Coffin-Siris Syndrome 1

Coffin-Siris syndrome 1 is a very rare genetic condition that affects how a child grows and develops, especially the brain, face, fingers, and toes. It usually starts before birth and is lifelong. Children often have learning problems, delays in sitting, walking, and talking, special facial features, and small or missing nails and bones of the fifth fingers or toes.

Coffin-Siris syndrome 1 (CSS1) is a rare genetic condition that mainly affects brain development, growth, the face, and the nails of the little fingers and toes. Children usually have developmental delay, learning difficulty, low muscle tone, feeding trouble, frequent infections, and short stature. The syndrome is also called “dwarfism-onychodysplasia” because of short height and under-developed nails. [1]

CSS1 is most often caused by a harmful change (variant) in the ARID1B gene, which is part of the BAF (SWI/SNF) chromatin-remodeling complex that helps turn many other genes on and off during development. The inheritance pattern is autosomal dominant, but in most families the variant appears for the first time in the affected child (de novo). [2]

The word “syndrome” means a group of signs and symptoms that tend to occur together. Coffin-Siris syndrome belongs to a family of conditions caused by changes in genes that help control how DNA is packed and read inside cells (the SWI/SNF chromatin-remodeling complex). In type 1, the main gene that is changed is called ARID1B.

Doctors say Coffin-Siris syndrome is inherited in an autosomal dominant way. This means that a change in just one copy of the gene can cause the condition. However, most children with Coffin-Siris syndrome 1 have a new (de novo) change that did not come from either parent.

Coffin-Siris syndrome 1 is part of a wider “ARID1B-related disorder” spectrum. Some people have the full classic Coffin-Siris picture, while others have mainly intellectual disability with only mild physical signs. This shows that the effects of ARID1B changes can be very different from person to person.

Other names

Coffin-Siris syndrome was first described in 1970 by two doctors named Coffin and Siris. Over time, doctors noticed that some people with Coffin-Siris features had changes in different genes, so they divided the condition into several “types.” Type 1 is the form linked to the ARID1B gene.

Older medical books and articles may use other names for Coffin-Siris syndrome, such as “dwarfism-onychodysplasia,” “fifth digit syndrome,” or “short stature-onychodysplasia.” These names describe short height and abnormal nails of the fifth fingers and toes. Today, the preferred name is “Coffin-Siris syndrome,” and for the ARID1B-related form, “Coffin-Siris syndrome 1” or “ARID1B-related Coffin-Siris syndrome.”

Some very old names include words like “mental retardation with hypoplastic 5th fingernails and toenails.” Doctors now avoid the term “mental retardation” and instead use “intellectual disability,” because it is more respectful and up-to-date.

Genetic classification often lists several types of Coffin-Siris syndrome:

• Coffin-Siris syndrome 1 (CSS1) – ARID1B gene

• CSS2 – SMARCA4 gene

• CSS3 – SMARCB1 gene

• CSS4 – SMARCE1 gene

• CSS5 – ARID1A gene

Coffin-Siris syndrome 1 is the most common type, because ARID1B is changed more often than the other genes in people with Coffin-Siris features.

Causes of Coffin-Siris syndrome 1

Remember: all of these “causes” are really different ways that the same basic problem can happen – the ARID1B gene does not work properly, and this affects how the child’s body and brain develop.

1. Loss-of-function variant in ARID1B
   The main cause of Coffin-Siris syndrome 1 is a “loss-of-function” change in one copy of the ARID1B gene. This means the gene cannot make a normal protein or makes much less protein than usual. When ARID1B protein is low, the SWI/SNF complex cannot correctly control many other genes needed for growth and brain development.

2. De novo (new) ARID1B variant in the child
   In many children, the ARID1B change is new, meaning it appears for the first time in the child and is not found in the parents’ blood. This kind of variant happens by chance around the time of conception and is not caused by anything the parents did or did not do.

3. Autosomal dominant inheritance from an affected parent
   In some families, an adult with a mild ARID1B-related disorder can pass the gene change to their child. Each child then has a 50% chance to inherit the changed gene and to develop Coffin-Siris syndrome 1 or another ARID1B-related condition.

4. Frameshift mutations in ARID1B
   Frameshift mutations add or remove small pieces of DNA so that the reading frame of the gene shifts. This usually creates a very short, non-working ARID1B protein. Frameshift changes are a common cause of ARID1B-related disorder.

5. Nonsense mutations in ARID1B
   Nonsense mutations act like a sudden “stop sign” inside the gene. They can cause the cell to cut the message early and destroy it, leading to very little ARID1B protein. This is another typical mechanism behind Coffin-Siris syndrome 1.

6. Splice-site mutations in ARID1B
   Splice-site mutations affect the signals the cell uses to cut and join pieces of the gene’s message. If these signals are wrong, the ARID1B message can lose or gain parts, making the protein abnormal or unstable.

