Prader-willi Syndrome
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.
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.
1. Obesity-Related Complications
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:
- Obesity → pharyngeal fat deposition → mechanical upper airway narrowing
- Hypotonia → pharyngeal dilator muscles (genioglossus, tensor palatini) are weak → airway collapse during sleep
- Adenotonsillar hypertrophy → especially if on GH therapy (IGF-1 stimulates lymphoid tissue growth)
- 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:
- Severe unrecognised OSA → fatal nocturnal hypoxaemia
- Choking → aspiration / complete airway obstruction
- Gastric rupture → peritonitis → septic shock
- Adrenal crisis → unrecognised CAI during febrile illness → circulatory collapse
- Respiratory infection → rapid deterioration due to weak cough + poor respiratory reserve
- 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.
Huntington Disease
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, with the rare juvenile form (onset before age 20) typically presenting with rigidity, cognitive decline, and seizures rather than the classic adult chorea.
Silver-russell Syndrome
Silver-Russell syndrome is a congenital growth disorder presenting in infancy and early childhood with intrauterine and postnatal growth restriction, relative macrocephaly, a triangular face, body asymmetry, and feeding difficulties, most commonly caused by hypomethylation at chromosome 11p15 or maternal uniparental disomy of chromosome 7.