Disease Overview
Signs & Symptoms
Causes
Affected Populations
Disorders with Similar Symptoms
Diagnosis
Standard Therapies
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Malan Syndrome

Last updated: 10/13/2023
Years published: 2023

Acknowledgment

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.

Disease Overview

Summary

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).

Introduction

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.

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Signs & Symptoms

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).

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Causes

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.

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Affected populations

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.

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Disorders with Similar Symptoms

Symptoms of the following genetic disorders can be similar to those of Malan syndrome.

Sotos syndrome
Sotos syndrome is a rare genetic disorder characterized by rapid growth before and after birth. Individuals with Sotos syndrome typically have a height 2 to 3 years ahead of their peers during childhood and adult height is above average. Medical problems can include developmental delays, low muscle tone (hypotonia), speech difficulties and intellectual disability. In most patients, Sotos syndrome is caused by a single genetic change (pathogenic variant) in the NSD1 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Sotos Syndrome” as your search term in the Rare Disease Database.)

Marshall-Smith syndrome
Marshall-Smith Syndrome (MSS) is a rare genetic disorder characterized by accelerated bone formation and problems with growth and nutrition.This syndrome is associated with low muscle tone (hypotonia), difficulty gaining weight, intellectual disability, developmental delays, frequent infections (weaker immune system), difference in the structure and shape of the brain and breathing difficulties. This genetic disorder is also caused by a change in the NFIX gene. The genetic changes that cause MSS are at a specific location within the NFIX gene. MSS is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Marshall-Smith Syndrome” as your search term in the Rare Disease Database.)

Snyder-Robinson syndrome
Snyder-Robinson syndrome (SRS) is a rare genetic syndrome associated with intellectual disability and tall stature and typically only affects males. Characteristics of this syndrome include above average height (tall stature), thin body shape (low muscle mass), vision issues, intellectual disability, seizures, bones in the chest grow inward making a dip in the chest (pectus excavatum) and weaker bones leading to fractures (osteoporosis). The genetic change (pathogenic variant) that causes SRS is in the SMS gene on the X chromosome. (For more information on this disorder, choose “Snyder-Robinson Syndrome” as your search term in the Rare Disease Database.)

Lujan-Fryns syndrome
Lujan-Fryns syndrome is a rare genetic syndrome that typically affects males and is characterized by above average height (tall stature) and intellectual disability. Features of this syndrome include a large head size (macrocephaly), extra or crowded teeth, differences in the shape or structure of the heart, bones in the chest growing inward making a dip in the chest (pectus excavatum), flexible joints, seizures, low muscle tone (hypotonia, and various behavioral problems. The genetic change (pathogenic variant) that causes Lujan-Fyrns syndrome is in the MED12 gene on the X chromosome.

Marfan syndrome
Marfan syndrome is a genetic disorder that varies significantly in symptoms and severity. The condition can affect multiple systems in the body, including the heart, blood vessels, skeleton, eyes, lungs and skin. Common physical findings in individuals with Marfan syndrome include a thin body shape with long limbs, slender fingers and facial features such as a long, narrow skull, deep-set eyes and a small jaw. Cardiovascular problems are common, such as a leaky valve in the heart (mitral valve prolapse) and enlarged aorta, the part of the heart that delivers oxygen to the body. Curvature in the spine (scoliosis) and trouble seeing far away items (nearsightedness) and dislocation of the lenses in the eyes (lens displacement, ectopia lentis) are also common. Marfan syndrome is caused by genetic changes (pathogenic variants) in the FBN1 gene and is inherited in an autosomal dominant manner. (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.)

