Linear Skin Defects Syndrome Research Articles

Term newborn with microphthalmia, encephalocele and linear skin defect

The presence of skin and ocular findings includes syndromes with X linked transmission, such as microphthalmia with linear skin defects (MLS) syndrome, focal dermal hypoplasia (Goltz syndrome), oculocerebrocutaneous syndrome, incontinentia pigmenti and Aicardi syndrome. We report the case of a term neonate with corneal opacities and unusual skin findings along with an encephalocele consistent with MLS syndrome.

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

Microphthalmia and linear skin defects syndrome (MLS) is a rare X-linked dominant disorder characterized by microphthalmia and linear atrophic plaques of the face and neck. The diagnosis of MLS can be challenging secondary to both its rarity and to clinical overlap with Goltz syndrome. Whereas the skin lesions of MLS are more likely to improve in appearance with age, the lesions of Goltz are typically persistent.

A mosaic form of microphthalmia with linear skin defects

BackgroundMicrophthalmia with linear skin defects (MLS) syndrome is a rare neurodevelopmental X-dominant disorder. It presents in females as it is normally lethal in males. Three causative genes for MLS syndrome (OMIM 309801) have been identified all taking part in mitochondrial respiratory chain and oxidative phosphorylation. In our case, we describe a newborn with mosaic deletion encompassing HCCS gene resulting in unilateral microphthalmia and facial skin lesions.Case presentationA girl was born with caesarean section at 40 weeks of gestation. Clinical findings revealed anophthalmia of the left eye. The left eyelids were intact, the orbit was empty and the right eye was normal, without any abnormalities. She had typical linear skin defects on the left cheek, one on the left side of the neck, and two on the 3th and 4th fingers of the left hand. The other clinical findings and the neurological exam were normal. US of the brain and EEG were normal. Molecular karyotyping using BlueGnome CytoChip Oligo 4× 180K array was performed detecting an approximately 18% mosaic 3.3 Mb deletion (arr[GRCh37] Xp22.31p22.2(8,622,553_11,887,361)× 1[0.18]). FISH using RPCI11-768H20 BAC clone on cultivated interphase and metaphase lymphocytes was used to confirm the array results. The observed deletion was present in 29% of cells (46,XX,ish del(p22.2p22.31)(RPCI11-768H20)[60/205]).ConclusionsIn this report we present a female proband with MLS syndrome. To our knowledge, there have been only few other cases of mosaic MLS syndrome described in the literature. Our case shows that low grade mosaicism does not preclude full clinical presentation and further supports the critical role of the X inactivation pattern in the development of the clinical findings.

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

Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related).

Investigating the Catalytic Mechanism of Yeast Cytochrome c Heme Lyase (CCHL) Through Mutation of Highly Conserved Amino Acid Residues

Cytochrome c is a vital component in energy transduction pathways, as well as in the process of programmed cell death (apoptosis). As a functional holoform, cytochrome c contains at least one covalently attached heme cofactor. In fungi, metazoans, and some protozoa, heme attachment is catalyzed by the enzyme cytochrome c heme lyase (CCHL), which is also known as holocytochrome c synthase (HCCS). In humans, genetic mutations leading to nonfunctional CCHL are lethal to males and cause microphthalmia with linear skin defects syndrome (MLS) in females. Despite this association with human disease, little is known about the mechanistic and structural properties of CCHL. Here, we used yeast CCHL to carry out site‐directed mutagenesis to evaluate the role of highly conserved residues adjacent to histidine at position 128 (H128), which has been found to be critical for catalytic activity. Generated mutants were co‐expressed with yeast apocytochrome c in an Escherichia coli system, in which successful holocytochrome c formation in vivo is indicated by the development of red colored cells (red phenotype). Cells coexpressing yeast apocytochrome c and CCHL mutants H128N and H128C lost the ability to ligate heme to apoprotein substrates (white phenotype). This ability was retained at varying levels, however, in M124C, V125C, Q126C, 127C, F130C, L131C, and N132C mutants. Absorbance spectroscopy confirmed these findings, revealing characteristic spectra for holocytochrome c in the lysates of red (but not white) colored cells. In some mutants, it has also been observed that the redox behavior of produced holocytochrome c differs from that in wildtype. These mutants are being investigated for potential altered enzyme‐substrate interactions.

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome.

BackgroundSegmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.MethodsWe characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.ResultsTwo terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.ConclusionOur findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.

Dermatoscopic aspects of the Microphthalmia with Linear Skin Defects (MLS) Syndrome

The association of microphthalmia and linear skin defects was named microphthalmia with linear skin defects syndrome (MLS) or MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea), an X-chromosomal disorder manifesting mainly in females. We examined a female newborn with facial linear skin defects following the Blaschko lines. Computer tomography and ophthalmological examination confirmed bilateral microphthalmia. An interstitial microdeletion at Xp22.2, encompassing the entire HCCS gene, was identified. Dermatoscopic examination showed erythematous linear areas with telangectasias and absence of sebaceous glands, which appear as brilliant white dots. Vellus hairs were also absent in the red areas. Dermatoscopy could help to establish the diagnosis of MLS/MIDAS syndrome by confirming the aplastic nature of the lesions.

