BWS arises from dysregulation at chromosome 11p15.5 — the so-called BWS critical region ^[1][2][3]. This region contains a cluster of imprinted genes regulated by two imprinting centres (ICs).

Before diving into the genetics, let's build understanding from first principles:

• Generally, BOTH maternal and paternal inherited alleles of each autosomal gene pair are expressed for most genes in the genome ^[2].
• Imprinting means only one copy of a gene gets expressed, which differs from most genes. For a given imprinted gene pair, one parental allele is exclusively or preferentially expressed whereas the other allele is silenced or weakly expressed ^[2].
• < 100 genes across the genome are imprinted and expressed monoallelically ^[2].
• Genomic imprinting is regulated by epigenetic mechanisms ^[2].

Epigenetics = Heritable changes in gene function WITHOUT a change in the DNA sequence — i.e., molecular alteration of a chromosome that does not involve a change in primary nucleotide sequence of DNA but still affects gene function ^[2].

Mechanisms of Epigenetic Regulation [2]:

• DNA methylation (the most clinically relevant in BWS — methylation of CpG islands at imprinting control regions silences genes)
• Histone modification
• Chromatin remodelling
• Telomerase modification

Think of 11p15.5 as having two "control switches" — IC1 and IC2 — each regulating a set of genes. In general, paternally-expressed genes promote growth while maternal genes inhibit growth ^[1].

Normal balance: The system is finely calibrated — paternal alleles drive growth (IGF2 ↑) while maternal alleles brake growth (H19 ↑, CDKN1C ↑). BWS occurs when this balance tips toward excessive growth signalling.

Epigenetic or genomic alterations cause abnormal regulation of gene transcription in 2 imprinted centres on chromosome 11p15.5 ^[2]. The net effect is gain of growth-promoting signals and/or loss of growth-suppressing signals.

The following molecular alterations can be detected in BWS ^[2]:

Let us now connect each molecular disturbance to the clinical phenotype:

The molecular subtype determines tumour risk and tumour type, which directly guides surveillance strategy:

BWS exists on a clinical spectrum:

• Classic BWS: Full phenotype with multiple cardinal features
• Isolated lateralised overgrowth (ILO): Previously termed "isolated hemihyperplasia" — may represent the mildest end of the BWS spectrum (often pUPD mosaic)
• BWS spectrum also includes patients with only one or two features who may have subclinical molecular changes

The consensus scoring system (2018 international consensus) uses cardinal and suggestive features for clinical diagnosis:

Clinical diagnosis requires:

• ≥ 2 cardinal features (score ≥ 4), OR
• 1 cardinal + ≥ 2 suggestive features (score ≥ 4)
• A score of ≥ 2 warrants molecular testing

From the lecture slides — Approach to LGA ^[1]:

History:

• Antenatal history: parity, maternal obesity, excess weight gain (> 18 kg), maternal DM
• Family history: ethnicity, consanguinity, learning difficulty, parental height/weight

Physical examination:

• Generalised vs segmental overgrowth
• Dysmorphic features: craniofacial, hairline, ear pits/creases, macroglossia, camptodactyly, deep palmar crease, loose skin folds
• Cardiac abnormalities

BWS is strongly associated with omphalocele ^[7]:

BWS carries an increased risk of malignancy (~8%) ^[1] with the following tumour types:

"The overall cancer risk is highest in the first 2 years of life, then declines progressively before puberty. The tumour risk and types vary between different molecular subgroups" ^[1].

These are the conditions most commonly confused with BWS because they share the "big baby" phenotype. The key is to identify the constellation of features that distinguishes each.

Macroglossia is one of the most visually striking features of BWS. When you see a baby with a large tongue, think through this differential:

This is a critical differential because hypoglycaemia in the neonate is a medical emergency requiring immediate management regardless of cause.

Omphalocele is likely syndromal: Beckwith-Wiedemann, trisomy ^[7][11]. When you encounter an omphalocele, think:

Important contrast — Gastroschisis is unlikely syndromal (usually isolated) ^[7][11]:

If the clinical question is centred on a child with an embryonal tumour + overgrowth, consider:

Since BWS is an imprinting disorder, it is logical to compare it with other classic imprinting disorders:

If molecular testing is POSITIVE (any of the known 11p15.5 alterations confirmed) → diagnosis of BWS is established regardless of clinical score.

If molecular testing is NEGATIVE but clinical score ≥ 4 → diagnosis remains clinical BWS — manage as BWS (remember ~15-20% of clinically-confirmed BWS has no identifiable molecular defect with current technology).

