Marshall syndrome

Definition

Marshall syndrome is a very rare genetic disorder with an autosomal dominant pattern that equally affects males and females. It is caused by an abnormality in collagen, which is a key part of connective tissue.

Description

Marshall syndrome was first described by Dr. D. Marshall in 1958 and it has been studied periodically by researchers since then. The disease is most apparent in the facial features of those affected, which include an upturned nose, eyes spaced widely apart, making them appear larger than normal, and a flat nasal bridge. This facial formation gives subjects a childlike appearance. The upper part of the skull is unusually thick, and deposits of calcium may appear in the cranium. Patients may also have palate abnormalities. In addition, they may experience early osteoarthritis , particularly in the knees.

Myopia (nearsightedness), cataracts and glaucoma are common in Marshall syndrome. Moderate to severe hearing loss is often preceded by many incidents of otitis media (middle ear infection) and can occur in children as young as age three. Some patients also have osteoarthritis, particularly of the knees.

In the 40 years following Dr. Marshall's discovery, some physicians have argued that Marshall syndrome is actually a subset of Stickler syndrome , a more common genetic disorder. Individuals with both syndromes have similar facial features and symptoms. However, other experts have argued against this view, stating that Marshall syndrome is a distinct disorder on its own. For example, most patients with Stickler syndrome have cataracts, while this problem is less common among those with Marshall syndrome. In addition, most subjects with Marshall syndrome have moderate to severe hearing loss, which rarely occurs among those with Stickler syndrome, who have normal hearing.

Genetic research performed in 1998 and 1999 revealed that both sides were right. There are clear genetic differences between the two syndromes. There are also patients who have apparent overlaps of both syndromes.

In 1998, a study used genetic testing to establish that a collagen genetic mutation on COL11A1 caused Marshall syndrome and that a change on COL2A1 caused Stickler syndrome. It also found that other types of mutations could cause overlaps of both syndromes.

A study in 1999 described a genetic study of 30 patients from Europe and the United States, all of whom were suspected to have either Marshall or Stickler syndrome. These genetic findings confirmed those of the previous (1998) study. Twenty-three novel mutations of COL11A1 and COL2A1 were found among the subjects. Some patients had genetic overlaps of both Marshall and Stickler syndromes.

Physical differences were also noted between the two syndromes. For example, all the patients with Marshall syndrome had moderate to severe hearing loss, while none of the patients with Stickler syndrome had hearing loss. About half the patients with overlapping disorders of both diseases had hearing loss. All the patients with Marshall syndrome had short noses, compared to about 75% of the patients with Stickler syndrome. Palate abnormalities occur in all patients with Stickler syndrome, comparaed to only about 80% of those with Marshall syndrome. Also, about a third of the Stickler patients had dental abnormalities, compared to 11% of the patients with Marshall syndrome. Those with Stickler (71%) had a higher percentage of cataracts than those with Marshall syndrome (40%). Patients with Marshall syndrome were much more likely to have short stature than those with Stickler syndrome.

Genetic profile

The gene name for Marshall syndrome is Collagen, Type XI, alpha 1. The gene symbol is COL11A1. The chromosomal location is 1p21. Marshall syndrome is an autosomal dominant genetic trait and the risk of an affected parent transmitting the gene to the child is 50%. Human traits are the product of the interaction of two genes from that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the abnormal gene (received from either parent) dominates the normal gene and results in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Demographics

Because of the rarity of this disease, very little demographic data is available. Less than 100 cases of individuals with this syndrome have been reported worldwide in medical literature. Some cases are probably undiagnosed because of the high expense of genetic testing. It is known that Marshall syndrome presents in infancy or early childhood and severe symptoms such as hearing loss and cataracts manifest before the age of 10 years. Adults with the syndrome retain the facial traits that are characteristic of this disease, such as flat nose, large nasal bridge and widely spaced eyes. Among those with Stickler syndrome, in contrast, these distinctive facial characteristics diminish in adulthood.

Signs and symptoms

Characteristic features of this disease are short upturned nose with a flat nasal bridge. Some patients also have glaucoma, crossed eyes, detached retinas, and protruding upper teeth. Patients often have short stature compared to other family members without the disease.

Diagnosis

Individuals are diagnosed by their features as well as by the very early onset of serious eye and ear disease. Because Marshall syndrome is an autosomal dominant hereditary disease, physicians can also note the characteristic appearance of the biological parent of the child. Genetic testing is costly, thus, it is not ordered for most people. As a result, people may be diagnosed as possible Marshall syndrome or possible Stickler syndrome, based on their symptoms and appearance.

Treatment and management

Marshall syndrome cannot be cured; however, the symptoms caused by the disease should be treated. Children with Marshall syndrome should have annual eye and ear checkups because of the risk for cataracts and hearing loss. Cataract surgery will be needed if cataracts develop. At present, the only treatment for the progressive hearing loss is a hearing aid. The flat "saddle nose" can be altered with cosmetic surgery. If a child with Marshall syndrome has osteoarthritis, doctors may advise against contact sports.

Prognosis

As they age, vision and hearing problems will generally worsen for patients with Marshall syndrome. Many will also develop osteoarthritis at an earlier age than for patients without Marshall syndrome, such as in the teens or twenties. Because there are so few identified cases, it is unknown what the life expectancy is of afflicted individuals.

Resources

PERIODICALS

Annunen, Susanna, et al. "Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome, but other mutations cause overlapping Marshall/Stickler phenotypes." American Journal of Human Genetics 64 (1999).

Griffith, Andrew J., et al. "Marshall syndrome associated with a splicing defect at the COL11A1 locus." American Journal of Human Genetics 62, no. 4 (1998).

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

Stickler Involved People. 15 Angelina, Augusta, KS 67010. 316) 775-2993. <http://www.sticklers.org/sip>.

WEBSITES

Annunen, Susanna. "From rare syndromes to a common disease: Mutations in minor cartilage collagen genes cause Marshall and Stickler syndromes and intervertebral disc disease." Academic dissertation, Oulu University Library, Oulu, Finland. <http:/herkules.oulu.fi/isbn9514254139/>. (1999).

"Entry 120280: Collagen, Type XI, Alpha-1; COL11A1." OMIM—Online Mendelian Inheritance in Man. <http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?120280>.

Christine Adamec