Intracranial Hemorrhage in Infants and Children With Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)

Terry Morgan, MD, PhD*; Jamie McDonald, MS, CGC‡; Christina Anderson, MD§; Magdy Ismail, MD§; Franklin Miller, MD‡; Rong Mao, MD‡; Ashima Madan, MD§; Patrick Barnes, MDʈ; Louanne Hudgins, MD¶; and Melanie Manning, MD¶

ABSTRACT. Objective. Hereditary hemorrhagic tel- ereditary hemorrhagic telangiectasia (HHT), angiectasia (HHT) is an autosomal dominant vascular also known as Osler-Weber-Rendu syn- dysplasia. Most cases are caused by mutations in the drome, is an autosomal dominant vascular endoglin gene on chromosome 9 (HHT type 1) or the H dysplasia with a high degree of penetrance but ex- activin receptor-like kinase 1 gene on chromosome 12 tremely variable expression. It occurs in approxi- (HHT type 2), which leads to telangiectases and arterio- 1–4 venous malformations (AVM) of the skin, mucosa, and mately 1 in 10 000 individuals. Most cases of HHT viscera. Epistaxis is the most frequent presentation. Vis- are caused by mutations in the endoglin gene on ceral involvement includes pulmonary, gastrointestinal, chromosome 95–7 or the activin receptor-like kinase-1 and cerebral AVMs, which have been reported predom- (ALK-1) gene on chromosome 12,8 which can lead to inantly in adults. The purpose of this article is to describe telangiectases and arteriovenous malformations 9 children who presented with intracranial hemorrhage (AVM) of the skin, mucosa, and viscera. (ICH) secondary to cerebral AVM. None of these children Epistaxis is the most frequent presentation; Ͼ90% was suspected of having HHT before the incident, de- 9 spite family histories of the disease. of cases manifest by the age of 21. Telangiectases of Methods. We report the first case of an ICH secondary the tongue, lips, and skin are also common. Gastro- to a cerebral AVM in a neonate confirmed to have HHT intestinal involvement presenting as hemorrhage oc- type 1 by molecular analysis. We also describe a series of curs in approximately 16% of patients; half of these 8 additional cases of ICH secondary to cerebral AVM in require transfusion.10 Additional visceral involve- children presumed to have HHT. Examination of multi- ment includes pulmonary, hepatic, and cerebral ple affected members from each of these families, using AVMs, which have been reported predominantly in well-accepted published criteria, confirmed the diagno- 3,10–13 sis of HHT. In addition, genetic linkage studies and/or adults. mutation analysis identified endoglin as the disease- Approximately 20% of adults with HHT have cere- causing gene in 6 of these families. Autopsy, imaging brovascular malformations.13 Most are asymptomatic, studies, and/or surgery confirmed the presence of cere- but some present with acute headache associated with bral AVMs and ICH in all 9 cases. intracranial hemorrhage (ICH). The prevalence of cere- Conclusion. Our report shows that infants and chil- brovascular malformations among children with HHT dren with a family history of HHT are at risk for sudden is unknown. and catastrophic ICH. A preemptive diagnosis may po- The purpose of this article was to describe the first tentially identify and prevent more serious sequelae. Pediatrics 2002;109(1). URL: http://www.pediatrics.org/ molecularly confirmed case of HHT presenting with cgi/content/full/109/1/e12; hereditary hemorrhagic telangi- ICH secondary to a cerebral AVM in a neonate (case ectasia, intracranial hemorrhage, neonates, infants, chil- 1). Eight additional cases of infants and children who dren, linkage analysis. had a family history of HHT and presented with ICH are also described (cases 2–9). ABBREVIATIONS. HHT, hereditary hemorrhagic telangiectasia; ALK-1, activin receptor-like kinase 1; AVM, arteriovenous malfor- mation; ICH, intracranial hemorrhage; MRI, magnetic resonance CLINICAL REPORT imaging; TGF-␤, transforming growth factor-␤. Examination of multiple affected members, using accepted published criteria,14 confirmed the diagno- sis of