Coffin-Siris syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Coffin-Siris syndrome is a condition that affects several body systems. Although there are many variable signs and symptoms, hallmarks of this condition include developmental disability, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features.

Most affected individuals have mild to severe intellectual disability or delayed development of speech and motor skills such as sitting and walking. Another feature of Coffin-Siris syndrome is underdevelopment (hypoplasia) of the tips of the fingers or toes, or hypoplasia or absence of the nails. These abnormalities are most common on the fifth fingers or toes.

In addition, most people with Coffin-Siris syndrome have facial features described as coarse. These features typically include a wide nose with a flat nasal bridge, a wide mouth with thick lips, and thick eyebrows and eyelashes. Affected individuals can have excess hair on other parts of the face and body (hirsutism), but scalp hair is often sparse. People with Coffin-Siris syndrome can have a range of facial features, and not all affected individuals have the typical features. In addition, people with this condition may have an abnormally small head (microcephaly).

Additionally, some infants and children with Coffin-Siris syndrome have frequent respiratory infections, difficulty feeding, and an inability to gain weight at the expected rate (faltering weight). Other signs and symptoms that may occur in people with this condition include short stature, low muscle tone (hypotonia), and abnormally loose (lax) joints. Abnormalities of the eyes, brain, heart, and kidneys may also be present.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Coffin-Siris syndrome is caused by variants (also known as mutations) in one of several genes. Variants in the ARID1B gene are the most common known cause of the condition. Variants in the ARID1A, SMARCA4, SMARCB1, SMARCE1, or SOX11 gene can also cause the condition. In addition, variants in a few other genes (listed below) have been found to each cause a very small number of cases. In some of these cases, it is unclear if the condition should be considered Coffin-Siris syndrome or a similar but separate disorder. In many cases of Coffin-Siris syndrome, the genetic cause is unknown.

The above genes are involved in controlling the activity (expression) of other genes. The ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1 genes, as well as some of the genes involved in rare cases of Coffiin-Siris syndrome, provide instructions for making single pieces (subunits) of several different SWI/SNF protein complexes. SWI/SNF complexes regulate gene expression by a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly regions of DNA are packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is often lower than when DNA is loosely packed.

Through their ability to regulate gene activity by remodeling chromatin, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells.

Although it is unclear what effect variants in the ARID1A, ARID1B, SMARCA4, SMARCB1, or SMARCE1 gene have on SWI/SNF complexes, researchers suggest that the variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, which could explain the diverse signs and symptoms of Coffin-Siris syndrome.

Research suggests that the SOX11 gene, another gene associated with Coffin-Siris syndrome, is one of many genes regulated by SWI/SNF complexes. The protein produced from this gene acts as a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Other genes involved in rare cases of Coffin-Siris syndrome also provide instructions for making proteins that act as transcription factors.

The SOX11 protein is particularly important for development of the brain and differentiation of nerve cells (neurons). SOX11 gene variants disrupt the ability of the SOX11 protein to control gene activity, which is thought to alter development of the brain, neurons, and possibly other tissues, leading to intellectual disability and other signs and symptoms of Coffin-Siris syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Coffin-Siris syndrome appears to follow an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, the condition is not usually inherited from an affected parent, but occurs from new (de novo) variants in the gene that likely occur during early embryonic development.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Coffin-Siris syndrome is a rare condition that, for unknown reasons, is diagnosed in females more frequently than in males. Approximately 200 cases have been reported in the medical 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.

Coarse facial features · Very frequent (99-80%)

Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.

Feeding difficulties · Very frequent (99-80%)

Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.

Hypertrichosis · Very frequent (99-80%)

Hypertrichosis is increased hair growth that is abnormal in quantity or location.

Prominent eyelashes · Very frequent (99-80%)

Eyelashes that draw the attention of the viewer due to increased density and/or length and/or curl without meeting the criteria of trichomegaly.

Small nail · Very frequent (99-80%)

A nail that is diminished in length and width, i.e., underdeveloped nail.

Thick eyebrow · Very frequent (99-80%)

Increased density/number and/or increased diameter of eyebrow hairs.

Thick lower lip vermilion · Very frequent (99-80%)

Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).

Wide mouth · Very frequent (99-80%)

Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).

Other findings in the same source

From: Orphanet

Additional reported features include Abnormal facial shape (Frequent (79-30%)); Abnormal heart morphology (Frequent (79-30%)); Abnormality of the genitourinary system (Frequent (79-30%)); Anteverted nares (Frequent (79-30%)); Aspiration pneumonia (Frequent (79-30%)); Atypical behavior (Frequent (79-30%)); Broad nasal tip (Frequent (79-30%)); Broad philtrum (Frequent (79-30%)); Clinodactyly (Frequent (79-30%)); Cryptorchidism (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 Coffin-Siris 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 Coffin-Siris 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.