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marshall syndrome

Marshall syndrome

Marshall syndrome is an inherited condition characterized by a distinctive facial appearance, eye abnormalities, hearing loss, and early-onset arthritis. Those with Marshall syndrome can also have short stature. Some researchers have argued that Marshall syndrome represents a variant form of Stickler syndrome; but this remains controversial 1. Marshall syndrome is caused by mutations in the COL11A1 gene and is inherited in an autosomal dominant fashion 2. However, one Saudi family has been reported with two sons with Marshall syndrome with homozygous missense mutations of COL11A1. In this family there was concern for possible autosomal recessive inheritance, as each parent carried one missense mutation with glycine substitution, and these parents had short stature, thick calvaria, and mild hearing loss with normal ophthalmologic examination and did not have a diagnosis of Stickler or Marshall syndrome. Recessive genetic disorders occur when a child inherits two abnormal copies of a gene, one from each parent, who is unaffected. It may be in this family that both parents are mildly affected by Stickler syndrome and in this situation the inheritance would be termed double dominant. In either situation, the recurrence risk would be 25% with each pregnancy. The risk is the same for males and females.

Marshall syndrome cause

Marshall syndrome, which may be a variant of Stickler syndrome, is also caused by COL11A1 gene mutations located on chromosome 1p21.1. Typically mutations causing Marshall syndrome are splice site mutations involving base pair insertions or deletions of intron 50. The COL11A1 gene provides instructions for making a component of type XI collagen called the pro-alpha1(XI) chain. Collagens are molecules that provide structure and strength to the connective tissues that support the body’s muscles, joints, organs, and skin. Type XI collagen is normally found in cartilage, a tough but flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears. Type XI collagen is also part of the inner ear; the vitreous, which is the clear gel that fills the eyeball; and the nucleus pulposus, which is the center portion of the discs between the bones of the spine (vertebrae).

Collagens begin as rope-like procollagen molecules that are each made up of three chains. The pro-alpha1(XI) chain combines with two other collagen chains, pro-alpha2(XI) and pro-alpha1(II), to form a triple-stranded procollagen molecule. Then the ropelike procollagen is processed by enzymes to create mature collagen. Mature collagen molecules arrange themselves into long, thin fibrils that form stable interactions (cross-links) with one another in the spaces between cells (the extracellular matrix). The cross-links result in the formation of very strong type XI collagen fibers.

Type XI collagen also helps maintain the spacing and width (diameter) of another type of collagen molecule, type II collagen. Type II collagen is an important component of the vitreous and cartilage. The arrangement and size of type II collagen fibrils is essential for the normal structure of these tissues.

Marshall syndrome inheritance pattern

Marshall syndrome typically has an autosomal dominant pattern of inheritance.

Often autosomal dominant conditions can be seen in multiple generations within the family. If one looks back through their family history they notice their mother, grandfather, aunt/uncle, etc., all had the same condition. In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

  • When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
  • There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

There are cases of autosomal dominant gene changes, or mutations, where no one in the family has it before and it appears to be a new thing in the family. This is called a de novo mutation. For the individual with the condition, the chance of their children inheriting it will be 50%. However, other family members are generally not likely to be at increased risk.

Figure 1 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 1. Marshall syndrome autosomal dominant inheritance pattern

Marshall syndrome autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Marshall syndrome symptoms

Marshall syndrome is characterized by facial dysmorphism, severe hypoplasia of the nasal bones and frontal sinuses, ocular involvement, early-onset hearing loss, skeletal and anhidrotic ectodermal anomalies and short stature with spondyloepiphyseal dysplasia and early-onset osteoarthritis.

Patients with Marshall Syndrome have a distinctive flat sunken midface with a flattened nasal bridge (saddle nose), nostrils that turn upward, and a wide space between the eyes (hypertelorism). The dome-like upper portion of the skull (calvaria) is thicker than normal and calcium deposits can be found in the skull (cranium). Frontal sinuses may be absent. Eye defects found in patients with Marshall Syndrome are nearsightedness, a disease of the eye in which the lens loses its clarity (cataract), and a wide space between the eyes making the eyeballs appear to be larger than normal. Hearing loss may range from slight to severe; the distortion of the sound is a consequence of the nerve damage (sensorineural). Other symptoms exhibited by some patients with Marshall Syndrome are: crossed eyes (esotropia), a condition in which the line of vision is higher in one eye than the other (hypertropia), retinal detachment, glaucoma, protruding upper incisors (teeth) and a smaller than normal or missing nasal bone.

