Clinical characteristics.

Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects, usually involving the face and neck, which are present at birth and heal with age, leaving minimal residual scarring. Other findings can include a wide variety of other ocular abnormalities (e.g., corneal anomalies, orbital cysts, cataracts), central nervous system involvement (e.g., structural anomalies, developmental delay, infantile seizures), cardiac concerns (e.g., hypertrophic or oncocytic cardiomyopathy, atrial or ventricular septal defects, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, hearing impairment, and genitourinary malformations. Inter- and intrafamilial variability is described.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Use of a prosthesis under the guidance of an oculoplastics specialist for severe microphthalmia and anophthalmia; routine dermatologic care for significant skin lesions; treatment of seizures and/or other neurologic abnormalities by a pediatric neurologist; appropriate developmental therapies and special education as indicated for developmental delay and intellectual disability; routine care for other medical concerns when present.

Surveillance: Monitoring and follow up with ophthalmologist, dermatologist, pediatric neurologist, cardiologist, and other professionals as needed.

Genetic counseling.

MLS syndrome is inherited in an X-linked manner and is generally lethal in males. Most cases are simplex (i.e., a single occurrence in a family), but rare familial occurrences have been described. Women who are affected or have an MLS syndrome-associated pathogenic variant have a 50% chance of passing the genetic alteration to each offspring. Because male conceptuses with an MLS syndrome-associated pathogenic variant are typically nonviable, the likelihood of a live-born affected child is less than 50%. Molecular genetic testing of at-risk female relatives to determine their genetic status, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for MLS syndrome are possible if the disease-causing genetic alteration has been identified in an affected family member.

Suggestive Findings

Microphthalmia with linear skin defects (MLS) syndrome should be suspected in females with one or both major criteria especially in the presence of a family history consistent with X-linked inheritance with male lethality (see Figures 1, 2, and 3). Almost all individuals with MLS syndrome are female; however, a few affected males, typically with an XX karyotype, have been reported.

Figure 1.

Reticulolinear scar lesions on the neck of a female age 36 years with an otherwise normal phenotype. Cytogenetic analysis revealed 46,X,del(X)(p22.3 pter) [Lindsay et al 1994].

Figure 2.

Bilateral microphthalmia and irregular linear skin areas involving the face and neck in a female infant with MLS syndrome who has a single-nucleotide variant in exon 6 of HCCS [Wimplinger et al 2006]

Figure 3.

Typical linear skin lesions on the face and neck of a newborn female with MLS syndrome who has a deletion of exons 1-3 of HCCS [Morleo et al 2005, Wimplinger et al 2006]

Establishing the Diagnosis

The clinical signs observed in MLS syndrome are considered major if they are present in at least 70% of affected individuals and minor if they are less frequent (see Clinical Description, Minor Criteria).

The clinical diagnosis of MLS syndrome can be made when the two major criteria are present [al-Gazali et al 1990, Happle et al 1993]; 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 (see Figure 1); others show eye abnormalities without skin defects [Morleo & Franco 2008].

Minor criteria in the presence of a family history consistent with X-linked inheritance with male lethality supports the clinical diagnosis of MLS syndrome.

Female proband. The diagnosis of MLS syndrome is established in a female proband by identification of a heterozygous pathogenic variant in COX7B, HCCS, or NDUFB11 on molecular genetic testing (see Table 1).

Male proband. The diagnosis of MLS syndrome is established in a male proband by identification of a hemizygous pathogenic variant in COX7B, HCCS, or NDUFB11 on molecular genetic testing (see Table 1).

Molecular testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MLS syndrome is broad, individuals with both major criteria are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MLS syndrome has not been considered due to atypical findings are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia or anophthalmia (see Figure 2) and/or jagged skin defects on the face and neck (see Figure 3). MLS syndrome is usually lethal in males [Kono et al 1999, Kherbaoui-Redouani et al 2003, Wimplinger et al 2006, Wimplinger et al 2007a, Wimplinger et al 2007b, Kapur et al 2008, Sharma et al 2008, Hobson et al 2009, Steichen-Gersdorf et al 2010, Alberry et al 2011].

Phenotypic variability. Inter- and intrafamilial phenotypic variability has been described. The manifestations differ among affected individuals and, although most display the classic phenotype of MLS syndrome, many have only a subset of characteristic features: some show the characteristic skin defects without ocular abnormalities, whereas others have eye abnormalities without skin defects [Morleo & Franco 2008]. For example, a female with a normal phenotype except for typical MLS syndrome skin defects (see Figure 1) had an affected female fetus with anencephaly.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Nomenclature

MLS syndrome, first described by al-Gazali et al [1990], was initially known as Gazali-Temple syndrome.