7. Missense mutations in important parts of ARID1B
   Some people have missense mutations, where only one “letter” of DNA is changed. If this change affects a critical part of the ARID1B protein, such as a domain that binds DNA or other proteins, it can still cause Coffin-Siris syndrome 1.

8. Microdeletion of the ARID1B gene
   In some children, a small piece of chromosome 6 that includes the ARID1B gene is missing. Losing the entire gene or part of it has the same effect as a damaging mutation and leads to ARID1B-related disorder.

9. Larger 6q deletions including ARID1B and nearby genes
   Some patients have a bigger deletion on chromosome 6q that removes ARID1B and other genes. These children can show Coffin-Siris features plus extra signs caused by the loss of nearby genes.

10. Variants in exon 1 of ARID1B
    Changes limited to exon 1 of ARID1B may sometimes cause a milder form of ARID1B-related disorder, but they still fit within the Coffin-Siris type 1 spectrum. This shows that not all ARID1B variants have the same strength of effect.

11. Gonadal mosaicism in a parent
    In rare families, a parent’s egg or sperm cells carry the ARID1B change, but the parent’s body does not show the variant on standard blood testing. This is called gonadal mosaicism and can lead to more than one child with Coffin-Siris syndrome 1 in the same family.

12. Somatic mosaicism for ARID1B in the child
    Sometimes, the ARID1B variant appears after the embryo has already started to divide. Then only some cells carry the change. This is called somatic mosaicism and may cause a milder or uneven pattern of symptoms.

13. Pathogenic variants in ARID1B regulatory regions
    Changes in the parts of DNA that control when and how strongly ARID1B is switched on can reduce its activity. These regulatory variants are harder to find but can still lead to ARID1B-related disorder and Coffin-Siris features.

14. Balanced rearrangements disrupting ARID1B
    Some chromosomal rearrangements, such as translocations or inversions, may look “balanced” on standard tests but split the ARID1B gene in the middle. This physical break can stop the gene from working.

15. Changes that reduce ARID1B protein (haploinsufficiency)
    All of the above DNA changes share a common result: only one working copy of ARID1B remains. This is called haploinsufficiency. One copy is not enough to support normal function of the SWI/SNF complex, so development is affected.

16. Disturbed SWI/SNF chromatin-remodeling complex
    ARID1B is a key piece of the SWI/SNF complex, which helps open and close parts of DNA so that genes can be turned on or off at the right time. When ARID1B is missing or faulty, the complex does not work properly, and many downstream genes in brain and organ development are mis-regulated.

17. Effects on early brain development
    Because ARID1B is active in early brain development, its loss can change how brain cells divide, move, and connect. This is why developmental delay and intellectual disability are central features of Coffin-Siris syndrome 1.

18. Effects on bone, nail, and hair development
    The same gene network also helps shape bones, nails, and hair. Disturbed ARID1B function can lead to the typical small or missing fifth finger and toe nails, bone differences, and a pattern of coarse facial features and body hair.

19. Unknown modifying genes and environment
    Some people with the same ARID1B variant show very different symptoms. Researchers think that other genes and general health factors may modify how strongly ARID1B loss is expressed. However, common everyday factors like parenting style or minor infections do not cause the syndrome.

20. Other ARID1B-related phenotypes within the same spectrum
    ARID1B changes can sometimes present first as isolated intellectual disability or autism-like features without obvious finger or nail changes. These cases still belong to the ARID1B-related spectrum and help explain why the syndrome can look different between families.

Symptoms and signs

Not every person with Coffin-Siris syndrome 1 has all of these features. Symptoms can be mild, moderate, or severe, even within the same family.

1. Global developmental delay
   Many babies and children learn skills later than other children their age. They may roll over, sit, stand, walk, and speak later than expected. Support with early-intervention programs and therapies can help them progress over time.

2. Intellectual disability or learning difficulties
   Most people with Coffin-Siris syndrome 1 have some level of intellectual disability. This can range from mild learning problems to more severe difficulties in understanding, problem-solving, and independent living. Special education and structured teaching can support learning.

3. Characteristic facial features
   Many children have a “coarse” facial appearance with thick eyebrows and eyelashes, a wide mouth, full lips, and a broad or flat nose tip. These features are harmless but help doctors recognize the syndrome.

4. Hypoplastic or absent fifth finger and toe nails
   One of the classic signs is very small (hypoplastic) or missing nails and sometimes shortened bones of the fifth fingers or toes. Sometimes other fingers and toes are also affected. This is why older names mention “onychodysplasia,” meaning nail problems.

5. Short fifth fingers or toes (digital hypoplasia)
   The bones at the tips of the fifth digits may be small or missing. The fingers may look short or slightly curved. This usually does not cause pain but can affect fine hand movements in some people.

6. Low muscle tone (hypotonia)
   Babies often feel “floppy” because of low muscle tone. They may have trouble holding up their head or sitting without support. Over time, tone can improve with physical therapy, but some degree of weakness or tiredness may remain.

