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Ian R Munro - One of the best experts on this subject based on the ideXlab platform.
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trigonocephaly associated Hypotelorism is treatment necessary
Plastic and Reconstructive Surgery, 1996Co-Authors: Jeffrey A Fearon, John C Kolar, Ian R MunroAbstract:This study was designed to examine whether Hypotelorism associated with trigonocephaly might be self-correcting. Only patients who required surgical treatment and had undergone preoperative and postoperative anthropometric measurements were included. In no case was any attempt made to correct the Hypotelorism surgically. The study sample consisted of 16 patients, of whom 10 underwent preoperative and postoperative computed tomography in addition to anthropometric examinations. The results were compared with sex- and age-matched pooled normal standards, converted to standard Zscores, and analyzed by means of Student's t tests. Both intercanthal and interorbital widths increased significantly postoperatively, with improvements in AZ scores of 0.445 (p ≤ 0.01) and 0.638 (p ≤ 0.05). These increases exceeded average growth increments by 1.6 mm for intercanthal width and 1.3 mm for interorbital width. Improvement in the intercanthal widths was significantly greater in the more severely affected children than in those whose conditions were less severe. A greater improvement in interorbital width also was noted in children treated at less than 6 months of age compared with those treated later. The younger the patient at surgery, the greater was the improvement, suggesting that early surgery may somehow release a constraint on interorbital growth.
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trigonocephaly associated Hypotelorism is treatment necessary
Plastic and Reconstructive Surgery, 1996Co-Authors: Jeffrey A Fearon, John C Kolar, Ian R MunroAbstract:This study was designed to examine whether Hypotelorism associated with trigonocephaly might be self-correcting. Only patients who required surgical treatment and had undergone preoperative and postoperative anthropometric measurements were included. In no case was any attempt made to correct the Hypotelorism surgically. The study sample consisted of 16 patients, of whom 10 underwent preoperative and postoperative computed tomography in addition to anthropometric examinations. The results were compared with sex- and age-matched pooled normal standards, converted to standard Z scores, and analyzed by means of Student's t tests. Both intercanthal and interorbital widths increased significantly postoperatively, with improvements in delta Z scores of 0.445 (p < or = 0.01) and 0.638 (p < or = 0.05). These increases exceeded average growth increments by 1.6 mm for intercanthal width and 1.3 mm for interorbital width. Improvement in the intercanthal widths was significantly greater in the more severely affected children than in those whose conditions were less severe. A greater improvement in interorbital width also was noted in children treated at less than 6 months of age compared with those treated later. The younger the patient at surgery, the greater was the improvement, suggesting that early surgery may somehow release a constraint on interorbital growth.
Laurent Pasquier - One of the best experts on this subject based on the ideXlab platform.
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first occurrence of aprosencephaly atelencephaly and holoprosencephaly in a family with a six3 gene mutation and phenotype genotype correlation in our series of six3 mutations
Journal of Medical Genetics, 2005Co-Authors: Laurent Pasquier, Leila Lazaro, Marie Gonzales, Christèle Dubourg, Sylvie Odent, Ferechte EncharazaviAbstract:Aprosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage.1 The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated.1,2 At least six causal genes, namely SHH , ZIC2 , SIX3 , TGIF , PATCHED , and CRIPTO ( TDGF1 ), are linked to HPE and to ventral and dorsal patterning defect of the neural tube.3–7 We report the first occurrence of AP/AT and HPE in a non-consanguineous family with three affected sibs, carrying a maternally inherited mutation of the SIX3 gene. A phenotype/genotype correlation in the series of seven SIX3 mutations found