MLS syndrome appears to be the most appropriate designation for this disorder.

Happle et al [1993] coined the acronym MIDAS (for microphthalmia, dermal aplasia, and sclerocornea) for what is now known as MLS syndrome.

Prevalence

The disorder is rare; 64 individuals with a clinical diagnosis of MLS syndrome have been reported to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with microphthalmia with linear skin lesions (MLS) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Ophthalmologic examination
• Dermatologic evaluation for skin lesions
• Brain MRI for corpus callosum dysgenesis and other neurologic abnormalities
• Developmental assessment, with further evaluation if significant delays are identified
• Cardiac evaluation
• Hearing evaluation, as hearing loss is observed in 8% of cases
• Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

Surveillance

Monitoring and follow up with ophthalmologist, dermatologist, pediatric neurologist, and other professionals as needed is appropriate.

Affected individuals with cardiac concerns should have regular complete evaluation at intervals determined by the cardiologist.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Microphthalmia with linear skin lesions (MLS) syndrome is inherited in an X-linked manner and is generally lethal in males.

Most affected individuals represent simplex cases (i.e., a single occurrence in a family).

Risk to Family Members

Parents of a female proband

• Most females with MLS syndrome have a de novo pathogenic variant.
• In rare cases, a female proband has inherited an MLS syndrome-related pathogenic variant from her mother, who may or may not be affected [Allanson & Richter 1991, Lindsay et al 1994, Mücke et al 1995, Wimplinger et al 2006, Wimplinger et al 2007a, Vergult et al 2013, Kluger et al 2014, van Rahden et al 2015]. Significant intrafamilial phenotypic variability has been observed.
• Detailed clinical evaluation of the mother and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant.
  • If the mother has clinical findings of MLS syndrome or if she has another affected relative, she is an obligate heterozygote for a pathogenic variant in COX7B, HCCS, or NDUFB11.
  • If a COX7B, HCCS, or NDUFB11 pathogenic variant has been identified in the proband, molecular genetic testing of the mother is appropriate to more accurately assess recurrence risk to sibs.

Parents of a male proband

• Live-born affected males with MLS syndrome are rare and are the result of a new chromosomal aberration (46,XX karyotype and an X/Y translocation).
• Affected males who do not survive pregnancy may have inherited the pathogenic variant from their mothers or may have a de novo pathogenic variant.

Sibs of a proband. The risk to sibs depends on the genetic status of the mother.

• If the mother of a proband is affected and/or is known to have a COX7B, HCCS, or NDUFB11 pathogenic variant, the chance of transmitting the pathogenic variant at conception is 50%. Because male conceptuses who inherit such a pathogenic variant are typically nonviable, the likelihood of a live-born affected child is less than 50%.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the COX7B, HCCS, or NDUFB11 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to the sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Offspring of a female proband. Women with a COX7B, HCCS, or NDUFB11 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

• Males who inherit the pathogenic variant will be affected, often with lethality during gestation.
• Females who inherit the pathogenic variant will be heterozygotes and will have a range of clinical manifestations (see Clinical Description).
• Note: If the proband is mosaic for a pathogenic variant, the risk to her offspring is as high as 50%, depending on the level of mosaicism in her germline.

Offspring of a male proband. Affected males are not known to reproduce.

Other family members. If the mother of the proband also has a pathogenic variant, her female family members may be at risk of having the pathogenic variant (and may or may not have clinical findings).

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous for this X-linked disorder will have a range of clinical manifestations (see Clinical Description). (2) Identification of female heterozygotes requires either (a) prior identification of the pathogenic variant in the family or (b) if an affected individual is not available for testing, molecular genetic testing as detailed in Establishing the Diagnosis.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes or who are at increased risk of being heterozygotes or affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once a COX7B, HCCS, or NDUFB11 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MLS syndrome are possible.

Introduction

COX7B, HCCS, and NDUFB11 encode proteins necessary for the proper functioning of the mitochondrial respiratory chain (MRC). "Canonic" mitochondrial diseases are usually characterized by postnatal organ failure rather than impaired development: in that regard microphthalmia with linear skin defects (MLS) syndrome can be defined as an unconventional mitochondrial disorder. A combined effect of mitochondrial respiration defects and enhanced cell death are hypothesized to result in the brain and eye abnormalities observed in MLS syndrome.

The three genes associated with MLS syndrome are all X-linked. Females with MLS syndrome show high inter- and intrafamilial phenotypic variability. Individuals can show the full MLS syndrome phenotype, or they can show isolated ocular manifestations, or aplastic skin areas restricted to face and neck with no additional abnormalities. Females with MLS syndrome may also show no features at all. A possible explanation for this clinical variability is the degree of skewed X chromosome inactivation observed in different tissues [Morleo & Franco 2008].

