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PubMed This is a summary of 11 peer-reviewed journal articles Updated
Medical Genetics

Genetics and Differentiating MLS

At a Glance

MLS syndrome is most often linked to HCCS changes or Xp22.2 deletions; COX7B and NDUFB11 can cause overlapping features. Genetic testing helps distinguish MLS from Goltz syndrome, while X-chromosome inactivation and mosaicism make severity difficult to predict.

Confirming a diagnosis of MLS syndrome (also called MIDAS syndrome) involves looking closely at your child’s physical features and their genetic “blueprint.” Because the condition is so rare and its symptoms vary widely, genetic testing is the most definitive way to understand what is happening at a cellular level [1][2].

The Genetic Causes of MLS

MLS is caused by changes in genes that help cells produce energy. Most cases involve one of three specific genes located on the X chromosome:

  • HCCS: This is the most common gene involved. It provides instructions for a protein that helps mitochondria produce energy for the eyes and skin [1][3].
  • COX7B & NDUFB11: These genes also help the “powerhouses” (mitochondria) of the cell work correctly. Changes here can cause overlapping MLS-like phenotypes, though their associated risks may differ [2][3].
  • Xp22.2 Deletions: Sometimes, a whole section of the X chromosome (called the Xp22.2 region) is missing. This section includes the HCCS gene and often several neighboring genes [4][5].

Why Severity Varies: The Role of X-Inactivation

You may notice that some children with MLS have more significant challenges than others. This “variable expressivity” is largely due to a natural process called X-chromosome inactivation [1][6].

In females, who have two X chromosomes, one X is randomly turned off in every cell. If, by chance, the “healthy” X is turned off in more cells, the symptoms may be more severe. If the X with the mutation is turned off in more cells—a process called skewing—the symptoms may be milder [1][4]. This process is random and happens very early in development, which is why even identical twins with MLS can look very different [6].

Understanding Mosaicism

Some children have mosaicism, which means the genetic change is not in every cell of their body. Instead, they have two populations of cells: some with the MLS mutation and some without [4][2].

  • Low-grade mosaicism: This occurs when only a small percentage of cells carry the mutation [4].
  • Why it’s tricky: A blood test might show a low percentage of mosaicism (the report should state its detection limit and specimen type), but that doesn’t always reflect what’s happening in the eyes or the brain. The mutation might be more common in those tissues than it is in the blood [4]. Neither X-inactivation nor mosaicism results can perfectly predict an individual child’s medical course.

Why Males Are Rarely Affected

MLS is an X-linked dominant condition that is typically male-lethal [1][3]. Because males have only one X chromosome, severe loss of function in these genes is typically male-lethal, as the embryo cannot survive without them [1].
However, some males do survive if:

  1. The genetic change is “mild” and allows the gene to still work a little bit [2][7].
  2. The male has mosaicism, meaning the mutation is only in some of his cells [3].

Families should receive explicit genetic counseling to explain parental testing, recurrence risk, the possibility of maternal mosaicism, and how a result can be inherited by future sons or daughters. Families should not infer their specific reproductive risk from the general ‘male lethality’ explanation.

MLS vs. Goltz Syndrome

MLS is often confused with Goltz syndrome (also called focal dermal hypoplasia), because both involve eye and skin issues on the X chromosome [8][9]. However, they are distinct conditions:

Feature MLS Syndrome Goltz Syndrome
Skin Streaks Linear, raw-looking red streaks on face/neck; usually heal into thin scars [4][8]. Streaks of dark or light skin, often with “fat herniation” (yellowish bumps) [9].
Skin Change Over Time Lesions tend to improve and fade with age [8]. Lesions may be more persistent and may become more noticeable [8].
Other Features Associated with severe eye issues (small eyes, cloudy corneas) and heart issues [10][11]. Often includes limb differences (split hand/foot), nail issues, and wart-like growths [9].
Primary Gene HCCS, COX7B, or NDUFB11 [1]. PORCN [9].

The clinical pattern combined with molecular testing—not skin appearance alone—distinguishes the conditions.

Diagnostic Pathway and Genetic Report

When reviewing your child’s genetic report with a specialist, they will guide the diagnostic pathway. Depending on the test method (such as sequencing, chromosomal microarray, or a gene panel), consider discussing:

  • Gene Sequencing: Was HCCS sequencing or a panel including COX7B and NDUFB11 used depending on the phenotype? [1][2]
  • Deletion/Duplication Analysis: Does the test also look for missing pieces of the X chromosome (Xp22.2 region)? [4][5]
  • Mosaicism Check: Did the lab look for “low-level” results that might suggest mosaicism? [4]
  • Coordinates: For deletions, does the report list the exact starting and ending points? (These are important for interpreting the deletion, though not mandatory for diagnosis) [4]
  • Neighboring Genes: Are other genes included in a deletion (like MID1 or NLGN4X)? (This helps interpretation but is not a diagnostic requirement) [5]

