distinguish between the three genetic mechanisms (deletion vs UPD vs IC defect) — need further testing for this, which is crucial for genetic counselling and recurrence risk estimation.

High-resolution chromosomal analysis and FISH should be followed up if methylation analysis is abnormal to detect deletions ^[6]

FISH (Fluorescence In Situ Hybridisation): uses a fluorescent probe complementary to the 15q11-q13 region. In a normal individual, two signals appear (one per chromosome 15). In PWS with deletion, only ONE signal appears (the maternal copy).
Chromosomal Microarray (CMA) / SNP array: modern alternative to FISH; provides higher resolution; can detect deletions AND may give clues to UPD (loss of heterozygosity patterns). Increasingly used as the first cytogenetic step.

Why do we need this step? Even though methylation confirms PWS, we need to know the mechanism:

Deletion → low recurrence risk → straightforward counselling
No deletion → need to test for UPD or IC defect → different recurrence implications

DNA polymorphism analysis should be followed up if chromosomal deletions are not detected to differentiate between biparental and uniparental inheritance of chromosome 15q ^[6]

Uses microsatellite markers (short tandem repeats) or SNP genotyping on chromosome 15 in the child AND both parents
If the child has inherited BOTH chromosome 15 copies from the mother (and none from the father) → maternal UPD confirmed
Requires blood samples from both parents

If deletion excluded AND UPD excluded → IC defect
IC microdeletion: detected by sequencing or targeted deletion analysis of the imprinting centre region within SNRPN
IC epimutation: no structural change found; the paternal allele simply carries an abnormal maternal-type methylation mark — this is a diagnosis of exclusion

Why does this matter clinically? IC microdeletions can be inherited from the father → up to 50% recurrence risk (if father is a carrier, each child who inherits the allele paternally will have PWS). Epimutations are sporadic → < 1% recurrence.

Parental Testing is Essential

After confirming the mechanism in the child, always test the parents:

If deletion → check parental karyotypes for balanced translocations (rare but changes recurrence risk)
If IC microdeletion → check father for carrier status
If UPD → parents are usually normal; the error was in meiosis

Failure to test parents means you cannot accurately counsel the family about recurrence risk for future pregnancies.

3.2 Endocrine Investigations

Once PWS is genetically confirmed, a comprehensive endocrine workup is essential because the hypothalamic dysfunction affects multiple axes. The principle follows the general endocrine investigation sequence ^[7]: history & PE → baseline bloods → screening biochemistry → confirmatory/dynamic tests → imaging → invasive tests (least → most invasive).

↓ IGF-1 level in patients with PWS suggests that GH secretion is a primary abnormality instead of obesity (low GH but normal IGF-1 in exogenous obesity) ^[6]

Investigation	Finding in PWS	Interpretation
Serum IGF-1	Low for age	Suggests GH deficiency; in exogenous (simple) obesity, IGF-1 is typically NORMAL despite low GH — this distinction is key
IGFBP-3	Low	Supports GH deficiency
Insulin tolerance test (ITT) ^[6]	Failure to adequately stimulate GH after insulin-induced hypoglycaemia	Gold-standard GH stimulation test; however, in paediatrics, caution is needed (risk of severe hypoglycaemia); often glucagon stimulation test or clonidine stimulation test is preferred in children
Bone age (left wrist X-ray)	Delayed compared to chronological age	GH deficiency → delayed skeletal maturation

Why test GH in PWS? Because GH replacement is a key treatment. In many countries (including Hong Kong), PWS is an approved indication for GH therapy regardless of GH stimulation test results — the rationale is that the metabolic benefits (improved body composition, lean mass, possibly cognition) justify treatment even in those who may "pass" a stimulation test.

Paediatric note: GH stimulation tests in young children require careful monitoring. The ITT involves inducing hypoglycaemia (blood glucose < 2.2 mmol/L) with IV insulin — this is a provocation test. In PWS children who are already hypotonic and may have impaired counter-regulatory responses, the glucagon stimulation test is often safer.

Hypogonadism in PWS is characterized by low LH but high FSH ^[6]

Investigation	Typical Finding	Interpretation
LH	Low or low-normal	Central component: hypothalamic GnRH deficiency → inadequate LH secretion
FSH	Often elevated (especially in males)	Primary gonadal component: intrinsic testicular dysfunction → loss of negative feedback → FSH rises
Testosterone (males)	Low	Combined hypogonadism
Oestradiol (females)	Low	Combined hypogonadism
Inhibin B	Low in males	Reflects Sertoli cell dysfunction → primary gonadal problem
AMH (anti-Müllerian hormone)	Low in males	Further evidence of primary gonadal dysfunction

Why is PWS hypogonadism "combined"? This is unusual — most conditions cause either central OR primary hypogonadism, not both. In PWS, the hypothalamus produces insufficient GnRH (central), AND the gonads themselves are inherently dysfunctional (primary). The result is a mixed biochemical picture: low LH (central) but paradoxically elevated FSH (primary) in some patients, though in others both may be low. The pattern can evolve with age.

Paediatric relevance: In neonatal boys, the "mini-puberty" (surge of LH/FSH/testosterone in the first 3–6 months of life) may be absent or blunted → this is an early diagnostic clue and can be tested in the neonatal window.

Screening for hypothyroidism is appropriate in any child with growth failure or decreased bone density and in whom there is inadequate response to GH therapy ^[6]

Investigation	Typical Finding	Interpretation
fT4	May be low	Central hypothyroidism (hypothalamic TRH deficiency)
TSH	Inappropriately normal or low	In central hypothyroidism, TSH does NOT rise as it should → relying on TSH alone will MISS the diagnosis

Key paediatric point: Always measure fT4, not just TSH. In central hypothyroidism (which is what PWS causes), the problem is in the hypothalamus/pituitary → TSH is not appropriately elevated despite low fT4. If you only screen with TSH (as in neonatal screening programs for congenital hypothyroidism), you may miss PWS-related central hypothyroidism.

Investigation	Rationale	Key Findings
Fasting glucose	Screen for T2DM	≥ 7.0 mmol/L diagnostic of DM
HbA1c	Screen for T2DM	≥ 48 mmol/mol (6.5%) diagnostic
OGTT (75g for children > 40 kg; 1.75 g/kg for smaller children)	More sensitive for early glucose intolerance	2-hour glucose ≥ 11.1 mmol/L = DM; 7.8–11.0 = IGT
Fasting lipid profile	Metabolic syndrome screening	Dyslipidaemia common with obesity
Fasting insulin	Assess insulin resistance	HOMA-IR calculation

When to start screening? From the onset of obesity (typically around age 5–6 years) or earlier if GH therapy is initiated (GH can worsen insulin resistance).

Investigation	Rationale	Key Points
Morning cortisol (8–9 AM)	Screen for central adrenal insufficiency (CAI)	If low (< 100 nmol/L), proceed to dynamic testing
Synacthen (ACTH) stimulation test	Confirm adrenal reserve	Cortisol should rise to > 500 nmol/L at 30 or 60 minutes; inadequate response → CAI

Why check the adrenal axis? Central adrenal insufficiency has been reported in a subset of PWS patients (estimated 5–60% depending on the study and test used). This is clinically important because unrecognised CAI can lead to adrenal crisis during physiological stress (illness, surgery) — potentially fatal. The evidence is still debated, but prudent practice is to screen and have a low threshold for stress-dose steroids during illness ^[7].

