Malan syndrome is a genetic, overgrowth and neurodevelopmental condition caused by genetic changes in the NFIX gene, which is important for the proper development of the brain, muscles and skeletal system.^1,2 Individuals with Malan syndrome may have excessive growth of the head (macrocephaly) and/or body during childhood. Additional characteristic features of Malan syndrome include distinct facial features, intellectual disability, hypotonia (low muscle tone), seizures, and gross/fine motor and speech delay.^3,4

Malan syndrome was previously referred to as Sotos-2 or Sotos-like syndrome due to similarity to Sotos syndrome.¹ Malan syndrome has so far been reported in approximately 100 individuals in the medical literature.

Synonyms: Sotos syndrome 2, Sotos-like syndrome.^5,6

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:420179 Malan overgrowth syndrome

ICD-11: LD2C Overgrowth syndromes

Symptoms and severity of Malan syndrome can vary between individuals, and between children and adults.^1,4

Common signs and symptoms may include:^1-3,6,7

• certain facial features such as large head size (macrocephaly), high and broad forehead, down-slanting eyes, long or triangular face, short nose, and low-set ears
• intellectual disabilities and learning difficulties
• speech and language delay
• behavioural features such as anxiety, attention deficit and hyperactivity disorder (ADHD), autism-like behaviours, sensitivity to noise, aggressiveness, and social challenges
• low muscle tone (hypotonia) and feeding difficulties in infants
• differences in bones and muscles such as advanced bone age, a thin/slender body build, scoliosis, or a sunken chest (pectus excavatum)
• taller than average height for their age during childhood
• problems with movement or coordination
• vision problems such as misaligned eyes (strabismus), optic nerve abnormality, short-sightedness (myopia), limited or no depth perception, and cerebral/cortical vision impairment (CVI)
• brain differences revealed in brain MRI such as ventricular dilation, underdevelopment of corpus callosum (nerve fibres that connect both sides of the brain) and Chiari I malformation

Other possible symptoms may include seizures and/or epilepsy, hearing loss, heart issues, dental problems, digestive (gastrointestinal) and sleep-related problems.^4,7

With age, individuals with Malan syndrome often have improvement in their speech, language and social skills, and overgrowth tends to become less noticeable.⁴

Please speak to your medical team to learn more about the symptoms and health implications of Malan 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.

Malan syndrome is a genetic condition. It is caused by disease-causing genetic changes (variants) in the nuclear factor one X-type/NFIX gene on chromosome 19.⁵ NFIX gene produces NFIX protein which controls genes involved in the development of the brain, muscles and skeletal system.²

All individuals have two copies (alleles) of the NFIX gene – one on each chromosome that is inherited from each parent. Malan syndrome is an autosomal dominant condition, which means that having a disease-causing genetic variant in just one of the NFIX gene copies can result in Malan syndrome.⁶

For most individuals with Malan syndrome, their genetic variant in the NFIX gene occurs randomly (de novo) prior to birth and is not passed down from their parents.⁶ In rare cases, the genetic variant was inherited from a parent who has the genetic variant in some but not all of their cells (this is called genetic mosaicism). More information on genetic mosaicism 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 Malan syndrome may be considered in individuals with characteristics symptoms and features associated with the condition. Diagnosis is confirmed with genetic testing to look for genetic variants in the NFIX gene.¹

Other tests may be performed, including:^1,3,8

• brain MRI to look for differences in the size and structure of the brain
• electroencephalogram (EEG) to assess brain activity
• neuropsychological tests to assess cognition (thinking) and social skills
• neurological tests to check the activity and health of nerves such as walking and balance
• musculoskeletal assessment to look for bone and muscle health

As part of the diagnosis process, doctors may rule out other conditions that have similar symptoms, such as Sotos syndrome, Weaver syndrome, Marfan syndrome, Marshall-Smith syndrome, Snyder–Robinson syndrome, marfanoid mental retardation syndrome and Lujan–Fryns syndrome.^1,5,8

Please speak to your medical team to learn more about the available diagnostic pathways for Malan syndrome.

There is currently no curative treatment for Malan syndrome. Treatment is targeted at managing symptoms (symptomatic management) and involves a multidisciplinary care team. This may include physiotherapy, occupational therapy, mobility aid, visual aid, speech and language therapy, augmentative and alternative communication tools such as the use of visual schedules, communication boards and digital devices, and behavioural interventions.^2,3

It is recommended that individuals are monitored for their growth and body mass index (BMI), skeletal health, vision, heart, neurological functions and managed accordingly.⁸

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.

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.

Healthcare professionals involved in the treatment of Malan syndrome may include general practitioners (GP), paediatricians, neurologists, cardiologists, optometrists, audiologists, endocrinologists, orthopaedic specialists, psychiatrists, physiotherapists, speech pathologists and others.⁷ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.

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

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context, and may not be up to date:

• A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report developed by a multidisciplinary team with expertise in Malan syndrome from Italy, published in 2022.
• Natural history in Malan syndrome: survey of 28 adults and literature review includes recommendations for management and follow-up in Malan syndrome adulthood, developed by Italian and Dutch Malan Syndrome centers of expertise in collaboration with Malan Syndrome Foundation, published in 2024.
• GeneReviews®: NFIX-related Malan syndrome published in 2024.

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.

It may be important to consider the following when managing individuals living with Malan syndrome at emergency departments/services:

• may have a high pain threshold
• may be prone to seizures
• may be anxious and have challenging physical behaviours (It is important for first responders to react calmly and de-escalate the situation)

Malan Syndrome Foundation: Research has information about research on Malan syndrome in Australia and overseas.

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.

Please note that RVA does not necessarily monitor or endorse each group/organisation’s operational governance and activities.

Global Organisation:
Malan Syndrome Foundation (United States of America)
Website: https://www.malansyndrome.org/
Malan Syndrome Foundation aims to improve the lives of individuals and families affected by Malan syndrome in the global community through support, outreach and research.

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.

Malan 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.

Malan Syndrome Foundation: Resources has resources to support parents/caregivers and peer support.

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 Malan syndrome can be found at:

• National Organization for Rare Disorders (NORD): Malan Syndrome
• Unique: Malan syndrome (NFIX-related disorder)
• Malan Syndrome Foundation: Parent Education Webinars
• Malan Syndrome Foundation: Resources

GeneReviews®: NFIX-Related Malan Syndrome

Online Mendelian Inheritance in Man, OMIM^®:#614753 Malan syndrome; MALNS

Orphanet: Malan overgrowth syndrome

Human Phenotype Ontology (HPO): Malan overgrowth syndrome

This page has been co-developed by Rare Voices Australia (RVA)’s RARE Portal team in consultation with Malan Syndrome Foundation.

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.