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Photographs of the six patients with MLS syndrome and a heterozygous HCCS mutation or Xp22 monosomy. A and B. Patient 2 died at the age of 4 months. She presented with microphthalmia and sclerocornea of the right eye and anophthalmia of the left eye (A). Linear skin defects were observed on her neck (B). C. In the 7-year-old patient 5, linear skin defects and small hemangiomas were noted. She showed microphthalmia and sclerocornea of the left eye and anophthalmia of the right eye. D. Microphthalmia and sclerocornea of both eyes were present in patient 1, while linear skin defects were absent. E. In patient 3 (age 11 months), microphthalmia and sclerocornea of the left eye were diagnosed. No linear skin defects were noted. F, G and H. Linear skin defects on the face of patient 4 were very prominent at birth (F, 4 days old), but healed with age (3 weeks old in G and 2 years old in H). Severe bilateral microphthalmia was observed in the patient. I. Bilateral microphthalmia and sclerocornea were observed in patient 6; she also had typical linear skin defects on her face (photographs submitted with written consent from the patients’ legal guardians for publication in print and online).
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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) an...
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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 de...
Citations
... Three previous studies reported the presence of CA in MLS patients, and in all of them, a corneal opacification with neovascularization was present (Banganho et al., 2019;Thompson et al., 2018;van Rahden et al., 2014). Two of them had molecular confirmation of an Xq22 deletion encompassing the HCCS gene and described the phenotype as sclerocornea, but most likely it was related to the absence of the lens (Banganho et al., 2019;van Rahden et al., 2014). ...
... Three previous studies reported the presence of CA in MLS patients, and in all of them, a corneal opacification with neovascularization was present (Banganho et al., 2019;Thompson et al., 2018;van Rahden et al., 2014). Two of them had molecular confirmation of an Xq22 deletion encompassing the HCCS gene and described the phenotype as sclerocornea, but most likely it was related to the absence of the lens (Banganho et al., 2019;van Rahden et al., 2014). ...
... MLS syndrome is characterized by wide inter-and intra-familial phenotypic variability, which has been associated with skewed Xinactivation of the three genes involved (HCCS, COX7B, and NDUFB11) (Indrieri & Franco, 2021). There are reported cases with eye abnormalities in the absence of skin defects and vice versa (Kono et al., 1999;van Rahden et al., 2014;Wimplinger et al., 2006Wimplinger et al., , 2007. ...
To describe the anterior segment (AS) findings in patients with microphthalmia with linear skin defects syndrome (MLS), also known as microphthalmia, dermal aplasia, and sclerocornea (MIDAS). A retrospective chart review was conducted to identify patients with a diagnosis of MLS syndrome seen at UPMC Children's Hospital of Pittsburgh. Ophthalmic examination, high‐frequency ultrasound, AS optical coherence tomography, and molecular testing were reviewed. Five female patients (10 eyes) were identified. One eye was anophthalmic, one was in a status post penetrating keratoplasty, and eight eyes presented with congenital corneal opacity (CCO). Of these, one showed a normal lens and a very small faint CCO; five showed congenital aphakia and characteristic silvery appearance of the cornea with vascularization; and two showed irido‐corneal adhesions in association with normal or abnormal lens and localized avascular CCO. Genetic testing was performed and revealed involvement of HCCS in four patients. In MLS patients, kerato‐irido‐lenticular dysgenesis can be associated with secondary CCO. It is important to distinguish these CCO from sclerocornea, in order to refine the appropriate management and counseling the parents about the prognosis.
... First, point mutations and a small deletion were identified in HCCS, thus providing the evidence that this gene is indeed responsible for LSDMCA1 [2]. Specifically, de novo heterozygous point mutations, i.e., a nonsense mutation (c.589C > T/p.R197*) which was subsequently identified in an additional case [13] and a missense mutation (c.649C > T/p.R217C), were identified in two patients showing a normal karyotype [2]. Later, a novel missense mutation (c.475G > A/p.E159K) was identified in a sporadic case with bilateral microphthalmia and sclerocornea without skin lesions, indicating that the phenotypic variability described in LSDMCA1 is not correlated to the extent of the Xp deletion [14]. ...
... Later, a novel missense mutation (c.475G > A/p.E159K) was identified in a sporadic case with bilateral microphthalmia and sclerocornea without skin lesions, indicating that the phenotypic variability described in LSDMCA1 is not correlated to the extent of the Xp deletion [14]. Finally, a mosaic 2-bp HCCS deletion, (c.[=/524_525delAG] (p.[=/E175Vfs*30]), was identified in a patient with unilateral ocular anomalies and no skin defects [13]. This patient showed a variable degree of mosaicism that may have contributed to her mild phenotype. ...
