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3.
Sci Immunol ; 3(24)2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29907691

RESUMO

Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

5.
Pediatr Neurol ; 76: 20-26, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28811058

RESUMO

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant condition associated with epilepsy, benign tumors, and variable neurodevelopmental outcomes. The diagnosis is most commonly made after epilepsy onset, although a proportion are diagnosed prenatally. Presymptomatic or early treatment with agents such as vigabatrin offers the hope of improved neurodevelopmental outcome. Therefore early diagnosis, before the onset of seizures, is important. In a cohort of children with TSC, we evaluated the age and mode of initial presentation, assessed the neurocognitive and epilepsy outcome, and analyzed whether those diagnosed before the onset of seizures have a different outcome compared with those diagnosed postseizures. METHODS: We reviewed patients at the TSC clinic at Sydney Children's Hospital who were born between 2001 and 2015. RESULTS: A total of 74 patients were identified: 34 (46%) diagnosed preseizure (21 prenatally) and 40 (54%) postseizure. In the preseizure cohort, 77% presented with cardiac rhabdomyoma(s) and 72% developed seizures. The postseizure cohort had more severe epilepsy, requiring more antiepileptic drugs for seizure control (median five, compared with three in the preseizure cohort [P = 0.01]). Developmental disability occurred in 65% of the preseizure cohort compared with 72% of the postseizure cohort. Severe developmental disability most often occurred in children who had their first seizure before age 12 months. CONCLUSION: Children who are diagnosed with TSC before the onset of seizures have less severe epilepsy and better developmental outcome.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/diagnóstico , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Precoce , Epilepsia/etiologia , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
6.
Circulation ; 136(11): 1037-1048, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28687708

RESUMO

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.


Assuntos
Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação em Linhagem Germinativa/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Receptor EphB4/genética , Proteína p120 Ativadora de GTPase/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Linhagem
7.
Australas J Dermatol ; 58(2): 155-159, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28251611

RESUMO

Although most infantile haemangiomas do not require treatment due to a natural history of spontaneous involution, some require early intervention. The Australasian Vascular Anomalies Network and the Australasian Paediatric Dermatology Network have developed a consensus statement for the treatment of infantile haemangiomas with oral propranolol. Infants with haemangiomas that are life threatening, at risk of ulceration, or at risk of causing a significant functional impairment, psychological impact or physical deformity should be treated early with oral propranolol. Oral propranolol is safe and effective and in most healthy infants oral propranolol can be started in an outpatient setting.


Assuntos
Consenso , Hemangioma Capilar/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Propranolol/uso terapêutico , Vasodilatadores/uso terapêutico , Monitoramento de Medicamentos , Humanos , Seleção de Pacientes , Propranolol/administração & dosagem , Vasodilatadores/administração & dosagem
9.
J Paediatr Child Health ; 53(8): 737-741, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28169477

RESUMO

Venous malformations are slow-flow congenital vascular malformations that enlarge as the child ages and may be associated with localised intravascular coagulation, a consumptive coagulopathy characterised by elevated D-dimer and decreased fibrinogen levels. The authors review the known correlations between localised intravascular coagulation and venous malformation number, size and planes involved, and call attention to the concept of the progression of localised intravascular coagulopathy as the child ages and their venous malformations enlarge. The authors also discuss the identified therapeutic options for its investigation, management and treatment, including compression garments, anti-coagulation therapy, sclerotherapy, endovascular laser, surgical excision and sirolimus (rapamycin). Evidence for protocol improvements that may be instigated for the optimal physical and medical therapy of venous malformations complicated by localised intravascular coagulopathy is reviewed.


Assuntos
Anticoagulantes/uso terapêutico , Coagulação Intravascular Disseminada/sangue , Coagulação Intravascular Disseminada/tratamento farmacológico , Malformações Vasculares/etiologia , Aspirina/uso terapêutico , Criança , Fibrina/uso terapêutico , Heparina/uso terapêutico , Humanos , Fatores de Risco
10.
J Paediatr Child Health ; 53(1): 38-42, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27701785

