What are the main health concerns and long-term management strategies for a child with Beckwith-Wiedemann syndrome?

The primary health concerns include an increased risk of certain childhood cancers, particularly Wilms tumor (kidney cancer) and hepatoblastoma (liver cancer), especially in the first 8 years of life. Management involves regular cancer screening, such as abdominal ultrasounds and blood tests (alpha-fetoprotein levels), every 3 months until age 8. Other concerns include feeding difficulties due to macroglossia, hypoglycemia (low blood sugar) in infancy, and potential orthopedic issues related to hemihyperplasia, which may require surgery or orthotics.

If a child is diagnosed with Beckwith-Wiedemann syndrome, what are the chances of it occurring in future pregnancies or other family members?

The inheritance pattern of Beckwith-Wiedemann syndrome varies. About 85% of cases are sporadic (not inherited) due to new genetic changes. The remaining 15% are inherited, often in an autosomal dominant pattern, meaning a parent may carry the genetic alteration. If the cause is a new mutation, the recurrence risk for future children is low. If an inherited cause is identified in a parent, the recurrence risk can be as high as 50%. Genetic counseling is crucial to determine the specific risk for each family.

What are the key signs that might lead a doctor to suspect Beckwith-Wiedemann syndrome in an infant, and how is it confirmed?

Key signs in infants include being larger than average at birth (macrosomia), an enlarged tongue (macroglossia), an omphalocele (abdominal wall defect where organs protrude through the navel), and sometimes hemihyperplasia (one side or part of the body growing larger than the other). An ear crease or pits on the earlobes can also be indicators. Diagnosis is confirmed through genetic testing, often involving methylation studies or chromosomal microarray, to detect the specific genetic changes on chromosome 11p15.5.

What is hemihyperplasia, which is sometimes seen in Beckwith-Wiedemann syndrome, and how is it managed?

Hemihyperplasia, also known as lateralized overgrowth, is a condition where one side or a specific part of the body grows larger than the corresponding part on the other side. In Beckwith-Wiedemann syndrome, this can affect limbs, the face, or internal organs. Management depends on the severity and impact. It may involve orthopedic interventions like shoe lifts for leg length discrepancy, physical therapy, or in some cases, surgical procedures to correct significant asymmetry. Regular monitoring for associated cancer risk is also important, as hemihyperplasia itself is a risk factor.

Chromosome 11

Chromosome 11 is one of the 23 pairs of human chromosomes, spanning about 135 million DNA building blocks and containing an estimated 1,300 to 1,400 genes. Changes in its structure or number are associated with various health conditions, including Beckwith-Wiedemann syndrome, Ewing sarcoma, and WAGR syndrome.

Overview

Humans normally have 46 chromosomes in each cell, divided into 23 pairs. Two copies of chromosome 11, one copy inherited from each parent, form one of the pairs. Chromosome 11 spans about 135 million DNA building blocks (base pairs) and represents between 4 and 4.5 percent of the total DNA in cells.

Identifying the genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. Chromosome 11 likely contains 1,300 to 1,400 genes that provide instructions for making proteins. These proteins perform a variety of different roles in the body.

Health Conditions Related to Chromosomal Changes

The following chromosomal conditions are associated with changes in the structure or number of copies of chromosome 11.

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome is classified as a growth disorder. Affected infants are typically larger than normal, and specific body parts may grow abnormally large on one side of the body in some people with this condition. It is caused by the abnormal regulation of genes on part of the short (p) arm of chromosome 11. The genes are located close together in a region designated 11p15.5.

People normally inherit one copy of chromosome 11 from each parent. For most genes on this chromosome, both copies of the gene are active (expressed) in cells. For some genes, however, only the copy derived from the sperm cell is expressed. For other genes, only the copy derived from the egg cell is expressed. These parent-specific differences in gene expression are called genomic imprinting.

Researchers have determined that changes in genomic imprinting disrupt the regulation of several genes located in the 11p15.5 region, including CDKN1C, H19, IGF2, and KCNQ1OT1. Because these genes are involved in directing normal growth, problems with their regulation lead to overgrowth and the other characteristic features of Beckwith-Wiedemann syndrome.

