RESUMEN
Hereditary haemorrhagic telangiectasia (HHT) is a rare vascular multisystemic disease that leads to epistaxis, anaemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain. HHT prevalence is estimated at 1/6000, i.e. around 85,000 European citizens, and is served by the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN). HHT treatments depend on clinical manifestations, and span multiple different medical, surgical and interventional disciplines. Separate to local treatments in the nose, in severe settings, intravenous bevacizumab has been proposed as treatment option, and the purpose of the current article is to assess the use of intravenous bevacizumab in patients with HHT in 2022 according to available data.
Asunto(s)
Malformaciones Arteriovenosas , Telangiectasia Hemorrágica Hereditaria , Bevacizumab/uso terapéutico , Epistaxis/tratamiento farmacológico , Humanos , Enfermedades Raras , Telangiectasia Hemorrágica Hereditaria/tratamiento farmacológicoRESUMEN
Vascular contribution to cognitive impairment and dementia (VCID) is a clinical label encompassing a wide range of cognitive disorders progressing from mild to major vascular cognitive impairment (VCI), which is also defined as vascular dementia (VaD). VaD diagnosis is mainly based on clinical and imaging findings. Earlier biomarkers are needed to identify subjects at risk to develop mild VCI and VaD. In the present meta-analysis, we comprehensively evaluated the role of inflammatory biomarkers in differential diagnosis between VaD and Alzheimer's disease (AD), and assessed their prognostic value on predicting VaD incidence. We collected literature until January 31, 2021, assessing three inflammatory markers [interleukin(IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α] from blood or cerebrospinal fluid (CSF) samples. Thirteen cross-sectional and seven prospective studies were included. Blood IL-6 levels were cross-sectionally significantly higher in people with VaD compared to AD patients (SMD: 0.40, 95% CI: 0.18 to 0.62) with low heterogeneity (I2: 41%, p = 0.13). Higher IL-6 levels were also associated to higher risk of incident VaD (relative risk: 1.28, 95% CI: 1.03 to 1.59, I2: 0%). IL-6 in CSF was significantly higher in people with VaD compared to healthy subjects (SMD: 0.77, 95% CI: 0.17 to 1.37, I2: 70%), and not compared to AD patients, but due to limited evidence and high inconsistency across studies, we could not draw definite conclusion. Higher blood IL-6 levels might represent a useful biomarker able to differentiate people with VaD from those with AD and might be correlated with higher risk of future VaD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Vascular , Enfermedad de Alzheimer/diagnóstico , Biomarcadores , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Demencia Vascular/diagnóstico , Humanos , Interleucina-6 , Estudios ProspectivosRESUMEN
BACKGROUND: Left atrial appendage (LAA) closure represents a novel therapeutic chance for patients with contraindications to long-term anticoagulation therapy, such as those affected by hereditary hemorrhagic telangiectasia (HHT) and atrial fibrillation (AF). Nevertheless, current experts' indications suggest the postprocedural administration of antithrombotic therapies to minimize the residual thromboembolic risk due to AF and to the need for device endothelialization. The aim of our study was to investigate the safety and effectiveness of LAA closure in preventing arterial thromboembolism in a very high-bleeding risk group, such as HHT patients, who are at risk not to tolerate even the mild postprocedural antithrombotic therapy usually recommended. METHODS: Eight HHT-affected patients with non-valvular AF, high-bleeding risk and/or known intolerance to antiplatelet and anticoagulant therapy were treated with interventional LAA occlusion with the Amplatzer™ Cardiac Plug™ and Amplatzer™ Amulet™ devices. Device implantation was successful in all patients. RESULTS: Postprocedural antiplatelet/anticoagulation therapy was attempted in seven patients: adherence to therapy exceeded 6 months only for one, while four patients suspended all antithrombotic medications within 30 days from the procedure due to an increase in bleeding frequency and/or severity and the other two discontinued treatment within 6 months; a single patient was not prescribed any antithrombotic therapy. At a medium follow-up of 22.4±14.3 months no thromboembolic episodes attributable to AF or device related thrombosis were reported. Two deaths were recorded 1231 and 783 days after the procedure which were classified as unrelated to any cerebral or cardiovascular accident. CONCLUSIONS: Our study suggests that the percutaneous LAA closure in HHT patients with AF could be safe and effective in preventing arterial systemic thromboembolism, also in the presence of reduced or absent postinterventional antithrombotic treatment. LAA occluder implantation can represent a valid and potentially life-saving alternative to lifelong anticoagulant therapy in HHT, as in other very high-bleeding risk patients.