in our cohort of 210 HPE probands is provided. Systematic sequencing of the entire coding region of the SHH , ZIC2 , TGIF , and SIX3 genes has been performed in a series of 210 non-chromosomal HPE probands including 56 patients reported previously.8 Probands were included in the study after brain imaging, karyotyping, and detailed clinicopathological studies, referring to the protocol for fetuses.9 Mutational analyses were performed as detailed elsewhere.10 Of the 210 patients screened, seven had mutations in the SIX3 gene but none in other HPE causing genes. The findings are illustrated in figs 1, 2, and 3. HPE was associated with AP/AT in three affected sibs carrying a maternally inherited mutation of SIX3 . Figure 1 SIX3 mutations in HPE: representative pedigrees showing probands and relatives. Filled symbols indicate alobar HPE with synophthalmy or cyclopy. Three quarters filled symbols indicate alobar or semi-lobar HPE without synophthalmy. Half filled symbols indicate minor features of the HPE spectrum with Hypotelorism, single upper incisor, and mental retardation. Quarter filled symbols indicate isolated Hypotelorism. M, SIX3 mutation carrier; N, no mutation. (A) Familial case with missense mutation in the SIX domain leading …
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first occurrence of aprosencephaly atelencephaly and holoprosencephaly in a family with a six3 gene mutation and phenotype genotype correlation in our series of six3 mutations
Journal of Medical Genetics, 2005Co-Authors: Laurent Pasquier, Leila Lazaro, Marie Gonzales, Christèle Dubourg, Sylvie Odent, Ferechte EncharazaviAbstract:Aprosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage.1 The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated.1,2 At least six causal genes, namely SHH , ZIC2 , SIX3 , TGIF , PATCHED , and CRIPTO ( TDGF1 ), are linked to HPE and to ventral and dorsal patterning defect of the neural tube.3–7 We report the first occurrence of AP/AT and HPE in a non-consanguineous family with three affected sibs, carrying a maternally inherited mutation of the SIX3 gene. A phenotype/genotype correlation in the series of seven SIX3 mutations found in our cohort of 210 HPE probands is provided. Systematic sequencing of the entire coding region of the SHH , ZIC2 , TGIF , and SIX3 genes has been performed in a series of 210 non-chromosomal HPE probands including 56 patients reported previously.8 Probands were included in the study after brain imaging, karyotyping, and detailed clinicopathological studies, referring to the protocol for fetuses.9 Mutational analyses were performed as detailed elsewhere.10 Of the 210 patients screened, seven had mutations in the SIX3 gene but none in other HPE causing genes. The findings are illustrated in figs 1, 2, and 3. HPE was associated with AP/AT in three affected sibs carrying a maternally inherited mutation of SIX3 . Figure 1 SIX3 mutations in HPE: representative pedigrees showing probands and relatives. Filled symbols indicate alobar HPE with synophthalmy or cyclopy. Three quarters filled symbols indicate alobar or semi-lobar HPE without synophthalmy. Half filled symbols indicate minor features of the HPE spectrum with Hypotelorism, single upper incisor, and mental retardation. Quarter filled symbols indicate isolated Hypotelorism. M, SIX3 mutation carrier; N, no mutation. (A) Familial case with missense mutation in the SIX domain leading …
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a new mutation in the six domain of six3 gene causes holoprosencephaly
European Journal of Human Genetics, 2000Co-Authors: Laurent Pasquier, Leila Lazaro, Martine Blayau, Le B Marec, V David, Christèle Dubourg, Sylvie OdentAbstract:: Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to Hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region.
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a new mutation in the six domain of six3 gene causes holoprosencephaly
European Journal of Human Genetics, 2000Co-Authors: Laurent Pasquier, Leila Lazaro, Martine Blayau, Le B Marec, V David, Christèle Dubourg, Sylvie OdentAbstract:: Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to Hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region.
Sylvie Odent - One of the best experts on this subject based on the ideXlab platform.
