Franklin J. Miller

A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7

Hereditary hemorrhagic telangiectasia (HHT) is a genetically and clinically heterogeneous multisystem vascular dysplasia. Mutations of the endoglin and ACVRL1 genes are known to cause HHT. However, existence of HHT families in which linkage to these genes has been excluded has suggested that other gene(s) can cause HHT in some families. Recently, a family was reported to be linked to chromosome 5q, the HHT3 locus. Here we report on linkage results on a family with classic features of HHT, albeit a less severe phenotype with regards to epistaxis and telangiectases, in which linkage to HHT1, HHT2, and HHT3 is ruled out. Whole genome linkage analysis and fine mapping results suggested a 7 Mb region on the short arm of chromosome 7 (7p14) between STR markers D7S2252 and D7S510. We obtained a maximum two point LOD score of 3.60 with the STR marker D7S817. This region was further confirmed by haplotype analysis. These findings suggest the presence of another gene causing HHT (HHT4). The features in this family that strongly suggest the presence of a hereditary, multisystem vascular dysplasia would be easily missed during the typical evaluation and management of a patient with an AVM. This family helps emphasize the need to obtain a very detailed, targeted medical and family history for even mild, infrequent but recurring nosebleed, subtle telangiectases. Further studies of the candidate region and the identification of the gene responsible for the vascular anomalies in this family will add to our understanding of vascular morphogenesis and related disorders.

Genotype–phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations

Hereditary hemorrhagic telangiectasia (HHT) is a genetically heterogeneous vascular dysplasia with multiple telangiectases and arteriovenous malformations and it is caused by mutations in endoglin gene (ENG) (HHT1) and activin A receptor type II‐like 1 gene (ACVRL1) (HHT2). We evaluated 111 patients with HHT from 34 families by history, examination, screening for vascular malformations, and sequencing of both genes. We found mutations in 26 of the 34 kindreds (76%) analyzed—54% were in ENG and 46% were in ACVRL1. Mutations in ACVRL1 cluster largely in exons 7 and 8, but ENG mutations were widely distributed within that gene. We found that epistaxis had an earlier onset in patients with HHT1 than those with HHT2, but the severity by middle ages was similar. Pulmonary arteriovenous malformations were more frequent and on the average of larger size in HHT1. Hepatic vascular malformations were more common in patients with HHT2. Cerebral arteriovenous malformations were more common in patients with HHT1, but spinal arteriovenous malformations were seen only in patients with HHT2. Truncating mutations in ENG were associated with more affected organs and more severe hemorrhaging than were missense mutations. We conclude that HHT2 has a later onset than HHT1 and the former may disproportionately involve smaller vessels in tissues with more significant vascular remodeling.

Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.

Abstract: Study Purpose: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process.

Clinical Outcomes of Patients after a Negative Spiral CT Pulmonary Arteriogram in the Evaluation of Acute Pulmonary Embolism

PURPOSE To examine 6-month clinical outcomes of patients after acquisition of a spiral computed tomography (CT) pulmonary arteriogram interpreted as negative for acute pulmonary embolism (PE). MATERIALS AND METHODS A retrospective review was performed on a consecutive series of 143 patients who underwent spiral CT pulmonary arteriography for possible acute PE during a 19-month period. All studies were performed on a HiSpeed Scanner with use of 3-mm collimation with a pitch between 1.3 and 2.0, depending on patient size. All imaging was performed during dynamic contrast material injection at rates between 3.0 and 4.0 mL/sec, timed to peak pulmonary arterial enhancement. For the studies interpreted as negative for PE through the segmental (fourth order) pulmonary arteries, follow-up data were collected by telephone interviews with patients or surviving relatives, and by medical record reviews. RESULTS Among 143 patients, 22 studies (15%) were positive for PE, eight (6%) were suboptimal to exclude PE to the segmental artery level, and 113 (79%) were interpreted as negative for acute PE. Among the 113 negative studies, 13 patients were lost to follow-up, leaving a study population of 100 patients. Eighty-one patients were alive a minimum of 6 months after acquisition of a negative spiral CT pulmonary arteriogram (mean, 9 months; range, 6-24 months) and were without interim diagnosis of PE. Nineteen patients died within the follow-up period after a negative spiral CT pulmonary arteriogram (mean, 3 months; range, 0-8 months); however, in none of these cases was acute pulmonary embolus reported as the cause of death. No documented PE was identified by subsequent imaging studies or autopsy within the study population. CONCLUSION A series of 100 patients with a negative spiral CT pulmonary arteriogram did not experience significant morbidity and mortality as a result of pulmonary embolic disease within a 6-month follow-up period.

Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred

HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 or 2. This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

Definitive radiation therapy in bile duct carcinoma

Between 1980 and 1985, 24 patients with primary adenocarcinoma of the bile duct were treated with various combinations of surgery, biliary intubation, external irradiation, and transcatheter brachytherapy. Seventy-five percent of tumors were in the proximal bile ducts. Ten patients received no or only palliative radiation, Group 1, whereas 14 patients received definitive courses of radiation (4 by external beam irradiation, 2 by transcatheter irradiation, and 8 by both modalities), Group 2. Survival in Group 1 and Group 2 was significantly different (p less than 0.005) with median survivals of 2.0 and 12.8 months, respectively. This result may be in part due to differences in treatment and in part due to selection bias because the series is small, uncontrolled, and retrospective. Median survival of the 8 patients treated with combined modalities was 13.2 months (range 7.4-30.3) with 4 patients alive 8.7 to 16.2 months, 3 without cholangiographic evidence of disease. Complications of therapy were common, including bacterial sepsis (58%), cholangitis (38%), gastrointestinal bleeding (46%), intra or extrahepatic abscesses (33%), and recurrent biliary obstruction (25%). Cholangitis, hemorrhage, abscesses, and ulcers appeared more frequently in definitively treated patients, whereas recurrent biliary obstruction was absent in this group and frequent in Group 1. Differences in complication rates between groups were not statistically significant. Early diagnosis and management usually reversed a downhill clinical course in patients with abscess and hemorrhage. Both surgical and percutaneous techniques of biliary decompression, the usual initial form of therapy in bile duct cancer, are associated with frequent and serious complications. Although many of our complications may have derived from biliary decompression, it is possible that definitive treatment may have increased the frequency of serious complications.

Insensitivity of color Doppler flow imaging for detection of acute calf deep venous thrombosis in asymptomatic postoperative patients.

PURPOSE Although color Doppler flow imaging (CDFI) has been shown to accurately depict calf vein thrombosis in symptomatic patients, this technique has not been proved accurate for detection of calf vein thrombosis in a population restricted to asymptomatic postoperative patients. PATIENTS AND METHODS To evaluate the accuracy of CDFI in asymptomatic postoperative patients, both CDFI and contrast venography were performed on 78 limbs of 76 patients without symptoms of deep venous thrombosis (DVT) who had undergone either hip or knee replacement. CDFI and venographic examination were interpreted blindly with respect to the results of the other modality or clinical findings. Venography was the standard for comparison of results. RESULTS Fifty-six percent of CDFI examinations of the calf vein were technically adequate. The remaining studies were compromised technically by limb swelling and/or obesity. For the technically adequate CDFI studies, calf vein thrombosis was detected in eight of 10 patients. Calculated sensitivity in this cohort was 80%, and specificity was 97%. The sensitivity of CDFI for acute calf DVT in all patients, regardless of image quality, was 42%. CONCLUSION These observations suggest that state-of-the-art CDFI is not an accurate examination for acute calf vein DVT in asymptomatic postoperative patients. CDFI is associated with a high rate of technically compromised studies and relatively low sensitivity in studies that are deemed technically satisfactory. These observations do not preclude the use of CDFI in postoperative patients for detection of thrombus extension into the popliteal vein or for detecting thrombosis of more proximal lower extremity veins.

