Genetics · Microdeletion · 7q11.23

Williams
Syndrome

The deletion that kills one elastin gene, narrows the aorta above the valve, gives a child the face of an elf, the friendliness of a golden retriever, and a serum calcium that will not quit.

7q11 Deletion
ELN Key gene lost
Supra Valvular AS
Hi Ca Hypercalcemia
Start

Section 1 of 5

The Deletion

One small chunk of chromosome 7 is missing. The elastin gene goes with it. What follows is a cascade that changes the heart, the face, the brain, and the blood.

Step 1 of 3 · Normal Chromosome 7

7p 7q

Normal chromosome 7 has two arms: the short arm (7p) above the centromere, and the long arm (7q) below. The critical region for Williams syndrome sits on the long arm at band q11.23.

Step 2 of 3 · The 7q11.23 Deletion

q11.23 DELETED 7p 7q

The deletion at 7q11.23 removes approximately 1.5 to 1.8 megabases of DNA. This region contains over 25 genes. The clinically critical one is ELN, the gene encoding elastin. When it goes, so does the structural integrity of every large artery.

Step 3 of 3 · ELN Loss: The Downstream Cascade

ELN deleted Low elastin in artery walls Supravalvular AS Pulm artery stenosis Smooth muscle hyperplasia

Without elastin, arterial walls stiffen. Smooth muscle cells multiply to compensate. The lumen narrows. In the aorta, the narrowing forms above the valve: supravalvular aortic stenosis. The valve itself is usually normal. This is the elastin arteriopathy.

Confirming the Diagnosis

Standard karyotypeG-banded chromosomes: detects big rearrangements but misses small microdeletions. Resolution is about 5-10 megabases; the Williams deletion is only 1.5-1.8 Mb. cannot reliably detect the 7q11.23 microdeletion. You need a higher-resolution method.

First-line: FISHFluorescence In Situ Hybridization: a fluorescent probe binds specifically to the 7q11.23 region. One signal instead of two = deletion confirmed. using a probe targeted to the 7q11.23 locus. One signal instead of the expected two = deletion confirmed.

Alternative: Chromosomal microarrayAlso called array CGH or SNP array: surveys the entire genome for copy number changes at very high resolution. Detects the deletion and also tells you exactly which genes are missing. (array CGH) is equally confirmatory and also tells you exactly which genes were deleted. On boards, FISH and microarray are both accepted answers for confirmation.

Walk the Chain · Tap each beat

Tap each step to reveal the next link in the mechanism.

Q: What gene is inside the 7q11.23 deletion? ELN: the gene encoding elastin, the spring protein in every large artery wall.
Q: Elastin is gone. What happens to the artery wall? It loses its stretch. The wall stiffens, and smooth muscle cells multiply to fill in.
Q: Smooth muscle multiplying inside the aorta: where does the lumen narrow? Above the aortic valve. Supravalvular aortic stenosis. The valve cusps are normal; the problem is the ring of thickened aortic wall just above.
Q: What does a murmur from supravalvular AS sound like on exam? Systolic ejection murmur, loudest at the right upper sternal border, radiating to the neck. Same territory as aortic stenosis from any cause.
Q: Board move: child with supravalvular AS, elfin facies, and Ca 11.8 mg/dL. What do you confirm first? FISH for 7q11.23 deletion. One missing signal on the Williams probe = Williams confirmed.
🔑 Memory Hook: Chromosome 7
7 letters in ELASTIN. Chromosome 7 loses elastin.
Count them: E-L-A-S-T-I-N. Seven. Every time you see chromosome 7 in a genetics question, ask: is elastin involved? If yes, think Williams first.

Tap to reveal

Section 2 of 5

The Whole Patient

Elfin face. Friendly to a fault. Aorta in trouble. Calcium too high. Each feature has a mechanism. Tap the cards.

Child with Williams syndrome showing elfin facies
Elfin Facies
Four children with Williams syndrome showing characteristic features
Facial Spectrum
Chromosome 7 ideogram showing deletion region
Chr 7 Ideogram
👁 Elfin Facies Tap to see features

The Face

Broad forehead · periorbital fullness · short upturned nose · long philtrum · wide mouth · full lips · small chin · widely spaced teeth.

Board tip: "Elfin" is the descriptor on every exam. The face is distinctive enough that experienced clinicians recognize it at a glance.

❤ Cardiac Tap to see defects

Elastin Arteriopathy

Supravalvular aortic stenosis (SVAS): narrowing above the aortic valve. The signature lesion. Valve leaflets are normal.

Peripheral pulmonary artery stenosis: elastin loss in the branch pulmonary arteries. Both driven by smooth muscle hyperplasia from elastin deficiency.

🧠 Cognition Tap to see profile

The Unusual Brain

Intellectual disability (mild to moderate) with a paradoxical relative verbal strength: vocabulary and language skills exceed what IQ predicts.

Severe visuospatial deficits: can't draw a simple house but can tell you stories all day.

Hyperacusis: loud sounds cause genuine distress. Cocktail party personality: approaches strangers, hyperloquacious.

⚠ Hypercalcemia Tap for mechanism

Why the Calcium?

Infantile hypercalcemia from increased sensitivity to vitamin DThe exact mechanism is debated but involves increased 1-alpha-hydroxylase activity and dysregulated intestinal calcium absorption. It usually improves with age. leads to increased intestinal calcium absorption.