Investigation	Purpose	Key Findings
MRI Brain	Evaluate pituitary/hypothalamic anatomy	May show small anterior pituitary, absent/reduced posterior pituitary bright spot (loss of vasopressin-containing neurosecretory granules); important to exclude craniopharyngioma or other hypothalamic mass if diagnosis is uncertain
Bone age X-ray (left wrist)	Assess skeletal maturation	Delayed bone age in GH deficiency
Spine X-ray	Screen for scoliosis	Scoliosis present in up to 80% by adolescence; Cobb angle determines severity and need for bracing/surgery
DEXA scan ^[6]	Monitoring bone density — low BMD should prompt consideration of sex hormone replacement or growth hormone treatment ^[6]	Reduced BMD due to GH deficiency, hypogonadism, and reduced physical activity
Renal USS	Screen for structural renal anomalies	Occasionally reported in PWS; not universal but reasonable in initial workup
Cardiac echocardiography	If obese → screen for cardiac dysfunction	May show left ventricular hypertrophy, diastolic dysfunction, or rarely dilated cardiomyopathy in severe obesity

Investigation	Purpose	Key Findings
Polysomnography (PSG)	Diagnose obstructive sleep apnoea (OSA) and central sleep apnoea	AHI (apnoea-hypopnoea index) elevated; both obstructive events (obesity + hypotonia → pharyngeal collapse) and central events (hypothalamic dysregulation) may be seen
Oximetry studies	Screening for nocturnal desaturation	Desaturations may indicate significant OSA; less sensitive than PSG

Why is sleep assessment so important in PWS? Two reasons:

Before starting GH therapy: GH can worsen OSA (via adenotonsillar hypertrophy stimulated by IGF-1) → PSG is recommended within the first 3 months of starting GH, and certainly if symptoms develop
Excessive daytime sleepiness: A cardinal feature; hypothalamic sleep-wake dysregulation contributes independently of OSA

Paediatric note: PWS children are at higher risk of sudden death, with some cases attributed to undiagnosed severe OSA → adenotonsillectomy may be needed before or after starting GH.

Investigation	Purpose	Key Findings
Visual acuity testing	Detect refractive errors	Myopia common
Cover test / ocular motility	Detect strabismus	Esotropia in ~50–60% (extraocular muscle hypotonia + central oculomotor dysfunction)
Fundoscopy	Baseline retinal assessment	Usually normal (unlike Bardet-Biedl where retinitis pigmentosa is expected — this distinction is clinically useful)

Assessment	Purpose	Tools
Formal developmental assessment	Quantify developmental delay; guide early intervention	Bayley Scales of Infant Development (infants); WISC (school-age)
Behavioural / psychiatric assessment	Identify OCD, ASD features, skin picking, anxiety, psychosis (especially UPD subtype in adolescence)	CBCL (Child Behaviour Checklist); specialist psychiatric evaluation
Speech and language assessment	Articulation difficulties due to orofacial hypotonia	Speech-language pathologist evaluation

Investigation	Purpose	Rationale
CK (creatine kinase)	Exclude primary muscle disease	Normal in PWS ^[8] — because the hypotonia is central, not myopathic; CK > 1000 would point toward muscular dystrophy (e.g., DMD) instead
EMG / NCS	Exclude peripheral neuromuscular causes of hypotonia	Normal in PWS — reinforces the diagnosis of central hypotonia
Karyotype	If clinical picture is ambiguous	To exclude chromosomal abnormalities (e.g., Down syndrome, Turner, Klinefelter)
Newborn metabolic screening	Exclude inborn errors of metabolism presenting with hypotonia	Hypotonia is a recognised presentation of some IEMs ^[9]; tandem mass spectrometry; amino acids; organic acids
Dental assessment	Thick saliva + poor oral hygiene → dental caries	Regular dental follow-up from early childhood

Phase	Investigations	Key Purpose
Phase 1: Confirm Diagnosis	DNA methylation analysis of 15q11-q13	Confirm or exclude PWS
Phase 2: Subtype	FISH / CMA → UPD analysis → IC analysis; parental studies	Determine mechanism → recurrence risk → genetic counselling
Phase 3: Endocrine	IGF-1, GH stimulation test, LH/FSH, fT4/TSH, fasting glucose/HbA1c/OGTT, morning cortisol ± Synacthen	Characterise and manage hypothalamic-pituitary dysfunction
Phase 4: Complications	PSG, spine X-ray, DEXA, echocardiography, ophthalmology, developmental assessment	Screen for and monitor complications
Phase 5: Exclusions	CK, EMG/NCS (if diagnosis uncertain); karyotype; metabolic screen	Rule out mimics (muscular dystrophy, IEM, chromosomal disorders)

High Yield Summary — Diagnosis of PWS

DNA methylation analysis at 15q11-q13 is the first-line and ONLY single test that detects all three PWS mechanisms ^[6] — sensitivity ~99%.
Methylation confirms PWS but cannot distinguish deletion vs UPD vs IC defect → must proceed to subtyping (FISH/CMA → UPD analysis → IC analysis) for recurrence risk counselling ^[6].
If methylation analysis is abnormal → FISH or chromosomal microarray to detect deletion; if no deletion → DNA polymorphism analysis for UPD; if biparental inheritance → IC analysis ^[6].
Holm criteria (1993): clinical scoring system — useful framework to recognise PWS features, but in modern practice, genetic testing is sent directly when clinical suspicion arises.
IGF-1 is low in PWS (primary GH deficiency) vs normal in exogenous obesity (functional GH suppression) ^[6] — key distinguishing investigation.
Hypogonadism biochemistry: low LH but high FSH ^[6] — reflecting combined central + primary gonadal dysfunction.
Always check fT4 (not just TSH) for central hypothyroidism — TSH may be misleadingly "normal."
DEXA scan for bone density monitoring; low BMD should prompt consideration of sex hormone replacement or GH treatment ^[6].
Polysomnography before and after starting GH therapy — PWS children are at risk of OSA and sudden death.
CK and EMG/NCS are NORMAL in PWS — confirms central (not peripheral) hypotonia ^[8].

Active Recall - Diagnosis and Investigations for Prader-Willi Syndrome

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 861, Diagnosis — DNA methylation, biochemical tests, and radiological tests) ^[7] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p. 1–3, Principles of endocrine investigation sequence) ^[8] Senior notes: Maksim Medicine Notes.pdf (p. 274–276, Myopathy section — CK levels and neuromuscular investigation interpretation) ^[9] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (p. 11, Clinical presentations of IEM including hypotonia)

Management of Prader-Willi Syndrome

PWS is a lifelong, multisystem disorder with no cure. Management is therefore:

Multidisciplinary — endocrinology, genetics, dietetics, physiotherapy, occupational therapy, speech therapy, psychology/psychiatry, orthopaedics, ophthalmology, respiratory/sleep medicine, dentistry
Anticipatory — proactively preventing complications at each developmental stage rather than reacting to them
Family-centred — parents are the primary carers; they need education, support, and empowerment
Phase-specific — the management priorities shift dramatically from the neonatal period to adulthood

The overarching goals are:

Optimise growth and body composition (GH therapy)
Prevent obesity (environmental food control + dietary management)
Maximise developmental potential (early intervention therapies)
Manage endocrine deficiencies (GH, sex hormones, thyroid, cortisol)
Prevent and treat complications (OSA, scoliosis, T2DM, behavioural/psychiatric)
Support the family and plan for transition to adult services

3. Treatment Modalities — Detailed Breakdown

3.1 Growth Hormone (GH) Therapy

This is the single most impactful medical treatment for PWS. It addresses the GH deficiency that is central to the condition's metabolic and growth pathology.

