CLINICAL
AND
LABORATORY OBSERVATIONS
Pulmonary Arteriovenous Malformations and Cerebral Abscess Recurrence in a Child With Hereditary Hemorrhagic Telangiectasia Paola Giordano, MD, PhD,* Maria Sangerardi, MD,* Patrizia Suppressa, MD, PhD,w Patrizia Lastella, MD, PhD,w Ettore Attolini, MD,z Federica Valente,* Maria L. Fiorella, MD,y Gennaro M. Lenato, PhD,w and Carlo Sabba`, MD, PhDw
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. Key Words: hereditary hemorrhagic telangiectasia, Rendu-OslerWeber disease, recurrent brain abscess, pulmonary arteriovenous malformation, diagnostic delay
(J Pediatr Hematol Oncol 2015;37:e200–e203)
H
ereditary hemorrhagic telangiectasia (HHT), or RenduOsler-Weber disease (OMIM: #187300), is an autosomal dominant angiogenic disorder associated with arteriovenous shunts, often manifesting as mucocutaneous telangiectatic lesions and/or affecting visceral organs. HHT is characterized by high penetrance and age-related expression and has an estimated prevalence of 1:5000 to 1:10,000 inhabitants.1 Clinical diagnosis is established according to Curacao criteria: epistaxis, mucocutaneous telangiectases, visceral arteriovenous malformations (AVMs), and first-degree affected relative.2 Mutations in either ENG or ALK1/ACVRL1 gene are responsible for the HHT disease in about 85% of cases.3 As the disease does not often reach full clinical expression in youngsters, the knowledge of the diseasecausing mutation in a given family permits to assess a firm Received for publication March 19, 2014; accepted August 7, 2014. From the *Department of Biomedical Science and Human Oncology, Unit of Paediatrics “F. Vecchio”; wCenter for Rare Diseases, Unit of Internal Medicine “C. Frugoni”; yUnit of Otorynolaringology, University Hospital of Bari; and zRegional Agency of HealthApulia, Via Gentile, Bari, Italy. P.G., M.S., and P.S. contributed equally and are joint first authors. The authors declare no conflict of interest. Reprints: Carlo Sabba`, MD, PhD, Center for Rare Diseases, Unit of Internal Medicine “C. Frugoni,” University Hospital of Bari, P.zza G. Cesare, Bari 70124, Italy (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
e200 | www.jpho-online.com
HHT diagnosis also in asymptomatic or paucisymptomatic children who do not meet clinical criteria.3–5 In pediatric age, pulmonary AVMs (PAVMs) occur in 30% to 45% of HHT patients, 25% to 40% of those will develop PAVMrelated symptoms.4–6 Manifestations of PAVMs include hypoxemia features (dyspnea, cyanosis, and polycythemia), hemoptysis, as well as risk of developing neurological complications, such as stroke or cerebral abscess, by paradoxical embolization.7,8 Neurological complications can be associated with respiratory symptoms or, in some cases, occur as the first clinical manifestation of otherwise asymptomatic PAVMs. Therefore, the association between PAVM and brain abscess (BA) should be borne in mind in cases of BA of unexplained etiology.
