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Microphthalmia with Linear Skin Defects Syndrome

Synonyms: Microphthalmia, Dermal Aplasia, and Sclerocornea; Microphthalmia with Linear Skin Lesions Syndrome

, PhD and , MD.

Author Information
, PhD
Telethon Institute of Genetics and Medicine (TIGEM)
Naples, Italy
, MD
Telethon Institute of Genetics and Medicine (TIGEM)
Department of Pediatrics
Federico II University
Naples, Italy

Initial Posting: ; Last Update: August 18, 2011.

Summary

Disease characteristics. Microphthalmia with linear skin defects (MLS) syndrome is characterized by unilateral or bilateral microophthalmia 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 central nervous system involvement (e.g., structural anomalies, infantile seizures), developmental delay, heart defects (e.g., hypertrophic cardiomyopathy, oncocytic cardiomyopathy, arrhythmias), short stature, diaphragmatic hernia, nail dystrophy, preauricular pits and hearing loss, and genitourinary malformations. Inter- and intrafamilial variability is considerable.

Diagnosis/testing. Diagnosis is based on clinical findings and detection of either a chromosomal abnormality that results in monosomy for Xp22 or mutation of HCCS, the only gene known to be associated with MLS syndrome.

Management. Treatment of manifestations: Use of a prosthesis 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 stimulation and special education as indicated for developmental delay; routine care for other malformations when present.

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

Genetic counseling. MLS syndrome is inherited in an X-linked manner and mainly affects females as it is usually lethal in males. Most cases are simplex (i.e., a single occurrence in a family), but familial occurrences have been described. Women who are affected or have either the deleted X chromosome or an HCCS mutation have a 50% chance of passing the genetic alteration to each offspring. 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%. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing genetic alteration has been identified in an affected family member.

Diagnosis

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 1

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 2

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 3

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.

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].

Molecular Genetic Testing

Gene. HCCS, encoding the mitochondrial holocytochrome c-type synthase, is the only gene in which mutation is known to cause MLS syndrome.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Microphthalmia with Linear Skin Defects Syndrome

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
HCCSCytogenetic and FISH analysesMonosomy of Xp22 region (>11 Mb) 2; 3.2-Mb interstitial deletion 377%
Sequence analysis3 single-nucleotide mutations (c.589C>T, c.649C>T, c.475G>A4, 53 affected females
Deletion/ duplication analysis 6Deletion of exons 1-32 affected sisters and their healthy mother
X-chromosome inactivation studiesSkewed X-chromosome inactivationNA

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Caused by deletions or unbalanced translocations

3. Detected by FISH analysis

4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

5. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.

Interpretation of test results. Failure to identify an abnormal karyotype or deletion of the MLS region does not rule out the diagnosis of MLS syndrome.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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.

Clinical Description

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.

Differential Diagnosis

Goltz syndrome, also known as focal dermal hypoplasia, is characterized by distinctive skin findings (dermal hypoplasia) and ophthalmologic manifestations similar to those observed in microphthalmia with linear skin defects (MLS) syndrome. However, limb and skeletal malformations that are common in Goltz syndrome are rarely seen in MLS syndrome. Goltz syndrome is caused by deletions and point mutations of PORCN; thus, MLS syndrome and focal dermal hypoplasia are not allelic, as had been previously proposed. Inheritance is X-linked with male lethality.

Incontinentia pigmenti (IP) affects the skin, hair, teeth, nails, eyes, and central nervous system. Characteristic skin lesions evolve through four stages: (I) blistering (birth to age ~4 months); (II) a wart-like rash (for several months); (III) swirling macular hyperpigmentation (age ~6 months into adulthood); (IV) linear hypopigmentation. Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Ocular abnormalities are reported in 35% of individuals with IP and include neovascularization of the retina, pigment epithelial mottling, microphthalmia, and anophthalmia. Neurologic findings including cognitive delays/intellectual disability are occasionally seen. NEMO is the only gene known to be associated with IP. Inheritance is X-linked with male lethality.