PWS is an approved indication for GH therapy in most countries regardless of GH stimulation test results — based on the rationale that virtually all PWS patients are GH-deficient on a functional level, even if some may pass a stimulation test
In Hong Kong, GH therapy for PWS can be accessed through the Hospital Authority paediatric endocrinology service; it is an accepted indication
Start as early as possible — current evidence supports starting between 3–6 months of age (after initial feeding stabilisation), well before obesity develops

Effect	Mechanism	Clinical Impact
↑ Linear growth	GH → ↑ hepatic IGF-1 production → stimulates epiphyseal growth plate chondrocyte proliferation	Improved final height (average gain ~1 SD without early treatment → near-normal height with early treatment)
↑ Lean body mass	GH → protein anabolic effect → ↑ muscle mass	Better motor function; ↑ muscle strength → improved hypotonia
↓ Fat mass	GH → lipolytic effect → ↓ adipose tissue, especially visceral fat	Delays/prevents obesity; improves body composition
↑ Bone mineral density	GH → ↑ IGF-1 → stimulates osteoblast activity	Reduces osteoporosis and fracture risk
Possible cognitive benefit	GH/IGF-1 receptors in hippocampus and cortex → neurotrophic effects	Some studies suggest improved cognitive and motor development with early GH
↑ Energy expenditure	↑ Lean mass → ↑ basal metabolic rate	Helps offset the reduced caloric requirement inherent to PWS

Starting dose: 0.5 mg/m²/day (or approximately 0.035 mg/kg/day)
Titrate based on IGF-1 levels (target: upper half of normal range for age, but NOT above +2 SDS)
Route: Subcutaneous injection, once daily (typically evening to mimic physiological GH secretion peak during early sleep)
Formulation: Recombinant human GH (somatropin) — available as pen devices or vials; various brands (e.g., Genotropin, Norditropin, Humatrope)

Parameter	Frequency	Rationale
Height velocity	Every 3–6 months	Assess growth response
IGF-1	Every 6–12 months	Titrate dose; avoid supraphysiological levels (risk of adverse effects)
Fasting glucose / HbA1c	Annually (more frequently if obese)	GH is diabetogenic (↑ insulin resistance, ↑ gluconeogenesis)
Thyroid function (fT4)	Every 6–12 months	GH can unmask or worsen central hypothyroidism (GH ↑ peripheral T4→T3 conversion → ↓ fT4 → may need T4 replacement)
Scoliosis assessment	Every 6–12 months	GH-induced growth acceleration may worsen pre-existing scoliosis
PSG / Sleep assessment	Within first 3 months of starting GH; then as clinically indicated	GH can worsen OSA by stimulating adenotonsillar hypertrophy via IGF-1 → can cause or worsen upper airway obstruction
Bone age	Every 1–2 years	Ensure no excessive skeletal maturation
Adrenal function	Baseline; repeat if symptomatic	GH can unmask central adrenal insufficiency (GH inhibits 11β-HSD1, reducing cortisol reactivation in tissues)

Contraindication	Reason
Severe obesity with uncontrolled OSA	GH can worsen OSA → sudden death risk; must treat OSA first (adenotonsillectomy, CPAP)
Active malignancy	GH/IGF-1 promote cell proliferation → theoretical risk of tumour growth
Severe respiratory impairment	Same mechanism as OSA concern
Uncontrolled diabetes	GH is diabetogenic → will worsen glycaemic control
Closed epiphyses (for growth indication)	No further linear growth possible; however, GH continues for metabolic/body composition benefits in adults even after epiphyseal closure
Known hypersensitivity to somatropin or excipients	Allergic reaction

GH and Sudden Death in PWS — Must Know

There have been case reports of sudden death in young PWS children (typically < 3 years) shortly after starting GH therapy. The proposed mechanism is:

GH stimulates IGF-1 → lymphoid tissue hypertrophy → adenotonsillar enlargement
Combined with pre-existing hypotonia of pharyngeal muscles + obesity → severe OSA
Unrecognised severe OSA → nocturnal hypoxaemia → cardiorespiratory arrest

Practical consequence:

Always perform PSG before starting GH or within the first 3 months
ENT assessment for adenotonsillar size — consider adenotonsillectomy if significant enlargement
If the child develops snoring, observed apnoeas, or excessive daytime sleepiness after starting GH → urgent reassessment with PSG
GH should be temporarily discontinued if severe OSA develops until treated

Current evidence suggests GH is safe when appropriate sleep monitoring is in place. The benefits far outweigh the risks.

3.2 Nutritional Management / Obesity Prevention

This is arguably the most important long-term intervention — the difference between a well-managed PWS patient and one with morbid obesity is almost entirely down to environmental food control.

Why is caloric restriction necessary in PWS? Three converging factors:

Hyperphagia: insatiable appetite due to hypothalamic dysfunction → the child will eat whenever food is available
Low resting energy expenditure: reduced lean body mass → lower metabolic rate → fewer calories needed
Reduced physical activity: hypotonia + obesity → less exercise → even lower caloric needs

The typical caloric requirement for a PWS child is 60–80% of normal for age and height — roughly 10–11 kcal/cm of height per day for weight maintenance (compared to ~14–15 kcal/cm for typical children).

Phase	Age	Strategy
Infancy (FTT phase)	0–2 years	Support feeding: specialised nipples, NGT if needed, frequent small feeds, high-calorie formula if required; involve SLT for swallowing assessment; goal is adequate weight gain along a centile
Pre-hyperphagic	2–4 years	Establish healthy eating habits BEFORE hyperphagia begins: structured meal/snack times; balanced diet; avoid sugary drinks and highly processed food; begin caloric awareness
Hyperphagic phase	4–8+ years → lifelong	Strict environmental food control: locked pantries, locked refrigerators; supervised meals; no unsupervised access to money (can buy food); school and carers must be informed and compliant; dietician-guided low-calorie balanced diet

Macronutrient balance: ~25% protein, ~20% fat, ~55% carbohydrate (higher protein to promote satiety and preserve lean mass)
Regular exercise: incorporated into daily routine; swimming, walking, physiotherapy exercises — improves body composition and mood
No "food rewards": fundamental behavioural principle — food should never be used as a reward or punishment; this reinforces food-seeking behaviour
All environments must be consistent: home, school, respite care, extended family — any "leak" in food control will be exploited

No currently approved pharmacological agent specifically treats PWS-related hyperphagia, but several are under investigation:

Agent	Mechanism	Status
Setmelanotide	MC4R agonist → activates downstream satiety pathway	Approved for POMC/LEPR/PCSK1 deficiency obesity; clinical trials in PWS (results mixed but promising)
Diazoxide choline controlled-release	K-ATP channel opener → reduces insulin secretion → may reduce fat storage	Phase 3 trials showed modest benefit in some PWS subgroups
GLP-1 receptor agonists (e.g., liraglutide, semaglutide)	↑ Satiety signalling, ↓ gastric emptying, ↓ appetite	Case reports and small trials show potential benefit; not yet standard of care in PWS
Topiramate	Appetite suppression (mechanism unclear); also treats seizures	Used off-label in some centres; limited evidence
Oxytocin intranasal	Hypothalamic neuropeptide involved in social bonding and satiety	Clinical trials show possible behavioural benefits; obesity effects uncertain

No Bariatric Surgery in PWS

Bariatric surgery (e.g., gastric bypass, sleeve gastrectomy) is generally NOT recommended in PWS because:

The hyperphagia is a central/hypothalamic problem, not a gastric capacity problem — patients will continue to eat
High complication rates in PWS (gastroparesis, poor wound healing, compliance issues)
Post-surgical dietary restrictions are difficult to enforce in cognitively impaired patients
Risk of gastric rupture (PWS patients may have impaired vomiting reflex)

Some centres have reported mixed results with restrictive procedures, but this remains controversial and not standard practice.