... Moreover, it should be noted that in LSDMCA1, the severity of the phenotype is not strictly related to the extent of the Xp-chromosome deletion that represents the underlying genetic cause in the majority of cases. Molecular characterization indeed demonstrated that patients with very large deletion of distal Xp, such as patient 2 from Lindsay et al., show a mild phenotype [1] while patients with point mutations in HCCS display the full phenotype [2,13] (Table S1). A specific patient only displayed the typical linear skin defects, presented a 46,X,del (X) (pter-p22.2) karyotype, and was referred to the genetics clinic following the abortion of an anencephalic female fetus with the same karyotype [1]. ...
Mitochondrial disorders, although heterogeneous, are traditionally described as conditions characterized by encephalomyopathy, hypotonia, and progressive postnatal organ failure. Here, we provide a systematic review of Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), a rare, unconventional mitochondrial disorder which presents as a developmental disease ; its main clinical features include microphthalmia with different degrees of severity, linear skin lesions, and central nervous system malformations. The molecular basis of this disorder has been elusive for several years. Mutations were eventually identified in three X-linked genes, i.e., HCCS, COX7B, and NDUFB11, which are all endowed with defined roles in the mitochondrial respiratory chain. A peculiar feature of this condition is its inheritance pattern: X-linked dominant male-lethal. Only female or XX male individuals can be observed, implying that nullisomy for these genes is incompatible with normal embryonic development in mammals. All three genes undergo X-inacti-vation that, according to our hypothesis, may contribute to the extreme variable expressivity observed in this condition. We propose that mitochondrial dysfunction should be considered as an underlying cause in developmental disorders. Moreover, LSDMCA should be taken into consideration by clinicians when dealing with patients with microphthalmia with or without associated skin phenotypes.
... Specifically, de novo heterozygous point mutations, i.e., a nonsense mutation (c.589C>T/p.R197*) which was subsequently identified in an additional case [13] and a missense mutation (c.649C>T/ p.R217C) were identified in two patients showing a normal karyotype [2]. Later, a novel missense mutation (c.475G>A/p.E159K) was identified in a sporadic female patient with bilateral microphthalmia and sclerocornea without skin lesions, indicating that the phenotypic variability described in LSDMCA1 is not correlated to the extent of the Xp-terminal deletion [14]. ...
... Later, a novel missense mutation (c.475G>A/p.E159K) was identified in a sporadic female patient with bilateral microphthalmia and sclerocornea without skin lesions, indicating that the phenotypic variability described in LSDMCA1 is not correlated to the extent of the Xp-terminal deletion [14]. Finally, a mosaic 2-bp HCCS deletion, (c.[=/524_525delAG] (p.[=/E175Vfs*30]), was identified in a patient with unilateral ocular anomalies and no skin defects [13]. This patient showed a variable degree of mosaicism in different tissues that may have contributed to her mild phenotype. ...
Mitochondrial disorders, although heterogeneous, are traditionally described as conditions characterized by encephalomyopathy, hypotonia and progressive postnatal organ failure. Here we provide a systematic review of Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), a rare unconventional mitochondrial disorder which presents as a developmental disease; its main clinical features include microphthalmia with different degrees of severity, linear skin lesions, and central nervous system malformations. The molecular basis of this disorder has been elusive for several years. Mutations were eventually identified in three X-linked genes, i.e., HCCS, COX7B, and NDUFB11, which are all endowed with defined roles in the mitochondrial respiratory chain. A peculiar feature of this condition is its inheritance pattern: X-linked dominant male-lethal. Only female or XX male individuals can be observed, implying that nullisomy for these transcripts is incompatible with normal embryonic development in mammals. All three genes undergo X-inactivation that, according to our hypothesis, may contribute to the extreme variable expressivity observed in this condition. We propose that mitochondrial dysfunction should be considered as an underlying cause in developmental disorders. Moreover, LSDMCA should be taken into consideration by clinicians when dealing with patients with microphthalmia with or without associated skin phenotypes.
... Holocytochrome c synthase (HCCS) effects cellular levels of cytochrome C, impacting mitochondrial physiology and cell death [44]. The disease, microphthalmia with linear skin defects (MLS), is due to mutations in the HCCS gene [45,46]. There has been no publication that reports an association of HCCS with any cancer. ...
Simple Summary
A biomarker to predict survival is a critical need in pancreatic cancer treatment. We hypothesized that a four-gene score, which was previously reported to reflect cell proliferation, can be used as a predictive biomarker for pancreatic cancer. A total of 954 patients were analyzed for both discovery and validation of the four-gene score from publicly available datasets for pancreatic cancer, in order to investigate the relationship between the score and clinical features of pancreatic cancer, such as metastasis, cancer aggressiveness, immune cell infiltration, patient survival, and resectability. We found that the score correlated with clinical aggressiveness in pancreatic cancer, and did so to a higher degree compared to breast cancer cohorts. We found that the four-gene score identified poor survival in pancreatic cancer, and has potential as a predictive biomarker of treatment response in metastatic pancreatic cancer, as well completion of a pathologically complete (R0) resection. Appropriately utilized, the four-gene score could be a valuable prognostic and predictive tool for pancreatic cancer in the future.