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first occurrence of aprosencephaly atelencephaly and holoprosencephaly in a family with a six3 gene mutation and phenotype genotype correlation in our series of six3 mutations
Journal of Medical Genetics, 2005Co-Authors: Laurent Pasquier, Leila Lazaro, Marie Gonzales, Christèle Dubourg, Sylvie Odent, Ferechte EncharazaviAbstract:Aprosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage.1 The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated.1,2 At least six causal genes, namely SHH , ZIC2 , SIX3 , TGIF , PATCHED , and CRIPTO ( TDGF1 ), are linked to HPE and to ventral and dorsal patterning defect of the neural tube.3–7 We report the first occurrence of AP/AT and HPE in a non-consanguineous family with three affected sibs, carrying a maternally inherited mutation of the SIX3 gene. A phenotype/genotype correlation in the series of seven SIX3 mutations found in our cohort of 210 HPE probands is provided. Systematic sequencing of the entire coding region of the SHH , ZIC2 , TGIF , and SIX3 genes has been performed in a series of 210 non-chromosomal HPE probands including 56 patients reported previously.8 Probands were included in the study after brain imaging, karyotyping, and detailed clinicopathological studies, referring to the protocol for fetuses.9 Mutational analyses were performed as detailed elsewhere.10 Of the 210 patients screened, seven had mutations in the SIX3 gene but none in other HPE causing genes. The findings are illustrated in figs 1, 2, and 3. HPE was associated with AP/AT in three affected sibs carrying a maternally inherited mutation of SIX3 . Figure 1 SIX3 mutations in HPE: representative pedigrees showing probands and relatives. Filled symbols indicate alobar HPE with synophthalmy or cyclopy. Three quarters filled symbols indicate alobar or semi-lobar HPE without synophthalmy. Half filled symbols indicate minor features of the HPE spectrum with Hypotelorism, single upper incisor, and mental retardation. Quarter filled symbols indicate isolated Hypotelorism. M, SIX3 mutation carrier; N, no mutation. (A) Familial case with missense mutation in the SIX domain leading …
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first occurrence of aprosencephaly atelencephaly and holoprosencephaly in a family with a six3 gene mutation and phenotype genotype correlation in our series of six3 mutations
Journal of Medical Genetics, 2005Co-Authors: Laurent Pasquier, Leila Lazaro, Marie Gonzales, Christèle Dubourg, Sylvie Odent, Ferechte EncharazaviAbstract:Aprosencephaly/atelencephaly (AP/AT) refers to rudimentary prosencephalon, while holoprosencephaly (HPE) is a failure of telencephalon cleavage.1 The question of whether AP/AT results from a disruptive lesion or a growth failure is still debated.1,2 At least six causal genes, namely SHH , ZIC2 , SIX3 , TGIF , PATCHED , and CRIPTO ( TDGF1 ), are linked to HPE and to ventral and dorsal patterning defect of the neural tube.3–7 We report the first occurrence of AP/AT and HPE in a non-consanguineous family with three affected sibs, carrying a maternally inherited mutation of the SIX3 gene. A phenotype/genotype correlation in the series of seven SIX3 mutations found in our cohort of 210 HPE probands is provided. Systematic sequencing of the entire coding region of the SHH , ZIC2 , TGIF , and SIX3 genes has been performed in a series of 210 non-chromosomal HPE probands including 56 patients reported previously.8 Probands were included in the study after brain imaging, karyotyping, and detailed clinicopathological studies, referring to the protocol for fetuses.9 Mutational analyses were performed as detailed elsewhere.10 Of the 210 patients screened, seven had mutations in the SIX3 gene but none in other HPE causing genes. The findings are illustrated in figs 1, 2, and 3. HPE was associated with AP/AT in three affected sibs carrying a maternally inherited mutation of SIX3 . Figure 1 SIX3 mutations in HPE: representative pedigrees showing probands and relatives. Filled symbols indicate alobar HPE with synophthalmy or cyclopy. Three quarters filled symbols indicate alobar or semi-lobar HPE without synophthalmy. Half filled symbols indicate minor features of the HPE spectrum with Hypotelorism, single upper incisor, and mental retardation. Quarter filled symbols indicate isolated Hypotelorism. M, SIX3 mutation carrier; N, no mutation. (A) Familial case with missense mutation in the SIX domain leading …
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a new mutation in the six domain of six3 gene causes holoprosencephaly
European Journal of Human Genetics, 2000Co-Authors: Laurent Pasquier, Leila Lazaro, Martine Blayau, Le B Marec, V David, Christèle Dubourg, Sylvie OdentAbstract:: Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to Hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region.
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a new mutation in the six domain of six3 gene causes holoprosencephaly
European Journal of Human Genetics, 2000Co-Authors: Laurent Pasquier, Leila Lazaro, Martine Blayau, Le B Marec, V David, Christèle Dubourg, Sylvie OdentAbstract:: Holoprosencephaly (HPE) is a severe brain malformation which results from incomplete cleavage of the forebrain during early embryogenesis. The aetiology of HPE is very heterogeneous. Among the genetic factors, SIX3, which is considered to be the functional orthologue of Drosophila genes sine oculis (so) and optix, has been found to be mutated in the homeodomain, in some patients with HPE (HPE2 on chromosome 2p21). We report a new HPE family, presenting a wide spectrum of clinical features, ranging from cyclopia to Hypotelorism, in which a mutation was found for the first time in the SIX domain of SIX3: a GG insertion creates a frameshift leading to a nonsense mutation downstream in the homeodomain region.
Marja W Wessels - One of the best experts on this subject based on the ideXlab platform.
