Williams Syndrome: 7q11.23 Deletion, SVAS & Hypercalcemia

Williams syndrome (Williams-Beuren syndrome) is a contiguous gene deletion syndrome: a heterozygous 1.5-1.8 Mb deletion at chromosome 7q11.23 that removes about 25-27 genes, including ELN (elastin). Losing one ELN copy causes an elastin arteriopathy, classically supravalvular aortic stenosis (SVAS) and peripheral pulmonary stenosis, while the wider deletion gives elfin facies, usually mild intellectual disability with relatively strong language but very weak visuospatial skills, and an overfriendly, anxious personality. Hypercalcemia (20-40%, most often symptomatic before age 2) is the classic lab clue. Most cases are de novo but the deletion is autosomal dominant, and a normal karyotype does not exclude it: chromosomal microarray or FISH confirms it.

The 5-second rule: in Williams, everything is "above"

When a stem gives you a chatty, overfriendly child with a murmur, say it in one breath: "7q11.23 deletion, ELN lost, everything is above."

Then add the face: "elfin" facies, with a broad forehead, periorbital fullness, a stellate (lacy) iris, a short nose with a broad tip, a long philtrum, a wide mouth with full lips, a small jaw and, in young children, small widely spaced teeth. A hoarse voice (about 90%) is another connective tissue clue.

Flip it for DiGeorge. The other microdeletion classic, 22q11.2 deletion (DiGeorge) syndrome, brings calcium below normal (hypoparathyroidism), conotruncal heart defects instead of SVAS, and T-cell deficiency from thymic hypoplasia.

What is deleted, and why one deletion does so much

• The lesion: a heterozygous 1.5-1.8 Mb deletion at 7q11.23 containing about 25-27 genes. One event removes a row of neighboring genes, which is what contiguous gene deletion syndrome means, and it is why so many organ systems are involved.
• Why the same deletion recurs: the region is flanked by low-copy repeats with nearly identical sequence. When these repeats misalign, nonallelic homologous recombination deletes the segment between them, so unrelated patients carry nearly identical deletions.
• ELN haploinsufficiency: with one ELN copy, elastin production falls by about half. Arterial walls become thick, stiff and narrow (elastin arteriopathy), and reduced elastin also contributes to connective tissue problems in the skin and joints.
• The other genes: loss of GTF2I, GTF2IRD1 and LIMK1 is thought to shape the cognitive and behavioral profile (LIMK1 with visuospatial difficulty). Patients whose deletion includes NCF1 have less hypertension.
• Inheritance: autosomal dominant. Most cases are de novo, so parents are usually unaffected, but each child of an affected person has a 50% chance of inheriting the deletion.
• How common: about 1 in 7,500 to 1 in 18,000 people.

Heart and vessels: an elastin arteriopathy

Cardiovascular disease affects about 80% of patients and is the main cause of illness and death.

Because the obstruction sits above the valve, there is usually no ejection click; in congenital valvular aortic stenosis, a click can be heard while the stiff leaflets are still mobile. The right arm reads higher than the left because of the Coanda effect: the jet clings to the aortic wall and streams into the innominate artery.

Calcium: the lab clue

• Who and when: hypercalcemia occurs in 20-40% and is most often symptomatic in the first 2 years (irritability, vomiting, constipation). It can cause dehydration and hypercalciuria (about 30%); nephrocalcinosis is uncommon (fewer than 5%).
• Why: unknown. Gut calcium absorption is increased, and vitamin D promotes that absorption.
• Management: avoid vitamin supplements that contain vitamin D, especially in young children; keep dietary calcium at no more than 100% of the recommended intake; encourage fluids; use oral corticosteroids for refractory cases and IV pamidronate for severe symptomatic hypercalcemia. Serum calcium is checked every 4-6 months before age 2.
• Exam framing: "Williams = hypercalcemia" is the classic pairing, but only a minority have it. For the other causes of high and low calcium, see hypocalcemia vs hypercalcemia.

Brain, behavior and the rest of the body

• Cognition: intellectual disability, usually mild, in about 75%. Adults may read at a high-school level, but writing, drawing and math are hard.
• Personality: the distinctive Williams personality (overfriendliness, social disinhibition, empathy) is present in about 95%. Non-social anxiety (about 80%, including specific phobias), ADHD (about 65% of children) and autism spectrum disorder (10-20%) are common. About 35% have hyperacusis (discomfort with ordinary sounds), and many do well at music.
• Endocrine: early puberty (about 50%), hypothyroidism (about 10%), and diabetes (about 20%, mostly in adults).
• GI and connective tissue: feeding difficulties in infancy (about 70%), constipation (about 50%), umbilical and inguinal hernias, colon diverticula (about 30%), soft lax skin, lax joints in infancy and contractures later, dental malocclusion and growth deficiency.

Diagnosis: why the karyotype is normal

• Confirm with chromosomal microarray (CMA) or targeted deletion testing such as FISH; both detect the recurrent deletion. In practice it is often found on CMA ordered for developmental delay, intellectual disability or autism.
• A routine G-banded karyotype cannot detect it: 1.5-1.8 Mb is below the resolution of conventional banding. On exams, "karyotype normal" never rules out a microdeletion.
• Workup after diagnosis: echocardiogram and ECG, blood pressure in all four limbs, serum calcium and urine calcium-to-creatinine ratio, thyroid function, and developmental, vision and hearing assessment.

Management in one minute

There is no cure; care is lifelong and directed at complications.

