Years published: 2023
NORD gratefully acknowledges Qinxiao (Allison) Wu, NORD Editorial Intern from the University of Notre Dame; Kate Richardson, MS, CGC, McGovern Medical School, UTHealth Houston; Manuela Priolo, MD, Head, Medical and Molecular Genetics Unit, AORN Cardarelli, Naples, Italy and Christal Delagrammatikas, PhD, Director of Research, Malan Syndrome Foundation, for the preparation of this report.
Malan syndrome is a rare genetic disorder that belongs to a larger group of disorders known as overgrowth syndromes. In general, overgrowth syndromes are characterized by a faster rate of growth before or after birth and can occur in any part of the body including bone, skin, muscles and organs. Malan syndrome is caused by genetic changes (pathogenic variants) in the NFIX gene. The age of onset is typically in infancy. Characteristics of this disorder include mild to moderate overgrowth in height at an early age, large head size (macrocephaly), weak muscles (hypotonia), intellectual disability, speech delay, motor delay, vision problems, brain abnormalities seen on MRI, breastbone abnormalities, curvature of the spine (scoliosis), seizures, autistic-like traits and mental health concerns such as anxiety. Less commonly, individuals with Malan syndrome can have differences in the shape or structure of their heart (congenital heart defect) and might have an abnormally wide aorta (aortic dilatation).
Malan syndrome was first described in 2010 by Dr. Valerie Malan. Prior to 2010, individuals with these symptoms and characteristics were diagnosed with “Sotos-like syndrome” because many of the medical problems associated with Malan syndrome are similar to a different genetic disorder, known as Sotos syndrome.
Symptoms of Malan syndrome generally appear in infancy. Most symptoms are related to a child’s size or developmental milestones. Malan syndrome is reported to have variable expressivity. Variable expressivity means that there is a range of symptoms that can occur in people affected with the same genetic condition.
Most affected individuals have a larger head size (macrocephaly, 75%), intellectual disability, motor delay, speech delay, autism or autistic-like behaviors (such as difficulty with social situations, understanding emotions, repetitive behaviors or dislike of certain sounds or textures), mental health concerns such as anxiety, weak muscles (hypotonia), seizures, differences noted on brain MRI imaging (such as underdevelopment of corpus callosum [part of the brain that connects the left and the right side], wide ventricles, brain atrophy [smaller size of the brain], and Chiari malformation [brain tissue extends into the spinal canal], misaligned eyes (strabismus), involuntary shaking of eyes (nystagmus), vision issues (difficulty seeing near or far away), smaller size in the optic nerve causing vision loss (optic nerve hypoplasia or atrophy), above average height for age (tall stature), slender or thin body shape, advanced bone age, spine curvature, bones in the chest growing inward making a dip in the chest (pectus excavatum) or bones in the chest grow outward causing a bulge in the chest (pectus carinatum).
Less common medical problems include hearing problems or reduced tolerance of sound (hyperacusis), increased risk for bone fractures, difference in shape or structure of the heart (congenital heart defect), including a larger aorta, which is the part of the heart that carries blood to the rest of your body (aortic dilatation). Malan syndrome is an exceptionally rare condition, and other medical problems might be found to be associated with this condition in the future.
Individuals with Malan syndrome can look similar to one another, and geneticists or other healthcare providers may use specific terms to describe what they see on the physical exam. Things they might note may include a long, narrow, triangular-shaped face, broad forehead, down-slanting eyes, prominent chin, small mouth, misaligned and twisted teeth because of lack of space in the mouth (dental crowding), roof of the mouth that is deeper than expected (high arched palate), anteverted nose (tip of the nose is upturned), short nose, long fingers and toes, increased range of movement of joints (hypermobility) and blue tint to the whites of the eyes (blue sclera).
Malan syndrome is caused by genetic changes (pathogenic variants) in the nuclear factor I X (NFIX) gene. Genes are the body’s instruction manual for creating proteins that play critical roles in how the body grows and develops properly. When a pathogenic variant in a gene occurs, it causes the protein to stop working. Depending on the function of the protein, it can affect many parts of the body. The NFIX gene encodes for a transcription factor and is important for brain, muscle, and bone development and differentiation. Transcription factors turn specific genes ‘on’ and ‘off’ in the body. Pathogenic variants in the NFIX gene cause this transcription factor to be partially unavailable for the body to use (haploinsufficiency), and as a result, other genes in the body do not know when to properly turn ‘on’ or ‘off.’ The transcription factor is needed for normal development, and when not working properly leads to the signs and symptoms of Malan syndrome. Malan syndrome can also be caused by microdeletions in the region of chromosome 19 where the NFIX gene is located (19p13.2).
Malan syndrome is an autosomal dominant disorder. This means that a genetic change (pathogenic variant) in only one of the two copies of the NFIX gene is necessary to cause the disease. The risk of passing the genetic change from an affected person to a child is 50% for each pregnancy. The risk is the same for males and females. So far, most individuals reported to be diagnosed with Malan syndrome did not inherit the pathogenic variant from either parent. In these patients, the variant occurred for the first time in them (referred to as de novo). There are a few reports of siblings who both have a diagnosis of Malan syndrome due to the same pathogenic variant, but their parents do not have the same pathogenic variant as the children. This is referred to as germline mosaicism, meaning the genetic change was only present in either the parents’ egg or sperm.
There are approximately 300 individuals worldwide who have a diagnosis of Malan syndrome, making this an exceptionally rare diagnosis. Malan syndrome affects males and females equally and does not occur more frequently in any specific ethnic group. As of 2023, the oldest person living with Malan syndrome is 60 years old.
A thorough evaluation by a clinical geneticist is necessary to accurately diagnose Malan syndrome. Genetic testing is the primary method of diagnosis. Exome or NFIX sanger sequencing can be used to read the letters of the genetic code to look for pathogenic changes in the NFIX gene. Another genetic test that may be ordered is a chromosome microarray, which is a test that looks for extra or missing pieces of the genetic code. Individuals who have a partial or completely missing copy of the NFIX gene are also affected with Malan syndrome.
Clinical Testing and Work-Up
Physical exam and imaging can evaluate for medical problems associated with Malan syndrome. An electroencephalogram (EEG) is used to assess brain activity for the risk of seizures. A brain MRI can be used to look for differences in the size and structure of the brain.
An echocardiogram, or a scan of the heart, can identify structural or functional differences in the heart. If any are identified, long-term follow-up with a cardiologist may be needed. Routine screening is recommended for aortic dilatation.
Scoliosis can be monitored by a pediatrician and a referral to orthopedics (bone doctor) can be provided, if needed.
There currently is no cure for Malan syndrome and treatment is focused on the management of the medical problems that are present. Treatment and management is often coordinated by a neurologist. Seizures can be treated with antiepileptic drugs.
For vision issues, an optometrist, low vision specialist, ophthalmologist and/or neuro-ophthalmologist can monitor and provide glasses or other therapies as needed. Routine eye evaluations may be recommended to monitor for vision loss or other eye problems such as small optic nerves or cataracts.
For individuals with developmental delays or a diagnosis of autism, interventional therapies including speech, occupational, physical and behavior therapies may be recommended. Mental health concerns such as anxiety may be treated with medication.
Academic support for individuals with intellectual disability may include but is not limited to a 504 plan, teacher’s aide or an individualized educational plan (IEP).
Genetic counseling is recommended for families with an affected child.
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