7. Feeding problems and poor weight gain in infancy
   Many infants with Coffin-Siris syndrome 1 have trouble sucking, swallowing, or coordinating breathing and feeding. They may gain weight slowly and sometimes need special feeding support or feeding tubes in early life.

8. Sparse scalp hair with extra body hair (hypertrichosis)
   Some children have thin hair on the scalp but extra hair on other parts of the body, such as arms, legs, or back. This pattern is a typical but harmless feature of Coffin-Siris syndrome.

9. Small head size (microcephaly) in some patients
   Some individuals have a head size that measures below the usual range for their age and sex. This may reflect differences in brain growth associated with the syndrome.

10. Short stature or growth problems
    Many children are shorter than expected for their age. Growth can be affected by feeding problems, recurrent illness, and the underlying genetic condition. Regular monitoring of height and weight helps guide nutrition and care.

11. Frequent respiratory or other infections
    Infants may have recurrent chest infections or other illnesses. Factors such as low muscle tone, feeding difficulties, and possible immune differences can contribute. Vaccinations and prompt treatment of infections are important.

12. Seizures in some individuals
    A portion of people with Coffin-Siris syndrome 1 develop seizures. Seizures can vary in type and severity and may need regular care from a neurologist and treatment with anti-seizure medicines.

13. Behavioral and social differences
    Some children have attention problems, hyperactivity, anxiety, or features similar to autism, such as difficulty with social communication. Behavioral therapy and structured routines can help many families manage these challenges.

14. Heart, kidney, or other organ anomalies in some cases
    A few people have congenital heart defects, kidney differences, or other internal organ problems. These are not present in everyone but should be checked for, because they may need specific medical or surgical care.

15. Spinal and skeletal differences
    Some patients have scoliosis (curved spine), sacral dimples, or other spinal and skeletal changes. Regular orthopedic follow-up may be needed to monitor posture, walking, and pain.

Diagnostic tests for Coffin-Siris syndrome 1

Diagnosis is based on both clinical features and genetic testing. Many tests are used to understand the child’s overall health, rule out other conditions, and confirm the ARID1B change.

Physical examination tests

1. General physical examination
   The doctor carefully checks the whole body, including height, weight, head size, muscle tone, skin, and body hair. They look for patterns that suggest a genetic syndrome, such as growth differences, coarse facial features, and unusual nails or bones.

2. Growth measurements and growth charts
   Height, weight, and head circumference are measured and plotted on charts to see how the child compares to age-matched peers. Many children with Coffin-Siris syndrome 1 show short stature or small head size, which can support the diagnosis and guide nutrition.

3. Facial feature assessment (dysmorphology exam)
   A clinical geneticist often examines facial features in detail, looking at the eyes, nose, mouth, jaw, ears, and hair pattern. The specialist looks for the typical Coffin-Siris “face,” which, together with other signs, can strongly suggest the diagnosis.

4. Hand and foot examination
   The doctor inspects the fingers and toes, especially the fifth digits, for small or missing nails and shortened bones. They may compare both sides and check for similar changes on other digits. This pattern is a classic clue for Coffin-Siris syndrome.

5. Neurological examination
   A neurologist or pediatrician checks muscle tone, strength, reflexes, coordination, and movement. Low tone, delayed motor skills, or abnormal reflexes support the idea that the brain and nerves are involved, as seen in Coffin-Siris syndrome 1.

Manual (bedside) tests and clinical assessments

6. Developmental screening tests
   Simple bedside tools and structured questionnaires are used to check fine motor skills, gross motor skills, language, and social interaction. These tests show whether a child is meeting milestones and help document developmental delay typical of Coffin-Siris syndrome 1.

7. Detailed neuropsychological or educational assessment
   Older children may see a psychologist or educational specialist for more formal testing of IQ, memory, attention, and behavior. The results help describe the level of intellectual disability and guide schooling and therapies.

8. Manual muscle strength and joint movement testing
   Clinicians test strength by asking the child to push or pull against their hands and move each joint. They look for weakness, joint laxity, or contractures. This helps plan physical therapy and monitor progress over time.

9. Vision and eye-movement checks
   Basic bedside checks, such as following a toy or light with the eyes, look for vision problems, squinting, or unusual eye movements. More detailed eye exams may be done later, especially since visual issues and early high myopia have been reported in some ARID1B-related cases.

Laboratory and pathological tests

10. Basic blood tests (complete blood count and chemistry)
    Routine blood tests check red and white blood cells, platelets, and organ functions such as liver and kidney. These tests do not diagnose Coffin-Siris syndrome 1 directly but help rule out other causes of poor growth or fatigue and prepare for sedation or surgery if needed.

11. Endocrine and metabolic screening
    Some doctors order tests for thyroid function, blood sugar, and basic metabolic markers. These help identify treatable problems that can worsen developmental delay or growth issues, even though they are not the primary cause of Coffin-Siris syndrome.

12. Chromosomal microarray analysis
    Chromosomal microarray is often one of the first genetic tests. It looks for gains or losses of chromosomal pieces. It can detect microdeletions involving the ARID1B gene or larger 6q deletions that explain the child’s features.

