Microphthalmia with linear skin defects syndrome

Alternate names

MCOPS7; MLS syndrome; Microphthalmia with linear skin defects; Microphthalmia Dermal Aplasia and Sclerocornea syndrome; MIDAS syndrome; Syndromic microphthalmia type 7; Micropthalmia syndromic 7; Linear skin defects with multiple congenital anomalies 1; Microphthalmia-dermal aplasia-sclerocornea syndrome

Definition

Microphthalmia with linear skin defects syndrome (MLS syndrome) is a genetic condition that affects the eyes and skin.

Summary

• It is mainly found in females and is characterized by small or poorly developed eyes (microphthalmia) and characteristic linear skin markings on the head and neck.
• Affected individuals also typically have unusual linear skin markings on the head and neck.
• These markings follow the paths along which cells migrate as the skin develops before birth (lines of Blaschko).
• The skin defects generally improve over time and leave variable degrees of scarring.

Epidemiology

The prevalence of microphthalmia with linear skin defects syndrome is unknown. More than 50 affected individuals have been identified.

Cause

Mutations in the HCCS gene or a deletion of genetic material that includes the HCCS gene cause microphthalmia with linear skin defects syndrome. The HCCS gene carries instructions for producing an enzyme called holocytochrome c-type synthase. This enzyme is active in many tissues of the body and is found in the mitochondria, the energy-producing centers within cells.

Within the mitochondria, the holocytochrome c-type synthase enzyme helps produce a molecule called cytochrome c. Cytochrome c is involved in a process called oxidative phosphorylation, by which mitochondria generate adenosine triphosphate (ATP), the cell's main energy source. It also plays a role in the self-destruction of cells (apoptosis).

HCCS gene mutations result in a holocytochrome c-type synthase enzyme that cannot perform its function. A deletion of genetic material that includes the HCCS gene prevents the production of the enzyme. A lack of functional holocytochrome c-type synthase enzyme can damage cells by impairing their ability to generate energy. In addition, without the holocytochrome c-type synthase enzyme, the damaged cells may not be able to undergo apoptosis. These cells may instead die in a process called necrosis that causes inflammation and damages neighboring cells. During early development this spreading cell damage may lead to the eye abnormalities and other signs and symptoms of microphthalmia with linear skin defects syndrome.

Inheritance

X-linked dominant inheritance

This condition is inherited in an X-linked dominant pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In females (who have two X chromosomes), a mutation in one of the two copies of the gene in each cell is sufficient to cause the disorder. Some cells produce a normal amount of the holocytochrome c-type synthase enzyme and other cells produce none. The resulting overall reduction in the amount of this enzyme leads to the signs and symptoms of microphthalmia with linear skin defects syndrome.

In males (who have only one X chromosome), mutations result in a total loss of the holocytochrome c-type synthase enzyme. A lack of this enzyme appears to be lethal very early in development, so almost no males are born with microphthalmia with linear skin defects syndrome. A few affected individuals with male appearance but who have two X chromosomes have been identified.

Most cases of microphthalmia with linear skin defects syndrome occur in people with no history of the disorder in their family. These cases usually result from the deletion of a segment of the X chromosome during the formation of reproductive cells (eggs and sperm) or in early fetal development. They may also result from a new mutation in the HCCS gene.

Signs and symptoms

The signs and symptoms of MLS syndrome differ among individuals; however, the condition is characterized by eye and skin findings. Most commonly, individuals are found to have small or poorly formed eyes (microphthalmia). One or both eyes may also be missing (anophthalmia). People with this condition usually also have what is described as linear skin defects on the head and neck. These are characteristic skin markings that follow the paths along which cells migrate as the skin develops before birth. These paths are known as the lines of Blaschko.

Other eye symptoms in people with MLS syndrome may include:

• Poor development of the clear layer that covers the front of the eye (sclerocornea)
• Cysts in the cavity of the skull where the eye is located (orbital cysts)
• Congenital glaucoma

Other symptoms may include:

• Brain malformations
• [[Developmental delay
• Intellectual disability
• Short stature
• An abnormal opening in the diaphragm (diaphragmatic hernia)
• Finger and toenails that do not grow normally (nail dystrophy)
• A small pit in the outside part of the ear (preauricular pits)
• Hearing loss
• Heart defects
• Abnormalities in the development of the genitals and urinary tract
• A missing or blocked opening in the anus

Diagnosis

The clinical diagnosis is established when the two major criteria (microphthalmia and/or anophthalmia and linear skin defects) are present and confirmed by identification of a pathogenic variant in COX7B, HCCS, or NDUFB11. However, persons with a molecular diagnosis of MLS syndrome in whom only one of the two major criteria was present have been reported: some show characteristic skin defects without ocular abnormalities and others show eye abnormalities without skin defects. Chromosomal microarray analysis (CMA). CMA should be the first genetic test as about 90% of MLS syndrome is caused by large copy number variants (CNVs), which cannot be detected by sequence analysis of HCCS.

Treatment

The following are appropriate:

• Under the guidance of an oculoplastics specialist, use of a prosthesis in severe microphthalmia and anophthalmia
• Regular care by a dermatologist for individuals with significant skin lesions
• Referral to a pediatric neurologist for evaluation and treatment if microcephaly, seizures, and/or other neurologic abnormalities are present
• Appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability
• Standard care for cardiac concerns and other malformations, when present.

NIH genetic and rare disease info

• NIH info on Microphthalmia with linear skin defects syndrome

Microphthalmia with linear skin defects syndrome is a rare disease.

Microphthalmia with linear skin defects syndrome Resources
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