Microphthalmia with linear skin defects syndrome (MIDAS).
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ABSTRACT:
SUBMITTER: Banganho D
PROVIDER: S-EPMC6510122 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Microphthalmia 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 PRESENTATION:A 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]). CONCLUSIONS:In 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.
| S-EPMC6090767 | biostudies-literature
Project description:PURPOSE: Microphthalmia with linear skin defects syndrome (MLS or MIDAS, OMIM #309801) is a rare X-linked male-lethal disorder characterized by microphthalmia or other ocular anomalies and skin lesions limited to the face and neck. However, inter- and intrafamilial variability is high. Here we report a familial case of MLS. METHODS: A mother and daughter with MLS underwent a complete ophthalmological examination, and extensive imaging, including anterior segment pictures, corneal topography and keratometry, autofluorescence, infrared reflectance and red free images, as well as spectral-domain optical coherence tomography. The mother also underwent full-field flash electroretinography. In addition, high-resolution array comparative genomic hybridization analysis was performed in both as well as in the maternal grandparents of the proband. RESULTS: Microphthalmia and retinal abnormalities were noted in the proband and the mother, whereas only the mother presented with scars of the typical neonatal linear skin defects. Array comparative genomic hybridization analysis revealed a 185-220 kb deletion on chromosome band Xp22.2 including the entire HCCS gene. CONCLUSIONS: The identification of a deletion including HCCS led to the diagnosis of MLS in these patients. Retinal abnormalities can be part of the ocular manifestations of MLS.
| S-EPMC3566894 | biostudies-literature
Project description: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).
| S-EPMC5171697 | biostudies-literature
Project description: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.
| S-EPMC1698567 | biostudies-literature
Project description: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.
| S-EPMC2986635 | biostudies-literature
Project description: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.
| S-EPMC4385192 | biostudies-literature
Project description:The authors describe the clinical findings observed in a Brazilian girl that are suggestive of microphthalmia and linear skin defects (MLS) also known as MIDAS syndrome (OMIM #309801). She also presented with short stature, agenesis of corpus callosum, cleft palate, enamel defects, and genitourinary anomalies, which are rarely reported within the clinical spectrum of MLS. The 11,5 Mb deletion in Xp22.3p22.2 observed in the patient includes the entire HCCS gene (responsible for the MLS phenotype) and also encompasses several other genes involved with behavioral phenotypes, craniofacial and central nervous system development such as MID1, NLGN4X, AMELX , ARHGAP6, and TBL1X. The whole clinical features of our proband possibly represents an unusual MLS syndromic phenotype caused by an Xp22.3p22.2 continuous gene deletion.
| S-EPMC7396461 | biostudies-literature
Project description:A female patient is described with clinical symptoms of both microphthalmia with linear skin defects (MLS or MIDAS) and dental enamel defects, having an appearance compatible with X-linked amelogenesis imperfecta (XAI). Genomic DNA was purified from the patient's blood and semiquantitative multiplex PCR revealed a deletion encompassing the amelogenin gene (AMELX). Because MLS is also localized to Xp22, genomic DNA was subjected to array comparative genomic hybridization, and a large heterozygous deletion was identified. Histopathology of one primary and one permanent molar tooth showed abnormalities in the dental enamel layer, and a third tooth had unusually high microhardness measurements, possibly due to its ultrastructural anomalies as seen by scanning electron microscopy. This is the first report of a patient with both of these rare conditions, and the first description of the phenotype resulting from a deletion encompassing the entire AMELX gene. More than 50 additional genes were monosomic in this patient.
| S-EPMC2760392 | biostudies-literature
Project description:BACKGROUND: Segmental 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. METHODS: We 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. RESULTS: Two 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. CONCLUSION: Our 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.
| S-EPMC4021606 | biostudies-literature
Project description:BackgroundMicrophthalmia with linear skin defects (MLS) syndrome is a rare X-linked dominant male-lethal developmental disorder characterized by unilateral or bilateral microphthalmia and linear skin defects of the face and neck. Additional features affecting the eyes, heart, brain or genitourinary system can occur, corroborating the intra- and interfamilial phenotypic variability. The majority of patients display monosomy of the Xp22.2 region, where the holocytochrome c-type synthase (HCCS) gene is located.Case presentationWe describe a 15-year-old-female affected by MLS syndrome and autism spectrum disorder (ASD). ASD has not previously been reported as a component of MLS. Our patient shows a large deletion of 12.9 Mb, involving Xp22.32-p22.2, which encompasses both the HCCS gene and autism X-linked genes.ConclusionThus, patients with a large deletion at Xp22 might display MLS with ASD, due to the deletion of contiguous genes, although the highly variable phenotype of these patients could be influenced by several genetic mechanisms, including different tissue-specific X-inactivation and somatic mosaicism.
| S-EPMC4236679 | biostudies-literature