Omphalocele is often detected on prenatal USG. When found:

• Majority of cases can be detected by the end of 1st trimester (11–14 weeks) ^[13][14]
• Prenatal USG: appears as a midline abdominal wall defect covered by an outer membrane of amnion and inner membrane of peritoneum with Wharton's jelly between the two layers ^[13][14]
• Sac typically contains bowel and may contain liver, stomach or bladder ^[13][14]
• Omphalocele can be categorised as either liver-containing (80%) or non-liver-containing ^[13][14]

Additional prenatal investigations when omphalocele is found:

• Genetic studies: should be offered due to high risk of aneuploidy ^[13][14] — karyotype and/or chromosomal microarray
• Testing for Beckwith-Wiedemann syndrome may be reasonable ^[13][14] — methylation studies on amniotic fluid or CVS
• Fetal echocardiogram: should be offered due to increased incidence of cardiac anomalies ^[13][14]
• ↑ Maternal serum AFP level in most cases of omphalocele ^[13][14]

Other prenatal USS findings suggestive of BWS: polyhydramnios, placentomegaly, macrosomia, nephromegaly, macroglossia (can sometimes be visualised in late second/third trimester).

Interpretation Framework:

These should be performed at birth or within the first days of life for any neonate with clinical BWS:

This is arguably the most clinically important aspect of BWS management — subtype-specific screening. The overall cancer risk is ~8% and is highest in the first 2 years of life, then declines progressively before puberty ^[1]. The tumour risk and types vary between different molecular subgroups ^[1].

Subtype-Specific Surveillance Summary (2018 Consensus):

AFP interpretation is notoriously tricky in young infants because neonatal AFP is physiologically very high and declines with age:

What matters is the TREND — a single elevated AFP in a neonate is meaningless. What you are looking for is:

• Failure to decline along the expected trajectory
• A rise after a period of expected decline
• Absolute values that are disproportionately elevated for age

Why is this urgent? The enlarged tongue in BWS falls posteriorly in the supine neonate, obstructing the oropharynx. Unlike adults who can reposition themselves, neonates are obligate nose-breathers with limited airway-protective reflexes — making upper airway obstruction from macroglossia a genuine emergency.

Hyperinsulinism and hypoglycaemia ^[1] is one of the most dangerous acute complications. BWS-related hypoglycaemia arises from hyperinsulinism (β-cell hyperplasia + excess IGF2), making it characteristically:

• Hypoketotic (insulin suppresses lipolysis → no substrate for ketogenesis)
• Refractory to simple feeds (because insulin secretion is autonomously elevated)

Stepwise approach:

Contraindications to diazoxide:

• Heart failure (fluid retention can worsen cardiac status)
• Hypersensitivity to sulfonamides (structural similarity)

Monitoring during hypoglycaemia management:

• Serial point-of-care glucose (initially every 30-60 min until stable, then pre-feed)
• Target: maintain glucose > 3.5 mmol/L (some centres use > 2.6 mmol/L as minimum, but higher targets preferred to protect neonatal brain)
• Duration of hypoglycaemia risk: most BWS-related hyperinsulinism resolves by a few weeks to months as β-cell hyperplasia regresses; a minority require long-term diazoxide or surgery

From the lecture slides and senior notes — omphalocele management ^[7][11]:

Immediate resuscitation at birth:

• NPO (nil per os) ^[7]
• Fluid resuscitation via upper limb IV (possible IVC compression from herniated contents) ^[7]
• OGT (orogastric tube) decompression ^[7] — prevents bowel distension and aspiration
• Cover the bowel immediately with warm gauze and aseptic plastic wrap ^[7][11] — prevents heat and fluid loss; the intact amniotic sac acts as a biological dressing
• Gentle examination: avoid rupture of amniotic sac ^[7]
• IV antibiotics ^[7]

Pre-op: ensure haemodynamically stable, exclude life-threatening associated anomalies ^[7]

Surgical options ^[7]:

Post-op: monitor for abdominal compartment syndrome — difficult ventilation, reduced venous return (hypotension, reduced urine output, lower limb oedema), wound dehiscence ^[7]

• Macroglossia causes anterior open bite, prognathism, and malocclusion over time
• Early orthodontic referral (by age 3-4 years) for monitoring
• Definitive orthodontic intervention usually deferred until mixed/permanent dentition

Genetic counselling ^[15] is a critical component:

The omphalocele itself and its surgical management carry significant morbidity:

Pre-operative complications:

• Hypothermia and fluid loss — the exposed sac radiates heat and allows transepidermal water loss (even with intact covering membrane)
• Rupture of the sac → bowel exposure → infection, bowel ischaemia
• Associated anomalies — omphalocele is likely syndromal: Beckwith-Wiedemann, trisomy ^[7] → concomitant cardiac, renal, and chromosomal anomalies contribute to morbidity

Post-operative complications ^[7]:

• Abdominal compartment syndrome — difficult ventilation, reduced venous return (hypotension, reduced urine output, lower limb oedema), wound dehiscence ^[7]
  • Why does this happen? When herniated contents are reduced back into a small abdominal cavity that never fully developed to accommodate them, intra-abdominal pressure rises sharply. This compresses the IVC (↓ venous return → hypotension), the diaphragm (↓ ventilation), and the renal veins (↓ urine output).
• Wound infection and dehiscence
• Bowel obstruction (adhesions from surgery)
• Ventral hernia (if primary closure was not achieved)