Microphthalmia with Linear Skin Defects Syndrome

Microphthalmia with linear skin defects (MLS) or microcornea, dermal aplasia and sclerocornea (MIDAS) syndrome is a rare X-linked-dominant disorder. We present a patient with agenesis of corpus callosum, ocular abnormalities, and multiple skin defects. The cytogenetic studies of the MLS critical region (Xp22.2) were normal, but a skewed X-chromosome inactivation pattern (85:15) was observed.

Pseudotail as a feature of microphthalmia with linear skin defects syndrome

Pseudotail as a feature of microphthalmia with linear skin defects syndrome

A severe form of the X-linked microphthalmia with linear skin defects syndrome in a female newborn

A severe form of the X-linked microphthalmia with linear skin defects syndrome in a female newborn

Goltz–Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

Microphthalmia with Linear Skin Defects: A Case Report and Review

Microphthalmia with linear skin defects syndrome is an X-linked dominant disorder characterized by microphthalmia and other ocular anomalies as well as linear, jagged skin defects typically involving the scalp, face, neck, and upper trunk. Other associated characteristics include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. Microphthalmia with linear skin defects syndrome is now known to be associated with a deletion of the X chromosome at Xp22. This is an area that has been found to include the HCCS gene, which encodes a holocytochrome c-type synthase believed to be critical in the regulation of apoptosis. We present a patient with classic clinical and genetic findings of MLS syndrome and discuss the primary characteristics and management of this disorder.

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

The microphthalmia with linear skin defects (MLS or MIDAS) syndrome is a rare X-linked dominant inherited disorder with male lethality, associated with segmental aneuploidy of the Xp22.2 region in most of the cases. However, we recently described heterozygous sequence alterations in a single gene, HCCS, in females with MLS. Beside the classical MLS phenotype, occasional features such as sclerocornea, agenesis of the corpus callosum, and congenital heart defects can occur. Although the majority of cases are sporadic, mother-to-daughter transmission has been observed and a high intra- and interfamilial phenotypic variability exists. We describe an asymptomatic mother and her daughter presenting with the typical features of MLS syndrome. By cytogenetic analysis both females were found to have a terminal Xp deletion with the breakpoint in Xp22.2, mapping near to or within the MSL3L1 gene which is located centromeric to HCCS. FISH analysis revealed that the mother is a mosaic with 45,X[11]/46,X,del(X)(p22.2)[89], while in all cells of the MLS-affected daughter a hybridization pattern consistent with a 46,X,del(X)(p22.2) karyotype was detected. By haplotype analysis we identified the paternal X chromosome of the mother to carry the terminal Xp deletion. X-inactivation studies showed a completely skewed pattern in mother and daughter with the deleted X chromosome to be preferentially inactivated in their peripheral blood cells. We suggest that both chromosomal mosaicism as well as functional X chromosome mosaicism could contribute to the lack of any typical MLS feature in individuals with a heterozygous MLS-associated mutation. The 45,X cell population, that most likely is also present in other tissues of the mother, might have protected her from developing MLS. Nonetheless, a non-random X-inactivation pattern in favor of activity of the wild-type X chromosome in the early blastocyte could also account for the apparent lack of any disease sign in this female.

Microphthalmia with linear skin defects (MLS) syndrome evaluated by prenatal karyotyping, FISH and array comparative genomic hybridization

To explore the utility of comparative genomic hybridization to BAC arrays (array CGH) for prenatal diagnosis of microphthalmia and linear skin defects syndrome. We used karyotype analysis, FISH and array CGH to investigate an X;Y translocation. Replication studies were done on cultured amniocytes and lymphoblasts. We describe a severe case of MLS syndrome that presented prenatally with multiple anomalies including cystic hygroma, microphthalmia, intrauterine growth restriction and a complex congenital heart defect. Cytogenetic analysis of amniocytes revealed an unbalanced de novo translocation between chromosomes X and Y [karyotype 46,X,der(X)t(X;Y)(p22.3;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2 (Tuple1 x 2)]. MLS diagnosis was made at birth and the prenatal karyotype was confirmed. Replication studies showed the derivative X chromosome was the inactive X. Array CGH confirmed the X and Y imbalances seen in the karyotype and also showed twelve BACs in the MLS region were deleted as a result of the translocation. FISH with BAC clones verified the array findings and placed the X breakpoint in Xp22.2, resulting in the amended karyotype, 46,X,der(X)t(X;Y)(p22.2;q11.2).ish der(X)(DXZ1+,DMD+,KAL-,STS-,SRY-),22q11.2(Tuple1 x 2) arr cgh Xp22.33p22.2(LLNOYCO3M15D10 -->GS1-590J6)x 1,Yq11.222q23(RP11-20H21-->RP11-79J10)x 1. The sensitivity of array CGH was valuable in detecting monosomy of the MLS critical region. Array CGH should be considered for the prenatal diagnosis of this syndrome.

Mutations of the Mitochondrial Holocytochrome c–Type Synthase in X-Linked Dominant Microphthalmia with Linear Skin Defects Syndrome

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.