Oculocerebrocutaneous syndrome (OCCS), characterized by orbital cysts and anophthalmia or microphthalmia, focal skin defects, brain malformations that include polymicrogyria, periventricular nodular heterotopias, enlarged lateral ventricles, and agenesis of the corpus callosum, is predominant in males and has a pathognomonic mid-hindbrain malformation [Moog et al 2005] (see also Polymicrogyria Overview).

Aicardi syndrome was initially described as a triad of agenesis of the corpus callosum, typical chorioretinal lacunae, and infantile spasms; however, with the ascertainment of more cases, it has become clear that other neurologic heterotopias, polymicrogyria, and systemic defects including costovertebral anomalies are common. Moderate- to-severe global developmental delay and intellectual disability are expected. Medically refractory epilepsy with a variety of seizure types develops over time. Other features include characteristic facial features, microphthalmia, and pigmentary lesions of the skin. To date, the gene in which mutation is causative has not been mapped and is not known; however, mutations in HCCS have not been found in Aicardi syndrome. Hence, MLS and Aicardi syndrome are likely not allelic. Inheritance is presumed X-linked dominant, male-lethal because only females or males with 47,XXY karyotype are known.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.
  • 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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Children's Anophthalmia and Microphthalmia Network (ICAN)
    c/o Center for Developmental Medicine and Genetics
    5501 Old York Road
    Genetics, Levy 2 West
    Philadelphia PA 19141
    Phone: 800-580-4226 (toll-free)
    Email: ican@anophthalmia.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Microphthalmia with Linear Skin Defects Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HCCSXp22​.2Cytochrome c-type heme lyaseHCCS @ LOVDHCCS

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Microphthalmia with Linear Skin Defects Syndrome (View All in OMIM)

300056HOLOCYTOCHROME C SYNTHASE; HCCS
309801MICROPHTHALMIA, SYNDROMIC 7; MCOPS7

Normal allelic variants. HCCS has seven exons, six of which are coding exons. The gene spans 11.8 kb, and its transcribed mRNA is long at 2365 bp. It is not known to undergo alternative splicing (see Table 2).

Pathologic allelic variants. Disease-causing mutations include a nonsense mutation, c.589C>T (exon 6, p.Arg197X); two missense mutations, c.649C>T (exon 7, p.Arg217Cys) and c.475G>A (exon 5, p.Glu159Lys); as well as an HCCS deletion of exons 1-3 [Wimplinger et al 2006, Wimplinger et al 2007b] (see Table 2).

Table 2. Selected HCCS Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Normalrs2070163 p.Ala72ValNM_005333​.4
NP_005324​.3
rs34228583p.= 1
Pathologicc.589C>Tp.Arg197X
c.649C>Tp.Arg217Cys
c.475G>Ap.Glu159Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. p.= designates that protein has not been analyzed, but no change is expected.

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. Microphthalmia with linear skin defects (MLS) syndrome is caused by loss-of-function mutations in HCCS and cytogenetically visible deletions or microdeletions covering (part of) HCCS. It is currently unknown how the mutations in HCCS could cause a peculiar pathologic phenotype like MLS syndrome. 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, functional nullisomy of HCCS 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.

