NORD gratefully acknowledges Ingrid Chen, Leslie Chan, Taylor Dean, and Viridiana Murillo, Master of Science in Human Genetics and Genomic Data Analytics (MSGDA) students, NORD Editorial Interns from the Keck Graduate Institute and Barbara Bailus, PhD, Assistant Professor of Genetics at the Keck Graduate Institute, for assistance in preparation of this report.
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.
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.)
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.
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.
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.
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.
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.
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.
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:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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. http://www.sciencedirect.com/science/article/pii/S0002929710003575
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-;%20http://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.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100