Abstract
Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which was reported to reflect cell proliferation, is a translatable predictive biomarker for pancreatic cancer. A total of 954 pancreatic cancer patients from multiple cohorts were analyzed and validated. Pancreatic cancer had the 10th highest median score of 32 cancers in The Cancer Genome Atlas (TCGA) cohort. The four-gene score significantly correlated with pathological grade and MKI67 expression. The high four-gene score enriched cell proliferation-related and cancer aggressiveness-related gene sets. The high score was associated with activation of KRAS, p53, transforming growth factor (TGF)-β, and E2F pathways, and with high alteration rate of KRAS and CDKN2A genes. The high score was also significantly associated with reduced CD8⁺ T cell infiltration of tumors, but with high levels of interferon-γ and cytolytic activity in tumors. The four-gene score correlated with the area under the curve of irinotecan and sorafenib in primary pancreatic cancer, and with paclitaxel and doxorubicin in metastatic pancreatic cancer. The high four-gene score was associated with significantly fewer R0 resections and worse survival. The novelty of the study is in the application of the four-gene score to pancreatic cancer, rather than the bioinformatics technique itself. Future analyses of inoperable lesions are expected to clarify the utility of our score as a predictive biomarker of systemic treatments.
... HCCS is able to complement the yeast Cyc3 deficiency [288]. Mutations in HCCS have been associated with MLS, an X-linked, malelethal disorder described in the Complex III section [289]. It has been hypothesized that the characteristic phenotype of MLS patients is a consequence of the activation of non-canonical, caspase-9 mediated cell death in the brain and eyes as a result of HCCS impairment [290]. ...
The ease with which the unicellular yeast Saccharomyces cerevisiae can be manipulated genetically and biochemically has established this organism as a good model for the study of human mitochondrial diseases. The combined use of biochemical and molecular genetic tools has been instrumental in elucidating the functions of numerous yeast nuclear gene products with human homologs that affect a large number of metabolic and biological processes, including those housed in mitochondria. These include structural and catalytic subunits of enzymes and protein factors that impinge on the biogenesis of the respiratory chain. This article will review what is currently known about the genetics and clinical phenotypes of mitochondrial diseases of the respiratory chain and ATP synthase, with special emphasis on the contribution of information gained from pet mutants with mutations in nuclear genes that impair mitochondrial respiration. Our intent is to provide the yeast mitochondrial specialist with basic knowledge of human mitochondrial pathologies and the human specialist with information on how genes that directly and indirectly affect respiration were identified and characterized in yeast.
... Structural chromosomal anomalies in individuals with MLS syndrome cause deletion of the HCCS gene which encodes the holocytochrome c synthase involved in apoptosis and oxidative phosphorylation. [3][4][5] Case Report ...
... There is a wide spectrum of clinical presentations from no signs to the lethal form of MLS. 4 Cutaneous manifestations include atrophic linear skin defects and ectodermal anomalies such as nail dystrophy and congenital alopecia. 6 Ocular anomalies include microphthalmia, sclerocornea, anterior segment anomalies, and anophthalmia with cystic remnants. ...
... Inactivation of HCCS has been reported to result in respiratory chain deficiency and abnormal levels of cell proliferation, which lead to decreased pleural and peritoneal fold tissue and an increased risk of congenital diaphragmatic hernia [64][65][66]. HCCS mutation has been shown to be associated with the microphthalmia with linear skin defects or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality [67][68][69]. HCCS is speculated to play a role in central nervous system development by modulating cell death and a link between mitochondrial dysfunction, intrinsic apoptosis, and developmental disorders [70,71]. To the best of our knowledge, there is no publication that reports an association of HCCS with cancer. ...
We generated a 4-gene score with genes upregulated in LM2-4, a metastatic variant of MDA-MB-231 (DOK 4, HCCS, PGF, and SHCBP1) that was strongly associated with disease-free survival (DFS) in TCGA cohort (hazard ratio [HR]>1.2, p < 0.02). The 4-gene score correlated with overall survival of TCGA (HR = 1 .44, p < 0 .001), which was validated with DFS and disease-specific survival of METABRIC cohort. The 4-gene score was able to predict worse survival or clinically aggressive tumors, such as high Nottingham pathological grade and advanced cancer staging. High score was associated with worse survival in the hormonal receptor (HR)-positive/Her2-negative subtype. High score enriched cell proliferation-related gene sets in GSEA. The score was high in primary tumors that originated, in and metastasized to, brain and lung, and it predicted worse progression-free survival for metastatic tumors. Good tumor response to neoadjuvant chemotherapy or hormonal therapy was accompanied by score reduction. High scores were also predictive of response to neoadjuvant chemotherapy for HR-positive/Her2-negative subtype. High score tumors had increased expression of T cell exhaustion marker genes, suggesting that the score may also be a biomarker for immunotherapy response. Our novel 4-gene score with both prognostic and predictive values may, therefore, be clinically useful particularly in HR-positive breast cancer.
