PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

Siegel, Dawn H.

doi:10.1002/ajmg.c.31659

Cited by 23 publications

(11 citation statements)

References 58 publications

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“…However, it arguably could have been considered in the differential diagnosis, given the presence of a large forehead hemangioma, even if it did not fully occupy the frontonasal segment. e ocular findings included congenital cataracts, a minor diagnostic criterion for PHACE, as well as congenital hypertrophy of the retinal pigment epithelium (CHRPE), a posterior segment anomaly that could be counted as a major diagnostic criterion [10]. She also had a cardiac ventricular septal defect, another minor criterion for PHACE diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Her parents also reported that she had long roots of her teeth with one missing tooth and first primary tooth loss at 6-7 years of age ( Figure 6). Due to this important clinical observation and her cardiac history, genetic testing for this condition was performed, revealing a pathogenic monoallelic variant, c.2514del(G), p.Lys839Serfs * 17 consistent To further analyze any molecular genetic studies of PHACE that might shed light on BCOR's candidacy for this diagnosis, we performed a gene set enrichment pathway analysis (GSEA) (GSEA-Broad Institute [8,9], http:// software.broadinstitute.org/gsea/index.jsp) by adding BCOR to Sigel's (2018) gene list [10]. When BCOR is added among BRAF, GNA11, GNAQ, KRAS, MAP2K1, MTOR, NRAS, PIK3CA, PIK3R1, and RASA1, GSEA shows that BCOR overlaps significantly with other genes in the pathway of domain of "circulatory system development ( Figure 7).…”

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confidence: 99%

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Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

Morgan

Colazo

Duncan

et al. 2019

Case Reports in Genetics

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Background. Oculofaciocardiodental (OFCD) syndrome is due to mutations in BCOR (BCL-6 corepressor). OFCD has phenotypic overlaps with PHACE syndrome (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac defects, Eye anomalies). Infantile hemangiomas are a key diagnostic criterion for PHACE, but not for OFCD. A previous study reported two cases of infantile hemangiomas in OFCD, but the authors could not exclude chance association. Case Presentation. We describe two novel cases of female patients (one initially diagnosed with PHACE syndrome), both of whom had infantile hemangiomas. Ophthalmological findings were consistent with oculofaciocardiodental (OFCD) syndrome. Upon genetic testing, these two females were determined to have X-linked BCOR mutations confirming OFCD syndrome diagnoses. Conclusion. These case reports add support to the hypothesis that infantile hemangiomas may be a feature of OFCD. BCOR may potentially be within a pathway of genes involved in PHACE syndrome and/or in infantile hemangioma formation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

Morgan

Colazo

Duncan

et al. 2019

Case Reports in Genetics

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“…In addition, the genetics of PHACE syndrome has not been well-elucidated but is hypothesized to be secondary to low-level postzygotic variants. 20 Despite a candidate potential locus identified on 7q33 in 2 individuals, 21 more recent research suggests that the affected gene in PHACE syndrome has not been discovered because the variant allele frequency of the mosaic mutations is extremely low. 20 Further analysis with next-generation sequencing may provide causative mutations in PHACE syndrome.…”

