Clinical Diagnosis

The clinical signs observed in microphthalmia with linear skin defects (MLS) syndrome are considered major if they are present in at least 80% of affected individuals and minor if they are less frequent.

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].

Figure

Figure 1. Reticulolinear scar lesions on the neck of a 36-year-old female with an otherwise normal phenotype. Cytogenetic analysis revealed 46,X,del(X)(p22.3 pter) [Lindsay et al 1994].

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

Major criteria

• Microphthalmia and/or anophthalmia (reported in 93% of affected individuals), which can be unilateral or bilateral (see Figure 2).
• Linear skin defects (reported in 95% of affected individuals), which are present at birth and usually involve the face and neck (see Figure 3), although the scalp and occasionally the upper trunk may be involved [Zvulunov et al 1998]. The lesions heal with age, leaving minimal residual scarring.

Figure

Figure 2. Bilateral microphthalmia and irregular linear skin areas involving the face and neck in a female infant with MLS who has a single nucleotide mutation in exon 6 of HCCS [Wimplinger et al 2006]

Figure

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

Minor criteria (in order of frequency)

• Other ocular abnormalities that are variable and can include: 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, and hypopigmented areas of the retinal pigment epithelium [Kobayashi et al 1998, Cape et al 2004, Wimplinger et al 2006]
• Central nervous system involvement: agenesis of corpus callosum, anencephaly, microcephaly [Happle et al 1993], hydrocephalus, intellectual disability, and infantile seizures
• Developmental delay
• Congenital heart defects: hypertrophic cardiomyopathy, oncocytic cardiomyopathy [Bird et al 1994], atrial and ventricular septal defects, supraventricular tachycardia, ventricular fibrillation, and other arrhythmias
• Short stature
• Diaphragmatic hernia
• Nail dystrophy
• Preauricular pits and hearing loss
• Genitourinary malformations: anterior or imperforate anus [al-Gazali et al 1990], bicornuate uterus, ambiguous genitalia, penile hypospadias in rare males with a 46,XX karyotype, and pseudotail [Alberry et al 2011] (see Testing)

Testing

Cytogenetic analysis can reveal chromosomal abnormalities involving the Xp22 region.

• Approximately 79% of female probands have chromosomal abnormalities that result in monosomy for Xp22.
• Eight males with MLS syndrome with an XX karyotype with detectable Y-chromosome material (e.g., translocation of Y chromosome material onto an X chromosome) have been described [Morleo et al 2005, Kapur et al 2008].

Only one 46,XY male with a mosaic paracentric inversion of Xp: 46Y,inv(X)(p22.13~22.2 p22.32~22.33)[49]/46,XY[271]) has been reported; he died a few hours after birth [Kutsche et al 2002].

Testing Strategy

To confirm/establish the diagnosis in a proband. To make a presumptive diagnosis, clinical evaluation, including the history of skin lesions and detailed family history, should be performed.

To confirm the diagnosis, genetic tests are recommended in the following order:

• Cytogenetic analysis from peripheral blood lymphocytes to identify chromosomal rearrangements involving the Xp22 region. A karyotype should be considered in males with MLS syndrome to look for evidence of 46,XX karyotype or an X/Y translocation.
• X-chromosome inactivation studies on a blood sample to look for evidence of X-chromosome skewing. Note: X-chromosome inactivation studies on peripheral blood samples can be helpful in establishing the diagnosis of MLS syndrome in individuals with a normal karyotype. To date, totally skewed X-inactivation of the abnormal X-chromosome has been detected in 21 of the 22 individuals with MLS syndrome tested who had either an abnormal karyotype or an HCCS point mutation or deletion.
• Array GH in individuals with normal high-resolution karyotype, to detect possible interstitial deletions in the MLS syndrome minimal critical region in Xp22.2
• FISH analysis in individuals with normal high-resolution karyotype when aGH is not available. It is used to identify and define interstitial deletions.
• Sequencing of the HCCS coding region in individuals who meet diagnostic criteria but do not have cytogenetic abnormalities

Note: Histologic examination of a skin biopsy does not necessarily lead to the diagnosis.