13. Single-gene ARID1B sequencing
    If Coffin-Siris syndrome 1 or ARID1B-related disorder is strongly suspected, doctors may order sequencing of the ARID1B gene. This test reads through the gene’s coding regions to find pathogenic variants such as nonsense or frameshift mutations.

14. Multi-gene panel for Coffin-Siris and related syndromes
    Many laboratories offer panels that test ARID1B plus other Coffin-Siris genes (ARID1A, SMARCA4, SMARCB1, SMARCE1, etc.) at the same time. This is useful because several different genes can cause overlapping features, and a panel improves the chance of a diagnosis.

15. Whole exome or whole genome sequencing
    When simpler tests do not give an answer, exome or genome sequencing can look at almost all genes at once. Many people with Coffin-Siris syndrome 1 and other ARID1B-related disorders have been diagnosed through exome studies, especially in children with unexplained developmental delay.

Electrodiagnostic tests

16. Electroencephalogram (EEG)
    EEG records the brain’s electrical activity using small electrodes on the scalp. It is used when seizures are suspected or confirmed. In Coffin-Siris syndrome 1, EEG can help classify seizure types and guide anti-seizure treatment plans.

17. Nerve conduction studies and electromyography (EMG), when needed
    These tests measure how well signals travel along nerves and how muscles respond. They are not needed for every patient but may be used if there is concern about specific neuromuscular problems, such as unusual weakness or fatigue not explained by low tone alone.

Imaging tests

18. Brain MRI
    Magnetic resonance imaging (MRI) gives detailed pictures of the brain. In some people with Coffin-Siris syndrome 1, MRI shows structural differences, such as changes in the corpus callosum or other brain regions. These findings can support the diagnosis and help understand developmental challenges.

19. Echocardiogram (heart ultrasound)
    An echocardiogram uses sound waves to look at the heart’s structure and pumping function. Because some patients have congenital heart defects, this test checks for holes between heart chambers, valve problems, or other issues that may need treatment.

20. Skeletal X-rays and spine imaging
    X-rays of the hands, feet, and spine can show shortened or missing bones of the fifth digits, scoliosis, or other skeletal differences. These images provide objective documentation of bone changes that belong to the Coffin-Siris pattern and may guide orthopedic care.

Non-pharmacological treatments

Each of these approaches is tailored to the child’s age, abilities, and associated health problems.

1. Early intervention developmental program – A structured program started in infancy that combines therapies to support sitting, standing, walking, understanding, and communication. It uses play-based learning to build skills step by step and to prevent avoidable delays. Families are coached to repeat simple exercises at home every day. [1]

2. Physiotherapy (physical therapy) – A physiotherapist works on muscle strength, posture, balance, and joint stability, which are often weak in CSS1 because of hypotonia and joint laxity. Regular stretching, strengthening, and gait training reduce contractures, improve walking, and lower the risk of falls and spine deformities. [2]

3. Occupational therapy – Occupational therapists help children learn daily living skills such as feeding, dressing, writing, and using toys. They adapt tools (modified cutlery, grips, splints) and the home or school environment so the child can participate more safely and independently despite fine-motor and coordination problems. [3]

4. Speech and language therapy – Speech therapists assess understanding, expressive language, and oral-motor control. Many children with CSS1 have delayed or limited speech. Therapy uses pictures, sign language, or communication devices, together with mouth exercises, to improve communication and reduce frustration and behaviour problems. [4]

5. Feeding and swallowing therapy – A feeding specialist evaluates sucking, chewing, and swallowing in babies and children with poor feeding and reflux. Thickened feeds, special nipples, posture changes, and swallowing exercises are used to improve safety and growth and to reduce aspiration (food going into the lungs). [5]

6. Behavioural therapy / ABA-based support – Structured behavioural programs help manage hyperactivity, autism-like features, and challenging behaviours. Therapists use positive reinforcement, visual schedules, and predictable routines, teaching parents how to handle meltdowns and improve attention and social skills in everyday life. [6]

7. Special education services – Individual education plans in school adjust teaching speed, class size, and learning supports. Visual aids, repetition, and one-to-one help allow children with intellectual disability to learn at their own pace and remain included in mainstream or special classrooms as appropriate. [7]

8. Vision (low-vision) therapy and ophthalmology care – Regular eye exams detect strabismus, refractive errors, or structural eye problems reported in CSS. Glasses, patching, and vision exercises help the brain use both eyes better and support motor development and reading skills. [8]

9. Hearing and audiology services – Because recurrent ear infections and hearing loss can occur, periodic hearing tests and early use of hearing aids or grommet tubes are important. Better hearing improves speech development and reduces behavioural and learning difficulties. [9]

10. Respiratory physiotherapy and airway clearance – Children with weak muscles and frequent chest infections may need breathing exercises, chest physiotherapy, and suctioning techniques. These help clear mucus, improve oxygenation, and may reduce hospital admissions from pneumonia or bronchiolitis. [10]