... 7,16,18,19 Other events, such as genetic background, somatic mosaicism, or secondary cell selection mechanisms have also been proposed. 10,20,21 Pathogenic variations in two other genes, COX7B in Xq21.122 and NDUFB11 in Xp11.23, were also observed in females with MLS, indicating genetic heterogeneity for this condition. 22,23 Here, we describe a Brazilian girl with MLS, associated with callosal agenesis, cleft palate, abnormal enamel, and mild developmental delay caused by a 11,5 Mb Xp22.3p22.2 ...
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.
... Microphthalmia with linear skin defects syndrome (MLS; also known as microphthalmia, dermal aplasia and sclerocornea, or MIDAS) is recognizable due to characteristic manifestations of A/M, sclerocornea and corneal opacities, and patchy, erythrodermatous skin lesions (Al-Gazali et al. 1990;Morleo and Franco 2011;van Rahden et al. 2014). The skin lesions are congenital, frequently occur on the scalp, face and neck and often heal with minimal residual scarring in early childhood. ...
... Other ophthalmological findings are heterogeneous, comprising sclerocornea, corneal opacities and leukoma, iridocorneal adhesions, congenital glaucoma with anterior synechiae, aniridia and cataracts (Cape et al. 2004;Wimplinger et al. 2006;Morleo and Franco 2011). Central nervous system involvement with anencephaly, agenesis of the corpus callosum, hydrocephalus, mental retardation, infantile seizures and developmental delays, and congenital heart disease have also been described (Morleo and Franco 2011;van Rahden et al. 2014). Short stature, diaphragmatic hernia, nail dystrophy, preauricular pits and hearing loss, genitourinary tract malformations and anterior or imperforate anus are rare (Al-Ghazali et al. 1990;Wimplinger et al. 2006Wimplinger et al. , 2007Morleo and Franco 2011). ...
... MLS is predominantly caused by chromosome deletions involving all or part of the HCCS gene located at chromosome Xp22.2; rarer missense substitutions and nonsense variants have also been described (Temple et al. 1990;Wimplinger et al. 2006;van Rahden et al. 2014). Inheritance is X-linked dominant and the syndrome has been reported to be lethal in males (Morleo and Franco 2011). ...
As new genes for A/M are identified in the genomic era, the number of syndromes associated with A/M has greatly expanded. In this review, we provide a brief synopsis of the clinical presentation and molecular genetic etiology of previously characterized pathways involved in A/M, including the Sex-determining region Y-box 2 (SOX2), Orthodenticle Homeobox 2 (OTX2) and Paired box protein-6 (PAX6) genes, and the Stimulated by retinoic acid gene 6 homolog (STRA6), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and RA Receptor Beta (RARβ) genes that are involved in retinoic acid synthesis. Less common genetic causes of A/M, including genes involved in BMP signaling [Bone Morphogenetic Protein 4 (BMP4), Bone Morphogenetic Protein 7 (BMP7) and SPARC-related modular calcium-binding protein 1 (SMOC1)], genes involved in the mitochondrial respiratory chain complex [Holocytochrome c-type synthase (HCCS), Cytochrome C Oxidase Subunit 7B (COX7B), and NADH:Ubiquinone Oxidoreductase subunit B11 (NDUFB11)], the BCL-6 corepressor gene (BCOR), Yes-Associated Protein 1 (YAP1) and Transcription Factor AP-2 Alpha (TFAP2α), are more briefly discussed. We also review several recently described genes and pathways associated with A/M, including Smoothened (SMO) that is involved in Sonic hedgehog (SHH) signaling, Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) and Solute carrier family 25 member 24 (SLC25A24), emphasizing phenotype–genotype correlations and shared pathways where relevant.
... caused by segmental deletions of Xp22.2 that include the HCCS gene, and in smaller subgroups of individuals by heterozygous mutation in the X-linked genes HCCS, COX7B, or NDUFB11, all encoding components of the mitochondrial respiratory chain(van Rahden et al., 2015).The disorder is characterized by anophthalmia or microphthalmia plus a variety of other ocular defects including sclerocorneae, and by aplastic, typically linear, skin lesions that primarily affect the head and neck region and heal to become hyperpigmented areas with age. Other less common abnormalities include congenital heart defects, microcephaly, ACC or other unspecific brain anomalies, growth retardation, seizures, or ID(van Rahden et al., 2014). ...