COX7B

Gene structure. COX7B (RefSeq: NM_001866.2) has three coding exons. The gene spans 5.9 kb, and its transcribed mRNA is 456 bp. No information is available on alternative splicing.

Pathogenic variants. The clinically relevant variants reported to date include p.Gln19Ter, c.196delC, and c.41-2A>G [Indrieri et al 2012] (see Table 3).

Normal gene product. COX7B is ubiquitously expressed and encodes an 80-amino-acid mitochondrial protein that has been shown to be an integral component of cytochrome c oxidase (COX), the mitochondrial respiratory chain (MRC) complex IV. COX7B subunit is necessary for COX activity, COX assembly, and mitochondrial respiration [Indrieri et al 2013].

Abnormal gene product. Microphthalmia with linear skin defects (MLS) syndrome is caused by pathogenic loss-of-function variants in COX7B, which promote severe impairment of the MRC's terminal segment [Indrieri et al 2012]. Moreover, downregulation of the COX7B homolog (cox7B) in medaka fish (Oryzias latipes) results in microcephaly and microphthalmia, thus indicating an essential role for complex IV activity and MRC function in vertebrate CNS development [Indrieri et al 2013].

HCCS

Gene structure. HCCS has seven exons, six of which are coding exons. The gene spans 11.8 kb, and its transcribed mRNA is long at 2,365 bp. No information on alternative splicing for this transcript is available (see Table 4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of HCCS disease-causing aberrations are large deletions involving the Xp22.2 chromosome region [Vergult et al 2013]; other reported pathogenic variants include p.Arg197Ter, p.Arg217Cys, and p.Glu159Lys, and a deletion of exons 1-3 [Wimplinger et al 2006, Wimplinger et al 2007b] (see Table 4).

Normal gene product. HCCS is expressed in a wide variety of tissues and encodes a mitochondrial enzyme of 268 amino acids, the holocytochrome c-type synthase, which catalyzes the covalent attachment of heme to apocytochrome c, thereby leading to the mature form holocytochrome c [Bernard et al 2003].

The product of the HCCS-catalyzed reaction, cytochrome c, has two cellular functions: it is implicated in oxidative phosphorylation (OXPHOS), and it is released from mitochondria upon proapoptotic stimuli, thus playing an important role in caspase-dependent apoptosis [Jiang & Wang 2004].

Abnormal gene product. MLS syndrome is caused by pathogenic loss-of-function variants in HCCS. Recently it was hypothesized that deficiency of HCCS may not only cause functional deficits in OXPHOS, but may also lead to severe constraints in the process of apoptosis. Thus, loss of HCCS function may disturb the balance between necrosis and apoptosis and push cell death toward necrosis [Wimplinger et al 2006]. Necrosis bears the danger of inflammatory reactions, leading to substantial damage of neighboring cells that could be a key element in developing eye malformations as well as other MLS syndrome-specific features in affected individuals.

NDUFB11

Gene structure. NDUFB11 spans 3 kb; its transcribed mRNA is 2,365 bp long. The gene comprises three exons; exon 2 is alternatively spliced [Petruzzella et al 2007].

Pathogenic variants. Reported pathogenic variants include p.Arg88Ter and c.402delG [van Rahden et al 2015].

Normal gene product. The protein encoded by NDUFB11 is the 17.3-kd subunit 11 of the NADH dehydrogenase (ubiquinone) 1 beta subcomplex and is part of the MRC complex I (cI). The longer transcript encodes a 163-amino-acid (aa) protein, while the shorter one encodes a more abundant protein consisting of 153 aa. The NDUFB11 protein is indispensable for assembly of the cI membrane arm, for maturation of the cI holocomplex, and for cI-dependent mitochondrial respiration.

Abnormal gene product. MLS syndrome is caused by pathogenic loss-of-function variants in NDUFB11, resulting in defective cI assembly and activity leading to impairment of mitochondrial respiration [van Rahden et al 2015]. Moreover, reduced NDUFB11 is associated with slower cell growth and increased apoptosis [van Rahden et al 2015].

A combined effect of MRC defects and enhanced cell death has been shown to underlie the brain and eye abnormalities observed in an hccs-deficient medaka fish model [Indrieri et al 2013].

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Acknowledgments

Research by the authors is supported by the Italian Telethon Foundation. We thank the families and all individuals affected with MLS syndrome participating in our research programs.

Revision History

• 26 July 2018 (ha) Comprehensive update posted live
• 18 August 2011 (me) Comprehensive update posted live
• 8 September 2009 (cd) Revision: sequence analysis available clinically; deletion/duplication analysis no longer available
• 18 June 2009 (et) Review posted live
• 16 January 2009 (mm) Original submission