Bohring-Opitz syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Bohring-Opitz syndrome is a rare condition that affects the development of many parts of the body.

Most individuals with Bohring-Opitz syndrome have profound to severe intellectual disability, developmental delay, and seizures. Most affected individuals have a normal head shape and size with no brain abnormalities; however, some have abnormal development of the head. Abnormal development can lead to a small head size (microcephaly) and a skull abnormality called trigonocephaly, which gives the forehead a pointed appearance. Structural brain abnormalities can occur with or without head abnormalities. For example, the fluid-filled spaces near the center of the brain (ventricles) may be usually large (ventriculomegaly) or the tissue that connects the left and right halves of the brain (the corpus callosum) can be abnormally thin.

Eye problems that can affect vision also occur in people with Bohring-Opitz syndrome. People with this disorder may have protruding eyes (exophthalmos), eyes that do not point in the same direction (strabismus), widely spaced eyes (hypertelorism), or outside corners of the eyes that point upward (upslanting palpebral fissures). Affected individuals may have severe nearsightedness (high myopia) or abnormalities in the light-sensitive tissue at the back of the eye (the retina) or the nerves that carry information from the eyes to the brain (optic nerves).

Additional facial differences associated with Bohring-Opitz syndrome can include a flat nasal bridge, nostrils that open to the front rather than downward (anteverted nares), a high arch or opening in the roof of the mouth (high arched or cleft palate), a split in the upper lip (cleft lip), a small lower jaw (micrognathia), low-set ears that are rotated backward, a red birthmark (nevus simplex) on the face (usually the forehead), a low frontal hairline often with eyebrows that grow together in the middle (synophrys), and excessive body and facial hair (hirsutism) that increases with age.

Some individuals with Bohring-Opitz syndrome have poor growth before birth (intrauterine growth retardation). During infancy, they grow and gain weight slowly and often have severe feeding difficulties with recurrent vomiting.

People with this condition often have characteristic body positioning, known as Bohring-Opitz syndrome posture. This posture consists of slouching shoulders, bent elbows and wrists, hands positioned with the wrists or all of the fingers angled outward toward the fifth finger (ulnar deviation), with the legs usually extended straight. Affected individuals usually stop exhibiting the Bohring-Opitz syndrome posture as they get older. Other abnormalities include joint deformities (called contractures) that are apparent at birth in the knees, hips, or other joints and abnormal muscle tone. Affected individuals can have recurrent infections and heart, kidney, or genital abnormalities. In rare cases, a childhood form of kidney cancer known as Wilms tumor can develop.

Some individuals with Bohring-Opitz syndrome do not survive past early childhood, while others live into adolescence or early adulthood. The most common causes of death are heart problems, abnormalities of the throat and airways that cause pauses in breathing (obstructive apnea), and lung infections.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Bohring-Opitz syndrome is caused by mutations in the ASXL1 gene. This gene provides instructions for making a protein that is involved in a process known as chromatin remodeling. Chromatin is the complex of DNA and proteins that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Through its role in chromatin remodeling, the ASXL1 gene regulates the activity (expression) of many genes, including a group of genes known as HOX genes, which play important roles in development before birth. The ASXL1 protein can turn on (activate) or turn off (repress) HOX genes depending on when they are needed.

ASXL1 gene mutations reduce the amount of functional ASXL1 protein available, which likely disrupts the regulation of the activity of HOX genes and other genes during development. Altered activity of these genes probably leads to the neurological and physical features of this condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Bohring-Opitz syndrome is considered an autosomal dominant condition, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of the condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family. No one with Bohring-Opitz syndrome has been known to have children.

Very rarely, individuals with Bohring-Opitz syndrome inherit the altered gene from their unaffected mother, who has the mutation only in some cells, including egg cells, but not in others. This phenomenon is known as mosaicism.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Bohring-Opitz syndrome is thought to be a rare condition, although its exact prevalence is unknown. More than 40 affected individuals have been described in the scientific literature.

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.

Neurodevelopmental delay · Very frequent (99-80%)

Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.

Nevus flammeus · Very frequent (99-80%)

A congenital vascular malformation consisting of superficial and deep dilated capillaries in the skin which produce a reddish to purplish discolouration of the skin.

Agenesis of corpus callosum · Frequent (79-30%)

Absence of the corpus callosum as a result of the failure of the corpus callosum to develop, which can be the result of a failure in any one of the multiple steps of callosal development including cellular proliferation and migration, axonal growth or glial patterning at the midline.

Apnea · Frequent (79-30%)

Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.

Axial hypotonia · Frequent (79-30%)

Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.

Bradycardia · Frequent (79-30%)

A slower than normal heart rate (in adults, slower than 60 beats per minute).

Coloboma · Frequent (79-30%)

A developmental defect characterized by a cleft of some portion of the eye or ocular adnexa.

Congenital contracture · Frequent (79-30%)

One or more flexion contractures (a bent joint that cannot be straightened actively or passively) that are present at birth.

Other findings in the same source

From: Orphanet

Additional reported features include Facial hypotonia (Frequent (79-30%)); Feeding difficulties in infancy (Frequent (79-30%)); Food intolerance (Frequent (79-30%)); Full cheeks (Frequent (79-30%)); Happy demeanor (Frequent (79-30%)); Hypertrichosis (Frequent (79-30%)); Hypoplasia of the corpus callosum (Frequent (79-30%)); Inability to walk (Frequent (79-30%)); Intellectual disability, profound (Frequent (79-30%)); Intellectual disability, severe (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 Bohring-Opitz 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 Bohring-Opitz 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.