Rare Infectious Disease News

Disease Profile

Marshall-Smith syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

Q87.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Categories

Congenital and Genetic Diseases; Musculoskeletal Diseases

Summary

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]

Symptoms

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]

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.

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

Organizations

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

    Learn more

    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.

        References

        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.

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