Asunto(s)
Apéndice Atrial , Fibrilación Atrial , Accidente Cerebrovascular , Telangiectasia Hemorrágica Hereditaria , Tromboembolia , Anticoagulantes/efectos adversos , Apéndice Atrial/cirugía , Fibrilación Atrial/complicaciones , Fibrilación Atrial/tratamiento farmacológico , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/métodos , Fibrinolíticos/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Humanos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Telangiectasia Hemorrágica Hereditaria/tratamiento farmacológico , Telangiectasia Hemorrágica Hereditaria/terapia , Tromboembolia/tratamiento farmacológico , Tromboembolia/etiología , Tromboembolia/prevención & control , Resultado del TratamientoRESUMEN
Hereditary haemorrhagic telangiectasia (HHT) is a multisystemic vascular dysplasia inherited as an autosomal dominant trait. Approximately 10 % of patients have cerebral vascular malformations, a proportion being cerebral arteriovenous malformations (AVMs) and fistulae that may lead to potentially devastating consequences in case of rupture. On the other hand, detection and treatment related-risks are not negligible, and immediate. While successful treatment can be undertaken in individual cases, current data do not support the treatment of unruptured AVMs, which also present a low risk of bleeding in HHT patients. Screening for these AVMs is therefore controversial.Structured discussions, distinctions of different cerebrovascular abnormalities commonly grouped into an "AVM" bracket, and clear guidance by neurosurgical and neurointerventional radiology colleagues enabled the European Reference Network for Rare Vascular Disorders (VASCERN-HHT) to develop the following agreed Position Statement on cerebral screening:1) First, we emphasise that neurological symptoms suggestive of cerebral AVMs in HHT patients should be investigated as in general neurological and emergency care practice. Similarly, if an AVM is found accidentally, management approaches should rely on expert discussions on a case-by-case basis and individual risk-benefit evaluation of all therapeutic possibilities for a specific lesion.2) The current evidence base does not favour the treatment of unruptured cerebral AVMs, and therefore cannot be used to support widespread screening of asymptomatic HHT patients.3) Individual situations encompass a wide range of personal, cultural and clinical states. In order to enable informed patient choice, and avoid conflicting advice, particularly arising from non-neurovascular interpretations of the evidence base, we suggest that all HHT patients should have the opportunity to discuss knowingly brain screening issues with their healthcare provider.4) Any screening discussions in asymptomatic individuals should be preceded by informed pre-test review of the latest evidence regarding preventative and therapeutic efficacies of any interventions. The possibility of harm due to detection of, or intervention on, a vascular malformation that would not have necessarily caused any consequence in later life should be stated explicitly.We consider this nuanced Position Statement provides a helpful, evidence-based framework for informed discussions between healthcare providers and patients in an emotionally charged area.
