A child with vein of Galen aneurysmal malformation (VGAM) presented with cardiac failure in the neonatal period. The family history revealed his mother to have hereditary hemorrhagic telangiectasia. The child underwent an endoglin genetic analysis after the newborn period, which eventually demonstrated an endoglin mutation. The pathogenesis of VGAM is currently unknown. The findings of this case suggest that an endoglin mutation might be linked with VGAM.
Boynton and Morgan1 reported complicating cerebrovascular malformation in an infant with a family history of hereditary hemorrhagic telangiectasia (HHT) in 1973. The imaging and autopsy findings noted in that report suggested that the patient may have had vein of Galen aneurysmal malformation (VGAM).2
HHT is a disease of autosomal-dominant inheritance; thus, there is a 50% probability that the affected infant was a carrier of the disease. An autopsy of the patient revealed no extracranial vascular lesions, and no means of genetically diagnosing HHT had been discovered at that time. Consequently, it is unclear whether the patient had an HHT gene anomaly.
In this report we describe a case of VGAM in a patient with a family history of HHT. The patient underwent genetic testing for HHT. To our knowledge, this is the first report of a case of VGAM in a patient with a confirmed anomaly in a gene responsible for HHT.
The patient was a male who was delivered vaginally by a 36-year-old mother in cephalic presentation at a fetal age of 38 weeks. His birth weight was 2880 g, his length was 49.0 cm, his head circumference was 32.5 cm, and his Apgar scores at 1 and 5 minutes were 9 and 9, respectively. This was the mother's first pregnancy and childbirth, and there were no remarkable events in the mother's pregnancy and parturition history. There was a family history of lip telangiectasia and epistaxis in the patient's maternal grandmother, which was diagnosed as HHT on the basis of clinical symptoms. Lip telangiectasia was also seen in the mother, and she had experienced repeated epistaxis since she was in her teens. A definitive diagnosis of HHT was made on the basis of the diagnostic criteria.3
There was no skin telangiectasia or other remarkable findings in the child at birth. A cardiac bruit was noticed 12 hours after delivery, and plain chest radiography revealed cardiomegaly (cardiothoracic ratio: 70%). Echocardiography revealed no intracardiac malformation, but there was tricuspid and mitral valve regurgitation. VGAM was suspected on the basis of head sonography performed when the child was 3 days of age, and the patient was transferred to our facility (National Center for Child Health and Development, Tokyo, Japan).
This patient was admitted with a temperature of 36.6°C, and his blood pressure was 64/30 mm Hg. There were no abnormal skin findings. His anterior fontanel was flat. Respiratory sounds were clear. A systolic bruit was detected (Levine 2/6), and the liver was palpated 4 cm below the right subcostal margin. Laboratory testing revealed a hemoglobin level of 15.4 g/dL, a white cell count of 6.6 × 109/L, a platelet count of 118 × 109/L, an activated partial thromboplastin time of 56.5 seconds, a prothrombin time-international normalized ratio of 1.29, an aspartate aminotransferase level of 30 IU/L, an alanine aminotransferase level of 9 IU/L, a lactate dehydrogenase level of 465 IU/L, a total protein level of 5.0 g/dL, and a C-reactive protein level of <0.2 mg/dL. Head sonography revealed a dilated midline vessel corresponding to the dilated median vein of the prosencephalon.
MRI and magnetic resonance angiography revealed dilated vessels that were thought to be arteries that emptied into the dilated median vein of the prosencephalon at 3 days of age. The draining pathway was thought to involve the parietal superior sagittal sinus via the falcine sulcus (Fig 1). There were areas of high signal intensity on T1-weighted images of the left parietal lobe subcortical white matter, and a region of pronounced low signal intensity on T2-weighted images of the same area was also noted. This was seen as an isodense area on computed-tomography imaging performed at 4 days of age and was thought to indicate a prenatal hemorrhagic change.
