Beckwith-Wiedemann Syndrome

Beckwith-Wiedemann Syndrome is a rare genetic disorder, characterized by abnormal growth parameters (height, weight, head circumference…), issues with internal organs (enlarged organs, kidney problems…) and characteristic facial features.

Higher-than-normal birth weight (macrosomia).

Being taller than expected for age and gender (tall stature).

Enlarged tongue (macroglossia).

One side of the body growing larger than the other (hemihyperplasia, also known as 'lateralized overgrowth').

Issues during pregnancy:

Excess amniotic fluid (polyhydramnios): Amniotic fluid is the liquid that surrounds the baby in the womb (uterus). Polyhydramnios occurs when too much amniotic fluid builds up during pregnancy.
Preterm birth (prematurity): birth before the 37th week of pregnancy.

Low blood sugar as a newborn (neonatal hypoglycemia):

Low blood sugar in newborns can cause jittering (seizures) and other complications.

Abdominal wall issues:

Umbilical hernia: The bulging of the intestines through the opening in the abdominal muscles near the bellybutton (umbilicus).

Separation of the abdominal muscles (Diastasis recti): the separation between the left and right side of the rectus abdominis muscle, the muscle that covers the front surface of the belly area.

An opening (defect) of the abdominal wall (omphalocele): at birth, the infant's intestines, liver, or other organs stick outside of the belly through the belly button.

Kidney problems:

Abnormal kidney shape.

Enlarged kidney(s).

Calcium buildup in the kidneys (nephrocalcinosis).

Medullary sponge kidney: a rare disorder where fluid-filled sacs (cysts) form in the middle area (medulla) of the kidneys, possibly leading to urinary tract infections and kidney stones.

Enlarged internal organs (Visceromegaly):

Involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas.

Ear abnormalities:

Abnormal ear shape (ear lobe creases, helical ear pits).

Middle ear bone hardening (otosclerosis).

Blood vessel lumps or patches (Abnormal blood vessel growth):

Salmon patches (nevus simplex): a type of birthmark, in which a cluster of pink to reddish-purple blood vessels (capillaries) appear on a newborn’s skin on the back of their head or neck (stork bite), or on their face, eyelids or forehead (angel's kiss).

Blood vessel lumps (hemangiomas): harmless red or purple lumps caused by blood vessels, usually on the skin but sometimes elsewhere in the body.

Characteristic facial features:

Folds of skin under the eyes (infraorbital creases).

Sunken middle of the face (midface retrusion).

• Large lower jaw (prognathia).

Abnormal heart structure or enlarged heart.

Advanced bone age:

Bones growing faster than normal for a person’s age, which can lead to early closure of growth plates and shorter height in adulthood.

Developmental delay:

Slow to reach developmental milestones compared to his/her peers.

• Heart muscle diseases (cardiomyopathy).
• Cleft palate: A gap in the roof of the mouth at birth.
• Embryomas: Abnormal growths that begin in embryonic (fetal) tissue, and may be non-cancerous (benign) or cancerous (malignant).
• Hepatoblastoma: the most common type of childhood liver cancer.
• Neuroblastoma: a type of childhood cancer that forms from immature nerve cells. It usually begins in the adrenal glands but may also begin in the abdomen, chest, or in nerve tissue near the spine.
• Rhabdomyosarcoma: a cancerous (malignant) tumor of the muscles. Embryonal rhabdomyosarcoma is rare and occurs most often in the head and neck area or in the genital or urinary organs, but can occur anywhere in the body.

The diagnosis of Beckwith-Wiedemann Syndrome is established based on the clinical features and genetic testing, to determine the presence of the mutation on chromosome 11 responsible for the syndrome.

Genetic testing approaches that may be used for patients with suspected or confirmed Beckwith-Wiedemann include:

• DNA Methylation studies:
• Methylation studies help us understand how genes are turned "on" or "off" (gene expression) which controls whether they make important proteins, enzymes, or hormones.
• Methylation errors are the most common molecular abnormality that can be detected in BWS.

• Single-gene testing: targets mutations in the CDKN1C gene, which is detected in 5% of random cases (sporadic) and 40% of familial cases of Beckwith-Wiedemann Syndrome.

Approximately 80% of individuals with BWS have it as the result of a random (sporadic) mutation and have no other family members with the condition.

Approximately 10-15% have a familial Beckwith-Wiedemann Syndrome, and have had the mutation passed from a parent.

In familial cases of Beckwith-Wiedemann Syndrome, the inheritance is considered 'Autosomal dominant':

“Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes.

“Dominant” inheritance means one gene in a pair being abnormal is enough to cause the disease.

Recurrence risk:

The risk of having another child in the family with the disease (recurrence risk) depends on the type of genetic abnormality, which can be detected through genetic testing. While the majority of families have a recurrence risk of less than 1%, certain genetic mechanisms can cause a recurrence risk as high as 50%.

The estimated prevalence of Beckwith Wiedemann Syndrome is 1:10,000 to 1:13,700, but genetic experts believe it is an underestimate given many individuals with milder features remain undiagnosed.

A team of healthcare specialists should be involved in care, including:

• Eye specialist (ophthalmologist).
• Bone and joint specialist (orthopedist).
• Child health doctor (pediatrician).
• Movement specialist (physiotherapist).
• Genetic counselor.
• Dentist.
• Heart specialist (cardiologist).
• Brain and nerve specialist (neurologist).

Written by: Khawla Ben Yahia, MBBS.

Reviewed by: Dr. Ayman W. El-Hattab, MD, FAAP, FACMG.

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2. NORD. " Beckwith-Wiedemann Syndrome." National Organization for Rare Disorders [Internet] (2023). Accessed from: https://rarediseases.info.nih.gov/diseases/3343/beckwith-wiedemann-syndrome
3. Brioude, Frédéric, et al. "Clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement." Nature Reviews Endocrinology 14.4 (2018): 229-249.
4. Wang, Kathleen H., et al. "Diagnosis and management of Beckwith-Wiedemann syndrome." Frontiers in pediatrics 7 (2020): 478093.
5. Bethesda (MD). "Beckwith-Wiedemann Syndrome" National Library of Medicine (US); MedlinePlus [Internet]. (2021) Available from: https://medlineplus.gov/genetics/condition/beckwith-wiedemann-syndrome/.