Asunto(s)
Malformaciones Arteriovenosas Intracraneales , Telangiectasia Hemorrágica Hereditaria , Adulto , Encéfalo , Niño , Humanos , Malformaciones Arteriovenosas Intracraneales/diagnóstico , Tamizaje Masivo , Enfermedades Raras , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/genéticaRESUMEN
BACKGROUND: Liver involvement is a common manifestation of hereditary haemorrhagic telangiectasia (HHT). Although a number of studies have been carried out in adult patients, no study has ever been focused on investigating HHT-related hepatic involvement in paediatric patients. The present study aimed for the first time to systematically estimate the prevalence of HHT-associated liver involvement and to characterize HHT-associated hepatic angiodynamic features in paediatric age. PATIENTS AND METHODS: The study was designed as a cross-sectional survey in an HHT paediatric cohort, subclassified as HHT1 and HHT2 according to the mutated gene. The evaluation of the angiodynamic profile was performed by duplex ultrasound examination. Investigation by multi-slice computed tomography (MSCT) or magnetic resonance angiography (MRA) was performed in patients >12 years. RESULTS: MSCT/MRA examination disclosed silent hepatic involvement in 7/20 (35.0 %) children, and nodular regenerative hyperplasia in two cases. Diameter of common hepatic artery was significantly larger in HHT2 (0.45 ± 0.15 cm) compared to HHT1 (0.33 ± 0.09, p < 0.01) and control children (0.32 ± 0.08, p < 0.05). None of the patients had clinical manifestations of liver involvement. Angiodynamic profiles were different between paediatric and adult HHT patients. CONCLUSIONS: Liver involvement can be detected in paediatric HHT patients, albeit with a lower frequency compared to adults. Paediatric HHT2 children show a higher frequency of liver involvement and a trend to hepatic artery dilation when compared to HHT1 children.
Asunto(s)
Arteria Hepática/anomalías , Hígado/irrigación sanguínea , Receptores de Activinas Tipo II/genética , Adolescente , Factores de Edad , Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/epidemiología , Malformaciones Arteriovenosas/genética , Enfermedades Asintomáticas , Estudios de Casos y Controles , Niño , Preescolar , Angiografía por Tomografía Computarizada/métodos , Estudios Transversales , Dilatación Patológica , Progresión de la Enfermedad , Endoglina/genética , Femenino , Predisposición Genética a la Enfermedad , Arteria Hepática/diagnóstico por imagen , Humanos , Italia/epidemiología , Angiografía por Resonancia Magnética , Masculino , Tomografía Computarizada Multidetector , Mutación , Fenotipo , Vena Porta/anomalías , Vena Porta/diagnóstico por imagen , Valor Predictivo de las Pruebas , Prevalencia , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/epidemiología , Telangiectasia Hemorrágica Hereditaria/genética , Factores de Tiempo , Ultrasonografía Doppler DúplexRESUMEN
BACKGROUND: A 17-year-old boy was referred to our center with a history of brain abscess (BA) recurring after 9 years. The patient reported 2 previous treatments for pulmonary arteriovenous malformations, sporadic nosebleeds, and familial history for epistaxis. Clinical investigations revealed arteriovenous malformations in lung, brain, and liver, as well as mucocutaneous telangiectases. A definite diagnosis of hereditary hemorrhagic telangiectasia was made based on clinical criteria and confirmed by genetic analysis. This is the first report of BA recurrence at the end of pediatric age. CONCLUSIONS: The present case and the literature review of all cases of BA thus far reported highlight the need to raise the suspicion of a pulmonary arteriovenous malformations, both isolated and in the context of a possible hereditary hemorrhagic telangiectasia, for any case of BA of unexplained etiology, in children as well as in adults.
Asunto(s)
Fístula Arteriovenosa/complicaciones , Absceso Encefálico/etiología , Absceso Encefálico/patología , Arteria Pulmonar/anomalías , Venas Pulmonares/anomalías , Telangiectasia Hemorrágica Hereditaria/complicaciones , Adolescente , Adulto , Fístula Arteriovenosa/terapia , Absceso Encefálico/cirugía , Embolización Terapéutica , Humanos , Imagen por Resonancia Magnética , Masculino , Pronóstico , Recurrencia , Telangiectasia Hemorrágica Hereditaria/terapiaRESUMEN
OBJECTIVE: To evaluate the clinical features in a large cohort of pediatric patients with genetically confirmed hereditary hemorrhagic telangiectasia (HHT) and to identify possible predictors of arteriovenous malformation (AVM) onset or clinical significance. STUDY DESIGN: Prospective cross-sectional survey of all children subjected to screening for AVMs in the multidisciplinary HHT center. All patients proved to be carriers of endoglin mutations or activin A receptor type-II-like kinase 1 mutations, defined as HHT1 and HHT2, respectively. A full clinical-radiological protocol for AVM detection was adopted, independent from presence or absence of AVM-related symptoms. RESULTS: Forty-four children (mean age, 10.3 years; range, 1-18) were subjected to a comprehensive clinical-radiologic evaluation. This investigation disclosed cerebrovascular malformations in 7 of 44 cases, pulmonary AVMs in 20 of 44 cases, and liver AVMs in 23 of 44 cases. Large visceral AVMs were found in 12 of 44 children and were significantly more frequent in patients with HHT1. Only large AVMs were associated with symptoms and complications. CONCLUSIONS: Children with HHT have a high prevalence of AVMs; therefore, an appropriate clinical and radiological screening protocol is advisable. Large AVMs can be associated with complications in childhood, whereas small AVMs probably have no clinical risk.
