National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Marshall-Smith syndrome

Marshall-Smith syndrome (MRSHSS) is a genetic disorder in which individuals typically have advanced bone age, difficulties gaining weight (failure to thrive), unique facial features, and intellectual disability. Other signs and symptoms of this condition may include eye abnormalities, breathing difficulties, and neurological issues. Individuals may also have heart defects, an increased amount of body hair (hirsutism), and flat feet (pes planus).[1][2][3]

MRSHSS is caused by mutations in the NFIX gene. Most individuals with MRSHSS are the first in their family with this condition and are said to have a spontaneous (de novo) mutation.[3] Although there is no specific treatment or cure for MRSHSS, there may be ways to manage the symptoms. A team of doctors is often needed to figure out the treatment options based on each person’s symptoms. Aggressive management of the early breathing and feeding problems may improve survival in individuals affected by this condition.[2]
Last updated: 6/14/2017
The main features of MRSHSS include intellectual disability and developmental delay, severe breathing difficulties, distinctive facial features (a wide and prominent forehead, protruding and widely spaced eyes, a depressed nasal bridge, a small upturned nose, and a small jaw (micrognathia)), accelerated skeletal maturation, and issues with weight gain compared to height (relative failure to thrive).

The breathing difficulties individuals with this condition experience are due to a number of underlying airway issues, which may include upper airway obstruction related to a small and/or underdeveloped jaw, narrowing of the nasal airway (choanal stenosis), and/or an abnormal larynx. Additionally, aspiration pneumonia may be a factor, which is typically secondary to an underdeveloped epiglottis and pharyngeal incoordination. Sleep apnea may also be associated.[4]

Other common signs and symptoms are:[1][2][4]
  • A blue tint to the whites of the eyes (blue sclera)
  • An abnormal curve in the spine (scoliosis and kyphosis)
  • Loss of tissue in the gums
  • Heart defects, such as a hole in the heart between the different chambers (septal defects)
  • Protrusion of part of the intestines through the umbilical opening in the abdominal muscles (umbilical hernia)
  • An abnormal amount of hair growth over the body (hirsutism)
  • Hearing loss
Individuals with MRSHSS may also have neurological problems, including low muscle tone (hypotonia) and brain structural anomalies, such as enlarged ventricles in the brain (ventriculomegaly), and an abnormal number of folds in the brain (pachygyria or polymicrogyria). A condition caused by underdevelopment of the optic nerves and structures along the midline of the brain (septo-optic dysplasia) may also occur. Rarely, individuals experience seizures.[4]
Last updated: 6/14/2017