References

Literature Cited

  1. Alberry MS, Juvanic G, Crolla J, Soothill P, Newbury-Ecob R. Pseudotail as a feature of microphthalmia with linear skin defects syndrome. Clin Dysmorphol. 2011;20:111–3. [PubMed: 21200317]
  2. al-Gazali L, Mueller RF, Caine A, Antoniou A, McCartney A, Fitchett M, Dennis NR. Two 46,XX,t(X;Y) females with linear skin defects and congenital microphthalmia: a new syndrome at Xp22.3. J Med Genet. 1990;27:59–63. [PMC free article: PMC1016884] [PubMed: 2308157]
  3. Allanson J, Richter S. Linear skin defects and congenital microphthalmia: a new syndrome at Xp22.2. J Med Genet. 1991;28:143–4. [PMC free article: PMC1016789] [PubMed: 2002490]
  4. Anguiano A, Yang X, Felix JK, Hoo JJ. Twin brothers with MIDAS syndrome and XX karyotype. Am J Med Genet A. 2003;119A:47–9. [PubMed: 12707958]
  5. Bernard DG, Gabilly ST, Dujardin G, Merchant S, Hamel PP. Overlapping specificities of the mitochondrial cytochrome c and c1 heme lyases. J Biol Chem. 2003;278:49732–42. [PubMed: 14514677]
  6. Bird LM, Krous HF, Eichenfield LF, Swalwell CI, Jones MC. Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy? Am J Med Genet. 1994;53:141–8. [PubMed: 7856638]
  7. Cain CC, Saul D, Attanasio L, Oehler E, Hamosh A, Blakemore K, Stetten G. Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization. Prenat Diagn. 2007;27:373–9. [PubMed: 17286317]
  8. Cape CJ, Zaidman GW, Beck AD, Kaufman AH. Phenotypic variation in ophthalmic manifestations of MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea). Arch Ophthalmol. 2004;122:1070–4. [PubMed: 15249380]
  9. Eng A, Lebel RR, Elejalde BR, Anderson C, Bennett L. Linear facial skin defects associated with microphthalmia and other malformations, with chromosome deletion Xp22.1. J Am Acad Dermatol. 1994;31:680–2. [PubMed: 8089303]
  10. Enright F, Campbell P, Stallings RL, Hall K, Green AJ, Sweeney E, Barnes L, Watson R. Xp22.3 microdeletion in a 19-year-old girl with clinical features of MLS syndrome. Pediatr Dermatol. 2003;20:153–7. [PubMed: 12657015]
  11. Happle R, Daniëls O, Koopman RJ. MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Med Genet. 1993;47:710–3. [PubMed: 8267001]
  12. Hobson GM, Gibson CW, Aragon M, Yuan ZA, Davis-Williams A, Banser L, Kirkham J, Brook AH. A large X-chromosomal deletion is associated with microphthalmia with linear skin defects (MLS) and amelogenesis imperfecta (XAI). Am J Med Genet A. 2009;149A:1698–705. [PMC free article: PMC2760392] [PubMed: 19610109]
  13. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem. 2004;73:87–106. [PubMed: 15189137]
  14. Kapur R, Tu EY, Toyran S, Shah P, Vangveeravong S, Lloyd WC, Edward DP. Corneal pathology in microphthalmia with linear skin defects syndrome. Cornea. 2008;27:734–8. [PubMed: 18580270]
  15. Kherbaoui-Redouani L, Eschard C, Bednarek N, Morville P, Bednare N. Cutaneous aplasia, non compaction of the left ventricle and severe cardiac arrhythmia: a new case of MLS syndrome (microphtalmia with linear skin defects). Arch Pediatr. 2003;10:224–6. [PubMed: 12829336]
  16. Kobayashi M, Kiyosawa M, Toyoura T, Tokoro T. An XX male with microphthalmos and sclerocornea. J Pediatr Ophthalmol Strabismus. 1998;35:122–4. [PubMed: 9559515]
  17. Kono T, Migita T, Koyama S, Seki I. Another observation of microphthalmia in an XX male: microphthalmia with linear skin defects syndrome without linear skin lesions. J Hum Genet. 1999;44:63–8. [PubMed: 9929982]
  18. Kutsche K, Werner W, Bartsch O, von der Wense A, Meinecke P, Gal A. Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp. Cytogenet Genome Res. 2002;99:297–302. [PubMed: 12900578]