Asunto(s)
Malformaciones Arteriovenosas/etiología , Telangiectasia Hemorrágica Hereditaria/complicaciones , Adolescente , Malformaciones Arteriovenosas/epidemiología , Malformaciones Arteriovenosas/genética , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Prevalencia , Estudios Prospectivos , Telangiectasia Hemorrágica Hereditaria/genéticaRESUMEN
BACKGROUND: The difficulty in establishing a timely correct diagnosis is a relevant matter of concern for several rare diseases. Many rare-disease-affected patients suffer from considerable diagnostic delay, mainly due to their poor knowledge among healthcare professionals, insufficient disease awareness among patients' families, and lack of promptly available diagnostic tools. Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal-dominantly inherited vascular dysplasia, affecting 1:5,000-10,000 patients. HHT is characterized by high variability of clinical manifestations, which show remarkable overlapping with several common diseases. AIM: To perform a detailed analysis concerning the diagnostic time lag occurring in patients with HHT, defined as the time period spanning from the first clinical manifestation to the attainment of a definite, correct diagnosis. METHODS: A questionnaire was administered to the HHT patients previously recruited from 2000 and 2009. Clinical onset, first referral to a physician for disease manifestations, and first correct diagnosis of definite HHT were collected. Eventual misdiagnosis at first referral and serious complications occurring throughout the time elapsing between disease onset and definite diagnosis were also addressed. RESULTS: In the 233 respondents, the clinical onset of disease occurred at an age of 14.1 yrs, while the age of first referral and the age of first definite diagnosis of HHT were 29.2 yrs and 40.1 yrs, respectively. Only 88/233 patients received a correct diagnosis at first counseling. Thus, the diagnostic time lag, represented by the time elapsing from disease onset and first definite diagnosis of HHT, proved to be 25.7 yrs. Twenty-two patients suffered from severe complications during this time interval. The diagnostic delay was significantly longer (p < 0.001) in index patients (first patients who attained definite HHT diagnosis in a given family) than in non-index patients (relative of index patients). The diagnostic time lag was also significantly associated with education grade (p < 0.001). CONCLUSIONS: Our data report for the first time a systematic inquiry of diagnostic delay in HHT showing that patients receive a definite diagnosis only after nearly three decades from disease onset. Concerted efforts are still to be made to increase awareness of this disease among both families and physicians.
