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Opitz G/BBB syndrome


Other Names for this Disease
  • BBB syndrome
  • G syndrome
  • GBBB syndrome
  • Hypertelorism hypospadias syndrome
  • Hypertelorism with esophageal abnormality and hypospadias
More Names
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Overview



What is Opitz G/BBB syndrome?

What are the signs and symptoms of Opitz G/BBB syndrome?

What causes Opitz G/BBB syndrome?

How is Opitz G/BBB syndrome inherited?

How might Opitz G/BBB syndrome be treated?


What is Opitz G/BBB syndrome?

Opitz G/BBB syndrome is an inherited condition that affects several structures along the midline of the body. The most common features are wide-spaced eyes and defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing. Affected males usually have a urethra opening on the underside of the penis (hypospadias). Other features can include mild intellectual disability, cleft lip and/or a cleft palate, heart defects, an obstruction of the anal opening (imperforate anus), agenesis of the corpus callosum, and facial abnormalities.[1]

There are two forms of Opitz G/BBB syndrome, which are distinguished by their genetic causes and patterns of inheritance. The X-linked form is caused by mutations in the MID1 gene. Autosomal dominant Opitz G/BBB syndrome is caused by a deletion of 22q11.2, and is often referred to as 22q11.2 deletion syndrome.[1]

Last updated: 6/17/2011

What are the signs and symptoms of Opitz G/BBB syndrome?

Opitz G/BBB syndrome mainly affects structures along the midline of the body. The most common features of the condition are wide-spaced eyes (hypertelorism); defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing (dysphagia); and in males, the urethra opening on the underside of the penis (hypospadias). Mild intellectual disability occurs in fewer than 50 percent of people with Opitz G/BBB syndrome, and is most likely caused by structural defects in the brain. About half of affected individuals also have cleft lip with or without a cleft palate. Some have cleft palate alone. Heart defects, an obstruction of the anal opening (imperforate anus), and brain defects such as an absence of the tissue connecting the left and right halves of the brain (agenesis of the corpus callosum) occur in less than 50 percent of those affected. Facial abnormalities that may be seen in this disorder can include a flat nasal bridge, thin upper lip, and low set ears. These features vary among affected individuals, even within the same family. The signs and symptoms of the autosomal dominant form of the condition are comparable to those seen in the X-linked dominant form. However, the X-linked form of Opitz G/BBB syndrome tends to include cleft lip with or without cleft palate, while cleft palate alone is more common in the autosomal dominant form. Females with X-linked Opitz G/BBB syndrome are usually mildly affected, as hypertelorism may be the only sign of the disorder.[2]
Last updated: 6/17/2011

What causes Opitz G/BBB syndrome?

The X-linked form of Opitz G/BBB syndrome is caused by mutations in the MID1 gene. The MID1 gene provides instructions for making a specific protein called midin. This protein helps regulate the function of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules help cells maintain their shape, assist in the process of cell division, and are essential for the transport of materials within cells. The MID1 gene is a member of a group of genes called the TRIM (tripartite motif) family. The proteins produced from this large family of genes are involved in many cellular activities. Primarily, TRIM proteins play a role in the cell machinery that breaks down (degrades) unwanted proteins. As part of its protein degrading function, midin is responsible for the breakdown of an enzyme called protein phosphatase 2A (PP2A). This enzyme regulates a number of microtubule-associated proteins, as well as other proteins involved in critical cellular processes such as cell division. When a mutation causes the midin protein to malfunction, PP2A accumulates in the cell and alters the function of the microtubule-associated proteins. These changes disrupt microtubule function, and cells can have difficulty dividing properly. The nonfunctional midin protein binds with itself (aggregates) and forms protein clumps in the cells. However, it is currently unclear how these changes disrupt normal development and cause the birth defects associated with Opitz G/BBB syndrome. Some people who have a family history of X-linked Opitz G/BBB syndrome have no detectable MID1 mutation. The reason for this is not yet known, although some researchers have suggested the involvement of other unknown genes.[2]

The autosomal dominant form of Opitz G/BBB syndrome is caused by a deletion of a small piece of chromosome 22, specifically 22q11.2, which is why researchers consider this condition to be part of 22q11.2 deletion syndrome. It is not yet known which deleted gene(s) within this region of chromosome 22 specifically cause the signs and symptoms of Opitz G/BBB syndrome.[2]
Last updated: 6/17/2011

How is Opitz G/BBB syndrome inherited?

Opitz G/BBB syndrome often has an X-linked pattern of inheritance. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes (the other sex chromosome is the Y chromosome). In most cases, males experience more severe symptoms of the disorder than females. This is because females have two different X chromosomes in each cell, and males have one X chromosome and one Y chromosome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons, because fathers only pass a Y chromosome on to their sons (which is what makes them male). In some cases, an affected person inherits a MID1 mutation from an affected parent, while in other cases, it may result from a new mutation in the affected individual. These cases occur in people with no history of the disorder in their family.[2]

A female who has the X-linked form of Opitz G/BBB syndrome has a 25% (1 in 4) chance to have a daughter with the mutation, a 25% chance to have a son with the mutation, a 25% chance to have an unaffected daughter, and a 25% chance to have an unaffected son. This also means that there is a 50% chance, with each pregnancy, for the child to inherit the mutation. A male with the X-linked dominant form of Opitz G/BBB syndrome will pass the mutation on to all of his daughters and none of his sons.

Researchers have also described an autosomal dominant form of Opitz G/BBB syndrome caused by a deletion in one copy of chromosome 22 in each cell. In some cases, an affected person inherits the chromosome with a deleted segment from a parent, while in other cases, the condition results from a new deletion in the affected individual. These cases occur in people with no history of the disorder in their family. Males and females with the autosomal dominant form of Opitz G/BBB syndrome usually have the same degree of severity of symptoms.[2] A male or female who has the autosomal dominant form of Opitz G/BBB syndrome has a 50% (1 in 2) chance with each pregnancy for the child (male or female) to inherit the genetic abnormality.
Last updated: 6/17/2011

How might Opitz G/BBB syndrome be treated?

Because of the wide range of signs and symptoms that may be present in affected individuals, management of Opitz G/BBB syndrome typically incorporates a multidisciplinary team consisting of various specialists. Treatment for the condition may include surgery for significant abnormalities involving the larynx, trachea and/or esophagus; surgical intervention as needed for hypospadias, cleft lip and/or cleft palate, and imperforate anus; therapy for speech problems; surgical repair as needed for heart defects; neuropsychological support; and possibly special education for many males with the  X-linked form of the condition.[3]
Last updated: 6/17/2011

References
  1. Opitz G/BBB syndrome. Genetics Home Reference. November 2007; http://ghr.nlm.nih.gov/condition/opitz-g-bbb-syndrome. Accessed 5/23/2011.
  2. Opitz G/BBB syndrome. Genetics Home Reference. November 2007; http://ghr.nlm.nih.gov/condition/opitz-g-bbb-syndrome. Accessed 6/17/2011.
  3. Germana Meroni. X-Linked Opitz G/BBB Syndrome. GeneReviews. June 20, 2007; http://www.ncbi.nlm.nih.gov/books/NBK1327/. Accessed 6/17/2011.