• Cardiology at diagnosis, then at least yearly until age 5 and every 2-3 years after that; surgical repair for significant SVAS.
• Anesthesia consultation before any sedation or surgery, because of the risk of cardiac arrest.
• Development: early intervention; speech, occupational, physical and feeding therapy; special education; treatment of anxiety and ADHD.
• Genetic counseling: 50% risk for each child of an affected person; prenatal and preimplantation testing are possible once the deletion is known.

Williams vs the look-alikes

How USMLE tests it (and the traps)

• Supra- vs valvular. Williams narrows the aorta above a normal valve, so there is usually no ejection click. Congenital valvular AS (often a bicuspid valve) can have one while the leaflets are stiff but not yet immobile.
• Elastin vs fibrillin. ELN loss narrows arteries; FBN1 variants (Marfan syndrome) dilate the aortic root, with aneurysm and dissection. See the Marfan syndrome review.
• Hyper vs hypo. High calcium points to Williams; low calcium with tetany or seizures points to 22q11.2.
• "Karyotype normal." Microdeletions sit below karyotype resolution, so pick CMA or FISH.
• Happy is not always Williams. Angelman syndrome (loss of maternal UBE3A on chromosome 15) also brings a happy, excitable demeanor with frequent laughter, but with severe speech impairment, seizures and ataxia. Williams children talk a lot.

Practice question

A 4-year-old girl is evaluated for a heart murmur. She greets the nurse with a hug and chats happily with everyone in the room, but her preschool teacher says she cannot copy simple shapes or finish puzzles. In infancy she had irritability, vomiting and constipation, and her serum calcium was elevated. She has a broad forehead, periorbital fullness, a lacy (stellate) iris pattern, a wide mouth with full lips and a hoarse voice. A harsh systolic ejection murmur is heard at the upper right sternal border without an ejection click, and systolic blood pressure is higher in the right arm than the left. Echocardiography shows narrowing of the ascending aorta at the sinotubular junction with a normal trileaflet aortic valve. A G-banded karyotype is 46,XX. Which of the following best explains her condition?

A. Heterozygous deletion at 7q11.23 that includes ELN B. Heterozygous deletion at 22q11.2 that includes TBX1 C. Pathogenic variant in FBN1 D. Gain-of-function variant in PTPN11 E. Monosomy X

Answer: A. Overfriendliness, weak visuospatial construction, infantile hypercalcemia, elfin facies, a hoarse voice and supravalvular aortic stenosis add up to Williams syndrome. Losing one copy of ELN halves elastin production and narrows the aorta just above the valve. The karyotype is normal because a 1.5-1.8 Mb deletion is below its resolution; chromosomal microarray or FISH would confirm it.

• B: a 22q11.2 deletion causes hypocalcemia (hypoparathyroidism), conotruncal defects such as tetralogy of Fallot or truncus arteriosus, palatal anomalies and T-cell deficiency. A routine karyotype misses it too, so the calcium level and the heart lesion are what separate the two.
• C: FBN1 variants cause Marfan syndrome, which dilates the aortic root rather than narrowing the aorta above the valve; tall stature and lens subluxation are its clues.
• D: PTPN11 gain-of-function variants are the most common cause of Noonan syndrome, whose classic heart lesion is valvar pulmonary stenosis (or hypertrophic cardiomyopathy); calcium is normal.
• E: monosomy X (Turner syndrome) would show on the karyotype as 45,X and causes a bicuspid aortic valve and coarctation, not SVAS.

Key takeaways

• Williams = heterozygous 7q11.23 deletion (1.5-1.8 Mb, about 25-27 genes, including ELN): a contiguous gene deletion syndrome, autosomal dominant but usually de novo.
• Everything is above: stenosis above the valve (SVAS, about 75%), calcium above normal (hypercalcemia, 20-40%, most often symptomatic before age 2), sociability above normal, language above visuospatial skills.
• Elastin arteriopathy can narrow any artery: peripheral pulmonary stenosis (often improves), renal artery stenosis with hypertension, coronary stenosis with sudden death and anesthesia risk.
• Elfin face (broad forehead, periorbital fullness, stellate iris, wide mouth, full lips) and a hoarse voice.
• Diagnose with chromosomal microarray or FISH; the karyotype is normal.
• Avoid vitamin D-containing supplements, and get an anesthesia consultation before any sedation or surgery.
• DiGeorge is the mirror image: 22q11.2, hypocalcemia, conotruncal defects, T-cell deficiency.

Sources

• Williams Syndrome — GeneReviews, NCBI Bookshelf (2023)
• Williams syndrome — MedlinePlus Genetics, National Library of Medicine (2022)
• ELN gene — MedlinePlus Genetics, National Library of Medicine (2022)
• 7q11.23 Duplication Syndrome — GeneReviews, NCBI Bookshelf (2021)
• Williams Syndrome — StatPearls, NCBI Bookshelf (2025)
• Supravalvar Aortic Stenosis — StatPearls, NCBI Bookshelf (2023)
• Supravalvular aortic stenosis — MedlinePlus Genetics, National Library of Medicine (2012)
• Aortic Stenosis — Merck Manual Professional Edition (2025)
• 22q11.2 Deletion Syndrome — GeneReviews, NCBI Bookshelf (2025)
• Noonan syndrome — MedlinePlus Genetics, National Library of Medicine (2018)
• Turner syndrome — MedlinePlus Genetics, National Library of Medicine (2023)
• Angelman syndrome — MedlinePlus Genetics, National Library of Medicine (2022)