3.3 Sex Hormone Replacement

Intervention	Timing	Rationale
Cryptorchidism management	Infancy (ideally by 12 months)	Bilateral cryptorchidism very common; options: (1) hCG injections (human chorionic gonadotropin — mimics LH → stimulates testicular descent and testosterone production); (2) Orchidopexy (surgical fixation) if hormonal treatment fails
Testosterone replacement	Adolescence (if puberty fails to progress)	Low-dose testosterone (IM depot or transdermal); titrate slowly to mimic normal pubertal progression; avoid high doses (exacerbate behavioural problems, increase aggression)

hCG dosing: variable protocols; e.g., 250–500 IU IM 2–3× weekly for 3–6 weeks in infancy
Testosterone replacement: start with very low doses (e.g., 25–50 mg IM depot monthly → gradually increase to adult maintenance 200–250 mg every 2–4 weeks, or transdermal gel)

Intervention	Timing	Rationale
Oestrogen-progesterone replacement	Adolescence (if puberty absent/incomplete by age 13–14)	Low-dose oestradiol → titrate up → add progesterone once breakthrough bleeding occurs (to protect endometrium); induces breast development, normalises bone density

Paediatric note: Sex hormone replacement in PWS must be approached cautiously. While it promotes secondary sexual characteristics and bone health, there are behavioural concerns (testosterone → aggression; oestrogen → emotional lability in an already behaviourally challenging population). Start low, go slow, and monitor closely.

If central hypothyroidism is confirmed (low fT4 with inappropriately normal/low TSH) → start levothyroxine
Dose: 1–2 μg/kg/day in children (lower than primary hypothyroidism doses because TSH cannot guide titration)
Monitor fT4 (NOT TSH — TSH is unreliable in central hypothyroidism); aim for fT4 in the upper half of the normal range
Formulation: oral tablets (can be crushed for infants); liquid formulation available

Hydrocortisone is the replacement of choice in children
Maintenance dose: 8–10 mg/m²/day in 2–3 divided doses (lower than typical Addison's disease doses because mineralocorticoid axis is intact in central AI)
Stress dosing: double or triple the dose during febrile illness, vomiting, or surgical procedures — this is life-saving
Medic-Alert bracelet: all children with adrenal insufficiency should wear one
Emergency injection: parents should be trained to administer IM hydrocortisone (100 mg in children > 6 years; 50 mg in 1–5 years; 25 mg in < 1 year) in case of adrenal crisis (vomiting prevents oral intake)

Adrenal Crisis Prevention — Practical Point

PWS children may have impaired pain perception and reduced ability to communicate illness → they may not reliably report feeling unwell. Parents and carers must be educated to have a low threshold for stress-dose hydrocortisone during any illness, especially febrile episodes. Children with PWS rarely vomit (another PWS feature), so persistent vomiting in a PWS child is a RED FLAG for serious pathology (including adrenal crisis, gastric rupture, or acute abdomen).

Intervention	Target	Details
Structured environment	Temper tantrums, food-seeking, anxiety	Consistent daily routines; visual schedules; clear rules; advance warning of changes; food kept out of sight and locked
Positive behavioural support	All behavioural issues	Reward-based strategies (non-food rewards); ignore minor challenging behaviour; redirect
Cognitive behavioural therapy (adapted)	Anxiety, OCD features	Modified for cognitive level; can be effective for skin picking and obsessive thoughts
SSRI antidepressants	OCD, anxiety, depression, skin picking	First-line pharmacotherapy for OCD/anxiety in PWS; e.g., fluoxetine, sertraline; start at low dose
Atypical antipsychotics	Psychosis (especially in UPD subtype in adolescence)	E.g., risperidone, aripiprazole; use lowest effective dose; beware of metabolic side effects (weight gain, insulin resistance) — especially problematic in PWS
Skin picking management	Self-injurious skin excoriation	Behavioural strategies + SSRIs + wound care; keep nails short; gloves at night; topical antibiotics for secondary infection
Melatonin	Sleep disturbance	Commonly used for difficulty initiating sleep (hypothalamic dysregulation of melatonin rhythm); generally safe

Paediatric psychiatric note: The UPD subtype of PWS has a particularly high risk of affective psychosis in adolescence/early adulthood (not classic schizophrenia but cycloid-type psychosis with rapid onset, mood instability, confusion, and hallucinations). This is important to anticipate and communicate to families.

Condition	Prevalence	Management
Scoliosis	Up to 80% by adolescence	Regular spine examination; Cobb angle measurement; bracing if 20–40°; surgical correction (posterior spinal fusion) if > 40–50° or rapidly progressive
Hip dysplasia	~10–20%	Screening clinical examination; ultrasound in infancy; X-ray if older; may need surgical intervention
Osteoporosis	Common (GH deficiency + hypogonadism + reduced activity)	DEXA scan monitoring ^[6]; GH therapy + sex hormone replacement + calcium/vitamin D supplementation + weight-bearing exercise
Fractures	Increased risk	May go unnoticed due to high pain threshold → unexplained limping, swelling, or behavioural change should prompt X-ray

Intervention	Indication	Details
Adenotonsillectomy	Adenotonsillar hypertrophy contributing to OSA	Often performed before or soon after starting GH; may dramatically improve OSA
CPAP / BiPAP	Persistent OSA despite adenotonsillectomy	Titrated via PSG; compliance can be challenging in PWS (behavioural resistance, facial structure); behavioural strategies needed to establish use
Weight management	Obesity-related OSA	Caloric restriction + GH therapy → weight loss → improved OSA
Positional therapy	Mild OSA	Avoid supine sleeping position
Stimulant medication	Excessive daytime sleepiness unrelated to OSA	Modafinil has been used off-label in some PWS patients with persistent hypersomnolence despite adequate OSA treatment

Therapy	Target	Timing
Physiotherapy	Hypotonia, gross motor delay, exercise promotion	From diagnosis (neonatal period); ongoing
Occupational therapy	Fine motor skills, self-care skills, sensory processing	From infancy; ongoing
Speech and language therapy	Speech articulation, language development, oral motor skills	From infancy (initially for feeding support; later for speech)
Special educational support	Learning difficulties, cognitive support	From school age; individualised education plan (IEP)
Social skills training	ASD-like features, peer difficulties	School age and adolescence

Regular dental reviews (every 6 months minimum)
Thick, viscous saliva + reduced salivary flow → increased dental caries risk
Fluoride supplementation; sealants; meticulous oral hygiene education
Bruxism (teeth grinding) — common; may need dental guard

Subtype	Recurrence Risk	Counselling Point
Paternal deletion	< 1%	Low recurrence; reassure but offer prenatal testing in future pregnancies if desired
Maternal UPD	< 1%	Low recurrence; advanced maternal age was likely the precipitant
IC epimutation	< 1%	Sporadic event
IC microdeletion	Up to 50% if father is carrier	Must test father; if carrier, offer prenatal diagnosis (CVS at 10–12 weeks or amniocentesis at 15–18 weeks); preimplantation genetic testing (PGT) available
Chromosomal translocation	Variable	Parental karyotyping essential; genetic counselling by clinical geneticist