RESUMO

AIM: To define the clinical characteristics, investigations, management and outcomes of lymphoedema in a paediatric cohort. METHODS: A retrospective chart review of children with lymphoedema seen at two tertiary paediatric hospitals since 1998. Telephone interviews with parents were performed when information was missing. Information recorded included demographic data, features of diagnosis and clinical presentation, symptoms, complications and treatment. RESULTS: A total of 86 patients with lymphoedema were identified. Eighty cases (93%) were primary and six cases (7%) were secondary. Most were female (60%). Location of swelling was most commonly the lower limbs (94%). There were 13 cases (15%) of genital involvement. Swelling presented in the first 12 months of life in 60% of primary lymphoedema patients. Complications of lymphoedema occurred in 73% of patients. Lymphoscintigraphy was the most common investigation used (65%), followed by ultrasound (57%) and magnetic resonance imaging (MRI) (35%). Eight of the 48 (17%) lymphoscintigraphs produced a false negative result or were inconclusive with a correct diagnosis subsequently made clinically and using MRI. Average time to diagnosis was 9 months. Lymphoedema was managed with compression garments (99%), manual lymph drainage (97%) and multilayered bandaging (68%). Eight patients had an operative procedure as a part of management. CONCLUSIONS: Primary lymphoedema is more common than secondary lymphoedema in children. Onset tends to be during infancy for both males and females, and the lower limb is typically involved. Causes of secondary lymphoedema are diverse and rare. Diagnosis in children is often delayed but is possible based on history and physical examination alone and when further investigation is necessary MRI is effective.


Assuntos
Linfedema/diagnóstico , Linfedema/epidemiologia , Adolescente , Austrália/epidemiologia , Criança , Feminino , Humanos , Entrevistas como Assunto , Linfedema/fisiopatologia , Masculino , Auditoria Médica , Pesquisa Qualitativa , Estudos Retrospectivos
11.
12.
Pediatr Dermatol ; 33(5): 536-42, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27470532

RESUMO

BACKGROUND: Dysregulation of the mammalian target of rapamycin pathway is the underlying pathogenic mechanism in tuberous sclerosis complex (TSC). Other syndromes caused by genetic alterations in this pathway frequently manifest as vascular anomalies or asymmetric overgrowth. Rarely, these features have been documented in TSC. OBJECTIVE: To collate cases of TSC with vascular anomaly or overgrowth that have been published and to assemble additional recent cases, as this finding has been underreported. METHODS: TSC cases from three pediatric dermatology referral centers on two continents were reviewed to identify individuals noted to have hemihypertrophy or vascular anomalies. RESULTS: We report five additional cases of TSC associated with vascular anomalies or overgrowth that contribute to our understanding of some of the pathways and treatments involved in vascular anomalies. CONCLUSION: Hemihypertrophy and vascular anomalies may be more frequent in the setting of TSC than previously appreciated. A common pathogenetic mechanism may tie these manifestations together.


Assuntos
Predisposição Genética para Doença/epidemiologia , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/epidemiologia , Proteínas Supressoras de Tumor/genética , Malformações Vasculares/diagnóstico , Malformações Vasculares/epidemiologia , Adolescente , Distribuição por Idade , Comorbidade , Everolimo/uso terapêutico , Feminino , Humanos , Incidência , Lactente , Mutação , Prognóstico , Medição de Risco , Amostragem , Índice de Gravidade de Doença , Distribuição por Sexo , Sirolimo/uso terapêutico , Resultado do Tratamento , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Malformações Vasculares/tratamento farmacológico , Malformações Vasculares/genética
13.
Australas J Dermatol ; 56(4): 241-51, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25752907

RESUMO

Atopic eczema is a chronic inflammatory disease affecting about 30% of Australian and New Zealand children. Severe eczema costs over AUD 6000/year per child in direct medical, hospital and treatment costs as well as time off work for caregivers and untold distress for the family unit. In addition, it has a negative impact on a child's sleep, education, development and self-esteem. The treatment of atopic eczema is complex and multifaceted but a core component of therapy is to manage the inflammation with topical corticosteroids (TCS). Despite this, TCS are often underutilised by many parents due to corticosteroid phobia and unfounded concerns about their adverse effects. This has led to extended and unnecessary exacerbations of eczema for children. Contrary to popular perceptions, (TCS) use in paediatric eczema does not cause atrophy, hypopigmentation, hypertrichosis, osteoporosis, purpura or telangiectasia when used appropriately as per guidelines. In rare cases, prolonged and excessive use of potent TCS has contributed to striae, short-term hypothalamic-pituitary-adrenal axis alteration and ophthalmological disease. TCS use can also exacerbate periorificial rosacea. TCS are very effective treatments for eczema. When they are used to treat active eczema and stopped once the active inflammation has resolved, adverse effects are minimal. TCS should be the cornerstone treatment of atopic eczema in children.