11. Orthopaedic rehabilitation and bracing – Braces, splints, and orthotic shoes support unstable joints, flat feet, or spinal curvature. They reduce pain, prevent worsening deformity, and make standing and walking safer. Orthopaedic teams review X-rays and growth patterns regularly during childhood. [11]

12. Assistive communication and mobility devices – Tablets with communication apps, picture boards, wheelchairs, walkers, or standing frames are used when speech or mobility is limited. These devices give the child more independence, reduce caregiver strain, and improve participation at home and school. [12]

13. Hydrotherapy (aquatic therapy) – Supervised exercise in warm water makes it easier to move weak or stiff muscles by reducing the effect of gravity. Children feel safer and more comfortable, so they practice walking, balance, and joint movement with less pain and more enjoyment. [13]

14. Psychological support and counselling – Psychologists help children and families cope with stress, anxiety, grief, and long-term caregiving demands. Therapy can address attention problems, mood symptoms, and family communication, improving quality of life for everyone in the household. [14]

15. Family and caregiver training – Teaching parents and caregivers about the condition, seizure first aid, feeding strategies, and behaviour management turns them into confident partners in care. Clear written plans reduce emergency visits and make home care safer and more consistent. [15]

16. Social work and community support – Social workers help families access disability benefits, respite care, transport support, and inclusive schooling. This reduces financial and emotional burden and allows caregivers to rest, which is essential in long-term rare disease care. [16]

17. Sleep hygiene and environmental adjustments – Structured bedtime routines, dark quiet rooms, and behavioural strategies for sleep can improve disturbed sleep caused by neurological or behavioural issues. Better sleep often improves daytime behaviour, attention, and family wellbeing. [17]

18. Dental and oral-motor care – Regular dental checks and oral-motor exercises address drooling, chewing problems, and dental decay. Correct mouth care is important when facial features, crowding, or feeding issues increase the risk of cavities and swallowing difficulties. [18]

19. Regular multidisciplinary surveillance – Scheduled reviews by neurology, cardiology, nephrology, endocrinology, and genetics teams monitor seizures, heart defects, kidney function, growth, puberty, and behaviour. Early detection of complications allows gentler and safer treatment. [19]

20. Genetic counselling and family planning support – Genetic counsellors explain the cause, recurrence risk, and options for future pregnancies (such as prenatal or preimplantation genetic testing). This helps families make informed decisions and reduces guilt and confusion about the diagnosis. [20]

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Drug treatments

There is no single medicine that cures CSS1. Medicines are chosen to treat seizures, infections, breathing issues, reflux, behaviour, and other complications. Regulatory information comes from sources such as U.S. Food and Drug Administration (FDA) labeling for the individual drugs. [21]

Never use these examples to self-medicate. All doses and choices must be made by a specialist for each child.

1. Antiseizure drugs – levetiracetam – Levetiracetam is widely used as a first-line add-on drug for many seizure types. It is usually given twice daily by mouth or intravenously, with the dose adjusted to weight and kidney function. It reduces abnormal brain electrical activity and helps control generalized or focal seizures that can occur in CSS1. Common side effects include sleepiness, dizziness, and mood changes. [22]

2. Antiseizure drugs – valproate (where appropriate) – Valproate can control generalized seizures and myoclonic jerks when used under strict specialist supervision, usually in divided daily doses. It increases brain levels of GABA, a calming neurotransmitter. Side effects may include weight gain, tremor, hair changes, and liver or platelet problems; it is avoided or carefully controlled in females who may become pregnant because of strong safety warnings. [23]

3. Rescue benzodiazepines – diazepam or similar – For prolonged or cluster seizures, emergency benzodiazepines (rectal, buccal, or injectable forms) may be used following a written epilepsy action plan. They quickly enhance GABA activity to stop seizures. Side effects include drowsiness, breathing depression, and dependence risk with repeated use, so they are reserved for emergencies only. [24]

4. Bronchodilators – albuterol (salbutamol) inhaler or nebuliser – Children with recurrent wheeze or respiratory infections may receive short-acting beta-2 agonists by inhaler or nebuliser, usually every few hours as prescribed during attacks. These drugs relax airway muscles and open the breathing tubes. Possible side effects are fast heartbeat, tremor, and jitteriness. [25]

5. Inhaled or systemic corticosteroids – In selected children with significant airway inflammation or asthma, inhaled or short courses of oral steroids reduce airway swelling and help prevent severe attacks. They act by blocking many inflammatory pathways. Long-term use can cause weight gain, high blood pressure, and bone thinning, so doctors aim for the lowest effective dose. [26]

6. Antibiotics for recurrent infections – Because some children have frequent chest or ear infections, antibiotics are prescribed only when there is clear evidence of bacterial infection (fever, imaging, lab tests). The choice and dosage depend on age, kidney function, and local resistance. Overuse can lead to resistance, diarrhea, and allergic reactions, so prophylactic use is considered carefully. [27]