Age	Key Management Priorities
Prenatal (if known)	Delivery planning; neonatal team aware; genetic counselling
Neonate (0–1 month)	Feeding support (NGT/special nipples); physiotherapy for hypotonia; cryptorchidism assessment; genetic confirmation (methylation analysis)
Infant (1–24 months)	Continue feeding support; start GH therapy (3–6 months); baseline PSG, TFT, ophthalmology; early intervention (PT/OT/SLT); orchidopexy planning if needed
Early childhood (2–6 years)	Establish dietary control BEFORE hyperphagia; continue GH; developmental therapies; school planning; behavioural strategies; screen for scoliosis
Late childhood (6–12 years)	Strict caloric control; locked food environment; continue GH; metabolic screening (glucose, lipids); scoliosis monitoring; behavioural support; dental care
Adolescence (12–18 years)	Sex hormone replacement if needed; psychiatric monitoring (psychosis risk in UPD); DEXA scan; vocational planning; transition planning to adult services
Adult (≥ 18 years)	Ongoing GH (for metabolic benefits); sex hormone replacement; metabolic monitoring; supported living; psychiatric care; continued dietary supervision

High Yield Summary — Management of PWS

GH therapy is the cornerstone medical treatment — improves height, body composition (↑ lean mass, ↓ fat mass), bone density, and possibly cognition ^[6]. Start as early as 3–6 months of age. Approved for PWS regardless of GH stimulation test results.
PSG before/within 3 months of starting GH — GH can worsen OSA via adenotonsillar hypertrophy. Adenotonsillectomy may be needed. Sudden death risk exists in young PWS children with unrecognised severe OSA.
Nutritional management is critical — caloric requirement is only 60–80% of normal; strict environmental food control (locked pantries/fridges); dietary restriction must start BEFORE hyperphagia develops.
No bariatric surgery — hyperphagia is central, not a gastric problem; high complication risk.
Sex hormone replacement — for incomplete puberty; start low, go slow; testosterone in males (or orchidopexy/hCG for cryptorchidism in infancy); oestrogen-progesterone in females.
Central hypothyroidism → levothyroxine; monitor fT4 (NOT TSH).
Central adrenal insufficiency (if present) → hydrocortisone; stress dosing during illness is LIFE-SAVING; Medic-Alert bracelet.
Behavioural management — structured environment, positive behavioural support, SSRIs for OCD/anxiety/skin picking; atypical antipsychotics for psychosis (UPD subtype).
Scoliosis — monitor regularly; bracing or surgical correction as needed. DEXA scan for bone density monitoring ^[6].
Multidisciplinary team essential: endocrinology, genetics, dietetics, PT/OT/SLT, psychology, orthopaedics, ophthalmology, sleep medicine, dentistry.
Genetic counselling — subtype determines recurrence risk (< 1% for deletion/UPD; up to 50% for inherited IC microdeletion).

Active Recall - Management of Prader-Willi Syndrome

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome clinical features) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 861, Diagnosis and management — biochemical tests, DEXA scan, GH/IGF-1, LH/FSH)

Complications of Prader-Willi Syndrome

PWS is a multisystem disorder where complications arise from the intersection of hypothalamic dysfunction, chronic endocrine deficiencies, obesity, hypotonia, and behavioural features. Understanding WHY each complication occurs (tracing it back to the underlying pathophysiology) is essential for anticipatory management and exam performance.

The central pathology — hypothalamic satiety failure → hyperphagia → morbid obesity (if uncontrolled) — drives a cascade of metabolic and mechanical complications identical to those seen in severe childhood obesity, but earlier and more severe.

Prevalence: 10–25% of PWS patients by young adulthood (much higher than the general paediatric population)
Pathophysiology: Obesity → ↑ visceral adipose tissue → chronic low-grade inflammation (↑ TNF-α, IL-6, resistin) → insulin resistance → pancreatic β-cell compensation initially → eventual β-cell failure → hyperglycaemia → T2DM
GH therapy adds to insulin resistance (GH is a counter-regulatory hormone) → monitor glucose closely on GH
Screening for Type 2 DM as complication of Prader-Willi syndrome — via fasting glucose, HbA1c, or OGTT ^[6]

Why PWS patients are especially vulnerable: Their reduced lean body mass means lower glucose disposal capacity (skeletal muscle is the primary site of insulin-mediated glucose uptake). Combined with excess fat mass and GH-induced insulin resistance, even relatively modest obesity can tip them into T2DM.

Paediatric consideration: T2DM in a PWS child may present atypically — they may not complain of polyuria/polydipsia (communication difficulties) or may not display typical weight loss (already controlled diet). Regular screening is mandatory.

Mechanism: Morbid obesity → haemodynamic stress (↑ blood volume, ↑ cardiac output demand) → left ventricular hypertrophy → eventual cardiac insufficiency
Hyperphagia ± obesity can cause cardiac insufficiency ^[1]
Dyslipidaemia (↑ triglycerides, ↓ HDL) → accelerated atherosclerosis
Hypertension — from obesity-induced sympathetic overactivity + hyperinsulinaemia → sodium retention

Why PWS patients may not present classically: High pain threshold + reduced exercise tolerance already at baseline → may not report anginal-type symptoms. Heart failure may present as increased lethargy or reduced exercise tolerance rather than classic dyspnoea.

Hyperphagia ± obesity can cause OSA ^[1]
Multifactorial mechanism in PWS:
1. Obesity → pharyngeal fat deposition → mechanical upper airway narrowing
2. Hypotonia → pharyngeal dilator muscles (genioglossus, tensor palatini) are weak → airway collapse during sleep
3. Adenotonsillar hypertrophy → especially if on GH therapy (IGF-1 stimulates lymphoid tissue growth)
4. Central sleep apnoea component → hypothalamic respiratory drive dysregulation
Consequences: Intermittent hypoxaemia → pulmonary hypertension → cor pulmonale; daytime somnolence → worsened behavioural problems and cognitive function; sudden death (see below)

2. Gastrointestinal Complications

Gastric distension and rupture — may or may not be triggered by binge eating ^[6]

This is a unique and potentially fatal complication of PWS. Understanding why requires appreciating several convergent PWS features:

Hyperphagia: The child can consume enormous quantities of food in a single sitting if given unsupervised access (binge eating)
Impaired vomiting reflex: PWS patients have a markedly reduced ability to vomit — a well-documented PWS feature. The hypothalamic emetic centre is dysfunctional. This means the normal protective mechanism of vomiting when the stomach is overdistended FAILS.
High pain threshold: The child may not perceive or report the abdominal pain that would normally alert to gastric overdistension
Gastroparesis: Some evidence of delayed gastric motility in PWS → food accumulates

The result: massive gastric distension → gastric wall ischaemia (blood supply cannot perfuse the over-stretched wall) → necrosis → perforation → peritonitis → septic shock → death.

Clinical implication:

Any PWS child with acute abdominal distension must be taken seriously, even without pain complaints
The absence of vomiting does NOT exclude serious GI pathology — in PWS, gastric rupture can present as sudden deterioration without prior vomiting
Emergency: NPO, NGT decompression, IV fluids, urgent imaging (erect CXR for free air under diaphragm / CT abdomen), surgical consultation

Exam Pearl: Reduced Vomiting in PWS

Normal children vomit as a protective reflex when the stomach is overdistended, or during illness (gastroenteritis, raised ICP, etc.). PWS children rarely vomit. This means:

Gastric distension/rupture can occur without warning
Acute abdomen may present atypically (no vomiting, minimal pain)
If a PWS child DOES vomit — this is a RED FLAG indicating potentially serious pathology (obstruction, raised ICP, adrenal crisis) and should prompt urgent investigation

Choking episodes — attributed to oromotor incoordination, hypotonia, hyperphagia, voracious feeding habits and decreased mastication which can lead to death suddenly ^[6]

Pathophysiology: Multiple converging factors:

Oropharyngeal hypotonia → poor coordination of the swallow reflex (suck-swallow-breathe coordination remains impaired beyond infancy)
Hyperphagia + voracious eating → rapid food intake with inadequate chewing
Decreased mastication → food boluses that are too large for safe swallowing
High pain threshold → may not perceive food "stuck" until airway is compromised

Consequence: Aspiration or complete airway obstruction → can cause sudden death — this is one of the leading causes of premature mortality in PWS.

