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Disease Profile

Opitz G/BBB syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 100 000

3,310 - 29,790

US Estimated

1-9 / 100 000

5,135 - 46,215

Europe Estimated

Age of onset

Infancy

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ICD-10

Q87.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Hypospadias-dysphagia, syndrome; Opitz-Frias syndrome; G syndrome;

Summary

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. These features may vary, even among members of the same family.[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]

Treatment depends on the individual’s specific needs.[2]

Symptoms

Opitz G/BBB syndrome mainly affects structures along the midline of the body. The most common features of the condition, knwon as major anomalies, are:[3]

  • Wide-spaced eyes (hypertelorism)
  • Defects of the larynx, trachea, and/or esophagus causing breathing problems and difficulty swallowing (dysphagia
  • Urethra opening on the underside of the penis (hypospadias). 

Other frequent findings (minor anomalies) include:[3510[3]

  • Mild intellectual disability and developmental delay occur in about 50 percent of people with Opitz G/BBB syndrome
  • Delays in motor skills, speech delays, and learning difficulties 
  • Features similar to autistic spectrum disorders, including impaired communication and socialization skills 
  • Cleft lip with or without a cleft palate. Some have cleft palate alone.
  • Heart defects
  • Obstruction of the anal opening (imperforate anus)
  • Brain defects such as an absence of the tissue connecting the left and right halves of the brain (agenesis of the corpus callosum) which occur in less than 50 percent of those affected
  • Facial dysmorphism such as a flat nasal bridge, thin upper lip, and low set ears.

These features vary among affected individuals, even within the same family.[1] 

The signs and symptoms of the autosomal dominant form of the condition are comparable to those seen in the X-linked 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.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of the pharynx
0000600
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils

[ more ]

0000463
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
30%-79% of people have these symptoms
Abnormality of the voice
Voice abnormality
0001608
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Respiratory insufficiency
Respiratory impairment
0002093
5%-29% of people have these symptoms
Cleft palate
Cleft roof of mouth
0000175
Craniosynostosis
0001363
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Hypodontia
Failure of development of between one and six teeth
0000668
Increased number of teeth
Extra teeth
Increased tooth count
Supplemental teeth

[ more ]

0011069
Large fontanelles
Wide fontanelles
0000239
Low-set ears
Low set ears
Lowset ears

[ more ]

0000369
Pectus carinatum
Pigeon chest
0000768
Pectus excavatum
Funnel chest
0000767
Prominent metopic ridge
0005487
Sensorineural hearing impairment
0000407
Percent of people who have these symptoms is not available through HPO
Abnormal heart morphology
Abnormality of the heart
Abnormally shaped heart
Heart defect

[ more ]

0001627
Abnormal nasopharynx morphology
0001739
Abnormality of cardiovascular system morphology
0030680
Abnormality of the kidney
Abnormal kidney
0000077
Abnormality of the ureter
0000069
Absent gallbladder
0011467
Agenesis of corpus callosum
0001274
Anal atresia
Absent anus
0002023
Anal stenosis
Narrowing of anal opening
0002025
Aplasia/Hypoplasia of the cerebellar vermis
0006817
Aspiration
0002835
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers

[ more ]

0001631
Autosomal dominant inheritance
0000006
Bifid scrotum
Cleft of scrotum
0000048
Bifid uvula
0000193
Cavum septum pellucidum
0002389
Cerebellar vermis hypoplasia
0001320
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Cleft upper lip
Harelip
0000204
Coarctation of aorta
Narrowing of aorta
Narrowing of the aorta

[ more ]

0001680
Conductive hearing impairment
Conductive deafness
Conductive hearing loss

[ more ]

0000405
Cranial asymmetry
0000267
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Diastasis recti
Gap between large left and right abdominal muscles
0001540
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Frontal bossing
0002007
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn

[ more ]

0002020
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Global developmental delay
0001263
Hiatus hernia
Stomach hernia
0002036
High palate
Elevated palate
Increased palatal height

[ more ]

0000218
Hoarse cry
0001615
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Hypospadias
0000047
Infantile onset
Onset in first year of life

Cause

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 midline-1. 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 movement of cells (cell migration).[1] 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, midline-1 is responsible for recycling certain proteins, including phosphatase 2A (PP2A), integrin alpha-4 (ITGA4), and serine/threonine-protein kinase 36 (STK36). The recycling of these three proteins so they can be reused instead of broken down is essential because they are needed for normal cellular functioning. Mutations in the MID1 gene lead to a decrease in midline-1 function, which prevents this protein recycling. As a result, certain proteins are not recycled, and they buildup in cells. This buildup impairs microtubule function, resulting in problems with cell division and migration. Researchers speculate that the altered midline-1 protein affects how the cells divide and migrate along the midline of the body during development, resulting in the features of Opitz G/BBB syndrome.[4]

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.[1]

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. In others with autosomal dominant Opitz G/BBB syndrome, the cause is related to a mutation in the SPECCIL gene.[1]

Diagnosis

The diagnosis of Opitz G/BBB syndrome is usually based on clinical findings. In order to differentiate the X-linked form from 22q11.2 deletion syndrome (the autosomal dominant form), the pattern of inheritance within the family may be assessed. Molecular genetic testing for mutations in the MID1 gene is available for confirmation. Between 15 and 45% of males with clinically diagnosed Opitz G/BBB syndrome are found to have a mutation in this gene.[3][5]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    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 special education services.[3]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus Genetics contains information on Opitz G/BBB syndrome. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
            X-linked Opitz G/BBB syndrome
            Autosomal dominant Opitz G/BBB syndrome
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Opitz G/BBB syndrome. Click on the link to view a sample search on this topic.

            References

            1. Opitz G/BBB syndrome. Genetics Home Reference. January 2015; https://ghr.nlm.nih.gov/condition/opitz-g-bbb-syndrome.
            2. McDonald-McGinn DM, Emanuel BS, Zackai EH. 22q11.2 deletion syndrome. GeneReviews. February 28, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1523.
            3. Meroni G. X-Linked Opitz G/BBB Syndrome. GeneReviews. July 28, 2011; https://www.ncbi.nlm.nih.gov/books/NBK1327/.
            4. MID1. Genetics Home Reference. January 2015; https://ghr.nlm.nih.gov/gene/MID1.
            5. Germana Meroni. X-linked Opitz G/BBB syndrome. National Organization for Rare Disorders (NORD). 2015; https://rarediseases.org/rare-diseases/x-linked-opitz-gbbb-syndrome/.

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