Coffin-Lowry syndrome is a genetic condition caused by genetic changes in the RPS6KA3 gene on the X chromosome (X-linked condition).¹ It is characterised by developmental delay, intellectual disability, characteristic head, facial and hand features, neurological symptoms, and spine problems. Symptoms usually begin to appear in infants and young children. Males are often more severely affected than females.²

Synonyms: CLS, RPS6KA3-related intellectual disability, Coffin syndrome.^1-3

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:192 Coffin-Lowry syndrome

ORPHA:276630 Symptomatic form of Coffin-Lowry syndrome in female carriers

ICD-11: LD2F.1Y Other specified syndromes with multiple structural anomalies, not of environmental origin

Symptoms and severity of Coffin-Lowry syndrome vary between individuals.³ It tends to be more severe in males, while females usually have no to mild symptoms.

Some common symptoms of Coffin-Lowry syndrome include:^1-3

• developmental delay such as speech delay and motor skills delay
• intellectual disability, which ranges from mild to severe
• spine problems such as abnormal curvature of the spine (kyphoscoliosis), sunken or protruding chest wall which may lead to complications in the heart or lung function
• short stature
• neurological features such as hypotonia (low muscle tone), seizures, stimulus-induced drop attacks (brief collapse or fall without loss of consciousness; usually triggered by unexpected noise, excitement or emotional event), or partial paralysis of the legs
• characteristic head and facial features such as prominent forehead, widely spaced and down-slanted eyes, broad nose bridge with a thick septum (wall between left and right nasal spaces), protruding ears, open mouth and thick lips
• hands that are soft and padded, hyperextensible joints, stretchy skin, and short tapered fingers (fingers that are narrow from the knuckle towards the tips, giving them a cone-like shape)
• hearing loss

There may be other issues such as obstructive sleep apnoea and problems with the teeth, eyesight and heart.³

Please speak to your medical team to learn more about the symptoms and complications of Coffin-Lowry syndrome.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

Coffin-Lowry syndrome is a genetic condition caused by disease-causing genetic changes (variants) in the RPS6KA3 gene (also known as RSK2 gene) on X chromosome.^2,4 RPS6KA3 gene is important for cells signaling and development, and in the brain for cognitive function and learning.⁴

For most individuals with Coffin-Lowry syndrome, their genetic variant in RPS6KA3 gene occurs randomly without any family history (de novo).^3,4

In some cases, the genetic variant is inherited from their parent.³ Both males and females can be affected, but males are often more severely affected. As males only have one X chromosome, they have one copy of the RPS6KA3 gene, so if their RPS6KA3 gene has the disease-causing genetic variant, they will have Coffin-Lowry syndrome. Females have two X chromosomes and two copies of RPS6KA3 genes. A female with genetic variant in their RPS6KA3 gene is usually a carrier with mild to no symptoms. These genetic variants can be passed onto the next generation. More information on X-linked inheritance pattern can be found at Centre for Genetics Education: X-linked inheritance.

In rare cases, the genetic variant in the RPS6KA3 gene is inherited from an unaffected parent who has the genetic variants only in their egg or sperm cells but not in any other cells.³ This is called germline mosaicism, more information can be found at Centre for Genetics Education: Mosaicism.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Diagnosis of Coffin-Lowry syndrome may be made based on:^3,4

• physical examination
• family history
• evaluation of developmental milestones
• genetic testing
• brain imaging (MRI scans)
• radiology tests
• study of RSK2 protein activity

As part of the diagnostic process, doctors may do a differential diagnosis, where they rule out other conditions that have similar symptoms, such as Alpha-thalassemia-X-linked intellectual disability (ATRX) syndrome, Borjeson-Forssman-Lehmann syndrome, FG syndrome type 1, Williams syndrome and Pitt-Hopkins syndrome.²

Please speak to your medical team to learn more about the available pathways for diagnosis of Coffin-Lowry syndrome.

There is currently no curative treatment for Coffin-Lowry syndrome. Treatment is targeted at managing symptoms (symptomatic management) and involves a multidisciplinary care team. This may include:³

• medications to manage stimulus-induced drop attacks and seizures
• bracing or spine surgery to manage spine anomalies
• protective measures such as use of protective helmet or wheelchair to prevent fall and injury
• physiotherapy and use of mobility aids (i.e. walkers, bath chairs, adaptive strollers, orthotics)
• occupational therapy
• nutritional and feeding support
• augmentative and alternative communication
• hearing aid
• vision aid

It is recommended that individuals be monitored for their growth, hearing, vision, spine, heart function, and treated accordingly.^3,4

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities.

Healthcare professionals involved in the care of people with Coffin-Lowry syndrome may include general practitioners (GP), paediatricians, neurologists, orthopaedic specialists, physiotherapists, occupational therapists, cardiologists, dentists, audiologists, ophthalmologists, psychiatrists, respiratory and sleep physicians (sleep specialists).³ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

For many rare diseases, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. Palliative care is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. For more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

We are not aware of any clinical care guidelines for Coffin-Lowry syndrome in Australia or internationally. If you know of any relevant care guidelines, please let us know via the Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in any clinical trials with your medical team to determine suitability and eligibility.

Australian Organisation:
We are not aware of any rare disease organisations for Coffin-Lowry syndrome in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page.

International Organisation:
Coffin-Lowry Syndrome Foundation (United States of America)
Website: https://coffinlowry.org/

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

Coffin-Lowry syndrome varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease, including families and carers, often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many people find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information on Coffin-Lowry syndrome can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Coffin-lowry syndrome
• National Organization for Rare Disorders (NORD): Coffin Lowry Syndrome

GeneReviews®: RPS6KA3-Related Intellectual Disability

Online Mendelian Inheritance in Man, OMIM^®:#303600 Coffin-Lowry syndrome; CLS

Online Mendelian Inheritance in Man, OMIM^®:#300844 Intellectual developmental disorder, X-linked 19; XLID19

Orphanet: Coffin-Lowry syndrome

Orphanet: Symptomatic form of Coffin-Lowry syndrome in female carriers

Human Phenotype Ontology (HPO): Coffin-Lowry syndrome

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.