Fatal outcome after embolotherapy for hepatic arteriovenous malformations of the liver in two patients with hereditary hemorrhagic telangiectasia.

JVIR 2000; 11:855–858 PATIENTS with hepatic arteriovenous malformation (AVM) associated with hereditary hemorrhagic telangiectasia (HHT) present with diverse clinical manifestations ranging from cirrhosis to cholestasis and multiple biliary strictures (1–4). Left-to-right shunting may also lead to abdominal pain, weight loss, high output heart failure, pulmonary hypertension, and encephalopathy (5– 12). Therapeutic options reported for symptomatic AVMs include hepatic artery embolization, ligation, or liver transplantation (12–15). Hepatic artery embolization is assumed to be low risk and of benefit based on favorable results seen in the treatment of hepatomas, liver metastases, and hemangiomas (13,16,17). Although embolization is effective in the treatment of pulmonary AVMs in patients with HHT (18), successful implementation of this approach for the more complex HHT liver lesions remains unproven. Several previous reports (including ours) support embolization of HHT-related hepatic AVMs (8–10,12–15,19). However, the utility, morbidity, and mortality of the procedure has not been critically evaluated. We report the deaths of two patients with HHT after hepatic AVM embolization to treat their high flow-related symptoms.

Hepatic Actinomycotic Abscesses: Diagnosis and Management

ctinomycosis is a chronic suppurative and granulomatous disease usually caused by Actinomyces israelii. It is normal flora of the oropharynx, gastrointestinal tract, and female genital tract; inoculation occurs with mucosal disruption. Although most manifest as abscesses in the cervicofacial region, reports of thoracic, abdominal, pelvic, and CNS actinomycosis exist. Intraabdominally, the ileocecal region is most frequently affected. Hepatic involvement has been reported in 15% of those with abdominal disease and represents 5% of all cases of actinomycosis [1]. Gram staining and microscopy can be helpful, with the latter showing pale yellow clusters of tangled filaments surrounded by neutrophils, known as sulfur granules. To culture this bacterium, strict anaerobic processing and semiselective media in the presence of carbon dioxide is required. Without previous suspicion of actinomycosis, cultures are unlikely to elucidate the cause. Treatment consists of penicillin and drainage of the abscesses. We report two cases of hepatic actinomycotic abscesses with contrasting features, one featuring an inferior vena cava (IVC) thrombus (presumed infected) and septic pulmonary emboli.

Percutaneous Nephrostomy for Nonoperative Management of Fungal Urinary Tract Infections

PURPOSE Percutaneous nephrostomy has proved to be an important modality in the nonoperative treatment of bacterial pyonephrosis. The role of this technique in the management of fungal pyonephrosis continues to evolve. The authors retrospectively reviewed their experience with percutaneous nephrostomy in the management of fungal pyonephrosis. PATIENTS AND METHODS Seven patients, two neonates and five adults, were identified with proved fungal infections. Eleven percutaneous nephrostomy tubes were placed, all with use of the Seldinger technique. RESULTS Percutaneous nephrostomy allowed (a) prompt microbiologic diagnosis of fungal infection (Candida albicans in six patients, Torulopsis glabrata in one); (b) urinary diversion with subsequent improvement in renal function, enabling systemic administration of potentially toxic antifungal drugs 5-fluorocytosine and amphotericin B (four patients); (c) local irrigation with amphotericin B (four patients), (d) guidewire fragmentation of fungus balls (two patients); and (e) introduction of a Simpson atherectomy device to obtain biopsy specimens from an obstructing ureteral polypoid lesion (one patient). The funguria was successfully eradicated in six patients, one of whom died on the 39th hospital day of a pulmonary embolus and another of whom died of extensive small bowel infarction during hospitalization. The one patient whose outcome of antifungal treatment remains unknown died at home with a functioning percutaneous nephrostomy 23 days after the procedure. CONCLUSION Percutaneous nephrostomy may play a role in the non-operative management of fungal urinary tract infection.