Prevention:

Supervise all meals
Cut food into small pieces
Encourage slow eating (timed meals, enforced pauses)
Carers trained in choking first aid (back blows, abdominal thrusts / Heimlich manoeuvre appropriate for age)

3. Endocrine Complications

If GH is NOT replaced (or diagnosed late):

Short stature (final height without GH: males ~155 cm, females ~148 cm)
Increased body fat percentage (especially central/visceral fat)
Reduced lean body mass → further ↓ metabolic rate → vicious cycle of weight gain
Osteoporosis → pathological fractures (especially vertebral, femoral neck)
Reduced exercise capacity
Possible worse cognitive outcomes

Delayed/absent puberty → psychosocial impact; bone age delay
Infertility (both sexes) — though rare cases of PWS females conceiving have been reported
Osteoporosis — sex hormones are essential for bone mineralisation and maintenance; deficiency → ↓ BMD
Reduced secondary sexual characteristics → may affect self-esteem and social integration

If undiagnosed/untreated → further weight gain, constipation, cold intolerance, fatigue, reduced growth velocity
May compound the cognitive impairment
Easily treated with levothyroxine but MUST be suspected and screened (fT4, not just TSH)

Prevalence debated (5–60% depending on testing protocol)
If unrecognised → risk of adrenal crisis during physiological stress (febrile illness, surgery, trauma)
Presentation of adrenal crisis: hypotension, tachycardia, hypoglycaemia, altered consciousness → can be fatal if untreated
PWS children's reduced communication + high pain threshold means crisis may present LATE

4. Orthopaedic Complications

Scoliosis — common in patients with Prader-Willi syndrome ^[6]

Prevalence: Up to 80% develop some degree of scoliosis; ~30–40% require active intervention
Pathophysiology:
- Hypotonia → paraspinal muscle weakness → asymmetric loading of the spine
- Obesity → increased axial load on a structurally compromised spine
- GH therapy may accelerate curve progression during rapid growth phases
Types: Both infantile (develops in first 2 years) and juvenile/adolescent forms occur
Consequences: Progressive deformity → cardiopulmonary compromise (restrictive lung disease) if severe; pain; cosmetic concern
Management: Regular screening; bracing for moderate curves (20–40° Cobb angle); surgical fusion for severe/progressive curves (> 40–50°)

Mechanism:
- GH deficiency → ↓ IGF-1 → reduced osteoblast stimulation
- Hypogonadism → reduced sex hormone-mediated bone protection
- Reduced physical activity (hypotonia, obesity) → decreased mechanical loading → ↓ bone formation
- Possible vitamin D deficiency (indoor lifestyle, reduced sun exposure)
Low BMD should prompt consideration of sex hormone replacement or growth hormone treatment ^[6]
High pain threshold → fractures may go unrecognised → present as unexplained behavioural change, limping, or swelling without the child reporting pain

Present in 10–20%; related to hypotonia and abnormal loading
May progress to avascular necrosis if undetected

5. Neurological and Psychiatric Complications

Feature	Prevalence	Mechanism
Temper tantrums	Very common (> 70%)	Frustration from food restriction + cognitive rigidity + impaired emotional regulation (hypothalamic-limbic dysfunction)
OCD / repetitive behaviours	40–60%	Serotonergic dysfunction (SNORD115 → altered 5-HT2C receptor processing)
Skin picking	70–95%	Compulsive excoriation; combination of OCD-spectrum behaviour + altered pain perception + possible sensory-seeking
Food-seeking / foraging	Near-universal in hyperphagia phase	Hypothalamic satiety failure
Stubbornness / argumentativeness	Very common	Cognitive rigidity; difficulty with transitions

Complications of skin picking:

Chronic non-healing wounds → secondary bacterial infection (cellulitis, abscess)
Scarring → cosmetic distress
Rarely: septicaemia from infected excoriations

Affective/cycloid psychosis: Particularly associated with the UPD subtype (3–4× higher risk than deletion subtype)
- Presents in adolescence/early adulthood
- Features: rapid-onset confusion, emotional lability, hallucinations (visual and auditory), paranoia
- Often triggered by stress or transitions
- Responds to atypical antipsychotics; may recur
Anxiety disorders: Common; separation anxiety, generalised anxiety, specific phobias
Depression: Especially in adolescence when insight into their condition develops
ASD features: Present in a significant proportion; some meet full diagnostic criteria

Mild–moderate intellectual disability (IQ typically 60–70) → requires special educational provision
Learning difficulties particularly in mathematics and abstract reasoning
Difficulty with mainstream schooling → individualised education plan (IEP) essential
Relative strengths in reading, visual processing, jigsaw puzzles

6. Respiratory Complications

Encompasses both OSA (see above) and central sleep apnoea
Central apnoeas: hypothalamic respiratory centre dysfunction → reduced ventilatory drive during sleep → desaturation episodes
May contribute to cor pulmonale (right heart failure from chronic pulmonary hypertension)

Mechanism: Hypotonia → weak cough reflex → poor airway clearance; obesity → reduced functional residual capacity; aspiration risk from choking episodes
May lead to recurrent pneumonias, atelectasis, and chronic lung disease if severe

Incidence: Estimated 2–4% of PWS patients die suddenly and unexpectedly, particularly in childhood
Main proposed mechanisms:
1. Severe unrecognised OSA → fatal nocturnal hypoxaemia
2. Choking → aspiration / complete airway obstruction
3. Gastric rupture → peritonitis → septic shock
4. Adrenal crisis → unrecognised CAI during febrile illness → circulatory collapse
5. Respiratory infection → rapid deterioration due to weak cough + poor respiratory reserve
6. Cardiac arrhythmia → possibly related to autonomic dysfunction (hypothalamic)

Reducing sudden death risk:

Regular PSG and OSA treatment
Supervised meals, food cut small
Stress-dose hydrocortisone during illness
Carers trained in basic life support
Medic-Alert bracelet (if adrenal insufficiency)

Why PWS Has a Reduced Life Expectancy

Without optimal management, life expectancy in PWS was historically 20–30 years (mainly due to complications of morbid obesity). With modern management (early GH therapy, dietary control, multidisciplinary care), life expectancy has improved to 40–60+ years, but remains reduced compared to the general population. The leading causes of death are:

Cardiovascular disease (from obesity/metabolic syndrome)
Respiratory failure (OSA, respiratory infections, pulmonary hypertension)
Sudden death (choking, gastric rupture, adrenal crisis)
T2DM complications

Dental caries: Thick, viscous saliva (reduced salivary buffering capacity) + poor oral hygiene (reduced motor coordination) + carbohydrate-rich snacking (if food access is not controlled)
Enamel hypoplasia: Reported in some patients; makes teeth more vulnerable to decay
Bruxism: Teeth grinding → enamel wear, temporomandibular joint dysfunction
Dental crowding: Small jaw + normal-sized teeth → malocclusion

Chronic excoriation from skin picking → the most common dermatological issue
- Sites: arms, legs, perineum, face
- Can become infected (Staphylococcal) → cellulitis, abscess
- Scarring and disfigurement
Oedema: Lower limb oedema from inactivity, obesity, and possible lymphatic/venous insufficiency

Mechanism: Hypothalamic thermoregulatory centre dysfunction
Consequences:
- Hyperthermia during hot weather / exercise → risk of heat stroke (especially in obese patients)
- Hypothermia during cold exposure (more common in neonates/infants)
- Blunted febrile response → infections may not present with expected fever, leading to delayed recognition