CASE REPORT A 17-year-old boy presented to the observation of our Multidisciplinary HHT Centre with a history of 2 distinct episodes of BA. Medical history revealed a first occasional detection of a large PAVM at 4 years of age, which had resulted in a failed attempt of embolotherapy and no recommendation for subsequent treatment or monitoring. At 7 years of age, he had suffered from intense and throbbing right temporoparietal headache, due to a septic BA affecting the right frontal lobe, proximal to the insular region. Pulmonary angiography had shown that the same PAVM in the right lower lobe had considerably enlarged, likely resulting in paradox embolization and then cerebral abscess, as well as in hypoxemia (paO2 = 82 mm Hg). This AVM had been treated by pulmonary lobectomy and BA had been drained, with growth of Enterobacter agglomerans in the culture, whereas additional small PAVMs (diameter of feeding artery A; p.Arg479Gln). According to the current HHT guidelines,9 the large complex PAVM was treated by transcatheter embolotherapy, with marked improvement in his respiratory symptoms and rising of paO2 from 76 to 89 mm Hg. Periodical surveillance was undertaken to monitor his small PAVMs and other visceral lesions. Antibiotic therapy was recommended upon surgical intervention and/or dental care, and antiepileptic therapy was continued. Subsequent surveys showed remission of digital cyanosis, improvement of exercise intolerance, persistence of digital clubbing, hematocrit normalization, no recanalization of the treated PAVM, and no significant enlargement of small untreated PAVMs and brain lesions. Meanwhile, our Center was referred by some distant relatives of the patient for the purpose of genetic testing. Familial history disclosed that HHT had initially been diagnosed in a sister of the patient’s maternal grandmother, even though no information had been provided regarding autosomaldominant inheritance, risk of visceral involvement, and phenotypic variability of HHT disease.
DISCUSSION BA is a known manifestation of HHT-related PAVMs,7 with a recently estimated incidence of 155/100,000/y, around 400 times higher than general population.8 Although HHTrelated BA had initially been reported to occur in the third to fifth decade of life, more recent observations show that it may also occur earlier.10 A careful review of the English literature identified a total of 14 BA-affected pediatric patients, previously reported to have HHT, as listed in Table 1.5,7,10–15 BA recurrence in HHT has been described due to a number of mechanisms, including lack of underlying PAVM detection, lack of proper PAVM treatment, recanalization of previously treated PAVM, or growth over time of PAVM initially not amenable to treatment.16 However, data regarding HHT-related BA are mainly collected on adult patients, whereas more information is still required for
AVMs and Brain Abscess Recurrence in a Child With HHT
children, to optimize clinical care in this age group. Our patient is the first case of BA recurring at the end of pediatric age. Although the incidence of BA in HHT children is unknown, and might be lower than in adulthood,5,17 reports in the literature review demonstrate that BA episodes do occur in childhood, and the present case provides evidence that recurrence may also take place at pediatric age, similarly to what has been published for adult age. Currently accepted mechanisms responsible for HHT-related BA consider the shunting effect as a route for septic or sterile emboli to bypass the pulmonary capillary filter.7,15,18 Similar to observations in adults, all cases of HHT-related BA children with available anatomic details, have either 1 large PAVM (defined as size of the feeding artery Z3 mm) or diffuse PAVMs documented5,7,10–15 and display a supratentorial location of BA.13,15 Accordingly, our case shares overlapping features with cases of HHT-related BA recurrence in adult age, including the distinct location between initial infection and recurrence and the identification of a facultative anaerobic as the bacterial causative agent.15 All these observations thus suggest common mechanisms and risk factors underlying BA in children and adults with HHT. However, as arterial hypoxia and polycythemia have been shown to compromise