Board discriminator: Williams = hypercalcemia. DiGeorge = hypocalcemia. Exact opposites. Don't flip them.

Differential Challenge: Williams or DiGeorge?

A patient walks in with a cardiac defect and a genetic syndrome. Work through the clues.

Clue 1: The serum calcium is 11.8 mg/dL (normal: 8.5-10.5 mg/dL). Which direction does this push you?

Clue 2: Echo shows narrowing above the aortic valve with normal valve leaflets. Which syndrome?

Clue 3: No history of recurrent infections. T-cell counts are normal. Thymus is intact on chest imaging. Which syndrome fits?

Board Summary

Williams (7q11.23): hypercalcemia, supravalvular AS, elfin facies, cocktail personality, intact immune system.
DiGeorge (22q11.2): hypocalcemia from hypoparathyroidism, conotruncal defects, T-cell deficiency from thymic aplasia.

The calcium direction alone settles 80% of these questions. Williams is High. DiGeorge is Low.

🔑 Memory Hook: The Calcium Rule
Williams = HIGH calcium. DiGeorge = LOW calcium.

Williams = Way too much calcium. DiGeorge = Dropped calcium (lost parathyroids). The directions are opposite and locked. Know both or miss the question.

Tap to reveal

Genetics Discriminator Table · Tap table to reveal

Feature Williams 7q11 DiGeorge 22q11 Down Tri-21 Cri-du-chat 5p-
Cardiac Supravalvular AS Truncus, ToF AVSD, VSD, ASD VSD (variable)
Calcium HIGH LOW Normal Normal
Immunodeficiency None T-cell (thymic) None specific None specific
Intellect Mild-mod ID, verbal strength Variable Mild-mod ID Severe ID
Key clue Elfin face, friendly Cleft palate, thymic aplasia Round face, Brushfield spots High-pitched cry at birth
Diagnosis FISH 7q11 / microarray FISH 22q11 / microarray Karyotype FISH 5p / microarray

Williams 7q11.23

Cardiac: Supravalvular AS · Calcium: HIGH · Immune: intact · Face: elfin · Dx: FISH 7q11

DiGeorge 22q11.2

Cardiac: Truncus / ToF · Calcium: LOW · Immune: T-cell deficient · Dx: FISH 22q11

Down Syndrome Trisomy 21

Cardiac: AVSD/VSD/ASD · Face: round, Brushfield spots · Dx: karyotype

Cri-du-chat 5p-

Clue: high-pitched cat cry at birth · Severe ID · Dx: FISH 5p / microarray

Section 3 of 5

Where Elastin Fails

Aortic stenosis happens at three different levels. Williams fixes it above the valve. Work through each stage to lock in the discriminator.

Stage 1 of 5 Normal Aorta
Aorta Valve NORMAL

Normal aorta: wide lumen above and below the aortic valve. Blood flows freely. Elastin fibers in the wall maintain resilience and allow the artery to recoil between beats.

Thick wall NARROW HERE Valve SUPRA-VALVULAR (WILLIAMS)

Williams syndrome. The aortic wall above the valve is thickened from smooth muscle hyperplasia secondary to ELN loss. The valve itself is normal. The stenosis sits above the valve: supravalvular.

Thickened valve VALVULAR AS (NOT Williams)

Valvular aortic stenosis (NOT Williams). The obstruction is at the valve leaflets themselves: thickened, calcified, or bicuspid. The aortic wall is normal. Classic calcific AS of elderly patients or bicuspid aortic valve in younger adults.

Hyper- trophied septum SUB-VALVULAR (HOCM)

Subvalvular aortic stenosis (NOT Williams). The obstruction is below the valve, typically from hypertrophic cardiomyopathy (HOCM) where the interventricular septum bulges into the outflow tract. Valve is normal. Wall is normal. The heart muscle itself is the problem.

Location Supravalvular (above valve) = Williams syndrome. Valve = calcific AS / bicuspid AV. Subvalvular = HOCM.
Pathway ELN loss leads to low elastin in aortic wall, smooth muscle hyperplasia, and intimal thickening above the valve. Valve leaflets remain histologically normal.
Pearl Any child with supravalvular AS on echo = think Williams syndrome first. Confirm with FISH for 7q11.23.
Also Peripheral pulmonary artery stenosis co-occurs for the same reason: elastin loss in branch pulmonary arteries.
🔑 Memory Hook: The Valve Level Rule
SUPRA = Williams. AT the valve = calcific/bicuspid. BELOW = HOCM.

Imagine the aorta is a building. Williams syndrome locked the front door ABOVE the lobby. Calcific AS welded the lobby door itself shut. HOCM shoved furniture into the hallway below. Same building, three different choke points.

Tap to reveal

Section 4 of 5

Board Exam Practice

Five patients just walked in. You know what Williams syndrome looks like. Now prove it under exam conditions.

VIGNETTE 1 OF 5 SCORE 0 / 5
Sources: First Aid for the USMLE Step 1 (p.85, p.324); American College of Medical Genetics and Genomics (ACMG) clinical guidelines for Williams syndrome; published literature on ELN gene and elastin arteriopathy. Images: Wikimedia Commons (CC BY 3.0, CC BY-SA 4.0, Public domain). Clinical content reviewed by Kaitlyn Cocuzzo, MD and Fatima Ali, DO.
Intro