System	Complications	Key Mechanism
Metabolic	T2DM, dyslipidaemia, metabolic syndrome	Obesity → insulin resistance
Cardiovascular	Cardiac insufficiency, hypertension, cor pulmonale	Obesity + OSA → haemodynamic/pulmonary stress
Respiratory	OSA (obstructive + central), recurrent pneumonia, respiratory failure	Hypotonia + obesity + hypothalamic dysregulation
Gastrointestinal	Gastric distension/rupture; choking episodes ^[6]	Impaired vomiting + hyperphagia + high pain threshold; oropharyngeal incoordination
Endocrine	T2DM, osteoporosis, adrenal crisis	GH deficiency, hypogonadism, CAI
Orthopaedic	Scoliosis ^[6], hip dysplasia, fractures	Hypotonia + obesity + endocrine deficiency
Neuropsychiatric	Psychosis (UPD), OCD, anxiety, depression, skin picking	Serotonergic dysfunction; hypothalamic-limbic dysfunction
Dental	Caries, enamel hypoplasia, bruxism	Viscous saliva + poor hygiene
Thermoregulatory	Hyperthermia, hypothermia, blunted fever response	Hypothalamic dysfunction
Mortality	Sudden death (OSA, choking, gastric rupture, adrenal crisis)	Multiple mechanisms converging

High Yield Summary — Complications of PWS

Obesity complications dominate: T2DM, cardiovascular disease, OSA — all consequent to hypothalamic hyperphagia + reduced energy expenditure ^[1].
Gastric distension and rupture is a unique, potentially fatal PWS complication — occurs because patients lack the vomiting reflex, have high pain threshold, and overeat ^[6].
Choking episodes are a leading cause of sudden death — due to oromotor incoordination, hypotonia, voracious eating, and decreased mastication ^[6].
Scoliosis is present in up to 80% — due to hypotonia, obesity, and asymmetric spinal loading ^[6].
Osteoporosis from GH deficiency + hypogonadism + inactivity; fractures may be painless → missed.
Psychiatric complications — especially affective/cycloid psychosis in the UPD subtype during adolescence.
Sudden death (2–4%) — from unrecognised OSA, choking, gastric rupture, adrenal crisis, or respiratory infection.
Adrenal crisis during illness → stress-dose hydrocortisone is life-saving; PWS children's impaired communication means illness may not be reported.
Temperature dysregulation → both hyperthermia and hypothermia risk; blunted fever → infections may be missed.
The absence of vomiting in a PWS child is the norm; if vomiting OCCURS, it is a red flag for serious pathology.

Active Recall - Complications of Prader-Willi Syndrome

References

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 498, Section D: Imprinting and Uniparental Disomy — Prader-Willi syndrome: "Hyperphagia ± obesity can cause cardiac insufficiency, OSA, DM") ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 861, Additional risks: gastric distension and rupture, choking episodes, scoliosis; Diagnosis section: DEXA, OGTT screening)

High Yield Summary

PWS is the most common syndromic form of obesity and the first confirmed human imprinting disorder ^[1]^[2]
Caused by loss of paternally-expressed genes at 15q11-q13 — three mechanisms: paternal deletion (~60%), maternal UPD (~35%), imprinting centre defect (< 5%) ^[1]
Core pathophysiology = hypothalamic dysfunction → appetite dysregulation, GH deficiency, hypogonadism, temperature instability, sleep disturbance, high pain threshold
Biphasic nutritional phenotype: neonatal hypotonia/poor feeding/FTT → childhood hyperphagia/obesity
Craniofacial features: dolichocephaly, narrow bitemporal diameter, almond-shaped eyes, thin upper lip, downturned mouth, narrow nasal bridge ^[1]
Other features: short stature, small hands and feet, hypopigmentation relative to family, cryptorchidism/micropenis in males, mild–moderate ID, behavioural disturbances (skin picking, OCD, tantrums) ^[1]
Neonatal hypotonia with poor suck and weak cry should prompt DNA methylation testing ^[1]
Comparison with Angelman syndrome: same region (15q11-q13), but Angelman = loss of maternal UBE3A → severe ID, ataxia, happy demeanour, seizures
Recurrence risk depends on mechanism: < 1% for deletion/UPD; up to 50% for inherited IC microdeletions
Paediatric-specific: GH therapy started early; environmental food control; monitor for T2DM, OSA, scoliosis; family-centred, multidisciplinary care essential

High Yield Summary — Differential Diagnosis of PWS

The differential depends on the presenting feature: neonatal hypotonia, childhood obesity, short stature, hypogonadism, or intellectual disability each generates a different DDx list.
For neonatal hypotonia: distinguish CENTRAL (PWS, Down, HIE, congenital myotonic dystrophy) from PERIPHERAL (SMA, congenital myopathy, CMS) causes — reflexes present + dysmorphic = central.
PWS is the most common syndromic form of obesity ^[2] — the main syndromic obesity differentials are Bardet-Biedl (retinitis pigmentosa + polydactyly), Alström (visual/hearing loss + cardiomyopathy), Cohen (neutropenia + prominent incisors).
Short + obese child → always exclude secondary/syndromic causes; tall + obese child → likely exogenous obesity.
DNA methylation analysis of 15q11-q13 is the first-line diagnostic test ^[6] — 99% sensitive for all PWS mechanisms.
If methylation is negative but clinical suspicion high → consider Temple syndrome (14q32), Schaaf-Yang syndrome (MAGEL2 mutation), or other syndromic obesity conditions.
Angelman syndrome is the mirror-image condition: same locus, maternal allele loss, severe ID + seizures + happy demeanour + NO obesity ^[1].
Endocrine causes of secondary obesity (hypothyroidism, Cushing syndrome, GH deficiency, hypothalamic tumours) ^[4] should always be excluded alongside syndromic causes.

High Yield Summary — Diagnosis of PWS

DNA methylation analysis at 15q11-q13 is the first-line and ONLY single test that detects all three PWS mechanisms ^[6] — sensitivity ~99%.
Methylation confirms PWS but cannot distinguish deletion vs UPD vs IC defect → must proceed to subtyping (FISH/CMA → UPD analysis → IC analysis) for recurrence risk counselling ^[6].
If methylation analysis is abnormal → FISH or chromosomal microarray to detect deletion; if no deletion → DNA polymorphism analysis for UPD; if biparental inheritance → IC analysis ^[6].
Holm criteria (1993): clinical scoring system — useful framework to recognise PWS features, but in modern practice, genetic testing is sent directly when clinical suspicion arises.
IGF-1 is low in PWS (primary GH deficiency) vs normal in exogenous obesity (functional GH suppression) ^[6] — key distinguishing investigation.
Hypogonadism biochemistry: low LH but high FSH ^[6] — reflecting combined central + primary gonadal dysfunction.
Always check fT4 (not just TSH) for central hypothyroidism — TSH may be misleadingly "normal."
DEXA scan for bone density monitoring; low BMD should prompt consideration of sex hormone replacement or GH treatment ^[6].
Polysomnography before and after starting GH therapy — PWS children are at risk of OSA and sudden death.
CK and EMG/NCS are NORMAL in PWS — confirms central (not peripheral) hypotonia ^[8].