7. Acid suppression – proton pump inhibitors (PPIs) – Children with severe reflux, poor weight gain, or aspiration risk may receive PPIs such as omeprazole once or twice daily. These drugs block stomach acid production, relieving pain and protecting the oesophagus and lungs from acid injury. Long-term use can slightly increase risks of infections and affect mineral absorption, so monitoring is needed. [28]

8. Constipation and motility medicines – Stool softeners or osmotic laxatives are used for chronic constipation caused by low tone, reduced mobility, or medications. They work by drawing water into the bowel or stimulating movement. Proper use prevents abdominal pain, faecal impaction, and urinary problems, but doses must be adjusted to avoid diarrhoea and electrolyte imbalance. [29]

9. ADHD and behavioural medicines (when indicated) – In some older children, stimulant or non-stimulant ADHD medicines may be considered to improve attention and learning, together with behavioural therapy. They alter neurotransmitters like dopamine and norepinephrine. Potential side effects include appetite loss, sleep problems, and mood changes, so close monitoring by child psychiatry or neurology is essential. [30]

10. Supportive cardiovascular or endocrine drugs – If heart defects, arrhythmias, or hormonal problems (such as thyroid or growth hormone issues) are present, standard cardiology or endocrinology medicines are used according to guidelines for those specific diseases. Treatment is not for CSS1 itself but for associated organ problems, with dosing and monitoring tailored individually. [31]

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Dietary molecular supplements

Supplements should only be started after nutritional and blood assessment, because needs differ widely and overdoses can be harmful. [32]

1. Vitamin D – Vitamin D supports bone strength, muscle function, and immune regulation. It is usually given once daily or weekly in doses based on blood levels and age. In children with limited outdoor activity or anticonvulsant use, it helps prevent rickets and fractures by improving calcium absorption from the gut. [33]

2. Calcium – When intake from food is low or bone density is reduced, calcium supplements can be given in divided doses with meals. Calcium is essential for bones, nerve signalling, and muscle contraction. Combined with vitamin D and weight-bearing activity, it lowers fracture risk; too much can cause kidney stones or constipation. [34]

3. Iron – If blood tests show iron-deficiency anaemia from poor intake or chronic illness, iron drops or tablets are used once or twice daily. Iron is required to make haemoglobin for oxygen transport. Adequate iron improves energy, growth, and cognition, but excess iron can upset the stomach and, rarely, damage organs. [35]

4. Folate (folic acid) – Folate supports red blood cell production and DNA synthesis. It may be supplemented in children with poor diet, malabsorption, or certain antiseizure medicines. Correct folate levels help prevent anaemia and support growth, but high unnecessary doses may hide vitamin B12 deficiency. [36]

5. Vitamin B12 – Vitamin B12 is important for nerve function and blood formation. Supplementation (oral or injection) is considered when levels are low due to poor intake or absorption. Normalising B12 can improve fatigue and neurological symptoms, but it must be guided by lab tests to avoid missing other causes. [37]

6. Omega-3 fatty acids – Omega-3 fats from fish oil or algae oil may support brain development, behaviour, and heart health. They act partly by reducing inflammation and influencing cell membranes in the brain. Doses are usually calculated by body weight; common side effects are mild stomach upset or fishy aftertaste. [38]

7. Protein or peptide supplements – High-energy oral nutrition formulas provide extra protein and calories for children with poor appetite or increased needs. They supply amino acids that support muscle growth, immune function, and healing. A dietitian chooses the type and amount to avoid obesity or metabolic imbalance. [39]

8. Medium-chain triglyceride (MCT) oil – MCT oil is more easily absorbed and quickly converted to energy than long-chain fats. Adding small amounts to feeds can help children who struggle with weight gain. It must be introduced gradually because too much can cause diarrhoea or nausea. [40]

9. Probiotics – Selected probiotic strains may help with constipation, bloating, or antibiotic-associated diarrhoea by supporting a healthier gut microbiome. They work by competing with harmful bacteria and modulating immune responses in the intestine. Their use should be discussed in medically fragile children. [41]

10. Antioxidant vitamins (C and E with trace elements) – Antioxidant mixtures can support general cell protection by neutralising harmful free radicals, especially in children with chronic inflammation or frequent infections. Over-supplementation may cause gastrointestinal upset or interact with other medicines, so doses should stay within recommended ranges. [42]

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Immunity-booster, regenerative and stem-cell-related drugs

At present, there is no approved stem cell or gene therapy that specifically corrects CSS1. Any “regenerative” approach must be part of a regulated clinical trial. [43]

1. Routine childhood vaccines – Standard immunisations against infections such as pneumonia, influenza, and whooping cough are among the most powerful “immune boosters” because they prime the immune system safely. Keeping vaccines up to date reduces severe infections that children with CSS1 may be more vulnerable to. [44]

2. Additional risk-based vaccines – Depending on heart, lung, or spleen status, extra vaccines (for example against pneumococcus or RSV in some regions) may be recommended. They work by training immune cells to recognise specific microbes before real exposure happens, lowering hospitalisation risk. [45]

