Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome

Maclean, Kenneth N.; Smith, James E.; Heaps, Luke St; Chia, Nicole; Williams, R. H.; Peters, Gregory B.; Onikul, Ella; McCrossin, Tim; Lehmann, Ordan J.; Adès, Lesley C.

doi:10.1002/ajmg.a.30274

Cited by 70 publications

(48 citation statements)

References 31 publications

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“…A normal karyotype in infancy, normal vision, few other health problems and lack of genetics followup likely contributed to lack of recognition of a diagnosable syndrome until she was specifically assessed as an adult. The case supports recent evidence that 6p25 deletion syndrome has a recognizable clinical phenotype and supports recommendations for thorough investigations including FISH for patients presenting with characteristic features [Davies et al, 1999b;Le Caignec et al, 2005;Maclean et al, 2005].…”

Section: Discussionsupporting

confidence: 85%

Schizophrenia in an adult with 6p25 deletion syndrome

Caluseriu

Mirza

Ragoussis

et al. 2006

American J of Med Genetics Pt A

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Chromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld-Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 Mb 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation.

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Section: Discussionsupporting

confidence: 85%

Schizophrenia in an adult with 6p25 deletion syndrome

Caluseriu

Mirza

Ragoussis

et al. 2006

American J of Med Genetics Pt A

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“…De Hauwere syndrome (OMIM: 109120), characterized by anterior segment eye defects, hypertelorism, psychomotor retardation, hypotonia, hearing loss, hydrocephalus/enlarged ventricles, and femoral head anomalies, 21,22 displays a significant overlap with 6p25 deletion syndrome (OMIM: 612582), defined as a combination of ocular anomalies (primarily anterior segment), hearing loss, congenital heart disease, hydrocephalus, developmental delay, and a characteristic facial appearance and typically associated with terminal deletions of 6p25. 32,33 Review of the literature identified that the skeletal features observed in De Hauwere syndrome, such as flattening of the femoral epiphyses and other femoral head anomalies sometimes diagnosed as Perthes disease, were reported in several previously described patients with 6p25 terminal deletions (Table 3), 32,[34][35][36][37][38] suggesting that De Hauwere syndrome may be part of the 6p25 deletion syndrome spectrum. Case 28 in our study has the smallest and first interstitial deletion reported to date in association with the features of De Hauwere syndrome, thus defining a minimal deleted region for this phenotype.…”

Section: Foxc1 Mutations: Phenotypes and Genotypesmentioning

confidence: 97%

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

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“…Foxc1 has been implicated in several different human disorders including the most common cerebellar malformation, Dandy-Walker malformation (DWM), Axenfeld-Rieger syndrome (ARS), 6p25 deletion syndrome and iridogoniodysgenesis (Mears et al, 1998;Nishimura et al, 1998;Maclean et al, 2005;Aldinger et al, 2009;Delahaye et al, 2012). In addition to the function of Foxc1 in different diseases, it also has crucial roles in the development of multiple organs and tissues, including cerebellar, skull, ocular and cardiovascular development (Kume, 2009).…”

Section: Regulation Of Fox Genes By Yap and Taz And Their Potential Rmentioning

confidence: 99%

Yap and Taz play a crucial role in neural crest-derived craniofacial development

et al. 2015

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The role of the Hippo signaling pathway in cranial neural crest (CNC) development is poorly understood. We used the Wnt1Cre and Wnt1Cre2SOR drivers to conditionally ablate both Yap and Taz in the CNC of mice. When using either Cre driver, Yap and Taz deficiency in the CNC resulted in enlarged, hemorrhaging branchial arch blood vessels and hydrocephalus. However, Wnt1Cre2SOR embryos had an open cranial neural tube phenotype that was not evident in Wnt1Cre embryos. In O9-1 CNC cells, the loss of Yap and Taz impaired smooth muscle cell differentiation. RNA-sequencing data indicated that Yap and Taz regulate genes encoding Fox transcription factors, specifically Foxc1. Proliferation was reduced in the branchial arch mesenchyme of Yap and Taz CNC conditional knockout (CKO) embryos. Moreover, Yap and Taz CKO embryos had cerebellar aplasia similar to Dandy Walker spectrum malformations observed in human patients and mouse embryos with mutations in Foxc1. In embryos and O9-1 cells deficient for Yap and Taz, Foxc1 expression was significantly reduced. Analysis of Foxc1 regulatory regions revealed a conserved recognition element for the Yap and Taz DNA binding co-factor Tead. ChIP-pcr experiments further supported the conclusion that Foxc1 is directly regulated by the Yap/Tead complex. Our findings uncover important roles for Yap and Taz in CNC diversification and development.

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Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome

Cited by 70 publications

References 31 publications

Schizophrenia in an adult with 6p25 deletion syndrome

Schizophrenia in an adult with 6p25 deletion syndrome

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Yap and Taz play a crucial role in neural crest-derived craniofacial development

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