Candidate locus analysis for PHACE syndrome.
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ABSTRACT:
SUBMITTER: Mitchell S
PROVIDER: S-EPMC3356486 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PHACE syndrome (OMIM 606519) is a rare neurocutaneous vascular disorder, characterized by posterior fossa malformations, large cervicofacial infantile hemangiomas, arterial anomalies, aortic coarctation, cardiac abnormalities, and eye abnormalities. The long-term outcome of PHACE syndrome patients is unclear; however, it seems that they are at risk for childhood stroke. The radiologist has an important role on diagnosis of PHACE syndrome and in the assessment of potential complications. Investigation of infants with segmental craniofacial hemangiomas should include cranial magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the cerebral and cervical arteries. Brain MRI and MRA findings of a 5-year-old female patient with PHACE syndrome are presented.
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Project description:PHACE syndrome is the association of large segmental facial hemangiomas and congenital anomalies, such as posterior fossa malformations, cerebral arterial anomalies, coarctation of the aorta, eye anomalies, and sternal defects. To date, the reported cases of PHACE syndrome have been sporadic, suggesting that PHACE may have a complex pathogenesis. We report here genomic copy number variation (CNV) analysis of 98 individuals with PHACE syndrome as a first step in deciphering a potential genetic basis of PHACE syndrome. A total of 3,772 CNVs (2,507 duplications and 1,265 deletions) were detected in 98 individuals with PHACE syndrome. CNVs were then eliminated if they failed to meet established criteria for quality, spanned centromeres, or did not contain genes. CNVs were defined as "rare" if not documented in the database of genomic variants. Ten rare CNVs were discovered (size range: 134-406 ?kb), located at 1q32.1, 1q43, 3q26.32-3q26.33, 3p11.1, 7q33, 10q24.32, 12q24.13, 17q11.2, 18p11.31, and Xq28. There were no rare CNV events that occurred in more than one subject. Therefore, further study is needed to determine the significance of these CNVs in the pathogenesis of PHACE syndrome.
| S-EPMC3971866 | biostudies-literature
Project description:The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.
| S-EPMC5690843 | biostudies-literature
Project description:Less than 30% of the cases of Brugada syndrome (BrS) have an identified genetic cause. Of the known BrS-susceptibility genes, loss-of-function mutations in SCN5A or CACNA1C and their auxiliary subunits are most common. On the basis of the recent demonstration that fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-FGF14) regulate cardiac Na(+) and Ca(2+) channel currents, we hypothesized that FHFs are candidate BrS loci.The goal of this study was to test whether FGF12 is a candidate BrS locus.We used quantitative polymerase chain reaction to identify the major FHF expressed in the human ventricle and then queried a phenotype-positive, genotype-negative BrS biorepository for FHF mutations associated with BrS. We queried the effects of an identified mutant with biochemical analyses combined with electrophysiological assessment. We designed a novel rat ventricular cardiomyocyte system in which we swapped the endogenous FHF with the identified mutant and defined its effects on multiple ionic currents in their native milieu and on the cardiac action potential.We identified FGF12 as the major FHF expressed in the human ventricle. In 102 individuals in the biorepository, we identified a single missense mutation in FGF12-B (Q7R-FGF12). The mutant reduced binding to the NaV1.5 C terminus, but not to junctophilin-2. In adult rat cardiac myocytes, Q7R-FGF12, but not wild-type FGF12, reduced Na(+) channel current density and availability without affecting Ca(2+) channel function. Furthermore, the mutant, but not wild-type FGF12, reduced action potential amplitude, which is consistent with a mutant-induced loss of Na(+) channel function.These multilevel investigations strongly suggest that Q7R-FGF12 is a disease-associated BrS mutation. Moreover, these data suggest for the first time that FHF effects on Na(+) and Ca(2+) channels are separable. Most significantly, this study establishes a new method to analyze effects of human arrhythmogenic mutations on cardiac ionic currents.
| S-EPMC3870051 | biostudies-literature
Project description:BACKGROUND:PHACE is a neurocutaneous syndrome associated with: Posterior fossa brain malformations, large "segmental" facial hemangiomas, arterial cerebrovascular-, cardiovascular-, and eye anomalies. CASE VIGNETTE:We are reporting a girl with PHACE syndrome. The patient had a congenital right-sided facial hemangioma with plaque-morphology. At age 11?years and 2?months she presented with short stature, markedly decreased growth velocity and signs and symptoms suggestive of hypothyroidism. Magnetic Resonance Imaging (MRI) of the brain revealed complex structural and cerebrovascular arterial anomalies, including an empty sella. Testing of pituitary function revealed multiple pituitary dysfunctions, including absolute growth hormone deficiency, hypogonadotropic hypogonadism, central hypothyroidism, and secondary adrenal insufficiency. CONCLUSIONS:This case suggests the necessity to screen all patients with PHACE syndrome and intracranial malformations for pituitary dysfunction at regular intervals.
| S-EPMC3408334 | biostudies-literature
Project description:PHACE (posterior fossa brain malformation, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) syndrome is a neurocutaneous disorder often involving the cerebral vasculature. PHACE patients appear to have early-onset and severe headaches more commonly than children without PHACE. The objective of this study was to characterize the clinical features and prevalence of headache by conducting a cross-sectional survey of families in 2 large PHACE registries. Sixty-six percent of eligible families completed the survey in which 62.7% of respondents reported headaches. Average age of headache onset was 48.8 months. Females were more likely to have headaches (68.6% vs 30.8%, P = .014). Families reported associated migrainous features including nausea (62.5%), vomiting (37.5%), photophobia (75%), and phonophobia (75%). Headaches occurred at least weekly in 29.4%, lasted ≥1 hour in 85.4%, and led to ≥1 hospital admission in 15.7%. Three respondents with headaches had at least 1 ischemic stroke. We demonstrated that headaches are common among PHACE patients, develop at an early age, and have migrainous features.