About 20 percent of people who have Beckwith-Wiedemann syndrome have cells in which both copies of chromosome 11 come from the sperm cell. This is known as uniparental disomy (UPD). UPD can cause people to have two active copies of some imprinted genes and no active copies of others. This imbalance in the activity of imprinted genes on chromosome 11 causes the signs and symptoms of Beckwith-Wiedemann syndrome.

About 1 percent of all people with Beckwith-Wiedemann syndrome have a chromosomal abnormality such as a rearrangement (translocation) that involves 11p15.5 or abnormal copying (duplication) or deletion of genetic material in this region. Like the other genetic changes responsible for Beckwith-Wiedemann syndrome, these changes disrupt the normal regulation of genes in this part of chromosome 11.

Emanuel syndrome

Emanuel syndrome is caused by the presence of extra genetic material from chromosome 11 and chromosome 22 in each cell. In addition to the usual 46 chromosomes, people with Emanuel syndrome have an extra (supernumerary) chromosome consisting of a piece of chromosome 22 that is attached to a piece of chromosome 11. The extra chromosome is known as a derivative 22 or der(22) chromosome.

People with Emanuel syndrome typically inherit the der(22) chromosome from an unaffected parent. The parent carries a chromosomal rearrangement between chromosomes 11 and 22 called a balanced translocation. No genetic material is gained or lost in a balanced translocation, so these chromosomal changes usually do not cause any health problems. As the translocation is passed to the next generation, it can become unbalanced. Individuals with Emanuel syndrome inherit an unbalanced translocation between chromosomes 11 and 22 in the form of a der(22) chromosome. These individuals have two copies of chromosome 11, two copies of chromosome 22, and extra genetic material from the der(22) chromosome.

As a result of the extra chromosomal material, people with Emanuel syndrome have three copies of some genes in each cell instead of the usual two copies. The excess genetic material disrupts the normal course of development, leading to intellectual disabilities and birth defects. Researchers are working to determine which genes are included on the der(22) chromosome and what role these genes play in development.

Ewing sarcoma

A translocation involving chromosome 11 can cause a type of cancerous tumor known as Ewing sarcoma. These tumors develop in bones or soft tissues, such as nerves and cartilage. This translocation, written as t(11;22), fuses part of the EWSR1 gene from chromosome 22 with part of the FLI1 gene from chromosome 11, creating the EWSR1/FLI1 fusion gene. This translocation is somatic, which means that it is acquired during a person's lifetime and is present only in certain cells. In people with Ewing sarcoma, the translocation is present only in tumor cells.

The protein produced from the EWSR1/FLI1 fusion gene, called EWS/FLI, has functions of the proteins produced from both genes. The FLI protein, produced from the FLI1 gene, attaches (binds) to DNA and regulates an activity called transcription, which is the first step in the production of proteins from genes. The FLI protein controls the growth and development of some cell types by regulating the transcription of certain genes. The EWS protein, produced from the EWSR1 gene, also regulates transcription. The EWS/FLI protein has the DNA-binding function of the FLI protein as well as the transcription regulation function of the EWS protein. It is thought that the EWS/FLI protein turns the transcription of a variety of genes on and off abnormally. This abnormal gene activity affects cell growth and division, resulting in tumor development.

Jacobsen syndrome

People with Jacobsen syndrome have a variety of signs and symptoms, including cognitive impairment, delayed development of certain skills, learning difficulties, and behavioral problems. This condition, which is also known as 11q terminal deletion disorder, is caused by a deletion of genetic material at the end (terminus) of the long (q) arm of chromosome 11. The size of the deletion varies among affected individuals, with most affected people missing about 5 million to 16 million base pairs. In almost all affected people, the deletion includes the tip of chromosome 11, although deletions within the chromosome (interstitial deletions) can also cause the condition. Larger deletions tend to cause more severe signs and symptoms than smaller deletions.

The features of Jacobsen syndrome are likely related to the loss of multiple genes on chromosome 11. The deleted region can contain from about 170 to more than 340 genes. Genes in this region appear to be critical for the normal development of many parts of the body, including the brain, facial features, and heart. Only a few genes have been studied as possible contributors to the specific features of Jacobsen syndrome. Researchers are working to determine which additional genes may be associated with this condition.