Assuntos
Corticosteroides/efeitos adversos , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/efeitos adversos , Pele/patologia , Administração Cutânea , Corticosteroides/administração & dosagem , Atrofia/induzido quimicamente , Austrália , Doenças Ósseas Metabólicas/induzido quimicamente , Criança , Pré-Escolar , Consenso , Dermatite Alérgica de Contato/etiologia , Fármacos Dermatológicos/administração & dosagem , Oftalmopatias/induzido quimicamente , Humanos , Hipertricose/induzido quimicamente , Hipopigmentação/induzido quimicamente , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Osteoporose/induzido quimicamente , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Púrpura/induzido quimicamente , Rosácea/induzido quimicamente , Estrias de Distensão/induzido quimicamente , Taquifilaxia , Telangiectasia/induzido quimicamente
14.
N Engl J Med ; 372(8): 735-46, 2015 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-25693013

RESUMO

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Hemangioma/tratamento farmacológico , Propranolol/administração & dosagem , Administração Oral , Antagonistas Adrenérgicos beta/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipotensão/induzido quimicamente , Lactente , Masculino , Propranolol/efeitos adversos , Resultado do Tratamento
15.
Australas J Dermatol ; 55(3): 209-11, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24628677

RESUMO

Questions have been raised as to whether propranolol, which crosses the blood-brain barrier, when used early in life may have an adverse effect on gross motor development. A retrospective survey asking questions about gross motor development was sent to the families of children who had been prescribed oral propranolol for infantile haemangioma at Sydney Children's Hospital between 2008 and 2013. It was found that of the 84 patients surveyed, four were delayed in walking unassisted. There was a statistically significant influence if the child was taking other medications which included prednisolone, vincristine, omeprazole, ranitidine, salbutamol, Flixotide, Timoptol and antibiotics. This was not further analysed in this study because of the low numbers involved. There was no statistically significant influence of gestational age, birth weight or length of time on propranolol. This study adds to the retrospective data available; however large-scale prospective studies are needed to identify unexpected long-term side-effects.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Desenvolvimento Infantil/fisiologia , Hemangioma Capilar/tratamento farmacológico , Propranolol/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Desenvolvimento Infantil/efeitos dos fármacos , Seguimentos , Hospitais Pediátricos , Humanos , Lactente , Destreza Motora , New South Wales , Estudos Retrospectivos , Caminhada
16.
Australas J Dermatol ; 55(2): e24-8, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23330923

RESUMO

Proliferative nodules (PN) are benign lesions that arise in large congenital melanocytic naevi (LCMN). Clinically and histologically they can be difficult to differentiate from malignancies, which are also associated with LCMN. The PN in this case consisted of undifferentiated spindle cells and exhibited unusual histological features including negative stains for melanocytic markers (S100, HMB45 and MelA), negative stain for c-Kit, high mitotic index and unusual morphology of the lesional cells. As a result, a firm histological classification could not be made, which posed a challenge for the clinical management.


Assuntos
Neoplasias Primárias Múltiplas/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Dorso , Nádegas , Diferenciação Celular , Proliferação de Células , Feminino , Humanos , Recém-Nascido , Índice Mitótico , Proteínas de Neoplasias/análise , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/congênito , Nevo Pigmentado/química , Nevo Pigmentado/congênito , Neoplasias Cutâneas/química , Neoplasias Cutâneas/congênito , Coxa da Perna
17.
Australas J Dermatol ; 55(4): e60-4, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23713913

RESUMO

A 9-year old boy presented with a 4-month history of a truncal monomorphic eruption with self-healing papulonecrotic lesions. A skin biopsy revealed a dermal infiltrate of CD4, CD8 and CD30-positive T-cells, consistent with lymphomatoid papulosis. He responded to 4 months of treatment with narrowband UVB phototherapy (311 nm) which stabilised his disease. Five years later he presented with an acute onset of nausea and vomiting, dizziness, headache and ataxia. Magnetic resonance imaging of the brain revealed a lesion in the cerebellum and stereotactic resection was undertaken. Histology showed CD4, CD8 and CD30-positive T-cells similar to his skin lesions, with a monoclonal T-cell receptor (TCR) gamma gene rearrangement. Subsequent analysis of the skin detected a monoclonal band of the same size as the cerebellar lesion. Treatment was initiated for a primary central nervous system (CNS) lymphoma but ceased after one course of high-dose methotrexate. Opinion on the pathology was divided as to whether the cerebellar lesion represented an atypical reactive T-cell lymphoproliferative response or a T-cell lymphoma. On follow-up 2 years later, the patient remains clinically and radiologically clear, making CNS lymphoma unlikely.