| S-EPMC6457900 | biostudies-literature
Project description:Segmental hemangiomas of the head and neck can be associated with multiple congenital anomalies in the disorder known as PHACE syndrome (OMIM 606519) (posterior fossa malformations, hemangioma, arterial anomalies, cardiac defects, and eye anomalies). All reported cases of PHACE syndrome to date have been sporadic, and the genetic basis of this disorder has not yet been established. PHACE syndrome has a striking female predominance which has raised the question of X-linked inheritance. In this study, the X chromosome-inactivation (XCI) patterns of 31 females with PHACE syndrome and their mothers were analyzed using blood-derived DNA and X-chromosome locus methylation assay. This study was performed to test the hypothesis that some cases of PHACE syndrome are due to X-linked inheritance and favorable skewing in the mothers may protect against a severe phenotype, but the clinical phenotype may be unmasked in daughters with a random pattern of X-inactivation. XCI analysis was informative in 27/31 mothers. Our results identified skewed XCI in 5 of 27 (19%) informative mothers, which is not statistically significant with a p value of 0.41. None of the mothers reported significant medical problems, although a full PHACE work-up has not been performed in these individuals. Skewed XCI in the mothers of children with PHACE was identified in only a minority of cases. Based on these results, genetic heterogeneity is likely in PHACE syndrome, although it is possible a subset of cases are caused by a mutation in an X-linked gene.
| S-EPMC3638925 | biostudies-literature
Project description:An 11-month-old baby girl presented with white reflex in her left eye. On examination, there was a 6.5×5 mm(2)haemangioma present over her face involving on her lower lip. Systemic examinations were within normal limits. The left eye was small, with an axial length of 16.08 mm and had a cataract. Ultrasonography of the left eye was suggestive of the presence of a vascular stalk, persistent hyperplasia of a primary vitreous, or persistent fetal vasculature with vitreous haemorrhage. On MRI, the left eye was small with vitreous haemorrhage. Left eye lens aspiration was performed and the bleeding vascular stalk behind the lens was cauterised with diathermy. The right eye was normal. The patient was diagnosed as having PHACE syndrome (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Coarctation of the aorta and other cardiac defects, and Eye abnormalities syndrome). On follow-up, she was able to follow light with her left eye.
| S-EPMC4840598 | biostudies-literature
Project description:PurposeA previous study has reported evidence of a strong linkage, but no association, between paired box gene 6 (PAX6) and myopia. We attempted to replicate these findings and to conduct a candidate gene and locus evaluation of genetic involvement in common forms of myopia.MethodsSamples were collected from 517 individuals in 123 families with a myopic child participating in the Orinda Longitudinal Study of Myopia or the Contact Lens and Myopia Progression Study. Myopia in the proband children was defined as -0.75 D or more and as being present in both meridians on cycloplegic autorefraction (1% tropicamide). Affected status in parents and siblings was determined by survey. After DNA was extracted from buccal mucosal cells and genotyped using assays for microsatellite markers and single nucleotide polymorphisms (SNPs), DNA was analyzed for linkage disequilibrium. Markers on chromosomes 12 and 18 were selected as regions previously associated with pathological myopia. SNPs were also analyzed in genes where their expression pattern or their association with syndromes conveys myopia as part of the phenotype (FGF2, BDNF, COL2A1, COL18A1, and PAX6).ResultsThe SNP rs1635529 for COL2A1 on 12q13.11 showed highly significant over-transmission to affected individuals (p=0.00007). No SNP for FGF2, BDNF, COL18A1, or PAX6 showed significant over-transmission to affected individuals after correction for multiple comparisons. Markers on chromosome 12 and 18 previously associated with pathological myopia also showed no significant associations with the more common form of myopia in this study.ConclusionsAs reported previously by others, PAX6 showed no association with myopia. Associations in the current analysis are suggestive of involvement of COL2A1. Future studies should focus on replication in other samples and in genome-wide approaches.
| S-EPMC2776540 | biostudies-literature
Project description:Segmental infantile hemangiomas (IH) can be associated with congenital anomalies in a regional distribution. PHACE refers to large cervicofacial segmental IH in association with congenital anomalies of the aortic arch and medium-sized arteries of the head and neck, as well as structural anomalies of the posterior fossa and eye. A subset of PHACE patients have arterial anomalies that progress to moyamoya vasculopathy (MMV). MMV is defined as stenosis of the supraclinoid segment of the internal carotid arteries and/or their major branches, with subsequent development of a compensatory collateral vessel network. We describe a patient with MMV and segmental IH on the back and lower body who meets diagnostic criteria for PHACE based on a posterior segment eye anomaly and cerebral arterial anomalies. Whole exome sequencing demonstrated two inherited heterozygous variants in RNF213. Variants in RNF213 are associated with increased susceptibility to MMV. Our findings suggest that RNF213 variants may play a role in the development of MMV in patients with hemangioma syndromes associated with congenital cerebral arterial anomalies.
| S-EPMC5815368 | biostudies-literature