Portal Vein Cavernoma Associated with Goldenhar Syndrome

Abstract

INTRODUCTION Goldenhar syndrome, part of the oculoauriculovertebral spectrum of congenital malformations, is a rare disorder affecting derivatives of the first and second branchial arches, vertebrae, and eyes. The syndrome was first described in 1952, and various combinations of ocular (epibulbar dermoids, colobomas, microphthalmia), vertebral (particularly fusion and hemivertebrae affecting the cervical spine), orofacial (hemi-facial microsomia, cleft palate, mandibular hypoplasia), auricular (ear tags, aplasia or distortion of the pinna, middle ear abnormalities), skeletal (anomalous ribs, talipes equinovarus), cardiac (most commonly tetralogy of Fallot or ventricular septal defect), pulmonary (ipsilateral agenesis or hypoplasia), and renal (absent kidney) anomalies have since been described (1,2). Most cases are sporadic, but autosomal dominant inheritance is described (1). A 20 year study in Northern Ireland yielded a minimum prevalence rate of 1 in 45,000 live births (3). After the referral of a child with Goldenhar syndrome and extrahepatic portal hypertension (case 1), further communications at international meetings and by way of the Pediatric GI Bulletin Board ([email protected]) led to the discovery of two similar cases, one from the United Kingdom and one from Spain, suggesting an association between Goldenhar syndrome and extrahepatic portal hypertension. These three cases are presented and the relevant literature reviewed. PATIENTS Case 1 A 9-year-old girl with Goldenhar's syndrome was referred for management of extrahepatic portal hypertension secondary to portal vein occlusion. She had been the product of an uncomplicated full-term delivery. She had two healthy siblings, and there was no relevant family history. Her congenital anomalies also included left pulmonary hypoplasia and astigmatism. She had previously undergone insertion of a gastrostomy and Nissen fundoplication at 6 years of age for poor oral intake and gastroesophageal reflux, respectively. During a craniofacial assessment for mandibular reconstruction, she was found to have thrombocytopenia and palpable splenomegaly. On subsequent review, mild thrombocytopenia had first been noted at the age of 10 months, and this became consistent and more marked from the age of 6 years. Further investigations confirmed a portal vein cavernoma with esophageal varices, splenomegaly, and hypersplenism (white blood cell count 3.8 × 109/l, platelets 76 × 109/l). Liver function tests and liver biopsy were both normal, and a thrombophilia screen detected no underlying prothrombotic disorder (protein S, C, and antithrombin III levels normal, normal activated protein C resistance ratio, factor II gene mutation absent, negative lupus screen, and normal anticardiolipin antibody concentration). Her parents were keen for her to have corrective surgery for portal hypertension, especially because she had thrombocytopenia from hypersplenism and was going to require corrective maxillofacial surgery. She underwent a meso-portal bypass between the superior mesenteric vein and the umbilical segment of the left intrahepatic portal vein, using autologous internal jugular vein as a conduit (4). Good portal decompression was achieved with a fall in superior mesenteric venous pressure from 24 mm Hg to 13 mm Hg at the end of the procedure. Postoperatively, her portal hypertension and hypersplenism completely resolved, and she remains well with a patent shunt 3 years later. Her height and weight have increased from the 2nd and 9th percentiles, respectively, to between the 9th and 25th percentiles. Case 2 A 7-year-old boy with Goldenhar syndrome, absent left lung and pulmonary artery, absent left kidney, tracheal stenosis, hemivertebra, and a scoliosis was found to have extrahepatic portal vein obstruction. He had bled from esophageal varices 1 year previously, and these had been successfully controlled by endoscopic injection sclerotherapy. Splenomegaly and hypersplenism (white blood cell count 3.2 × 109/l and platelets 67 × 109/l) had prompted his referral for a meso-portal bypass. Correction of his portal hypertension was considered important in view of his anticipated orthopedic surgery and to minimize the need for future general anesthetics that would otherwise be necessary for endoscopic variceal surveillance. He had no relevant neonatal or family history. A thrombophilia screen revealed low levels of antithrombin III at 0.67 IU/mL (normal range 0.79-1.31), protein C at 0.45 IU/mL (normal range 0.70-1.49), and free protein S at 0.39 IU/mL (normal range 0.73-1.13) compatible with the acquired deficiency of coagulation-inhibitor proteins often seen in patients with a portal vein cavernoma (5). Biochemical liver function tests were normal, and magnetic resonance angiography confirmed a portal vein cavernoma with patent superior mesenteric and splenic veins (Fig. 1). Retrograde hepatic venography showed that the intrahepatic portal veins were widely patent. He underwent a portal bypass procedure using a segment of autologous internal jugular vein interposed between a large left gastric vein and the umbilical segment of the left intrahepatic portal vein. He made an uncomplicated recovery with resolution of his hypersplenism, and he remains well 3 years later. Abnormalities of his coagulation-inhibitor proteins had improved 3 months after surgery (antithrombin III 1.1 IU/mL, protein C 0.67 IU/mL, and protein S 0.69 IU/mL).FIG. 1: Magnetic resonance angiogram showing a portal vein cavernoma and splenomegaly. The splenic and superior mesenteric veins are