Carrier testing for at-risk female relatives requires prior identification of the disease-causing mutation in the family member. Alternatively, finding skewed X-chromosome inactivation in DNA isolated from peripheral lymphocytes can be helpful in identifying carriers if a cytogenetic abnormality or an HCCS mutation could not be identified in the proband. The finding of skewed X-chromosome inactivation would be supportive, but not definitive, evidence that an at-risk relative is a carrier of MLS syndrome.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

It is currently unknown if other disorders are allelic to MLS syndrome.

Natural History

Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microphthalmia or anophthalmia (see Figure 2) and jagged skin defects on the face and neck (see Figure 3). MLS syndrome is usually lethal in males.

Information is based on findings in the 56 affected individuals reported to date [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].

Intra- and interfamilial phenotypic variability has been described. The manifestations vary 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]. An example is a female with a normal phenotype except for typical MLS syndrome skin defects (see Figure 1) who had an affected female fetus with anencephaly. Cytogenetic analysis revealed that mother and fetus had the same Xp22 deletion − one of the largest Xp deletions described for MLS syndrome [Lindsay et al 1994].

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 that, 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 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] described focal areas of deficient collagen relative to the surrounding tissue, but absence of dermal aplasia.

Eng et al [1994] described a necrotic epidermis with an intact basement membrane and no signs of inflammation.

Paulger et al [1997] described smooth muscle hamartoma with overlying acanthotic epidermis, a thickened corneal layer, focal parakeratosis, foci of superficial erosion, and erector pili muscles in unusually large numbers in the surrounding dermis.

Stratton et al [1998] described smooth muscle hamartoma rather than dermal aplasia.

Zvulunov et al [1998] described a mild perivascular lymphocytic infiltrate in the upper dermis and regeneration of the epidermis. Electron microscopy revealed peculiar cytoplasmic bodies within keratinocytes.

Enright et al [2003] described irregular bundles of smooth muscle in the deep dermis resembling hypertrophied arrectores pilaris muscles, a basket-weave orthokeratosis, a granular layer of varying thickness vacuolar alteration of the basal layer, and an interface infiltrate of lymphocytes extending into the epidermis.

Eye findings. With microphthalmia and/or anophthalmia, developmental abnormalities are evident at birth in 92% of affected individuals (Figure 2) (see Anophthalmia/Microphthalmia Overview). Both microphthalmia and anophthalmia can be unilateral or bilateral. Other ocular abnormalities are described in Diagnosis.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Most individuals with MLS syndrome display the classic (highly variable) phenotype, which does not correlate with the extent of Xp-terminal deletion or the presence or nature of an HCCS mutation [Morleo & Franco 2008].

It has been proposed that the pattern of X-chromosome inactivation in affected individuals may influence the clinical findings [Lindsay et al 1994, Morleo & Franco 2008]. The authors hypothesize that the most severe MLS syndrome clinical manifestations are observed in females whose normal X chromosome is inactivated in the affected tissue or at a specific time of embryonic development.

Conversely, the authors hypothesize that a milder phenotype or the total absence of MLS syndrome clinical manifestations may result from totally skewed X-chromosome inactivation that forces preferential activation of the unaffected X, not only in blood cells, but also in tissues such as the eye and skin [Morleo & Franco 2008]. Moreover, skewed X-chromosome inactivation in blood cells can be detected in affected and non-affected females with Xp22 monosomy or an HCCS mutation. Thus, skewed X-chromosome inactivation does not explain non-penetrance in mutation-positive females.

Anticipation

Anticipation has not been reported

Nomenclature

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

MLS syndrome (also known as syndromic microphthalmia-7 [MCOPS7]) appears to be the most appropriate designation for this disease.