Weaver syndrome
Weaver syndrome (WS) is a rare genetic disorder primarily characterized by above average height (tall stature) and faster bone growth. Children with WS may show symptoms that include normal or high weight, a large head (macrocephaly) and uncoordinated movements. Muscle rigidity in the arms and legs, along with looser core muscles, can lead to poor coordination. Individuals with WS can have a range of intellectual abilities, from normal intelligence to severe intellectual disability. The condition is often caused by genetic changes (pathogenic variants) in the EZH2 gene and is inherited in an autosomal dominant pattern. (For more information on this disorder, choose “Weaver Syndrome” as your search term in the Rare Disease Database.)

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Diagnosis

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.

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Standard Therapies

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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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Alﬁeri P, Montanaro FAM, Macchiaiolo M, Collotta M, Caciolo C, Galassi P, Panﬁli FM, Cortellessa F, Zollino M, Chinali M, Accadia M, Seri M, Bartuli A, Mammì C, Tartaglia M, Vicari S and Priolo M. Behavioral proﬁling in children and adolescents with Malan syndrome. Front. Child Adolesc. Psychiatry 2023; 2:1106228. doi: 10.3389/frcha.2023.1106228

Alfieri P, Macchiaiolo M, Collotta M, Montanaro FAM, Caciolo C, Cumbo F, Galassi P, Panfili FM, Cortellessa F, Zollino M, et al. Characterization of cognitive, language and adaptive profiles of children and adolescents with Malan syndrome. Journal of Clinical Medicine. 2022; 11(14):4078. https://doi.org/10.3390/jcm11144078

Bellucco FT, de Mello CB, Meloni VA, Melaragno MI. Malan syndrome in a patient with 19p13.2p13.12 deletion encompassing NFIX and CACNA1A genes: Case report and review of the literature. Mol Genet Genomic Med. 2019 Dec;7(12):e997. doi: 10.1002/mgg3.997. Epub 2019 Oct 1. PMID: 31574590; PMCID: PMC6900369

Klaassens, M., Morrogh, D., Rosser, E. et al. Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature. Eur J Hum Genet, 2015; 23: 610–615. https://doi.org/10.1038/ejhg.2014.162

Langley E, Farach LS, Mowrey K. Case Report: Novel pathogenic variant in NFIX in two sisters with Malan syndrome due to germline mosaicism. Front Genet. 2022 Nov 9;13:1044660. doi: 10.3389/fgene. 2022.1044660. PMID: 36437934; PMCID: PMC9682143

Macchiaiolo, M., Panfili, F.M., Vecchio, D. et al. A deep phenotyping experience: up to date in management and diagnosis of Malan syndrome in a single center surveillance report. Orphanet J Rare Dis. 2022; 17: 235 (2022). https://doi.org/10.1186/s13023-022-02384-9

Priolo M, Schanze D, Tatton-Brown K, Mulder PA, et al. Further delineation of Malan syndrome. Hum Mutat. 2018 Sep;39(9):1226-1237. doi: 10.1002/humu.23563. Epub 2018 Jun 25. PMID: 29897170; PMCID: PMC6175110

Malan V, Rajan D, Thomas S, Shaw AC, Louis Dit Picard H, Layet V, Till M, van Haeringen A, Mortier G, Nampoothiri S, Puseljić S, Legeai-Mallet L, Carter NP, Vekemans M, Munnich A, Hennekam RC, Colleaux L, Cormier-Daire V. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. Am J Hum Genet. 2010 Aug 13;87(2):189-98. doi: 10.1016/j.ajhg.2010.07.001. Epub 2010 Jul 30. PMID: 20673863; PMCID: PMC2917711.

INTERNET
Priolo M, Zenker M and Hennekam RC.‘’Malan Syndrome, Overgrowth Syndromes: A Clinical Guide. Oxford Monographs on Medical Genetics (New York, 2019; online edn, Oxford Academic, 1 Mar. 2019), https://doi.org/10.1093/med/9780190944896.003.0008 AccessedSept 25, 2023.

Malan Syndrome Foundation: https://www.malansyndrome.org/ Accessed Sept 25, 2023.

Malan overgrowth syndrome. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=420179 Accessed Sept 25, 2023

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