Marshall syndrome symptoms:

  • Abnormal dentition
  • Anteverted nares (nasal tip upturned)
  • Arthralgia (joint pain)
  • Brachycephaly (short and broad skull)
  • Broad nasal bridge
  • Cataract (clouding of the lens of the eye)
  • Depressed bridge of nose
  • Flat facial shape
  • Wide-set eyes (hypertelorism)
  • Cheekbone underdevelopment (hypoplasia of the zygomatic bone)
  • Long philtrum
  • Malar flattening
  • Little lower jaw (micrognathia)
  • Near sightedness (Myopia)
  • Sensorineural hearing impairment
  • Short nose
  • Short stature
  • Increased volume of lower lip
  • Full upper lip

Marshall syndrome diagnosis

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis.

Marshall syndrome treatment

Plastic surgery can improve saddle nose in Marshall syndrome. Other surgical procedures are used to remove the lenses of eyes affected by cataracts, after which lens implants are used as replacements. Subsequently, contact lenses may help improve sharpness of vision. Laser techniques are used to loosen any material, such as the cornea or the lens capsule that may adhere to the lens. The use of a hearing aid may be beneficial in some cases. Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

Marshall syndrome prognosis

There is limited information on the average lifespan for an individual with Marshall syndrome. One article describes a family with many affected relatives in several generations and refers to individuals who have Marshall syndrome and are in their 30s and 40s 3. There are also specific reports of individuals who are suspected to have Marshall syndrome and are doing well at ages 29 and 35 4.

It appears from the medical literature that individuals with Marshall syndrome may have relatively normal life expectancy 5. The main features of Marshall syndrome are not expected to be life-threatening, though the severity of symptoms may vary among affected individuals 6. Only one article in the medical literature stated that lifespan may be shortened because of this condition; the authors suggested that respiratory problems related to Marshall syndrome may lead to a reduced lifespan 7. However, respiratory problems are currently not considered a feature of this disease and no other article mentions this concern 6.

Marshall syndrome life expectancy

There is limited information on the average lifespan for an individual with Marshall syndrome. One article describes a family with many affected relatives in several generations and refers to individuals who have Marshall syndrome and are in their 30s and 40s 5. There are also specific reports of individuals who are suspected to have Marshall syndrome and are doing well at ages 29 and 35 8.

It appears from the medical literature that individuals with Marshall syndrome may have relatively normal life expectancy 5. The main features of Marshall syndrome are not expected to be life-threatening, though the severity of symptoms may vary among affected individuals 6. Only one article in the medical literature stated that lifespan may be shortened because of this condition; the authors suggested that respiratory problems related to Marshall syndrome may lead to a reduced lifespan 9. However, respiratory problems are currently not considered a feature of this disease and no other article mentions this concern 6.

References
  1. Stickler syndrome. https://ghr.nlm.nih.gov/condition/stickler-syndrome
  2. Marshall syndrome. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=560
  3. Ala‐Kokko, L. and Shanske, A. L. (2009), Mosaicism in Marshall syndrome. Am. J. Med. Genet., 149A: 1327-1330. doi:10.1002/ajmg.a.32873
  4. Shanske AL, Bogdanow A, Shprintzen RJ, Marion RW. The Marshall Syndrome: Report of a New Family and Review of the Literature. American Journal of Medical Genetics. 1997; 70:52-57. http://www.ncbi.nlm.nih.gov/pubmed/9129742
  5. Griffith AJ, Sprunger LK, Sirko-Osadsa DA, Tiller GE, Meisler MH, Warman ML. Marshall syndrome associated with a splicing defect at the COL11A1 locus. American Journal of Human Genetics. 1998; 62:816-823. http://www.ncbi.nlm.nih.gov/pubmed/9529347
  6. MARSHALL SYNDROME. https://omim.org/entry/154780
  7. Fitch N. The syndromes of Marshall and Weaver. J Med Genet. 1980;17(3):174–178. doi:10.1136/jmg.17.3.174 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1048541/pdf/jmedgene00125-0014.pdf
  8. Ala-Kokko L, Shanske AL. Mosaicism in Marshall Syndrome. American Journal of Medical Genetics. Part A. 2009; 149A:1327-1330. http://www.ncbi.nlm.nih.gov/pubmed/19449424
  9. Fitch N. The syndromes of Marshall and Weaver. Journal of Medical Genetics. 1980; 17:174-178. http://www.ncbi.nlm.nih.gov/pubmed/7401127
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