Marshall-Smith Syndrome

Disease Overview

Summary

Marshall-Smith syndrome (MSS) typically begins before birth and is characterized by excessive and rapid physical growth, specifically in bone development (maturation). Other symptoms that may occur in an individual with Marshall-Smith syndrome are developmental delays, respiratory issues and infections, as well as distinguishing physical characteristics.

Introduction

The first cases of Marshall-Smith syndrome were identified in 1971 by physicians R.E. Marshall, C.B. Graham, C.R. Scott, and D.W. Smith. These two MSS cases were identified in male infant patients who died by the age of 20 months. (Note: Marshall-Smith syndrome is not to be confused with “Marshall” syndrome, which is very different from “Marshall-Smith” syndrome.)

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Synonyms

• MSS

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Signs & Symptoms

Marshall-Smith syndrome (MSS) is largely characterized with faster than normal bone growth. Due to their taller stature, patients have low muscle tone, muscle weakness, and may experience difficulties in gaining weight. Patients with Marshall-Smith syndrome may also have abdominal hernias (umbilical hernias), intellectual developmental delays, psychomotor delays (slowing down of thought and voluntary movements), and/or breathing difficulties. The breathing difficulties can sound like a high-pitched noisy breath, due to abnormal neck extension, with the tongue blocking the airway. Some traits related to the windpipe of Marshall-Smith syndrome patients include the abnormal development of the leaf-shaped structure in the throat that stops foods and liquids from entering the windpipe. The nasal passages may be smaller, and these patients may have an abnormal larynx with soft cartilage. Patients with Marshall-Smith syndrome typically have a long head with a prominent forehead, prominent eyes, an upturned nose with a low nasal bridge, and excessive hair growth. The patient’s eye whites may appear bluish, and the lower jawbone may be smaller than average. Their fingertips may appear narrow while the rest of the finger may appear broad.

Some patients with MSS may experience additional symptoms including a shorter breastbone, as well as a deep crease between the big toe and the second toe. Some brain abnormalities may occur, including atrophy (loss of brain cells), macrogyria (larger than normal grooves in the brain), or a missing corpus callosum. Patients with Marshall-Smith syndrome may have poor immune systems, and on rare occasions, babies with this syndrome could be born with part of their intestines outside of their bodies via the belly button.

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Causes

There are indications that Marshall-Smith syndrome is caused by a change (mutation) in the NFIX gene. This gene plays an important role in transcription initiation for various genes. In human embryonic development, expression of NFIX can be detected during brain and skeletal development. The most common variant types leading to Marshall Smith syndrome are frameshift and splice site variants. Most individuals with Marshall-Smith syndrome are the first individuals in their families to have this syndrome and as such they are “de-novo” cases.

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Affected populations

Marshall-Smith Syndrome is a rare disorder that has only been documented in about 50 individuals worldwide. It appears to affect males and females equally. Symptoms are typically present at birth, such as the previously escribed characteristic facial features.

There does not appear to be an ethnic population more at risk for the disorder and the fifty or so cases that have been described are part of an international cohort. The cases appear to be sporadic, in that there is no family history or parental relatedness that may lead to a disorder. Due to the infrequency of the disorder, demographic statistics are unavailable.

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Disorders with Similar Symptoms

Weaver syndrome is similar to Marshall-Smith syndrome in that growth and bone ages faster than normal, or advanced bone age. Patients with both Weaver and Marshall-Smith syndromes tend to have their growth spurt early in age but will stop growing sooner compared to normal individuals. However, patients with Weaver syndrome are usually overweight, whereas patients with Marshall-Smith syndrome are underweight. There are several other distinguishing physical and behavioral characteristics between Marshall-Smith and Weaver syndrome. (For more information on this condition, search for “Weaver” in the Rare Disease Database.)

Several features commonly found in Marshall-Smith syndrome – such as tallness, muscle myopathy, peripheral neuropathy – also appear in Klinefelter and Marfan syndrome. Patients with Marshall-Smith syndrome display an excess amount of growth hormones before puberty, leading to a significant growth in height and weight – gigantism – where they can grow up to 7 or 8 feet. In addition, patients with Marshall-Smith syndrome could experience muscle and nerve abnormalities. The muscle tissues soften gradually, and lead muscles to lose their strength – this condition is called muscle myopathy. Furthermore, patients can also have issues with their nerves – peripheral neuropathy – where the messages from the brain are not properly sent to the rest of the body.