The patient's cardiorespiratory failure worsened despite catecholamine, diuretic, and human atrial natriuretic peptide administration. Therefore, the patient was intubated and placed on mechanical ventilation at 4 days of age. Initial angiography was performed at 11 days of age. Digital subtraction angiography revealed that multiple shunts had formed in the median vein of the prosencephalon. The arterial supply, including the left pericallosal, right lenticulostriate, right anterior choroidal, and right posterior choroidal arteries, indicated a diagnosis of choroidal-type VGAM. The galenic vein drained into the parietal superior sagittal sinus via the persistent primitive falcine sinus. Stenosis was observed at the tentorium cerebelli in the drainage pathway. Further drainage pathways included the transverse, accessory transverse, sigmoid, occipital, and marginal sinuses (Figs 2 and 3).
A microcatheter was guided into a shunt vessel from the right medial posterior choroidal artery, which was the vessel with the largest caliber, and embolization was performed by using the mixture of n-butyl cyanoacrylate (n-BCA), ethiodized oil, and tantalum powder. The embolization procedure remarkably improved the patient's respiratory status, and the patient was extubated at 22 days of age. Additional embolization of the 2 shunt vessels of the right anterior and left posterior choroidal arteries was performed when the patient was 1 year of age. Spinal cord MRI and thoracoabdominal contrast-enhanced computed tomography at 1 year of age revealed nothing that was clearly suggestive of arteriovenous fistula in the lungs, liver, or spinal cord. MRI and magnetic resonance angiography performed when the patient was 2 years 6 months of age revealed a slight residual shunt lesion and mild dilation of the vein of Galen, but the patient's development was otherwise normal.
Genetic testing of both the patient and his mother was performed. The genomic DNA used in the testing was isolated from the peripheral blood. The regions that encode the proteins of the affected genes in HHT, the endoglin and activin receptor-like kinase (ALK1) genes, were directly sequenced. A deletion of 13 bases was seen in exon 11 of the endoglin gene, and a frame-shift mutation in the stop codon (c.1672_1684delGGGTCTCAAGACC p.Gln558fsX568) was seen. The mother carried the same mutation. No anomalies were seen in the ALK1 gene.
The pathogenesis of VGAM is unknown. One article concerning the genetics of VGAM reported an anomaly of the RASA1 gene.4 The RASA1 gene is the causative gene in capillary malformation-arteriovenous malformation (CM-AVM) and is seen in the proteins of transforming growth factor in vascular endothelial cells. CM-AVM has autosomal dominant inheritance. A diagnostic sign of this disease is multiple capillary malformations, which are highly expressive of its occurrence.
HHT, or Rendu-Osler-Weber disease, is a rare disorder with an incidence of 1 to 2 in 100 000 people5; however, this incidence may be an underestimation.6 Epistaxis is the most common presentation. More than 90% of cases manifest by the age of 21 years.7 Skin and mucosa telangiectasia and arteriovenous malformations in the lungs, brain, liver, and spinal cord are common manifestations. The phenotypes of HHT are diverse, and, as in the present case, there are often no symptoms such as epistaxis or skin/lip telangiectasia during the neonatal period.
Cerebral arteriovenous malformation is a common manifestation in patients with HHT. Maher et al8 reported the cases of 12 patients with a history of cerebral vascular malformations among 321 patients with HHT. Ten patients had arteriovenous malformations, 1 had a dural arteriovenous fistula, and 1 had a cavernous malformation.
There have been few reports concerning VGAM in patients with HHT. Although there has been a report of vein of Galen–like vascular malformations in familial HHT, it preceded the era in which genetic testing was performed.1
Several culprit genes have been identified for HHT. The endoglin (HHT type 1) gene has been identified on 9q34.1,9 and the ALK1 (HHT type 2) gene has been identified on 12q11-q14.10 The gene responsible for HHT type 3 has been identified on 5q31.3-q32.11 In addition, a genetic anomaly on 7p14 has been reported for HHT type 4.12
The anomaly of the endoglin gene seen in our patient was reported to be associated with intracranial arteriovenous malformation.13
We have described here a case of VGAM that occurred in combination with HHT. The accumulation of further genetic investigations in other patients may help to elucidate the pathophysiology of VGAM.
- Accepted June 24, 2011.
- Address correspondence to Yoshiyuki Tsutsumi, MD, National Center for Child Health and Development, 2-10-1 Okura Setagaya, Tokyo 157-8535, Japan. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
- HHT —
- hereditary hemorrhagic telangiectasia
- VGAM —
- vein of Galen aneurismal malformation
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- Copyright © 2011 by the American Academy of Pediatrics