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

Prevalence

To date, 56 affected individuals have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with microphthalmia with linear skin lesions (MLS) syndrome, the following evaluations are recommended:

• Ophthalmologic examination
• Dermatologic evaluation to look for skin lesions
• Brain MRI with and without contrast to evaluate for corpus callosum dysgenesis and other neurologic abnormalities
• Developmental assessment, with further evaluation if significant delays are identified
• Hearing evaluation
• Cardiac examination
• Consideration of abdominal MRI and standard protocols for management of diaphragmatic hernia
• Genetics consultation

Treatment of Manifestations

The following are appropriate:

• Use of a prosthesis in severe microphthalmia and anophthalmia. In some cases ophthalmologic surgery can be considered to expand the palpebral fissures and orbit by fitting the infant with prostheses of progressively increasing size.
• Considerations for surgical intervention in severe microphthalmia and anophthalmia are best made after age six months, when postnatal growth of the orbit can be assessed.
• Regular care of 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 stimulation and special education as indicated for developmental delay
• Routine care for diaphragmatic hernia, cardiomyopathy, congenital heart defects, and other malformations, when present

Surveillance

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

For those with cardiomyopathy, complete and periodic cardiac evaluation by a cardiologist experienced in the diagnosis and treatment of heart failure is needed.

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 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 mainly affecting females as it is generally lethal in males.

Most cases are simplex (i.e., a single occurrence in a family), but a few familial occurrences have been described.

Risk to Family Members

Parents of a proband

• Most females with MLS syndrome have de novo mutations. A few instances of familial occurrences have been described. In such cases, the mutation is usually transmitted through the mother [Allanson & Richter 1991, Lindsay et al 1994, Mücke et al 1995, Wimplinger et al 2006, Wimplinger et al 2007a].
• Recommendations for the evaluation of the mother of a proband with an apparent de novo mutation include clinical evaluation of the mother and molecular genetic testing because of the possibility of low-level mosaicism. Note: Because significant intra- and interfamilial phenotypic variability has been described, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• If the mother has clinical findings of MLS syndrome, or if she has another affected relative, she is an obligate carrier of Xp22 monosomy or an HCCS mutation (which may or may not be identifiable).
• If the disease-causing genetic abnormality has been identified in the proband, and if the mother has no symptoms, molecular testing should be offered, especially if she desires other pregnancies or has sisters who may also be asymptomatic carriers.

Sibs of a proband

• The risk to sibs depends on the genetic status of the mother.
• When the mother of an affected female is also affected or has either the deleted X chromosome or an HCCS mutation, the risk to sibs of inheriting either at conception is 50%. Because male conceptuses with the deleted X chromosome or the HCCS mutation are typically nonviable, the likelihood of a live-born affected child is less than 50%.
• When the mother is clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population.
  • Because non-penetrance of the phenotype occurs, molecular genetic testing of the clinically unaffected mother is appropriate to more accurately assess recurrence risk to sibs.
  • If monosomy of Xp22 or an HCCS mutation cannot be detected in the DNA of the mother of a proband with a known HCCS mutation or Xp22 monosomy, possible explanations are germline mosaicism in the mother or a de novo mutation in the 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 HCCS mutation or the abnormal X chromosome from their mothers or may have a de novo mutation.

Offspring of a proband

• The risk to the offspring of females with MLS syndrome must take into consideration the presumed lethality to affected males during gestation.
• At conception, the risk that Xp22 monosomy or the mutant HCCS allele will be transmitted is 50%; however, because affected male conceptuses are typically nonviable, as are some affected female fetuses, the likelihood of a live-born child with MLS syndrome is less that 50%.
• If the affected female has a mosaic mutation, the risk to her offspring can be as high as 50%, depending on the level of mosaicism in her germ cells.

Other family members of a proband. If the mother of the proband also has a disease-causing mutation, her female family members may be at risk of having the mutation (and may or may not have clinical findings). If a female relative has a disease-causing mutation, her male offspring are at risk of being affected and not surviving pregnancy and her female offspring are at risk of having MLS syndrome.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk of having MLS syndrome resulting from an HCCS mutation is possible by analysis of DNA extracted from fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Prenatal diagnosis for pregnancies at increased risk of having MLS syndrome resulting from Xp22 monosomy is possible by chromosome analysis and/or FISH analysis of fetal cells obtained by amniocentesis or chorionic villus sampling (CVS).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation or Xp22 monosomy has been identified.

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Suggested Reading

1. Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A. 2004;129A:136–43. [PubMed: 15316978]

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

• 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