Sotos syndrome is a rare, hereditary disorder characterized by excessive growth (over the 90th percentile) during the first 4 to 5 years of life. Abnormalities of the nervous system, including aggressiveness, irritability, clumsiness, an awkward gait, and intellectual developmental delay sometimes also occur. Physical characteristics include eyes which appear to be abnormally far apart (hypertelorism) and slanted. Both Sotos syndrome and Marshall-Smith syndrome share overlapping symptoms including advanced bone age, overly large head, intellectual delay, scoliosis, and abnormal facial features. (For more information, input “Sotos” as your search term in the Rare Disease Database.)

McCune-Albright syndrome (osteitis fibrosa disseminata) and Marshall-Smith syndrome have similar symptoms involving the endocrine, muscle and bone systems. However, McCune-Albright syndrome exhibits additional symptoms including a change in bone integrity which produces pain, increasing deformity and disability as well as changes in skin pigmentation. Marshall-Smith syndrome exhibits excessive secretion of growth hormone, resulting in early puberty as documented in a 4-year-old patient with high hormone levels, indicating she was undergoing puberty at an early age. Children with McCune-Albright syndrome are excessively tall during childhood, but their growth stops early and they usually don’t reach normal height during adulthood. (For more information, choose “McCune-Albright” as your search term in the Rare Disease Database.)

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Diagnosis

Patients with Marshall-Smith syndrome are diagnosed based on clinical findings and symptoms, as well as the use of x-ray exams to identify the skeletal indications. Genetic diagnosis can now be performed by looking for mutations in the NFIX gene.

Animal Model
Animals that have been studied to better understand Marshall-Smith syndrome include the NFIX-deficient mouse. Observable characteristics in NFIX-deficient mice include the inability to gain weight, death by the third week of life, bone mineralization, as well as spine deformities. Similarity between clinical presentations between these NFIX-deficient mice and physical characteristics in humans lead to the investigation of NFIX as a candidate gene for Marshall-Smith syndrome.

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Standard Therapies

Treatment
Treatment of Marshall-Smith Syndrome is based on treating the symptoms and giving supportive care to the patient. Malnutrition and respiratory infections should be treated aggressively and are dangerous complications of Marshall-Smith syndrome. Due to the developmental delays, special education programs and other supportive resources may be utilized in patients who are school-aged.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is available online 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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

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

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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
Schanze D, Neubauer D, Cormier-Daire V, Delrue M-A, Dieux-Coeslier A, Hasegawa T, et al. Deletions in the 3’ part of the NFIX gene including a recurrent Alu-mediated deletion of exon 6 and 7 account for previously unexplained cases of Marshall-Smith syndrome. Hum Mutat. 2014 Sep;35(9):1092–100.

Shaw AC, Balkom IDC van, Bauer M, Cole TRP, Delrue M-A, Haeringen AV, et al. Phenotype and natural history in Marshall-Smith syndrome. American Journal of Medical Genetics Part A.;2010.152A (11):27 14-26.

Malan V, Rajan D, Thomas S, Shaw AC, Louis dit Picard H, Layet V, et al. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. The American Journal of Human Genetics. 13 August 2010;87(2):189-98. https://www.sciencedirect.com/science/article/pii/S0002929710003575

INTERNET
Orphanet: Molecular Diagnosis of Marshall Smith Syndrome NFIX Gene. Updated August 2018. https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search.php?lng=EN&data_id=113345&search=ClinicalLabs_Search_Simple&data_type=Test&title=Molecular%20diagnosis%20of%20Marshall-Smith%20Syndrome%20NFIX%20gene&MISSING%20CONTENT=Molecular-diagnosis-of-Marshall-Smith-Syndrome–NFIX-gene-;%20https://ctgt.net/disorder/marshall-smith-syndrome;%20https://dnatesting.uchicago.edu/tests/marshall-smith-syndrome-testing-nfix. Accessed May 12, 2020.

Marshall-Smith Syndrome . Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Updated June 14, 2017. https://rarediseases.info.nih.gov/diseases/6985/marshall-smith-syndrome. Accessed May 12, 2020.

Marshall-Smith Syndrome. McKusick’s Online Mendelian Inheritance in Man (OMIM). Updated 04/14/2020. https://www.omim.org/entry/602535 Accessed April 1, 2020.

Marshall Smith Syndrome. Orphanet.Updated July 2006. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=561. Accessed May 12, 2020.

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