Microphthalmia With Linear Skin Defects Syndrome
Summary
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.
Diagnosis
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]
Major Criteria
- Microphthalmia and/or anophthalmia
- Reported in 81% of affected individuals
- Can be unilateral or bilateral (see Figure 2)
- Linear skin defects
- Reported in 75% of affected individuals
- Present at birth
- Usually involve the face and neck (see Figure 3), although the scalp and occasionally the upper trunk may be involved [Zvulunov et al 1998]
- Heal with age, leaving minimal residual scarring
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MLS syndrome, molecular genetic testing approaches can include chromosome microarray analysis or use of a multigene panel:
- 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.Note: (1) Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is used more frequently than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)); therefore, karyotype and/or FISH follow up may be necessary based on CMA results. (2) Apparently balanced translocations have been reported in affected individuals [Vergult et al 2013]. In an affected person in whom other testing does not reveal a causative variant, karyotype analysis may be considered.
- A multigene panel that includes COX7B, HCCS, NDUFB11, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition (if CMA is not diagnostic) at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of MLS syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is often performed. MLS syndrome is likely to be diagnosed by chromosome microarray (CMA), which is the best first test when multiple congenital abnormalities are present. If CMA is not diagnostic, additional genomic testing is indicated. Exome sequencing is most commonly used; genome sequencing is also possible.
Exome array (when clinically available) may be considered if CMA and exome sequencing are non-diagnostic.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: Although not used for diagnosis, X-chromosome inactivation studies have been performed in females with MLS syndrome. Skewed X-chromosome inactivation has been detected in 21 of the 22 individuals with MLS syndrome analyzed to date [Anguiano et al 2003, Wimplinger et al 2006, Cain et al 2007, Schluth et al 2007, Wimplinger et al 2007a, Wimplinger et al 2007b, Hobson et al 2009, Steichen-Gersdorf et al 2010, Alberry et al 2011]. In all individuals the abnormal X is inactive.
Table 1.
Molecular Genetic Testing Used in MLS syndrome
| Gene 1, 2 | Proportion of MLS Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | ||
|---|---|---|---|---|
| Sequence analysis 4, 5 | Gene-targeted deletion/duplication analysis 6 | CMA 7, 8, 9 | ||
| COX7B | ~5% 10 | 3/3 11 | Unknown 12 | N/A |
| HCCS | ~92% 10 | ~8% 13 | See footnote 14. | ~92% 15, 16 |
| NDUFB11 | ~3% 10 | 2/2 10 | Unknown 12 | N/A |
- 1.
Genes are listed alphabetically.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
ClinGen: ISCA-20454. Standardized clinical annotation and interpretation for genomic variants from the Clinical Genome Resource (ClinGen) project (formerly the International Standards for Cytogenomic Arrays [ISCA] Consortium)
- 8.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the Xp22.3 region.
- 9.
Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
- 10.
van Rahden et al [2015]
- 11.
Indrieri et al [2012]
- 12.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 13.
Vergult et al [2013], van Rahden et al [2014]
- 14.
All large deletions reported to date are large deletions that encompass HCCS and surrounding sequence. Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected. Thus, the detection rate for HCCS-targeted deletion assays would be ~92%; however, the deletion may not be fully characterized.
- 15.
Vergult et al [2013], van Rahden et al [2014]
- 16.
Note: Deletions reported in the literature were most frequently detected by karyotype and FISH analysis; however, CMA is more commonly used than karyotyping in clinical practice for individuals with complex medical issues and has greater resolution and precision than a karyotype. Some complex karyotypes have been reported (e.g., 45,X[18]/46,X,der(X)(p22q21)[24]/46,X,del(X)(p22)[58] and 46,X,der(X)t(X;Y)), therefore, karyotype and/or FISH follow up may be necessary based on CMA results.
Clinical Characteristics
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.