Section: Conventional Mr Imaging Findingsmentioning

confidence: 99%

Arterial Spin-Labeling Perfusion for PHACE Syndrome

Mamlouk

Vossough

Caschera

et al. 2020

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE: Arterial stroke is a rare-but-reported complication in patients with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome. Currently, stroke risk is inferred by the severity of arterial anomalies identified on MRA, though no evidenced-based data exist. The purpose of our study was to determine whether arterial spin-labeling MR imaging perfusion can detect alterations in CBF in patients with PHACE syndrome. MATERIALS AND METHODS: Records were reviewed from 3 institutions for all patients with PHACE syndrome who underwent arterial spin-labeling from 2000 to 2019. CBF was qualitatively investigated with arterial spin-labeling to determine whether there was decreased or normal perfusion. Arterial anomalies were characterized on MRA imaging, and parenchymal brain findings were evaluated on conventional MR imaging sequences. RESULTS: Forty-one patients with PHACE syndrome had arterial spin-labeling imaging. There were 30 females and 11 males (age range, 7 days to 15 years). Of the 41 patients, 10 (24%) had decreased CBF signal corresponding to a major arterial territory. Ten of 10 patients had decreased CBF signal in the anterior circulation, 2/10 had decreased anterior and posterior circulation CBF signal, 2/10 had decreased bilateral anterior circulation CBF signal, and 1/10 had globally decreased CBF signal. Forty of 41 (97.5%) patients had at least 1 arteriopathy, and in those with decreased CBF signal, the arteriopathy corresponded to the CBF signal alteration in 10/10 patients. CONCLUSIONS: Arterial spin-labeling can potentially characterize hemodynamic changes in patients with PHACE syndrome. ABBREVIATIONS: ASL ¼ arterial spin-labeling; PHACE ¼ posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities A rterial ischemic stroke is a rare-but-devastating complication in a minority of patients with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome. Stroke has been reported in multiple patients with PHACE syndrome, 1-6 but the etiology of stroke is poorly understood. 1 Possible mechanisms for stroke with PHACE include the following: 1) artery-to-artery embolisms, 2) ischemia from reduced blood flow, or 3) cardioembolism. These etiologies are predicated on arteriopathies in the brain, neck, and aortic arch, which are the most common extracutaneous finding in patients with PHACE syndrome. 7 In 1 study, arteriopathies were observed in 91% of 33 patients 8 and ranged from an anomalous course to marked stenosis with a Moyamoya pattern. 3 Currently, stroke risk is only inferred by the severity of these arteriopathies identified on MRA imaging. 9 Despite knowledge of the types of arteriopathies in PHACE, 3 it is unclear why certain patients with arteriopathies experience a stroke and others do not, even if there are s...

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“…Siegel reviews PHACE syndrome (MIM 606519) and the highly‐related phenotype, LUMBAR syndrome, that combine infantile hemangiomas with multiple recurrent congenital anomalies (Siegel, ). While the etiology for these entities is not yet known, Siegel makes the argument that tissue‐specific low level mosaicism for known cancer genes is a compelling hypothesis that requires further study.…”

Section: Themes Of the Issuementioning

confidence: 99%

Unsolved recognizable patterns of human malformation: Challenges and opportunities

2018

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Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms underlying most of the frequent and recognizable human malformation syndromes. However, some well‐established human malformation syndromes remain without a molecular diagnosis despite intensive investigation. This issue of Seminars mines the phenotypic entries in OMIM and estimates that of the documented 2,034 unsolved entries likely to represent a rare genetic disease, only 160 are well‐established and possibly amenable to investigation. This issue also reviews well‐characterized and extensively investigated human malformation syndromes and associations that remain unsolved, including the following: Dubowitz syndrome (MIM 223370%), Hallermann–Streiff syndrome (MIM 234100%), PHACE syndrome (MIM 606519), Oculocerebrocutaneous syndrome (MIM 164180), Aicardi syndrome (MIM 304050%), Gomez–Lopez–Hernandez syndrome and Rhombencephalosynapsis (MIM 601853%), VACTERL (MIM 192350%), and Nablus syndrome (MIM #608156). Possible explanations for their intractability to molecular diagnosis are explored, including genetic and phenotypic heterogeneity, mosaicism, epigenetics, gene–environment interactions, and other non‐Mendelian contributions. Finally, this issue of Seminars presents a path forward for these unsolved rare conditions and suggests a renewed focus on solving amendable OMIM disorders. It is clear that the way forward will require new technologies, global cooperation, and data sharing; these will also be necessary to help reach the vision of the International Rare Diseases Research Consortium (IRDiRC), that is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within 1 year of coming to medical attention.

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PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause

Cited by 23 publications

References 58 publications

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

Two Cases of Oculofaciocardiodental (OFCD) Syndrome due to X-Linked BCOR Mutations Presenting with Infantile Hemangiomas: Phenotypic Overlap with PHACE Syndrome

Arterial Spin-Labeling Perfusion for PHACE Syndrome

Unsolved recognizable patterns of human malformation: Challenges and opportunities

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