the brain’s resistance to infection,18 particularly in a context of a right-to-left shunt,19 we might speculate that PAVMassociated hypoxemia likely renders children more vulnerable to brain infection, when compared with PAVM children with normal blood oxygenation. E. agglomerans (now reclassified as Pantoea agglomerans) has never been reported as a causative agent of an HHT-related BA, but it is known as a plant pathogen responsible for human infections, due to plant-thorn–related trauma, nosocomial contamination and, more rarely, by spontaneous bacteremia,20 even though the infection source may remain undetected.21 Neither hospitalization nor dental care were reported at the time of the first BA, and hence we speculate that a previously overlooked exposure to soilencrusted object, plant thorn, fresh or salt water might have provided a potential entry route for this pathogen. Conversely, no bacterial agent was retrieved upon BA recurrence, likely due to the long-lasting prior antibiotic treatment, and/or the difficulty in isolating some anaerobic microorganisms.22 Several previously reported data pointed out at dental bacteremia
FIGURE 1. Brain abscess lesions in right frontal lobe, proximal to insula, and left frontal lobe (white arrows) in T2-weighted MRI (A) and T1-FLAIR MRI (B). Small arteriovenous malformation (nidus
AND
LABORATORY OBSERVATIONS
Pulmonary Arteriovenous Malformations and Cerebral Abscess Recurrence in a Child With Hereditary Hemorrhagic Telangiectasia Paola Giordano, MD, PhD,* Maria Sangerardi, MD,* Patrizia Suppressa, MD, PhD,w Patrizia Lastella, MD, PhD,w Ettore Attolini, MD,z Federica Valente,* Maria L. Fiorella, MD,y Gennaro M. Lenato, PhD,w and Carlo Sabba`, MD, PhDw
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. Key Words: hereditary hemorrhagic telangiectasia, Rendu-OslerWeber disease, recurrent brain abscess, pulmonary arteriovenous malformation, diagnostic delay
(J Pediatr Hematol Oncol 2015;37:e200–e203)
H
ereditary hemorrhagic telangiectasia (HHT), or RenduOsler-Weber disease (OMIM: #187300), is an autosomal dominant angiogenic disorder associated with arteriovenous shunts, often manifesting as mucocutaneous telangiectatic lesions and/or affecting visceral organs. HHT is characterized by high penetrance and age-related expression and has an estimated prevalence of 1:5000 to 1:10,000 inhabitants.1 Clinical diagnosis is established according to Curacao criteria: epistaxis, mucocutaneous telangiectases, visceral arteriovenous malformations (AVMs), and first-degree affected relative.2 Mutations in either ENG or ALK1/ACVRL1 gene are responsible for the HHT disease in about 85% of cases.3 As the disease does not often reach full clinical expression in youngsters, the knowledge of the diseasecausing mutation in a given family permits to assess a firm Received for publication March 19, 2014; accepted August 7, 2014. From the *Department of Biomedical Science and Human Oncology, Unit of Paediatrics “F. Vecchio”; wCenter for Rare Diseases, Unit of Internal Medicine “C. Frugoni”; yUnit of Otorynolaringology, University Hospital of Bari; and zRegional Agency of HealthApulia, Via Gentile, Bari, Italy. P.G., M.S., and P.S. contributed equally and are joint first authors. The authors declare no conflict of interest. Reprints: Carlo Sabba`, MD, PhD, Center for Rare Diseases, Unit of Internal Medicine “C. Frugoni,” University Hospital of Bari, P.zza G. Cesare, Bari 70124, Italy (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
e200 | www.jpho-online.com
HHT diagnosis also in asymptomatic or paucisymptomatic children who do not meet clinical criteria.3–5 In pediatric age, pulmonary AVMs (PAVMs) occur in 30% to 45% of HHT patients, 25% to 40% of those will develop PAVMrelated symptoms.4–6 Manifestations of PAVMs include hypoxemia features (dyspnea, cyanosis, and polycythemia), hemoptysis, as well as risk of developing neurological complications, such as stroke or cerebral abscess, by paradoxical embolization.7,8 Neurological complications can be associated with respiratory symptoms or, in some cases, occur as the first clinical manifestation of otherwise asymptomatic PAVMs. Therefore, the association between PAVM and brain abscess (BA) should be borne in mind in cases of BA of unexplained etiology.