Major Criteria
Eye findings. Microphthalmia and/or anophthalmia, when present, are evident at birth in 81% of affected individuals (Figure 2). Both microphthalmia and anophthalmia can be unilateral or bilateral.
Skin manifestations. In general, no new lesions are observed after birth and the skin defects heal variably with age, leaving minimal residual scarring. The cutaneous findings typically follow the lines of Blaschko corresponding to cell migration pathways evident during embryonic and fetal skin development, which (unlike dermatomes) do not correspond to innervation patterns. The restriction to the head and neck is thought to result from involvement of neural crest cells [al-Gazali et al 1990, Lindsay et al 1994].
Histologic skin findings. Happle et al [1993] coined the acronym MIDAS (for microphthalmia, dermal aplasia, and sclerocornea), and argued that (in contrast to focal dermal hypoplasia) the erythematous lesions of dermal aplasia do not show herniation of fatty tissue. Subsequent histologic examination of skin biopsies of the linear, reticulated skin defects in six reported individuals yielded varied results, all confirming that dermal aplasia is not a histologic feature of MLS syndrome [Bird et al 1994, Eng et al 1994, Paulger et al 1997, Stratton et al 1998, Zvulunov et al 1998, Enright et al 2003].
Minor Criteria (in <70% of affected individuals)
Note: Categories are in descending order of frequency.
Other ocular abnormalities reported [Kobayashi et al 1998, Cape et al 2004, Wimplinger et al 2006, Kapur et al 2008, Carman et al 2009, García-Rabasco et al 2013, Vergult et al 2013, Herwig et al 2014, van Rahden et al 2014, van Rahden et al 2015]:
- Sclerocornea
- Orbital cysts
- Microcornea
- Eyelid fissures
- Corneal leukoma
- Iridocorneal adhesion (Peters anomaly)
- Congenital glaucoma with total/peripheral anterior synechiae
- Aniridia
- Cataracts
- A remnant of the anterior hyaloid artery
- Vitreous opacity
- Hypopigmented areas of the retinal pigment epithelium
Central nervous system involvement
- Agenesis of corpus callosum
- Anencephaly
- Microcephaly
- Hydrocephalus
- Developmental delay / intellectual disability
- Infantile seizures
Cardiac concerns
- Cardiomyopathy (hypertrophic or oncocytic)
- Atrial and ventricular septal defects
- Arrhythmias such as supraventricular tachycardia and ventricular fibrillation
Other reported findings (including frequency)
- Short stature (18/42)
- Genitourinary or lower intestinal malformations: bicornuate uterus, ambiguous genitalia, anterior or imperforate anus, penile hypospadias in rare males with a 46,XX karyotype (14/64)
- Hearing impairment (5/64)
- Nail dystrophy (3/55)
- Diaphragmatic hernia (3/64)
- Pseudotail [Alberry et al 2011]; as a single case report. This may be a coincidental finding and not typical of MLS syndrome.
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.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of MLS Syndrome
| Disorder | Gene(s) | MOI | Clinical Features | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| Focal dermal hypoplasia (Goltz syndrome) | PORCN | XL |
| In focal dermal hypoplasia: limb & skeletal malformations |
| Incontinentia pigmenti (IP) | IKBKG (NEMO) | XL |
| In incontinentia pigmenti:
|
| Oculocerebro- cutaneous syndrome (OCCS) (OMIM 164180) | ? | ? |
| In OCCS:
|
| Aicardi syndrome | ? | XL |
| In Aicardi syndrome: 3
|
? = unknown; MOI = mode of inheritance; XL = X-linked
- 1.
MLS syndrome is male lethal.
- 2.
Polymicrogyria or periventricular heterotopia, agenesis of the corpus callosum, hypoplastic vermis of the cerebellum, hydrocephalus
- 3.
Two of the three classic features (agenesis of the corpus callosum, distinctive chorioretinal lacunae, infantile spasms) are needed to make the diagnosis of Aicardi syndrome; these features are rarely found associated with microphthalmia in MLS syndrome.
Management
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.