Correspondence
Hereditary Hemorrhagic Telangiectasia
N Engl J Med 1996; 334:330-332February 1, 1996
- Article
To the Editor:
With respect to the review of hereditary hemorrhagic telangiectasia by Guttmacher et al. (Oct. 5 issue),1 we would like to highlight some additional points in the recognition and management of this condition. A hallmark of hereditary hemorrhagic telangiectasia is profound variation in severity between members of the same family. In one family with a mutation in the endoglin gene,2 manifestations ranged from mild disease that was barely apparent clinically to severe visceral involvement. We have also seen families in which the disease is minor in multiple generations before being manifested as pulmonary arteriovenous malformations in one member in childhood. The phenotypic variation is not well understood; the underlying mutation cannot be solely responsible. One factor appears to be phenotypic modification by the female hormones, which may help in the treatment of hemorrhage,3 but may adversely affect disease progression, particularly in the lungs. There is a female predominance of pulmonary arteriovenous malformations, and deterioration in the vascular bed may occur with pregnancy.4 Furthermore, pulmonary arteriovenous malformations are not restricted to families with mutations in the endoglin gene2 (and unpublished observations).
These findings have implications for clinical screening of families with hereditary hemorrhagic telangiectasia, because no affected member can be assumed a priori not to have a pulmonary arteriovenous malformation. Clinical suspicion of pulmonary arteriovenous malformations stems from a history not just of stroke or cerebral abscess, but more often of multiple transient ischemic attacks, which may have been forgotten or dismissed by the patient. All those at risk in a family should be screened for pulmonary arteriovenous malformations once in childhood, once after puberty, before pregnancy, and then at 10-year intervals. Screening can be done inexpensively and safely with a method such as pulse oximetry (performed for 10 minutes each with the subject in the standing and supine positions) in conjunction with posteroanterior and lateral chest x-ray films.5 Suspicious results should lead to more extensive investigations with albumin microspheres labeled with technetium -99m, lung and kidney scanning, or contrast echocardiography.5 A policy of five-year follow-up of all persons with pulmonary arteriovenous malformations by means of helical computed tomography (CT), as suggested by Guttmacher et al.,1 would be very expensive and would expose young people to too much radiation. There are simpler, safer, and cheaper alternatives.
5 ReferencesClaire L. Shovlin, M.A., M.R.C.P.
Harvard Medical School, Boston, MA 02115J.M.B. Hughes, D.M., F.R.C.P.
Hammersmith Hospital, London W12 0NN, United Kingdom1
Guttmacher AE ,Marchuk DA ,White RI Jr . Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918-924
Full Text | Web of Science | Medline2
Shovlin CL ,Hughes JMB ,Tuddenham EGD , et al. A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 1994;6:205-209
CrossRef | Web of Science | Medline3
Van Cutsem E . Oestrogen-progesterone, a new therapy of bleeding gastrointestinal vascular malformations. Acta Gastroenterol Belg 1993;56:2-10
Web of Science | Medline4
Shovlin CL ,Winstock AR ,Peters AM ,Jackson JE ,Hughes JMB . Medical complications of pregnancy in hereditary haemorrhagic telangiectasia. Q J Med 1995;88:879-8875
Chilvers ER ,Whyte MK ,Jackson JE ,Allison DJ ,Hughes JM . Effect of percutaneous transcatheter embolization on pulmonary function, right-to-left shunt, and arterial oxygenation in patients with pulmonary arteriovenous malformations. Am Rev Respir Dis 1990;142:420-425
Web of Science | Medline
To the Editor:
We are currently screening all members of families with hereditary hemorrhagic telangiectasia in the Danish county of Funen (500,000 inhabitants) for the presence of pulmonary arteriovenous malformations. The prevalence of hereditary hemorrhagic telangiectasia in Funen is 1.38 per 10,000.1 All participants are clinically examined for the presence of telangiectatic lesions, and pulse oximetry with subjects in the supine and standing positions is performed. If hereditary hemorrhagic telangiectasia is diagnosed or if the oxygen saturation in either position is below 96 percent, contrast echocardiography is performed. Our preliminary data suggest that pulmonary arteriovenous malformation can be present in patients with normal oxygen saturation. Among 11 patients with untreated pulmonary arteriovenous malformations verified by contrast echocardiography, 6 had oxygen-saturation values >96 percent in the supine as well as the standing position.