High Yield Summary — Management of PWS

GH therapy is the cornerstone medical treatment — improves height, body composition (↑ lean mass, ↓ fat mass), bone density, and possibly cognition ^[6]. Start as early as 3–6 months of age. Approved for PWS regardless of GH stimulation test results.
PSG before/within 3 months of starting GH — GH can worsen OSA via adenotonsillar hypertrophy. Adenotonsillectomy may be needed. Sudden death risk exists in young PWS children with unrecognised severe OSA.
Nutritional management is critical — caloric requirement is only 60–80% of normal; strict environmental food control (locked pantries/fridges); dietary restriction must start BEFORE hyperphagia develops.
No bariatric surgery — hyperphagia is central, not a gastric problem; high complication risk.
Sex hormone replacement — for incomplete puberty; start low, go slow; testosterone in males (or orchidopexy/hCG for cryptorchidism in infancy); oestrogen-progesterone in females.
Central hypothyroidism → levothyroxine; monitor fT4 (NOT TSH).
Central adrenal insufficiency (if present) → hydrocortisone; stress dosing during illness is LIFE-SAVING; Medic-Alert bracelet.
Behavioural management — structured environment, positive behavioural support, SSRIs for OCD/anxiety/skin picking; atypical antipsychotics for psychosis (UPD subtype).
Scoliosis — monitor regularly; bracing or surgical correction as needed. DEXA scan for bone density monitoring ^[6].
Multidisciplinary team essential: endocrinology, genetics, dietetics, PT/OT/SLT, psychology, orthopaedics, ophthalmology, sleep medicine, dentistry.
Genetic counselling — subtype determines recurrence risk (< 1% for deletion/UPD; up to 50% for inherited IC microdeletion).

High Yield Summary — Complications of PWS

Obesity complications dominate: T2DM, cardiovascular disease, OSA — all consequent to hypothalamic hyperphagia + reduced energy expenditure ^[1].
Gastric distension and rupture is a unique, potentially fatal PWS complication — occurs because patients lack the vomiting reflex, have high pain threshold, and overeat ^[6].
Choking episodes are a leading cause of sudden death — due to oromotor incoordination, hypotonia, voracious eating, and decreased mastication ^[6].
Scoliosis is present in up to 80% — due to hypotonia, obesity, and asymmetric spinal loading ^[6].
Osteoporosis from GH deficiency + hypogonadism + inactivity; fractures may be painless → missed.
Psychiatric complications — especially affective/cycloid psychosis in the UPD subtype during adolescence.
Sudden death (2–4%) — from unrecognised OSA, choking, gastric rupture, adrenal crisis, or respiratory infection.
Adrenal crisis during illness → stress-dose hydrocortisone is life-saving; PWS children's impaired communication means illness may not be reported.
Temperature dysregulation → both hyperthermia and hypothermia risk; blunted fever → infections may be missed.
The absence of vomiting in a PWS child is the norm; if vomiting OCCURS, it is a red flag for serious pathology.

Prader-willi Syndrome

References

Prader-Willi Syndrome (PWS) — Paediatrics

4. Anatomy & Function of the 15q11.2-q13 Region

5. Aetiology & Pathophysiology

5.1 Genetic Mechanisms

6. Classification

7. Clinical Features

7.1 Symptoms (What the Caregivers Report)

7.2 Signs (What You Find on Examination)

8. Growth and Development Considerations (Paediatric-Specific)

9. Paediatric-Specific Considerations

Active Recall - Prader-Willi Syndrome (Definition, Epidemiology, Aetiology, Pathophysiology, Clinical Features)

Differential Diagnosis of Prader-Willi Syndrome

2. Differential Diagnosis by Presenting Feature

Active Recall - Differential Diagnosis of Prader-Willi Syndrome

References

Diagnostic Criteria, Algorithm & Investigations for Prader-Willi Syndrome

1.1 Holm Diagnostic Criteria (1993) — Still Referenced in Exams

3. Investigation Modalities — Detailed Breakdown

3.1 Genetic Testing (The Cornerstone)

3.2 Endocrine Investigations

Active Recall - Diagnosis and Investigations for Prader-Willi Syndrome

References

Management of Prader-Willi Syndrome

3. Treatment Modalities — Detailed Breakdown

3.1 Growth Hormone (GH) Therapy

3.2 Nutritional Management / Obesity Prevention

3.3 Sex Hormone Replacement

Active Recall - Management of Prader-Willi Syndrome

References

Complications of Prader-Willi Syndrome

2. Gastrointestinal Complications

3. Endocrine Complications

4. Orthopaedic Complications

5. Neurological and Psychiatric Complications

6. Respiratory Complications

Active Recall - Complications of Prader-Willi Syndrome

References

On this page

Prader-willi Syndrome

1. Definition

2. Epidemiology

3. Risk Factors

4. Anatomy & Function of the 15q11.2-q13 Region

4.1 The Imprinted Region

4.2 Why the Hypothalamus is Central

5. Aetiology & Pathophysiology

5.1 Genetic Mechanisms

Mechanism 1: De novo deletion (~60%) [1]

Mechanism 2: Maternal uniparental disomy (UPD) (~35%) [1]

Mechanism 3: Imprinting centre (IC) defect (< 5%) [1]

5.2 Pathophysiology — Connecting Genetics to Clinical Features

6. Classification

6.1 By Genetic Mechanism

6.2 By Clinical Phase (Nutritional Phases)

7. Clinical Features

7.1 Symptoms (What the Caregivers Report)

Prenatal

Neonatal Period (Birth to 1 Month)

Infancy to Early Childhood

Late Childhood to Adolescence (The Hallmark Phase)

Adolescence and Adulthood

7.2 Signs (What You Find on Examination)

General Inspection

Craniofacial Features

Limbs and Extremities

Neurological Examination

Genital Examination

Other Signs

7.3 Summary Table: Clinical Features by Age

7.4 Complications Mentioned in Clinical Features (Preview)

8. Growth and Development Considerations (Paediatric-Specific)

8.1 Growth

8.2 Development

8.3 Family-Centred Care

8.4 Consent and Communication

9. Paediatric-Specific Considerations

9.1 Why PWS Differs from Adult Practice

9.2 Normal Values for Age — Relevant to PWS Monitoring

Active Recall - Prader-Willi Syndrome (Definition, Epidemiology, Aetiology, Pathophysiology, Clinical Features)

References

1. Framework: Organising the Differential by Presenting Feature

2. Differential Diagnosis by Presenting Feature

2.1 Neonatal / Infantile Hypotonia ("The Floppy Baby")

2.2 Childhood Obesity with Hyperphagia

2.3 Short Stature

2.4 Hypogonadism / Cryptorchidism

2.5 Intellectual Disability with Behavioural Phenotype

3. Key Differentiating "Fingerprint" Features of PWS

4. Approach to Narrowing the Differential

5. Summary Table: Side-by-Side Comparison of Key Syndromic Obesity Differentials

Active Recall - Differential Diagnosis of Prader-Willi Syndrome

1. Diagnostic Criteria

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Genetic Testing (The Cornerstone)

3.1.1 DNA Methylation Analysis — THE First-Line Test

3.1.2 FISH / Chromosomal Microarray (CMA) — Subtyping Step 2a

3.1.3 UPD Analysis — Subtyping Step 2b

3.1.4 Imprinting Centre (IC) Analysis — Subtyping Step 2c

3.2 Endocrine Investigations

3.2.1 Growth Hormone Axis

3.2.2 Gonadal Axis

3.2.3 Thyroid Function

3.2.4 Glucose Metabolism & Metabolic Screening

3.2.5 Adrenal Axis

3.3 Imaging Studies

3.4 Sleep Studies

3.5 Ophthalmological Assessment

3.6 Developmental & Behavioural Assessment

3.7 Other Investigations

4. Summary: Investigation Pathway at a Glance

Active Recall - Diagnosis and Investigations for Prader-Willi Syndrome

1. Principles of Management

2. Management Algorithm

3. Treatment Modalities — Detailed Breakdown

3.1 Growth Hormone (GH) Therapy

Indications

Mechanism of Benefit