  19. Lindsay EA, Grillo A, Ferrero GB, Roth EJ, Magenis E, Grompe M, Hultén M, Gould C, Baldini A, Zoghbi HY, Ballabio A. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic and molecular characterization. Am J Med Genet. 1994;49:229–34. [PubMed: 8116674]
  20. Moog U, Jones MC, Bird LM, Dobyns WB. Oculocerebrocutaneous syndrome: the brain malformation defines a core phenotype. J Med Genet. 2005;42:913–21. [PMC free article: PMC1735958] [PubMed: 15879499]
  21. Morleo M, Franco B. Dosage compensation of the mammalian X chromosome influences the phenotypic variability of X-linked dominant male-lethal disorders. J Med Genet. 2008;45:401–8. [PubMed: 18463129]
  22. Morleo M, Pramparo T, Perone L, Gregato G, Le Caignec C, Mueller RF, Ogata T, Raas-Rothschild A, de Blois MC, Wilson LC, Zaidman G, Zuffardi O, Ballabio A, Franco B. Microphthalmia with linear skin defects (MLS) syndrome: clinical, cytogenetic, and molecular characterization of 11 cases. Am J Med Genet A. 2005;137:190–8. [PubMed: 16059943]
  23. Mücke J, Hoepffner W, Thamm B, Theile H. MIDAS syndrome (microphthalmia, dermal aplasia and sclerocornea): an autonomous entity with linear skin defects within the spectrum of focal hypoplasias. Eur J Dermatol. 1995;5:197–203.
  24. Paulger BR, Kraus EW, Pulitzer DR, Moore CM. Xp microdeletion syndrome characterized by pathognomonic linear skin defects on the head and neck. Pediatr Dermatol. 1997;14:26–30. [PubMed: 9050760]
  25. Schluth C, Cossee M, Girard-Lemaire F, Carelle N, Dollfus H, Jeandidier E, Flori E. Phenotype in X chromosome rearrangements: pitfalls of X inactivation study. Pathol Biol (Paris). 2007;55:29–36. [PubMed: 16690229]
  26. Sharma VM, Ruiz de Luzuriaga AM, Waggoner D, Greenwald M, Stein SL. Microphthalmia with linear skin defects: a case report and review. Pediatr Dermatol. 2008;25:548–52. [PubMed: 18950397]
  27. Steichen-Gersdorf E, Griesmaier E, Pientka FK, Kotzot D, Kutsche K. A severe form of the X-linked microphthalmia with linear skin defects syndrome in a female newborn. Clin Dysmorphol. 2010;19:82–4. [PubMed: 20179582]
  28. Stratton RF, Walter CA, Paulgar BR, Price ME, Moore CM. Second 46,XX males with MLS syndrome. Am J Med Genet. 1998;76:37–41. [PubMed: 9508062]
  29. Wimplinger I, Morleo M, Rosenberger G, Iaconis D, Orth U, Meinecke P, Lerer I, Ballabio A, Gal A, Franco B, Kutsche K. Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2006;79:878–89. [PMC free article: PMC1698567] [PubMed: 17033964]
  30. Wimplinger I, Rauch A, Orth U, Schwarzer U, Trautmann U, Kutsche K. Mother and daughter with a terminal Xp deletion: implication of chromosomal mosaicism and X-inactivation in the high clinical variability of the microphthalmia with linear skin defects (MLS) syndrome. Eur J Med Genet. 2007a;50:421–31. [PubMed: 17845869]
  31. Wimplinger I, Shaw GM, Kutsche K. HCCS loss-of-function missense mutation in a female with bilateral microphthalmia and sclerocornea: a novel gene for severe ocular malformations? Mol Vis. 2007b;13:1475–82. [PubMed: 17893649]
  32. Zvulunov A, Kachko L, Manor E, Shinwell E, Carmi R. Reticulolinear aplasia cutis congenita of the face and neck: a distinctiv cutaneous manifestation in several syndromes linked to Xp22. Br J Dermatol. 1998;138:1046–52. [PubMed: 9747372]

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]

Chapter Notes

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
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