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autosomal dominant syndrome of mental retardation Hypotelorism and cleft palate resembling schilbach rott syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Vered Shkalim, Hagit N Baris, Gavriel Gal, Ruth Gleiss, Shlomo Calderon, Marja W WesselsAbstract:We present a family segregating for an autosomal dominant syndrome of Hypotelorism, cleft palate/uvula, high-arched palate and mild mental retardation. Although these findings may suggest a form of holoprosencephaly, no holoprosencephaly was found on MRI of the proposita. Results of genetic studies were normal including FISH for deletion of 22q11, karyotype analysis, fragile X testing, high-resolution comparative genomic hybridization and SEPT9, SHH mutation analysis. The syndrome is reminiscent of the infrequently recognized autosomal dominant Schilbach-Rott syndrome.
Erich Roessler - One of the best experts on this subject based on the ideXlab platform.
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comparison of mutation findings in zic2 between microform and classical holoprosencephaly in a brazilian cohort
Birth Defects Research Part A-clinical and Molecular Teratology, 2012Co-Authors: Lucilene Arilho Ribeiro, Daniel E Pinedaalvarez, Settara C. Chandrasekharappa, Erich Roessler, Marypat Jones, Antonio Richiericosta, Ping Hu, Nan Zhou, Maximilian MuenkeAbstract:BACKGROUND Holoprosencephaly is the most frequent congenital malformation of the forebrain in humans. It is anatomically classified by the relative degree of abnormal formation and separation of the developing central nervous system. Mutations of ZIC2 are the second most common heterozygous variations detected in holoprosencephaly (HPE) patients. Mutations in most known HPE genes typically result in variable phenotypes that rage from classic alobar HPE to microforms represented by Hypotelorism, solitary central maxillary incisor (SCMI), and cleft lip/palate, among others. Patients with HPE owing to ZIC2 mutations have recently been described by a distinct phenotype compared with mutations in other HPE causative genes. METHODS We report the comparison of ZIC2 molecular findings by Sanger bidirectional DNA sequencing and ad hoc genotyping in a cohort of 105 Brazilian patients within the clinical spectrum of HPE, including classic and microform groups. RESULTS We detected a total of five variants in the ZIC2 gene: a common histidine tract expansion c.716_718dup (p.His239dup), a rare c.1377_1391del_homozygous (p.Ala466_470del, or Ala 15 to 10 contraction), a novel intronic c.1239+18G>A variant, a novel frameshift c.1215dupC (p.Ser406Glnfs*11), and a c.1401_1406dup (p.Ala469_470dup, or alanine tract expansion to 17 residues). CONCLUSIONS From these patients, only the latter two mutations found in classic HPE are likely to be medically significant. In contrast, variants detected in the microform group are not likely to be pathogenic. We show conclusively that the histidine tract expansion is a polymorphic alteration that demonstrates considerable differences in allele frequencies across different ethnic groups. Therefore, careful population studies of rare variants can improve genotype-phenotype correlations. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.
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mutations in the homeodomain of the human six3 gene cause holoprosencephaly
Nature Genetics, 1999Co-Authors: Deeann Wallis, Ute Hehr, Luisa Nanni, Gabriele Gillessenkaesbach, Erich Roessler, Tim Wiltshire, Elaine H. Zackai, Antonio Richiericosta, Johanna M RommensAbstract:Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, Hypotelorism, microcephaly, or other craniofacial findings that can be present with or without associated brain malformations1,2,3. The aetiology of HPE is extremely heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the causal involvement of specific teratogens acting at the earliest stages of neurulation4. The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE. A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients5. We describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation breakpoints in 2p21 are less than 200 kb from the 5´ end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE. We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans.
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mutations in the human sonic hedgehog gene cause holoprosencephaly
Nature Genetics, 1996Co-Authors: Erich Roessler, Elena Belloni, Karin Gaudenz, Philippe Jay, Philippe Berta, Stephen W Scherer, Lapchee Tsui, Maximilian MuenkeAbstract:Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes. HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CNS) with a broad spectrum of clinical severity. Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting. At the mild end of the spectrum, findings may include microcephaly, mild Hypotelorism, single maxillary central incisor and other defects (Fig. 1). This phenotypic variability also occurs between affected members of the same family. The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies and familial forms with autosomal dominant and recessive inheritance have been described. HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE. Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3-the first known gene to cause HPE. Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations. Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site.