patent.Case 3 A 16-month-old girl was referred for assessment of portal hypertension after the discovery of splenomegaly and hemorrhoids. She had been born at term after an uneventful pregnancy and was found to have Goldenhar syndrome. Specifically, she had bilateral preauricular tags, left microtia (and middle ear malformations), mandibular hypoplasia, a cervical hemivertebra, malformed first and second right ribs, and left talipes equinovarus. She had a normal karyotype. The neonatal period was uncomplicated without any episode of sepsis or dehydration and no attempt at umbilical cannulation. Surgery was required for a left inguinal hernia and for her foot deformity at 3 and 6 months of age, respectively, but this was uncomplicated. Imaging studies demonstrated a portal vein cavernoma with large esophageal varices. She had no evidence of a prothrombotic disorder. One year later, she presented with hematemesis and melena from bleeding esophageal varices, which were treated by endoscopic injection sclerotherapy. Her third sclerotherapy session was complicated by distal esophageal necrosis and perforation requiring thoracotomy and, eventually, a gastrostomy and diverting proximal esophagostomy. At 4 years of age, a meso-portal bypass procedure using autologous internal jugular vein was performed, but the graft thrombosed 2 days later, resulting in severe gastrointestinal bleeding. The patient underwent re-operation when a meso-caval shunt was constructed using the previous jugular vein graft. This portosystemic shunt has since remained patent, and the patient has had no further complications from portal hypertension. At 5 years of age, a retrosternal esophageal replacement was performed without major complications. Four years later, she remains well with a normal oral intake and growth parameters. DISCUSSION In children, cavernous transformation of the portal vein is frequently associated with relatively normal intrahepatic portal venous anatomy and a patent splenic and mesenteric venous system (6). An underlying prothrombotic disorder is rarely present (5), but associated congenital anomalies are seen in up to 40% of patients (6,7), suggesting that the portal vein cavernoma has an embryonic origin in many cases. Congenital cardiac malformations are the most common associated anomalies, but malformations of the inferior vena cava are well documented (7). Single cases of a portal vein cavernoma associated with a congenital craniofacial deformity such as Crouzon (7) and Pfeiffer (6) syndrome have also been described. The pathogenesis of congenital portal vein cavernoma is unknown. The portal vein is formed between 5th and 10th weeks of gestation from the paired vitelline veins and their cross communications (8). Obliteration of the cranial component of the left vitelline vein, the caudal component of the right vitelline vein, and the ventral intervitelline anastomosis results in normal portal vein development (9). Abnormal patterns of involution of these veins may cause various portal vein abnormalities such as a preduodenal vein, duplication of the vein, or its absence. A congenital portal vein cavernoma could be the result of intrauterine portal vein thrombosis of a normally developed portal vein but is more likely to be a primary venous malformation and therefore associated with other congenital anomalies. All three of our children had typical features of Goldenhar syndrome with otic and mandibular hypoplasia (dominantly affecting the left side), conductive hearing loss, and ocular and vertebral anomalies. They had each been reviewed by a medical geneticist and multiple pediatric specialists. Each had an isolated portal vein cavernoma with no evidence of splenomesenteric venous involvement, and none had a history of umbilical sepsis or cannulation. Intrahepatic portal venous anatomy was well preserved in all cases, enabling an attempt at curative meso-portal bypass, which was successful in two. Various congenital vascular anomalies have been described in Goldenhar syndrome in addition to well-recognized congenital cardiac malformations. Venous anomalies have included infradiaphragmatic total anomalous pulmonary venous drainage (10), anomalous inferior and superior vena cavae (11), and a persistent left superior vena cava with azygos continuation of the inferior vena cava (12). In the arterial system, pulmonary trunk hypoplasia (3), an isolated left innominate artery (12), and absence of the internal carotid artery have been reported (13). Two previous children with Goldenhar syndrome and a portal vein anomaly have been reported. Morse et al. (14) described an 8-year-old girl with a liver mass (initially diagnosed as focal nodular hyperplasia) and congenital absence of the portal vein; her superior mesenteric vein drained directly into the inferior vena cava and her splenic vein into the left renal vein. Two years later, she developed a multifocal hepatoblastoma that was treated by chemotherapy and liver transplantation (15). Kalifa et al. (16) reported a child with Goldenhar syndrome and a hypoplastic portal vein associated with a congenital portocaval shunt. This report of three cases and the existing literature strongly suggest an association between Goldenhar syndrome and portal vein anomalies, both individually rare conditions. It expands the possible manifestations of Goldenhar syndrome to include extrahepatic portal hypertension from a portal vein cavernoma. These patients require careful evaluation because they may be suitable for corrective meso-portal bypass surgery, thus avoiding the potentially life-threatening complications of portal hypertension.