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Accelerated skeletal maturation
Advanced bone age
Early bone maturation
[ more ] 		0005616
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils
[ more ] 		0000463
Bowing of the long bones
Bowed long bones
Bowing of long bones
[ more ] 		0006487
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation
[ more ] 		0001249
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Prominent forehead
Pronounced forehead
Protruding forehead
[ more ] 		0011220
Proptosis
Bulging eye
Eyeballs bulging out
Prominent eyes
Prominent globes
Protruding eyes
[ more ] 		0000520
Retrognathia
Receding chin
Receding lower jaw
Weak chin
Weak jaw
[ more ] 		0000278
Slender long bone
Long bones slender
Thin long bones
[ more ] 		0003100
Thin skin 0000963
30%-79% of people have these symptoms
Blue sclerae
Whites of eyes are a bluish-gray color
0000592
Bruising susceptibility
Bruise easily
Easy bruisability
Easy bruising
[ more ] 		0000978
Conductive hearing impairment
Conductive deafness
Conductive hearing loss
[ more ] 		0000405
Generalized hirsutism
Excessive hairiness over body
0002230
Hypertelorism
Wide-set eyes
Widely spaced eyes
[ more ] 		0000316
Increased susceptibility to fractures
Abnormal susceptibility to fractures
Bone fragility
Frequent broken bones
Increased bone fragility
Increased tendency to fractures
[ more ] 		0002659
Open mouth
Gaped jawed appearance
Gaped mouthed appearance
Slack jawed appearance
[ more ] 		0000194
Protruding tongue
Prominent tongue
Tongue sticking out of mouth
[ more ] 		0010808
Reduced bone mineral density
Low solidness and mass of the bones
0004349
Scoliosis 0002650
Short nose
Decreased length of nose
Shortened nose
[ more ] 		0003196
5%-29% of people have these symptoms
Abnormality of cardiovascular system morphology 0030680
Cerebellar hypoplasia
Small cerebellum
Underdeveloped cerebellum
[ more ] 		0001321
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity
[ more ] 		0000453
Craniosynostosis 0001363
Gingival overgrowth
Gum enlargement
0000212
Optic atrophy 0000648
Ventriculomegaly 0002119
Percent of people who have these symptoms is not available through HPO
Agenesis of corpus callosum 0001274
Apnea 0002104
Atlantoaxial dislocation 0003414
Atrial septal defect
An opening in the wall separating the top two chambers of the heart
Hole in heart wall separating two upper heart chambers
[ more ] 		0001631
Autosomal dominant inheritance 0000006
Bullet-shaped middle phalanges of the hand 0009845
Cerebral atrophy
Degeneration of cerebrum
0002059
Choanal stenosis
Narrowing of the rear opening of the nasal cavity
0000452
Death in childhood 0003819
Decreased body weight
Decreased weight
Low body weight
Low weight
Weight less than 3rd percentile
[ more ] 		0004325
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root
[ more ] 		0005280
Distal widening of metacarpals
Wide outermost end of long bone
0006048
Eclabion
Outward turned lips
0012472
Frontal bossing 0002007
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ] 		0001290
Glossoptosis
Retraction of the tongue
0000162
Hearing impairment
Deafness
Hearing defect
[ more ] 		0000365
Hypertension 0000822
Hypoplasia of the odontoid process 0003311
Irregular dentition
Irregular teeth
0040079
Large sternal ossification centers 0006642
Laryngomalacia
Softening of voice box tissue
0001601
Low-set ears
Low set ears
Lowset ears
[ more ] 		0000369
Macrogyria 0007227
Malar flattening
Zygomatic flattening
0000272
Midface retrusion
Decreased size of midface
Midface deficiency
Underdevelopment of midface
[ more ] 		0011800
Motor delay 0001270
Muscular hypotonia
Low or weak muscle tone
0001252
Obstructive sleep apnea 0002870
Omphalocele 0001539
Overfolded helix
Overfolded ears
0000396
Patent ductus arteriosus 0001643
Pectus excavatum
Funnel chest
0000767
Prominence of the premaxilla
Anterior position of the premaxilla
Anterior position of the primary palate bone
Prominence of the primary palate bone
[ more ] 		0010759
Pulmonary arterial hypertension
Increased blood pressure in blood vessels of lungs
0002092
Recurrent aspiration pneumonia 0002100
Shallow orbits
Decreased depth of eye sockets
Shallow eye sockets
[ more ] 		0000586
Short distal phalanx of finger
Short outermost finger bone
0009882
Short mandibular rami 0003778
Short philtrum 0000322
Short sternum 0000879
Sporadic
No previous family history
0003745
Synophrys
Monobrow
Unibrow
[ more ] 		0000664
Tall stature
Increased body height
0000098
Thick eyebrow
Bushy eyebrows
Dense eyebrow
Heavy eyebrows
Prominent eyebrows
Thick eyebrows
[ more ] 		0000574
Umbilical hernia 0001537
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Last updated: 7/1/2020
While most of the literature available on MRSHSS is made up of case reports, we have not been able to locate any articles which specifically address the issue of speech and/or language development. We recommend that you check the medical literature by searching PubMed, a searchable database of medical literature periodically for new reports. You may also find it useful to contact one of the organizations supporting this condition, such as the MSS Research Foundation. 

Last updated: 6/15/2017

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis should include Weaver syndrome and Sotos syndrome, which share similar skeletal findings but are not associated with recurrent respiratory infections or characteristic facies.
Visit the Orphanet disease page for more information.

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Financial Resources

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Marshall-Smith syndrome. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • I am a speech language pathologist with a child affected by Marshall-Smith syndrome on my caseload. Do the symptoms of this syndrome vary widely between patients? Is there any information regarding speech / language prognosis for these children? See answer


  1. McKusick VA. Marshall-Smith Syndrome. Online Mendelian Inheritance in Man (OMIM). July 6, 2016; https://www.omim.org/entry/602535.
  2. What is Marshall-Smith Syndrome?. MSS Research Foundation. https://www.marshallsmith.org/en/what-is-mss. Accessed 6/14/2017.
  3. Aggarwal A, Nguyen J, Rivera-Davila M, Rodriguez-Buritica D. Marshall-Smith syndrome: Novel pathogenic variant and previously unreported associations with precocious puberty and aortic root dilatation. Eur J Med Genet. July 2017; 60(7):391-394. https://www.ncbi.nlm.nih.gov/pubmed/28442439.
  4. Shaw AC, van Balkom ID, Bauer M et al. Phenotype and natural history in Marshall-Smith syndrome. Am J Med Genet. November 2010; 152A(11):2714-26. https://www.ncbi.nlm.nih.gov/pubmed/20949508.