3. Immunoglobulin therapy (select situations) – In rare cases with proven antibody deficiency and recurrent severe infections, intravenous or subcutaneous immunoglobulin may be used. It supplies pooled antibodies from donors to temporarily strengthen the immune system. Side effects can include headache, fever, and infusion reactions, so treatment is specialist-led. [46]

4. Hematopoietic stem cell transplant (only for specific co-existing disorders) – Stem cell transplant is not a standard therapy for CSS1 itself, but may be used if the child also has another serious bone-marrow disease. Donor stem cells repopulate the bone marrow, restoring blood formation. The procedure carries high risks (infection, graft-versus-host disease) and is considered only in carefully selected cases. [47]

5. Growth factors (for associated cytopenias if present) – If a child develops particular blood-cell deficiencies due to another overlapping condition, doctors may use drugs like G-CSF or erythropoietin to stimulate blood cell production. These are injected at schedules defined by haematology teams. They do not change CSS1 but help manage complications. [48]

6. Experimental gene- and cell-based therapies – Research on chromatin-remodelling disorders and ARID1B-related conditions is ongoing in laboratory and animal models. Theoretical approaches include gene repair or modulation of downstream pathways. At present these strategies are experimental only and should be accessed only through ethical clinical trials, never through unregulated clinics. [49]

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Surgeries

1. Repair of congenital heart defects – If echocardiography finds structural heart problems such as septal defects or valve issues, paediatric cardiac surgeons may close holes or repair valves. Correcting these defects can improve growth, exercise tolerance, and reduce the risk of heart failure or lung damage. [50]

2. Orthopaedic surgery for spine or limb deformities – Severe scoliosis, hip dislocation, or rigid foot deformities sometimes need surgery when bracing and therapy are not enough. Straightening bones and stabilising joints can reduce pain, improve sitting or walking, and prevent long-term lung or nerve problems. [51]

3. ENT surgery for airway and ear problems – Adenoidectomy, tonsillectomy, or grommet insertion may be used to manage obstructive sleep apnoea, recurrent ear infections, or chronic fluid behind the eardrum. These operations improve breathing, sleep quality, and hearing, which in turn support development. [52]

4. Ophthalmic surgery – If there is significant strabismus, cataract, or other operable eye disease, eye surgery can help align the eyes or clear the visual axis. Early correction optimises visual development and supports balance, learning, and communication. [53]

5. Gastrostomy tube placement (feeding tube) – For children with very poor oral intake, severe reflux, or unsafe swallowing, a small feeding tube may be placed into the stomach through the abdominal wall. It allows safe delivery of balanced nutrition and medicines, promoting growth and reducing aspiration risk. [54]

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Prevention of complications

Although the gene change itself cannot be prevented, many complications can be reduced by proactive care. [55]

1. Keep vaccinations up to date to prevent serious infections. [56]

2. Attend regular multidisciplinary clinic visits for early detection of heart, kidney, or neurological problems. [57]

3. Start therapies (physio, OT, speech) as early as possible to limit long-term disability. [58]

4. Maintain good hand hygiene, dental care, and respiratory hygiene to lower infection and aspiration risks. [59]

5. Optimise nutrition and growth with help from a dietitian, avoiding both under-nutrition and excessive weight gain. [60]

6. Provide safe home adaptations to prevent falls and injuries (rails, non-slip mats, supervised bathing). [61]

7. Ensure regular hearing and vision checks so problems are treated before they damage development. [62]

8. Monitor sleep and breathing; seek early assessment for snoring, pauses in breathing, or daytime sleepiness. [63]

9. Have a written seizure and emergency plan if epilepsy is present, shared with school and caregivers. [64]

10. Use genetic counselling for future pregnancies to understand recurrence risks and options. [65]

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When to see doctors urgently

Parents and caregivers should seek urgent medical help if the child has:

• Breathing difficulty, blue lips, fast breathing, or repeated chest infections. [66]

• Prolonged seizures, repeated seizures close together, or new seizure types. [67]

• Very poor feeding, vomiting, dehydration, or failure to gain weight. [68]

• Sudden loss of skills (such as walking or speaking) or major behaviour change. [69]

• High fever, lethargy, or signs of serious infection. [70]

Regular planned follow-up with genetics, neurology, cardiology, respiratory, and rehabilitation teams is also essential, even when the child seems stable. [71]

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What to eat and what to avoid

1. Focus on balanced, nutrient-dense meals – Offer a mix of vegetables, fruits, whole grains, proteins, and healthy fats to support growth, immunity, and healing. [72]

2. Prioritise adequate protein – Include eggs, milk, yoghurt, beans, fish, or meat to help build muscle and repair tissues, especially when mobility is reduced. [73]

3. Use energy-dense foods if weight gain is poor – Add healthy fats (olive oil, nut butters where safe, MCT oil as advised) to increase calories in small portions. [74]

4. Encourage fibre and fluids – Fruits, vegetables, and whole grains plus enough water help prevent constipation, a common problem in children with low tone and limited activity. [75]