CASE REPORT A 17-year-old boy presented to the observation of our Multidisciplinary HHT Centre with a history of 2 distinct episodes of BA. Medical history revealed a first occasional detection of a large PAVM at 4 years of age, which had resulted in a failed attempt of embolotherapy and no recommendation for subsequent treatment or monitoring. At 7 years of age, he had suffered from intense and throbbing right temporoparietal headache, due to a septic BA affecting the right frontal lobe, proximal to the insular region. Pulmonary angiography had shown that the same PAVM in the right lower lobe had considerably enlarged, likely resulting in paradox embolization and then cerebral abscess, as well as in hypoxemia (paO2 = 82 mm Hg). This AVM had been treated by pulmonary lobectomy and BA had been drained, with growth of Enterobacter agglomerans in the culture, whereas additional small PAVMs (diameter of feeding artery A; p.Arg479Gln). According to the current HHT guidelines,9 the large complex PAVM was treated by transcatheter embolotherapy, with marked improvement in his respiratory symptoms and rising of paO2 from 76 to 89 mm Hg. Periodical surveillance was undertaken to monitor his small PAVMs and other visceral lesions. Antibiotic therapy was recommended upon surgical intervention and/or dental care, and antiepileptic therapy was continued. Subsequent surveys showed remission of digital cyanosis, improvement of exercise intolerance, persistence of digital clubbing, hematocrit normalization, no recanalization of the treated PAVM, and no significant enlargement of small untreated PAVMs and brain lesions. Meanwhile, our Center was referred by some distant relatives of the patient for the purpose of genetic testing. Familial history disclosed that HHT had initially been diagnosed in a sister of the patient’s maternal grandmother, even though no information had been provided regarding autosomaldominant inheritance, risk of visceral involvement, and phenotypic variability of HHT disease.
DISCUSSION BA is a known manifestation of HHT-related PAVMs,7 with a recently estimated incidence of 155/100,000/y, around 400 times higher than general population.8 Although HHTrelated BA had initially been reported to occur in the third to fifth decade of life, more recent observations show that it may also occur earlier.10 A careful review of the English literature identified a total of 14 BA-affected pediatric patients, previously reported to have HHT, as listed in Table 1.5,7,10–15 BA recurrence in HHT has been described due to a number of mechanisms, including lack of underlying PAVM detection, lack of proper PAVM treatment, recanalization of previously treated PAVM, or growth over time of PAVM initially not amenable to treatment.16 However, data regarding HHT-related BA are mainly collected on adult patients, whereas more information is still required for
AVMs and Brain Abscess Recurrence in a Child With HHT
children, to optimize clinical care in this age group. Our patient is the first case of BA recurring at the end of pediatric age. Although the incidence of BA in HHT children is unknown, and might be lower than in adulthood,5,17 reports in the literature review demonstrate that BA episodes do occur in childhood, and the present case provides evidence that recurrence may also take place at pediatric age, similarly to what has been published for adult age. Currently accepted mechanisms responsible for HHT-related BA consider the shunting effect as a route for septic or sterile emboli to bypass the pulmonary capillary filter.7,15,18 Similar to observations in adults, all cases of HHT-related BA children with available anatomic details, have either 1 large PAVM (defined as size of the feeding artery Z3 mm) or diffuse PAVMs documented5,7,10–15 and display a supratentorial location of BA.13,15 Accordingly, our case shares overlapping features with cases of HHT-related BA recurrence in adult age, including the distinct location between initial infection and recurrence and the identification of a facultative anaerobic as the bacterial causative agent.15 All these observations thus suggest common mechanisms and risk factors underlying BA in children and adults with HHT. However, as arterial hypoxia and polycythemia have been shown to compromise the brain’s resistance to infection,18 particularly in a context of a right-to-left shunt,19 we might speculate that PAVMassociated hypoxemia likely renders children more vulnerable to brain infection, when compared with PAVM children with normal blood oxygenation. E. agglomerans (now reclassified as Pantoea agglomerans) has never been reported as a causative agent of an HHT-related BA, but it is known as a plant pathogen responsible for human infections, due to plant-thorn–related trauma, nosocomial contamination and, more rarely, by spontaneous bacteremia,20 even though the infection source may remain undetected.21 Neither hospitalization nor dental care were reported at the time of the first BA, and hence we speculate that a previously overlooked exposure to soilencrusted object, plant thorn, fresh or salt water might have provided a potential entry route for this pathogen. Conversely, no bacterial agent was retrieved upon BA recurrence, likely due to the long-lasting prior antibiotic treatment, and/or the difficulty in isolating some anaerobic microorganisms.22 Several previously reported data pointed out at dental bacteremia
FIGURE 1. Brain abscess lesions in right frontal lobe, proximal to insula, and left frontal lobe (white arrows) in T2-weighted MRI (A) and T1-FLAIR MRI (B). Small arteriovenous malformation (nidus