Asunto(s)
Diagnóstico Tardío , Enfermedades Raras , Encuestas y Cuestionarios , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Malformaciones Arteriovenosas/complicaciones , Malformaciones Arteriovenosas/diagnóstico , Niño , Femenino , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/genética , Adulto JovenRESUMEN
Hepatic arteriovenous malformations (HAVMs) in hereditary hemorrhagic telangiectasia (HHT) have long been considered to have scarce clinical significance in most cases. Nevertheless, data are lacking regarding the influence of HAVMs on the liver first-pass effect on drugs in HHT patients. To gain insight into the effect of HAVMs on hepatic drug clearance by means of two specific (13)C-labeled probes, namely the (13)C-methacetin and (13)C-aminopyrine, 46 HHT patients and 44-matched healthy controls were enrolled. The liver first-pass effect was studied by the (13)C-based breath test using methacetin and aminopyrine. The methacetin breath test showed statistically significant reduced metabolism rates (p < 0.0001) in HHT when compared with controls, both in patients with and without CT-detectable HAVMs, and when expressed both as cumulative (13)C-percentage dose per hour and as (13)C-percentage peak after 15 min. In contrast, no significant difference was found between HHT and controls regarding aminopyrin metabolism rates. In HHT, (13)C%-methacetin breath test values are significantly lower than those found in normal subjects, probably due to the effect of hepatic shunts. A reduced perfusion and an impaired hepatic metabolism might affect hepatic drug clearance in HHT. Therefore, an appropriate dosage adjustments should be considered when high-hepatic-metabolism drugs are administered to HHT patients.
Asunto(s)
Hígado/patología , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Adulto , Anciano , Aminopirina , Malformaciones Arteriovenosas , Pruebas Respiratorias/métodos , Estudios de Casos y Controles , Femenino , Humanos , Inactivación Metabólica , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Telangiectasia Hemorrágica Hereditaria/metabolismo , Telangiectasia Hemorrágica Hereditaria/patología , Adulto JovenRESUMEN
The purpose of this study was to estimate vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta1 serum levels in children with hereditary hemorrhagic telangiectasia (HHT) type 1 and type 2 and to correlate them to the presence of arteriovenous malformations (AVMs). High VEGF levels were initially found in an infant who had been hospitalized with intestinal bleeding and suspected HHT. This case led to the evaluation of VEGF and TGF-beta1 by standard enzyme-linked immunosorbent assay in 13 children with HHT and familiarity. Patients were divided into 2 groups on the basis of the presence/absence of pulmonary AVMs. No significant difference was found for VEGF and TGF-beta1 levels in HHT patients versus controls. Among HHT patients, serum levels of VEGF in those without AVM were significantly lower than those with AVM and normal controls. No difference for TGF-beta1 levels was found in these patient subgroups. Low VEGF levels may represent a protection factor against the onset of pulmonary AVMs in HHT children. However, neither VEGF nor TGF-beta1 can be used as biochemical markers for an early diagnosis in HHT. The diagnosis of HHT still requires clinical criteria, which permitted to confirm the presence of the disease in the infant with intestinal bleeding.
Asunto(s)
Enfermedades Pulmonares/sangre , Telangiectasia Hemorrágica Hereditaria/sangre , Factor de Crecimiento Transformador beta1/sangre , Factor A de Crecimiento Endotelial Vascular/sangre , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Enfermedades Pulmonares/etiología , Masculino , Fenotipo , Índice de Severidad de la Enfermedad , Telangiectasia Hemorrágica Hereditaria/complicacionesRESUMEN
BACKGROUND/AIMS: Hepatic arterio-venous malformations (HAVMs) have been found in 74% of hereditary hemorrhagic telangiectasia (HHT) patients with multislice CT (MSCT). This single-blind study aimed to compare the diagnostic accuracy of echo-color-Doppler with MSCT and identify the most sensitive ultrasound criteria indicating hepatic shunts. METHODS: One hundred and fifty-three HHT patients were systematically screened for HAVMs by biological tests, abdominal MSCT and echo-color-Doppler. Twenty-five normal subjects and 15 cirrhotic patients were also included as control groups. Both intrahepatic ("color spots" and hypervascularization) and extrahepatic parameters (diameter, flow velocity and tortuosity of hepatic artery and diameter and flow velocity of portal/hepatic vein) were utilized. "Color-spots" are defined as subcapsular vascular spots with a high-velocity arterial blood flow and low resistivity index and can identify extremely small HAVMs. RESULTS: CT was positive in 128/153 (84%) patients and Doppler color spots were found in 131/153 (86%) patients. The sensitivity, specificity and diagnostic accuracy of "color spots" compared to MSCT were 95.3%, 68.0% and 91.8%, respectively. The "color-spot" showed a greater correlation to CT (V(index)=0.655; p<0.0001) than extrahepatic criteria (V=0.317). In 20/29 (69%) subjects, echo-color-Doppler, confirmed by CT, identified the third criterion for definite HHT diagnosis. CONCLUSIONS: Intrahepatic criteria was superior to extrahepatic criteria for identification of HAVMs. A new Doppler parameter ("color-spots") with an optimal accuracy for detecting HAVMs is proposed for easy periodic screening of HHT patients.