Neuroblastoma

About 35 percent of people with neuroblastoma have a deletion of genetic material on the long arm of chromosome 11 at a position designated 11q23. Neuroblastoma is a type of cancerous tumor that is composed of immature nerve cells (neuroblasts). The deletion of genetic material on chromosome 11 can occur in the body's cells after conception or it can be inherited from a parent.

This deletion is associated with a more severe form of neuroblastoma than that caused by genetic changes in single genes. It is unknown how the deletion of this region contributes to the formation or progression of neuroblastoma.

Potocki-Shaffer syndrome

Potocki-Shaffer syndrome is caused by the deletion of a segment of the short arm of chromosome 11 at a position designated 11p11.2. Because of this change, Potocki-Shaffer syndrome is also known as proximal 11p deletion syndrome. The term "proximal" means that the missing piece is near the center of the chromosome. The characteristic features of Potocki-Shaffer syndrome include enlarged openings (foramina) in the two bones that form the top and sides of the skull (enlarged parietal foramina), multiple noncancerous bone tumors (osteochondromas), intellectual disabilities, developmental delays, a distinctive facial appearance, and problems with vision. Occasionally, people with this condition have defects in the heart, kidneys, and urinary tract.

The size of the deletion that causes Potocki-Shaffer syndrome varies among affected individuals. Studies suggest that an individual would need a deletion of at least 2.1 million base pairs, also written as 2.1 megabases (Mb), to develop all of the features associated with this condition. Within this region of chromosome 11 there are several genes. The deletion of a gene called ALX4 causes the enlarged parietal foramina in people with this condition, while the loss of the EXT2 gene causes the osteochondromas. The deletion of the PHF21A gene is responsible for the intellectual disabilities and distinctive facial features seen in affected individuals. Researchers are working to determine what other genes in the 11p11.2 region contribute to the features of Potocki-Shaffer syndrome.

Another condition called WAGR syndrome is caused by a deletion of genetic material from the short arm of chromosome 11 at a position designated 11p13. Occasionally, a deletion occurs that is large enough to include the 11p11.2 and 11p13 regions. More than 15 individuals with such a deletion have been described to have signs and symptoms of both Potocki-Shaffer syndrome and WAGR syndrome.

Silver-Russell syndrome

Like Beckwith-Wiedemann syndrome, Silver-Russell syndrome can be caused by changes in the 11p15.5 region. Specifically, Silver-Russell syndrome has been associated with changes that affect the H19 and IGF2 genes. Although both Silver-Russell syndrome and Beckwith-Wiedemann syndrome can be caused by abnormal regulation of these imprinted genes, the changes that lead to Silver-Russell syndrome result in slow growth before and after birth rather than overgrowth.

UPD that involves chromosome 11 is a very rare cause of Silver-Russell syndrome. In these cases, people with Silver-Russell syndrome have cells in which both copies of chromosome 11 come from the egg cell. This leads to an imbalance in the activity of the imprinted genes on chromosome 11, which can cause the signs and symptoms of Silver-Russell syndrome.

Some people with Silver-Russell syndrome have a rearrangement, duplication, or deletion of genetic material on chromosome 11. These changes can also disrupt the normal regulation of the H19 and IGF2 genes, causing the signs and symptoms of Silver-Russell syndrome.

WAGR syndrome

WAGR syndrome is caused by a deletion of genetic material on the short arm of chromosome 11 at a position designated 11p13. WAGR syndrome is a disorder that affects many body systems and is named for its main features: a childhood kidney cancer known as Wilms tumor, an eye problem called aniridia, genitourinary anomalies, and a range of developmental delays. The signs and symptoms of WAGR syndrome are related to the loss of multiple genes from this part of the chromosome.

The size of the deletion varies among affected individuals. Researchers have identified genes on the short arm of chromosome 11 that are associated with particular features of WAGR syndrome. The loss of the PAX6 gene disrupts normal eye development, leading to aniridia and other eye problems, and it may also affect the development of the brain. Deletion of the WT1 gene is responsible for the genitourinary abnormalities and the increased risk of Wilms tumor in affected individuals. Researchers are working to determine how the loss of other genes in people with WAGR syndrome leads to the features of the disorder.

Other chromosomal conditions

Other changes in the structure or number of copies of chromosome 11 can have a variety of effects, including intellectual disabilities, developmental delays, slow growth, distinctive facial features, and weak muscle tone (hypotonia). Changes that involve chromosome 11 include an