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 HHT in these families. The diagnosis was made From the *Department of Pathology, Stanford University, Stanford, Califor- if the patient met at least 3 of the following 4 criteria: nia; ‡Hereditary Hemorrhagic Telangiectasia Clinic, Department of Radiol- epistaxis, telangiectases, visceral lesions, and an ap- ogy, University of Utah Health Sciences Center, Salt Lake City, Utah; propriate family history. Before the ICH, none of the §Department of Pediatrics, Division of Neonatology, Stanford University, infants or children described in this report was sus- Stanford, California; ʈDepartment of Radiology, Stanford University, Stan- ford, California; and ¶Department of Pediatrics, Division of Medical Ge- pected of having HHT. netics, Stanford University, Stanford, California. In all, there were 6 boys and 3 girls (newborn to 16 Received for publication Jul 31, 2001; accepted Sep 25, 2001. years). Their clinical features are summarized in Ta- Reprint requests to (T.M.) Department of Pathology, Stanford University ble 1. Notably cases 2 to 9 were identified from a total Medical Center, Stanford, CA 94305. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- of 106 families being treated by the HHT clinic at the emy of Pediatrics. University of Utah Health Sciences Center. http://www.pediatrics.org/cgi/content/full/109/1/Downloaded from www.aappublications.org/newse12 PEDIATRICS by guest on October Vol. 2, 1092021 No. 1 January 2002 1of7 TABLE 1. Summary of Children Who Presented With ICH and a Family History of HHT* Case Age Gender AVM Family History Linkage to Outcome Number Confirmation Endoglin Gene 1 Newborn Male Autopsy Mother, uncle, maternal Yes Death grandmother, maternal great-grandmother 2 4 wk Female Autopsy Father, 2 aunts, uncle, paternal Yes Death grandfather 3 6 y Female MRI Mother, 2 aunts, uncle, Yes Significant cognitive and maternal grandmother, motor impairment cousins 4 7 y Male Autopsy Mother, 2 aunts, uncle, Not tested Death maternal grandfather 5 10 y Female Autopsy Father, brother, 2 aunts, Not tested Death paternal grandmother 6 10 y Male Surgery Mother, paternal grandfather Yes Hemiparesis 7 11 y Male Surgery Father, brother, 2 sisters, Yes Significant cognitive and paternal grandfather motor impairment 8 16 y Male Autopsy Mother, maternal Yes Death grandmother, 2 aunts 9 16 y Male CT scan Mother, aunt, maternal Not tested Significant cognitive and grandmother motor impairment * Six boys and 3 girls with ICH at an average age of 8.5 years, standard deviation is 5.5 years. CASE REPORTS mates. In addition to the markers examined for HHT type 1, 6 polymorphic markers were analyzed for the ALK-1 gene (HHT Case 1 type 2) on chromosome 12. There was no evidence for linkage to A male neonate was born at 38.5 weeks’ gestation to a primip- the ALK-1 gene. arous 34-year-old woman with good prenatal care. He was deliv- ered by cesarean section because of fetal bradycardia and loss of Case 2 beat-to-beat fetal heart rate variability. At birth, he was pale with no muscle tone or respiratory effort. He was intubated with an A female neonate was born after an unremarkable pregnancy endotracheal tube and received cardiopulmonary resuscitation and delivery. Her medical history was unremarkable. In particu- with epinephrine, normal saline, and sodium bicarbonate. Apgar lar, there was no history of seizures, abnormal posturing, or scores were 2 and 4 at 1 and 10 minutes, respectively. On exami- increased fussiness. At 4 weeks of age, however, she began nation, a full fontanelle and asymmetric pupils were noted. “screaming” while breastfeeding and turned blue. Emergency The neonate was transported to a local tertiary care center. Both transport was called, and her mother administered cardiopulmo- pupils were noted to be fixed and dilated. In addition, several nary resuscitation until their arrival. Emergency personnel could small telangiectases were identified on the forehead and nape of not revive the neonate. Autopsy attributed her death to an ICH the neck. A small telangiectasia was noted in the mucosa of the left secondary to an AVM. Her father’s family had multiple members nare. He had spontaneous respirations on the ventilator but no with HHT type 1 (her father, paternal grandfather, 2 aunts, and an other spontaneous movements. uncle) confirmed by molecular analysis. Head ultrasound showed a massive left parietal occipital hem- orrhage (Fig 1A and 1B). A noncontrast head computed tomo- Case 3 graphic scan revealed a massive subdural and subarachnoid hem- A 6-year-old girl with no significant medical history presented orrhage in the left hemisphere with extensive mass effect. A with an ICH secondary to cerebral AVM, which was confirmed by dumbell-shaped ring enhancing lesion in the left parietal/occipital magnetic resonance imaging (MRI). She now has significant cog- region, suspicious for an AVM, was identified (Figs 1C and 1D). nitive and motor impairment. Given the extent of ICH and poor neurologic status of the infant, Despite a strong family history of HHT type 1, this diagnosis ventilatory support was withdrawn after discussion with the fam- previously had not been suspected in this child. Her mother, ily. maternal grandfather, 2 aunts, 1 uncle, 4 cousins, and many ad- Autopsy confirmed the presence of an AVM in the left tempo- ditional relatives had a diagnosis of HHT with molecular confir- ral-parietal area associated with acute subarachnoid, intraventric- mation of an endoglin mutation. ular, and subdural hemorrhage (Figs 2A–2C). Secondary Duret hemorrhages were identified in the brainstem, consistent with mass effect. In addition, multiple remote and subacute hemor- Case 4 rhages were identified in both lungs and at the gastroesophageal A 7-year-old boy died from an ICH secondary to a cerebral junction (Figs 2D–2G). AVM, which was confirmed at autopsy. He had a history of Family history was significant for the patient’s mother, who nosebleeds but no history of significant headaches, seizures, or had a diagnosis of HHT, presenting with occasional epistaxis, other central nervous system manifestations.