Asunto(s)
Malformaciones Arteriovenosas/diagnóstico , Arteria Hepática/anomalías , Venas Hepáticas/anomalías , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Adolescente , Adulto , Anciano , Malformaciones Arteriovenosas/diagnóstico por imagen , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Telangiectasia Hemorrágica Hereditaria/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Ultrasonografía Doppler en ColorRESUMEN
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type allele.
Asunto(s)
Receptores de Activinas Tipo II/genética , Antígenos CD/genética , Regulación de la Expresión Génica , Receptores de Superficie Celular/genética , Telangiectasia Hemorrágica Hereditaria/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Análisis Mutacional de ADN , Endoglina , Variación Genética , Humanos , Persona de Mediana Edad , Mutación Missense , EspañaRESUMEN
Hereditary haemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by localized angiodysplasia due to mutations in endoglin, ALK-1 gene, and a still unidentified locus. The lack of highly recurrent mutations, locus heterogeneity, and the presence of mutations in almost all coding exons of the two genes makes the screening for mutations time-consuming and costly. In the present study, we developed a DHPLC-based protocol for mutation detection in ALK1 and ENG genes through retrospective analysis of known sequence variants, 20 causative mutations and 11 polymorphisms, and a prospective analysis on 47 probands with unknown mutation. Overall DHPLC analysis identified the causative mutation in 61 out 66 DNA samples (92.4%). We found 31 different mutations in the ALK1 gene, of which 15 are novel, and 20, of which 12 are novel, in the ENG gene, thus providing for the first time the mutational spectrum in a cohort of Italian HHT patients. In addition, we characterized the splicing pattern of ALK1 gene in lymphoblastoid cells, both in normal controls and in two individuals carrying a mutation in the non-invariant -3 position of the acceptor splice site upstream exon 6 (c.626-3C>G). Functional essay demonstrated the existence, also in normal individuals, of a small proportion of ALK1 alternative splicing, due to exon 5 skipping, and the presence of further aberrant splicing isoforms in the individuals carrying the c.626-3C>G mutation.
Asunto(s)
Receptores de Activinas Tipo II/genética , Angiodisplasia/genética , Antígenos CD/genética , Cromatografía Líquida de Alta Presión/métodos , Mutación , Receptores de Superficie Celular/genética , Análisis de Secuencia de ADN/métodos , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/genética , Empalme Alternativo , Estudios de Cohortes , Análisis Mutacional de ADN , Endoglina , Humanos , Italia , Polimorfismo Genético , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Sex tests based on amelogenin are part of various PCR multiplex reaction kits widely used for human gender identification and have important applications in forensic casework, prenatal diagnosis, DNA databasing and blood sample storage. The two most common sex tests based on amelogenin are represented by primer sets that delimit a 6-bp deletion on the X chromosome to produce X/Y fragments of 106/112 or 212/218 bp, respectively. Few cases of AMELY deletion, usually considered as polymorphisms, have been reported so far and a detailed characterization of the molecular alteration is still lacking. In this study, we describe a large interstitial deletion of the Y short arm encompassing the AMELY locus in two unrelated individuals. The first case was identified in an oligozoospermic, otherwise phenotypically normal, 32-year-old man during the screening for Y microdeletions performed on a sample of infertile males. The second one was found among amniotic liquid samples tested by quantitative fluorescence-polymerase chain reaction and cytogenetic analysis for prenatal diagnosis. The extent of the deletion, spanning approximately 2.5 Mb, was better characterised by pulsed-field gel electrophoresis, followed by fluorescence in situ hybridization and STS marker analysis.