Assuntos
Neoplasias Encefálicas/patologia , Papulose Linfomatoide/patologia , Neoplasias Cutâneas/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Criança , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Humanos , Papulose Linfomatoide/genética , Papulose Linfomatoide/radioterapia , Masculino , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/radioterapia
18.
J Clin Endocrinol Metab ; 98(12): E1936-40, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24081733

RESUMO

CONTEXT: The duration of hypothalamic-pituitary-adrenal (HPA) axis suppression after glucocorticoid treatment is uncertain. OBJECTIVE: We aimed to determine the duration of HPA axis suppression in prednisolone-treated infants and the age at which circadian variation in salivary cortisol is established in healthy infants. DESIGN, SETTING, AND PARTICIPANTS: Before the adoption of propranolol treatment by the Vascular Birthmarks Clinic, 12 infants with infantile hemangioma received high-dose prednisolone for 12 to 25 weeks' duration, weaned over 4 to 6 weeks, and ceased at age 21 to 31 weeks. Parents collected serial salivary samples at two time points per day (before first and last feed) until circadian variation in salivary cortisol (measured by radioimmunoassay) was observed, when a confirmatory 1 µg Synacthen test was performed. Ten healthy control infants had serial salivary cortisol measurements to determine the age at which circadian variation is established. MAIN OUTCOME MEASURE: We defined circadian variation as evening salivary cortisol <50% of the early morning level on two consecutive sampling weeks. RESULTS: Circadian variation appeared within 6 weeks (median 2.7, range 1.4-5.4) of prednisolone cessation. All confirmatory Synacthen tests were normal (peak serum cortisol >600 nmol/L) and were performed within 12 weeks of prednisolone cessation. Healthy controls developed circadian variation at median 16 weeks of age (range 8-24). CONCLUSION: HPA recovery occurred within 6 to 12 weeks, shorter than empirical recommendations, to give stress cover for 6 to 12 months. Reduced duration of stress-cover precautions may reduce parental anxiety and side effects from unnecessary glucocorticoid use. Healthy control infants established circadian variation in salivary cortisol between 2 and 6 months of age.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Desenvolvimento Infantil/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Prednisolona/efeitos adversos , Recuperação de Função Fisiológica , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Ritmo Circadiano/efeitos dos fármacos , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Hemangioma Capilar/sangue , Hemangioma Capilar/tratamento farmacológico , Hemangioma Capilar/metabolismo , Hemangioma Capilar/fisiopatologia , Humanos , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lactente , Masculino , Síndromes Neoplásicas Hereditárias/sangue , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/metabolismo , Síndromes Neoplásicas Hereditárias/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Estudos Prospectivos , Saliva/metabolismo , Fatores de Tempo
19.
Am J Cardiol ; 112(12): 1948-52, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24079520

RESUMO

PHACE syndrome represents the association of large infantile hemangiomas of the head and neck with brain, cerebrovascular, cardiac, ocular, and ventral or midline defects. Cardiac and cerebrovascular anomalies are the most common extracutaneous features of PHACE, and they also constitute the greatest source of potential morbidity. Congenital heart disease in PHACE is incompletely described, and this study was conducted to better characterize its features. This study of the International PHACE Syndrome Registry represents the largest central review of clinical, radiologic, and histopathologic data for cardiovascular anomalies in patients with PHACE to date. Sixty-two (41%) of 150 subjects had intracardiac, aortic arch, or brachiocephalic vessel anomalies. Aberrant origin of a subclavian artery was the most common cardiovascular anomaly (present in 31 (21%) of 150 subjects). Coarctation was the second most common anomaly, identified in 28 (19%) of 150 subjects, and can be missed clinically in patients with PHACE because of the frequent association of arch obstruction with aberrant subclavian origin. Twenty-three (37%) of 62 subjects with cardiovascular anomalies required procedural intervention. A greater percentage of hemangiomas were located on the left side of the head and neck in patients with coarctation (46% vs 39%); however, hemangioma distribution did not predict the presence of cardiovascular anomalies overall. In conclusion, PHACE is associated with a high risk of congenital heart disease. Cardiac and aortic arch imaging with detailed assessment of arch patency and brachiocephalic origins is essential for any patient suspected of having PHACE. Longitudinal investigation is needed to determine the long-term outcomes of cardiovascular anomalies in PHACE.


Assuntos
Aorta Torácica/anormalidades , Coartação Aórtica/epidemiologia , Tronco Braquiocefálico/anormalidades , Anormalidades do Olho/epidemiologia , Cardiopatias Congênitas/epidemiologia , Síndromes Neurocutâneas/epidemiologia , Sistema de Registros , Comorbidade , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Veia Subclávia/anormalidades , Grau de Desobstrução Vascular
20.
Hum Mutat ; 34(12): 1632-41, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24038909

RESUMO

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n = 100), common CM(s) (port-wine stain; n = 100), Sturge-Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the "second-hit" hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up.


Assuntos
Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação , Fenótipo , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Proteína p120 Ativadora de GTPase/genética , Substituição de Aminoácidos , Análise Mutacional de DNA , Feminino , Ordem dos Genes , Estudos de Associação Genética , Humanos , Masculino , Estudos Prospectivos , Estudos Retrospectivos
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