Mosaic variegated aneuploidy syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder in which some cells in the body have an abnormal number of chromosomes instead of the usual 46 chromosomes, a situation known as aneuploidy. Most commonly, cells have an extra chromosome, which is called trisomy, or are missing a chromosome, which is known as monosomy. In MVA syndrome, some cells are aneuploid and others have the normal number of chromosomes, which is a phenomenon known as mosaicism. Typically, at least one-quarter of cells in affected individuals have an abnormal number of chromosomes. Because the additional or missing chromosomes vary among the abnormal cells, the aneuploidy is described as variegated.

In MVA syndrome, growth before birth is slow (intrauterine growth restriction). After birth, affected individuals continue to grow at a slow rate and are shorter than average. In addition, they typically have an unusually small head size (microcephaly). Another common feature of MVA syndrome is an increased risk of developing cancer in childhood. Cancers that occur most frequently in affected individuals include a cancer of muscle tissue called rhabdomyosarcoma, a form of kidney cancer known as Wilms tumor, and a cancer of the blood-forming tissue known as leukemia.

Less commonly, people with MVA syndrome have eye abnormalities or distinctive facial features, such as a broad nasal bridge and low-set ears. Some affected individuals have brain abnormalities, the most common of which is called Dandy-Walker malformation. Intellectual disability, seizures, and other health problems can also occur in people with MVA syndrome.

There are at least three types of MVA syndrome, each with a different genetic cause. Type 1 is the most common and displays the classic signs and symptoms described above. Type 2 appears to have slightly different signs and symptoms than type 1, although the small number of affected individuals makes it difficult to define its characteristic features. Individuals with MVA syndrome type 2 grow slowly before and after birth; however, their head size is typically normal. Some people with MVA syndrome type 2 have unusually short arms. Individuals with MVA syndrome type 2 do not seem to have an increased risk of cancer. Another form of MVA syndrome is characterized by a high risk of developing Wilms tumor. Individuals with this form may also have other signs and symptoms typical of MVA syndrome type 1.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

BUB1B gene mutations cause MVA syndrome type 1, CEP57 gene mutations cause MVA syndrome type 2, and TRIP13 gene mutations cause the other form of MVA syndrome. Some people with MVA syndrome do not have mutations in any of these genes. Other genes that have not been identified are likely also involved in the condition.

The proteins produced from the BUB1B, CEP57, and TRIP13 genes have roles in the proper separation of chromosomes during cell division. Before cells divide, they copy all of their chromosomes. To aid in the equal sorting of chromosomes to the two new cells, structures called spindle microtubules attach to the chromosomes and pull one copy of each to opposite sides of the cell. Then the cell divides such that each new cell has a full set of chromosomes. The CEP57 protein helps organize and stabilize the spindle microtubules. The BUBR1 protein, produced from the BUB1B gene, and the TRIP13 proteins help ensure that each copy of the duplicated chromosomes is attached to a spindle microtubule, and they prevent cell division if any remain unattached.

The BUB1B gene mutations reduce the amount of functional BUBR1 protein, and TRIP13 gene mutations lead to an absence of TRIP13 protein in cells. Without BUBR1 or TRIP13, cell division can proceed, even if not all the chromosomes are attached to spindle microtubules. The resulting errors in the sorting of chromosomes typically leads to the aneuploidy that occurs in MVA syndrome. (Some people with TRIP13 gene mutations have chromosome abnormalities that indicate problems with chromosome sorting but do not develop aneuploidy. These individuals do have the other signs and symptoms of MVA syndrome.) Research suggests that impairment of the process that delays cell division until the correct time underlies the increased risk of cancer in MVA syndrome, although the mechanism is not completely understood. It is also unclear how BUB1B or TRIP13 gene mutations or aneuploidy is involved in the other features of the condition.

CEP57 gene mutations are thought to reduce the amount of functional CEP57 protein in cells. The resulting problems with spindle microtubule organization may prevent the normal separation of chromosomes during cell division, leading to aneuploidy, although the mechanism is unknown. Researchers are working to understand how these genetic changes lead to the other features of MVA syndrome type 2 and why individuals with this form of the condition do not seem to have an increased risk of cancer.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

All types of MVA syndrome are inherited in an autosomal recessive pattern, which means both copies of the BUB1B, CEP57, or TRIP13 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Parents of individuals with MVA syndrome type 1, who have a mutation in one copy of the BUB1B gene, can have a related problem with their chromosomes called premature chromatid separation trait. Although these individuals have chromosome abnormalities that indicate trouble with normal chromosome separation during cell division, affected individuals usually have no health problems related to the trait.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

MVA syndrome is a rare condition. Its prevalence is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Ascites · Very frequent (99-80%)

Accumulation of fluid in the peritoneal cavity (between the layers of the peritoneum that lines the abdomen).

Cataract · Very frequent (99-80%)

A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Corneal opacity · Very frequent (99-80%)

A reduction of corneal clarity.

Dandy-Walker malformation · Very frequent (99-80%)

A congenital brain malformation typically characterized by incomplete formation of the cerebellar vermis, dilation of the fourth ventricle, and enlargement of the posterior fossa. In layman's terms, Dandy Walker malformation is a cyst in the cerebellum (typically symmetrical) that is involved with the fourth ventricle. This may interfere with the ability to drain cerebrospinal fluid from the brain, resulting in hydrocephalus. Dandy Walker cysts are formed during early embryonic development, while the brain forms. The cyst in the cerebellum typically has several blood vessels running through it connecting to the brain, thereby prohibiting surgical removal.

Epicanthus · Very frequent (99-80%)

A fold of skin starting above the medial aspect of the upper eyelid and arching downward to cover, pass in front of and lateral to the medial canthus.

Glaucoma · Very frequent (99-80%)

Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.

Increased nuchal translucency · Very frequent (99-80%)

Nuchal translucency is the sonographic appearance of subcutaneous accumulation of liquid in the back of the fetal neck in the first trimester of pregnancy (11-14 gestational weeks of pregnancy).

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Other findings in the same source

From: Orphanet

Additional reported features include Microphthalmia (Very frequent (99-80%)); Muscular dystrophy (Very frequent (99-80%)); Polyhydramnios (Very frequent (99-80%)); Short stature (Very frequent (99-80%)); Ventriculomegaly (Very frequent (99-80%)); Abnormality of the eye (Frequent (79-30%)); Abnormality of vision (Frequent (79-30%)); Global developmental delay (Frequent (79-30%)); Intellectual disability (Frequent (79-30%)); Microcephaly (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Mosaic variegated aneuploidy syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Mosaic variegated aneuploidy syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.