Microphthalmia with linear skin defects (MLS) syndrome: Clinical, cytogenetic, and molecular characterization of 11 cases

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

Loss of holocytochrome c-type synthetase causes the male lethality of X-linked dominant microphthalmia with linear skin defects (MLS) syndrome.

Girls with MLS syndrome have microphthalmia with linear skin defects of face and neck, sclerocornea, corpus callosum agenesis and other brain anomalies. This X-linked dominant, male-lethal condition is associated with heterozygous deletions of a critical region in Xp22.31, from the 5' untranslated region of MID1 at the telomeric boundary to the ARHGAP6 gene at the centromeric boundary. HCCS, encoding human holocytochrome c-type synthetase, is the only gene located entirely inside the critical region. Because single gene analysis is not feasible in MLS patients (all have deletions), we generated a deletion of the equivalent region in the mouse to study the molecular basis of this syndrome. This deletion inactivates mouse Hccs, whose homologs in lower organisms (cytochrome c or c1 heme lyases) are essential for function of cytochrome c or c1 in the mitochondrial respiratory chain. Ubiquitous deletions generated in vivo lead to lethality of hemizygous, homozygous and heterozygous embryos early in development. This lethality is rescued by expression of the human HCCS gene from a transgenic BAC, resulting in viable homozygous, heterozygous and hemizygous deleted mice with no apparent phenotype. In the presence of the HCCS transgene, the deletion is easily transmitted to subsequent generations. We did obtain a single heterozygous deleted female that does not express human HCCS, which is analogous to the low prevalence of the heterozygous MLS deletion in humans. Through the study of these genetically engineered mice we demonstrate that loss of HCCS causes the male lethality of MLS syndrome.

Another observation of microphthalmia in an XX male: microphthalmia with linear skin defects syndrome without linear skin lesions

A case of microphthalmia with Xp microdeletion is reported. The patient was a boy who showed bilateral microphthalmia with corneal opacities, hypospadias without evidence of hypogonadism, and a conduction disturbance of the heart (Wenckebach conduction). No skin lesion was discerned. High-resolution chromosome analysis revealed the karyotype of 46,X,del(X)(p22). The phenotype was considered to be microphthalmia with linear skin defects (MLS) syndrome without skin lesions. Polymerase chain reaction and fluorescence in-situ hybridization analyses revealed that the chromosome aberration resulted from an X;Y translocation: the presence of pseudoautosomal boundary Y and the sex-determining region of Y was confirmed, while Xp deletion involving the region distal to DXS1129 was ascertained. Thus the chromosome designation using the ISCN 1995 nomenclature is 46,X,der(X),t(X;Y)(p22.13;q11.2). Despite the absence of skin lesions, the Xp deletion of our patient corresponded to those of previously reported typical cases of MLS syndrome. Our observation further supports the current hypothesis that the phenotypic variation of MLS syndrome represents tissue-different X inactivation rather than different genetic effects of two contiguous genes.

Genetic studies in the focal dermal hypoplasia of Goltz syndrome

The focal dermal hypoplasia of Goltz (FDH) syndrome is an X-linked disorder with skin, skeletal, and ocular defects. The FDH phenotype shares features with the microphthalmia with linear skin defects (MLS) syndrome, which is associated with deletions of Xp22. Familial cases of FDH are rare; no genetic studies were performed previously. We studied linkage to twelve polymorphic markers between DXS43 and OAI in an FDH family, including an affected mother (FDH7), her husband, affected daughter (FDH8), and unaffected son. Phenotypically, the mother's findings were limited mostly to the skin. Her karyotype was normal, 46, XX. She had patterned telangiectanc streaks, atrophic areas, scalp aplasia cutis congenita, perianal papillomas, and subepidermal lipomatosis. Her ocular exam was normal; there was no evidence of osteopathia striata on knee radiographs. Dentition was normal except for multiple caries and some grooving at the edges of her molars Breasts were symmetric; nails were relatively normal. Her 12 year old daughter has normal growth and development, similar cutaneous lesions, including scalp aplasia cuds congenita, an atrophic erythematous area of the face, hyper-and hypopigmented areas, multiple dystrophic nails, grooved surfaces of her teeth, high palate, mild scoliosis, 3-4 finger syndactyly, and 2-3-4 toe syndactyly. X-inactivation/methylauon analysis of FDH7 and FDH8, and six other FDH patients was performed in DNA from peripheral blood. FDH7 showed a skewed methylation pattern at the AR locus. FDH8 also showed skewed methylation at the AR and MAOA loci, but had a random pattern at the DXS16 locus, which lies closer to the MLS critical regioa Methylation patterns along the X-chromosome were also not homogenous in the other patients with FDH and did not correlate with phenotype severity. FDH7 was heterozygous at DXS43, DXS1053, DXS1224, DXS7104, DXS7109, DXS1043, KAL, and OAI. At each locus, her children inherited different maternal alleles. Thus, although limited, our linkage analysis is consistent with mapping of Ihe FDH syndrome to the MLS critical region in Xp22.