Microphthalmia with linear skin defects (MLS)

Definition

Microphthalmia with linear skin defects (MLS) is a rare genetic disorder that causes abnormalities of the eyes and skin. This disorder was first recognized as a distinct genetic condition in 1990.

Description

MLS is a rare disorder that is observed only in females because males with the disease do not survive to birth. This disorder is also called MIDAS (Microphthalmia, dermal aplasia, and sclerocornea) syndrome. People affected by MLS have:

• small sunken eyes (microphthalmia),
• irregular red streaks of skin on the head and neck (skin erythema),
• and abnormal development of the sclera and cornea of the eye.

The eye is composed of three layers: the sclera, the choroid, and the retina. The sclera is the tough white outer coat of the eyeball. As this coat passes over the

lens, it normally becomes clear. This clear portion of the sclera is the cornea. Both the sclera and the cornea are affected by MLS.

The choroid is the middle layer of the eye. It serves to nourish the retina and absorb scattered light. The retina is the inner, light-sensitive, layer of the eye. The retina receives the image transmitted by the lens and it contains the rods and cones that are responsible for color vision and vision in dim light. Both the choroid and the retina are unaffected by MLS.

Genetic profile

The gene responsible for MLS has been localized to a portion of the short arm (p) of the X chromosome (Xp22.3). The specific symptoms of MLS are believed to result from the premature cutoff (terminal deletion) of the X chromosome at this point. People with MLS do not have the portion of the short arm of the X chromosome beyond the Xp22.2 location.

Nearly all of the cases of MLS are believed to result from de novo mutations since parents of affected individuals do not carry the MLS mutation in their chromosomes. A de novo mutation is caused by a problem with the chromosomes of the parental egg or sperm cells. The remainder of the chromosomes in the parents are not affected. As the sex cells of one of the parents reproduce, an error occurs. This leads to the transmission of a new mutation from that parent to his or her child. This mutation is expressed for the first time in the child of that parent.

A typical female has two X chromosomes. A typical male has one X chromosome and one Y chromosome. Because no XY male has ever been diagnosed with MLS, it is assumed that MLS is dominant and X-linked with 100% fetal mortality in males. This type of genetic disorder is also called an X-linked male-lethal trait.

There have been a few reported cases of males affected with MLS. These individuals presumably survived because they were XXY males (genetically female with ambiguous or male sex organs), rather than the typical male with XY chromosomes. This condition (XXY) is called Klinefelter syndrome .

Demographics

Approximately 300 individuals, all without a Y chromosome, have been diagnosed with MLS worldwide. MLS is not associated with any particular sub-populations. It appears with equal frequency in all races and across all geographies. Because it is an X-linked male-lethal trait, it is observed exclusively in females or, in a few cases, in XXY males.

Signs and symptoms

MLS is characterized by:

• small, sunken, eyes (microphthalmia);
• defects of the sclera and cornea portions of the eye
• linear red streaking of the skin on the upper body, primarily the head and neck;
• abnormal protrusion of the abdominal contents upward through an opening in the diaphragm (diaphragmatic hernia), which causes difficulty with breathing (respiratory distress);
• a lack of the transparent membrane (septum pellucidum) in the brain that forms a wall between two of the normal cavities (the lateral ventricles) of the brain;
• and, a condition in which the heart is located on the right side, rather than the left side, of the chest (dextrocardia).

In individuals affected with MLS, the bony cavity that contains the eyeball (orbit) often contains small fluid-filled sacs (orbital cysts). The sclera is often not fully or properly formed, and the cornea generally has areas that are opaque rather than transparent. This corneal opacity causes blurring of vision and may result in blindness. Corneal opacities should not be confused with cataracts, which are opacities of the lens of the eye, not of the cornea.

Difficulty in breathing (respiratory distress) is seen at birth in some patients with MLS. This is caused by a hole in the muscle beneath the lungs (diaphragm) that is responsible for the flow of air into and out of the lungs. This condition will rapidly lead to death if it is not surgically repaired.

Seizures and mental retardation have been observed in some MLS patients. It is believed that these individuals do not have a septum pellucidum. The absence of this membrane may allow electrical transmissions between parts of the brain that are usually isolated from each other. These inadvertent electrical signals may cause the seizures and the mental retardation that is sometimes seen in MLS patients.

Diagnosis

MLS is generally diagnosed by the presence of the characteristic red striping of the skin on the head and neck accompanied by small eyes (microphthalmia) and opaque patches on the corneas.

MLS is differentiated from Goltz syndrome , which has a similar gene locus, in that the patient with MLS has skin irregularities only on the upper half of the body, most typically only on the head and neck. Goltz syndrome results in skin irregularities across the entire body. Also, patients with MLS do not have the abnormal fatty tissue deposits seen under the skin of Goltz syndrome patients. Finally, MLS does not have the clefting of the hands or feet (syndactyly) or incomplete formation of certain structures of the eyes (coloboma ) seen in Goltz syndrome.

Prenatal diagnosis for MLS syndrome is not yet available, but identification of the gene responsible for MLS makes genetic testing for this dominant trait possible.

Treatment and management

The treatment and management of MLS is directed toward the symptoms seen in each patient. All those affected with MLS will need eye care including surgeries to potentially repair damaged areas of the cornea and sclera. Some individuals may require skin care treatments depending on the severity of the skin abnormalities.

In cases of patients with a diaphragmatic hernia, emergency surgery shortly after birth may be necessary to attempt to repair the damaged area. Unfortunately, most cases of this type of hernia cannot be surgically corrected and the patient will die.

In cases of patients with a lack of the septum pellucidum in the brain, anti-seizure medication may be necessary to control the seizures.

Prognosis

MLS is lethal in males prior to birth. In females, a full life expectancy is possible if the complications are not severe and if medical treatment is followed.

Most problems of the cornea and sclera of the eye associated with MLS can be treated with corrective lenses or potentially surgically repaired with corneal implants or laser surgery.

Seizures, if present, can generally be controlled by anti-seizure medications.

Developmental delays in growth, motor ability, speech, and intellect occur in some, but not all, cases of MLS. The amount of delay that is observed is directly related to the severity of seizure activity in the brain caused by the malformation, or lack, of the septum pellucidum.

Resources

PERIODICALS

Kuno, T., and T. Migita. "Another observation of microphthalmia in an XX male: Microphthalmia with linear skin defects syndrome without linear skin lesions." Journal of Human Genetics (1999): 63-8.

ORGANIZATIONS

National Foundation for the Blind. 1800 Johnson St., Baltimore, MD 21230. (410) 659-9314. <http://www.nfb.org>.

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>.

WEBSITES

"Entry 309801: Micropthalmia with linear skin defects; MLS." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?309801>. (February 9, 2001).

"Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes." United States National Library of Medicine. <http://www.nlm.nih.gov/mesh/jablonski/syndromes/syndrome453.html>. (February 9, 2001).

Paul A. Johnson