Common questions in this guide

Which genes are linked to MLS syndrome?
HCCS is the gene most commonly involved in MLS syndrome. Changes in COX7B or NDUFB11 can produce overlapping MLS-like features, and some children have a deletion of the Xp22.2 region that includes HCCS.
Why can two children with MLS have different levels of severity?
In females, cells randomly turn off one of the two X chromosomes early in development. If more cells turn off the healthy X, features may be more severe; if more turn off the X with the genetic change, symptoms may be milder. This pattern cannot precisely predict an individual child’s medical course.
What does mosaicism mean in MLS, and can a blood test detect it?
Mosaicism means that the genetic change is present in some cells but not others. A blood test may not reflect how much of the change is present in the eyes or brain, so the report’s specimen type and detection limit matter. Mosaicism results do not reliably predict a child’s symptoms.
How is MLS syndrome different from Goltz syndrome?
MLS is most commonly associated with HCCS changes or an Xp22.2 deletion; COX7B and NDUFB11 can cause overlapping MLS-like features, whereas Goltz syndrome is associated with PORCN changes. MLS often causes linear red skin lesions that fade and may include severe eye or heart features; Goltz syndrome more often includes fat herniation, limb differences, nail changes, or persistent skin findings. Clinical features plus molecular testing are used because appearance alone is not enough.
What genetic tests and report details help confirm MLS?
Depending on a child’s features, testing may include HCCS sequencing, a panel that includes COX7B and NDUFB11, chromosomal microarray, or deletion/duplication analysis for Xp22.2 changes. The report may list deletion coordinates, neighboring genes, specimen type, mosaicism detection limit, and whether a variant is pathogenic, likely pathogenic, or uncertain. A genetics professional can explain what the result means for the child’s diagnosis and family.
Why are males rarely affected by MLS syndrome?
MLS is typically X-linked dominant, and severe changes are usually male-lethal because males have only one X chromosome. Rare surviving males may have a milder genetic change or mosaicism, in which only some cells carry the change. This general pattern cannot determine an individual family’s reproductive risk.
If my child’s variant is de novo, what does that mean for future pregnancies?
A de novo genetic change is new in the child rather than inherited from a parent. Parental testing and genetic counseling are still important because maternal mosaicism can affect recurrence risk even when a change is not detected in routine blood testing. Families should rely on individualized counseling rather than general rules about male lethality when planning future pregnancies.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific testing method was used to confirm the diagnosis (e.g., sequencing, chromosomal microarray, panel)?
  2. 2.Does the genetic report specify the genomic coordinates and which neighboring genes were included in the deletion?
  3. 3.Was evidence of mosaicism found in the sample, and how does that differ from X-chromosome inactivation?
  4. 4.Do my child's features suggest we should also test for the PORCN gene to rule out Goltz syndrome?
  5. 5.Was my child's genetic change 'de novo' (new to them), and what are the testing recommendations for our family to understand recurrence risk?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (11)
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    Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome.

    van Rahden VA, Fernandez-Vizarra E, Alawi M, et al.

    American journal of human genetics 2015; (96(4)):640-50.

    PMID: 25772934
  2. 2

    Revisiting LSDMCA: male lethality escape and genotype-phenotype correlations.

    D'Alessio AM, Indrieri A, Vitiello G, et al.

    European journal of human genetics : EJHG 2026; (34(7)):972-979 doi:10.1038/s41431-026-02098-7.

    PMID: 42014911
  3. 3

    Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA): An Unconventional Mitochondrial Disorder.

    Indrieri A, Franco B

    Genes 2021; (12(2)) doi:10.3390/genes12020263.

    PMID: 33670341
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    A mosaic form of microphthalmia with linear skin defects.

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    BMC pediatrics 2018; (18(1)):254 doi:10.1186/s12887-018-1234-4.

    PMID: 30068298
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    Microphthalmia, Linear Skin Defects, Callosal Agenesis, and Cleft Palate in a Patient with Deletion at Xp22.3p22.2.

    Vendramini-Pittoli S, Candido-Souza RM, Quiezi RG, et al.

    Journal of pediatric genetics 2020; (9(4)):258-262 doi:10.1055/s-0039-3402047.

    PMID: 32765930
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    Novel Intragenic and Genomic Variants Highlight the Phenotypic Variability in HCCS-Related Disease.

    Reis LM, Basel D, Bitoun P, et al.

    Genes 2024; (15(12)) doi:10.3390/genes15121636.

    PMID: 39766903
  7. 7

    A novel mutation in NDUFB11 unveils a new clinical phenotype associated with lactic acidosis and sideroblastic anemia.

    Torraco A, Bianchi M, Verrigni D, et al.

    Clinical genetics 2017; (91(3)):441-447 doi:10.1111/cge.12790.

    PMID: 27102574
  8. 8

    Microphthalmia and linear skin defects syndrome: Precise diagnosis guides prognosis.

    Satcher KG, Maegawa GHB, Schoch JJ

    Pediatric dermatology 2020; (37(1)):217-218 doi:10.1111/pde.13946.

    PMID: 31373408
  9. 9

    Focal Dermal Hypoplasia (Goltz Syndrome): A Cross-sectional Study from Eastern India.

    Ghosh SK, Dutta A, Sarkar S, et al.

    Indian journal of dermatology 2017; (62(5)):498-504 doi:10.4103/ijd.IJD_317_17.

    PMID: 28979012
  10. 10

    Variable phenotype of secondary congenital corneal opacities associated with microphthalmia with linear skin defects syndrome.

    Franco E, Scanga HL, Nischal KK

    American journal of medical genetics. Part A 2023; (191(2)):586-591 doi:10.1002/ajmg.a.63043.

    PMID: 36369709
  11. 11

    Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11.

    Rea G, Homfray T, Till J, et al.

    Cold Spring Harbor molecular case studies 2017; (3(1)):a001271 doi:10.1101/mcs.a001271.

    PMID: 28050600

This page explains MLS genetic testing and differences from Goltz syndrome for informational purposes only and does not constitute medical advice. A clinical geneticist or genetic counselor should interpret your child’s results and discuss inheritance and recurrence risk.

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