5. Limit sugary drinks and ultra-processed snacks – High-sugar foods add empty calories and increase dental decay risk, especially when oral hygiene is difficult. [76]

6. Avoid choking-risk foods where oral-motor control is weak – Hard nuts, raw carrot sticks, whole grapes, and hard candies can be dangerous; foods should be cut, mashed, or thickened according to swallowing safety assessments. [77]

7. Adjust textures for reflux and swallowing issues – Thickened liquids, smooth purees, or soft solids may reduce aspiration and discomfort, under guidance from feeding and speech specialists. [78]

8. Check interactions between diet and medicines – Some medicines work better away from certain foods or supplements, so pharmacists should review the full list of drugs and nutrients. [79]

9. Involve a paediatric dietitian – A dietitian can calculate calorie, protein, and micronutrient needs and design an individual meal plan or tube-feeding regimen that fits cultural and family preferences. [80]

10. Monitor growth and adjust regularly – Weight, height, and head size should be plotted on charts. Diet is then adjusted to promote steady growth without excessive weight gain that could worsen mobility or sleep apnoea. [81]

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Frequently asked questions

1. Is Coffin-Siris syndrome 1 the same as Coffin-Siris syndrome?
   CSS1 usually refers to the classic Coffin-Siris phenotype caused by ARID1B variants, but clinically it overlaps with other Coffin-Siris types caused by different genes. In practice, many clinicians simply say “Coffin-Siris syndrome” and then specify the gene on the report. [82]

2. How common is CSS1?
   CSS1 is very rare; only a few hundred cases of Coffin-Siris syndrome have been reported worldwide, and ARID1B variants are the most frequent cause among them. Many milder individuals may remain undiagnosed, so true numbers are likely higher. [83]

3. What are the main signs and symptoms?
   Typical signs include developmental delay, learning difficulties, hypoplastic or absent fifth fingernails or toenails, coarse facial features, sparse scalp hair, joint laxity, and short stature. Additional features can include heart, kidney, brain, eye, and skeletal differences, but not every child has all of these. [84]

4. Can children with CSS1 learn and go to school?
   Most children benefit from early therapies and tailored education. Many can attend school with special support, although some may need specialised settings. Progress is usually slower than peers, but with the right support many children gain communication and self-care skills. [85]

5. Is life expectancy always reduced?
   Life expectancy depends on the severity of organ problems such as heart defects, lung disease, or severe feeding difficulties. With good medical care and monitoring, many individuals can live into adulthood, but precise long-term data are still limited because the condition is rare. [86]

6. Is CSS1 inherited from parents?
   CSS1 follows an autosomal dominant pattern, but in most families the variant arises for the first time in the affected child. Once a disease-causing variant is known, each future pregnancy has a 50% chance of inheriting it if a parent carries the variant. [87]

7. Can prenatal or preimplantation testing be done?
   If the exact ARID1B (or other) variant is known in the family, targeted prenatal testing or preimplantation genetic testing may be possible in specialised centres. Genetic counselling helps families understand benefits, limits, and ethical aspects of these tests. [88]

8. Is there any cure or gene therapy now?
   At present there is no approved gene or stem cell therapy that cures CSS1. Research on chromatin-remodelling disorders is active, but current treatment is supportive and focused on symptoms and development. [89]

9. Do all children with CSS1 have seizures?
   No. Some children develop epilepsy, while others never have seizures. Those with seizures are treated with standard antiseizure medicines and monitored by a paediatric neurologist. [90]

10. Can CSS1 be confused with other syndromes?
    Yes. The facial features and developmental pattern can overlap with Nicolaides-Baraitser syndrome and other BAF-complex disorders. Detailed clinical assessment and genetic testing are usually needed to confirm the diagnosis. [91]

11. Will my child always need a wheelchair?
    Many children with CSS1 walk with or without aids, while others with more severe hypotonia or orthopaedic issues may need wheelchairs for long distances. Early physiotherapy, orthotics, and surgery when needed can maximise mobility. [92]

12. Does CSS1 affect puberty or fertility?
    Some individuals may have growth and pubertal differences, but detailed fertility data are limited. Endocrine review during adolescence helps detect treatable hormonal problems and allows individual counselling about future fertility. [93]

13. How can families cope emotionally?
    Living with a rare genetic condition is stressful. Psychological support, parent support groups, and rare-disease organisations can provide information and emotional connection, reducing isolation and helping families advocate for their children. [94]

14. Can adults with CSS1 live independently?
    Outcomes vary widely. Some adults need high levels of support for daily activities, while others can work in sheltered or supported environments and live semi-independently with community help. Planning for transition to adult services is important during teenage years. [95]

15. What is the single most important thing parents can do?
    The most powerful steps are early diagnosis, early therapies, and continuous coordinated care with a multidisciplinary team. Combined with love, patience, and advocacy, these give the child the best chance to reach their own maximum potential. [96]

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: February 01, 2025.