Screening for the presence of pulmonary arteriovenous malformation is recommended in late childhood and again at the end of adolescence. The pulmonary arteriovenous malformations are usually diagnosed in young age groups and have not been found as the first symptom of hereditary hemorrhagic telangiectasia in older patients. In our study we have found one 64-year-old man who was classified as not having hereditary hemorrhagic telangiectasia on clinical examination. Because there was a history of a transient ischemic attack and low values were found on pulse oximetry (oxygen saturation, 94 percent in the supine position and 95 percent in the standing position), contrast echocardiography was performed and showed a pulmonary arteriovenous malformation. The patient's father had hereditary hemorrhagic telangiectasia in a very mild form, without signs of pulmonary arteriovenous malformation on contrast echocardiography, whereas two uncles and two aunts had pulmonary arteriovenous malformations with severe symptoms.2 This particular case is of interest because the patient had no history of either epistaxis or gastrointestinal bleeding. On clinical examination he only had a few telangiectatic lesions on the trunk and none at the typical sites, such as the nose, lips, mouth, conjunctivae, or fingers.
Our findings suggest that contrast echocardiography is a safe and sensitive method for the diagnosis of pulmonary arteriovenous malformations. The method should be used when there are broad indications, especially in persons with a family history of hereditary hemorrhagic telangiectasia with a high prevalence of pulmonary arteriovenous malformations.
2 ReferencesAnette D. Kjeldsen, M.D.
Poul Vase, M.D., Ph.D.
Svendborg Hospital, 5700 Svendborg, DenmarkHenrik Oxhøj, M.D., Ph.D.
Odense University Hospital, 5000 Odense C, Denmark1
Vase P. Telangiectasia haemorrhagica hereditaria Mb. Osler: en epidemiologisk, genetisk og klinisk undersøgelse. (Thesis. Odense, Denmark: Odense University, 1988.)
2
Vase P ,Holm M ,Arendrup H . Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand 1985;218:105-109
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Author/Editor Response
The authors reply:
To the Editor: Drs. Shovlin and Hughes highlight the profound variations within families in manifestations of hereditary hemorrhagic telangiectasia, as well as the serious complications sometimes seen with pregnancy. Determining whether the causes of such variations and complications are hormonal, genetic, or environmental (or some combination of the three) will be critical to a full understanding of this condition.
Although pulmonary arteriovenous malformations can occur in anyone with hereditary hemorrhagic telangiectasia, they are significantly more common in those in whom the disease is due to a mutation in the endoglin gene than in those whose disease is due to mutations in other genes.1 Thus, we believe that variations among families are also crucial and that clinicians need to be more aggressive in screening for these malformations in families in which hereditary hemorrhagic telangiectasia is linked to the endoglin gene.
The question of how best to screen for pulmonary arteriovenous malformations is complex. Kjeldsen et al. point out that pulse oximetry can be a helpful tool when the results are positive, but it misses a substantial number of these lesions. This has been our experience as well. More sensitive screening methods include contrast echocardiography,2 shunt studies involving albumin microspheres labeled with technetium-99m,3 and high-resolution helical CT without contrast medium.4 Of these, both shunt studies and CT have the disadvantage of involving exposure to radiation (at similar levels in each). However, CT is the most widely available method and the best at determining which lesions are clinically important.4
Follow-up with helical CT is expensive and poses a risk from radiation exposure. However, many patients with a history of a pulmonary arteriovenous malformation due to hereditary hemorrhagic telangiectasia have small, untreated malformations that are growing.5 Because these lesions may grow sufficiently to lead to such complications as brain abscess or stroke, in our view they warrant follow-up with techniques that are more sensitive than positional oximetry and that can detect the lesions before they become large enough to cause neurologic sequelae.
The current debate about screening for pulmonary arteriovenous malformations underscores the point that it is impossible to define optimal practice for a number of aspects of hereditary hemorrhagic telangiectasia without rigorous prospective trials. Although such trials are often important in common disorders, they are particularly necessary for conditions that both are rare and exhibit genetic heterogeneity. Until rigorous prospective studies are conducted of hereditary hemorrhagic telangiectasia, reasonable and experienced people will continue to disagree about a number of areas of diagnosis and management for this family of conditions.
5 ReferencesAlan E. Guttmacher, M.D.
University of Vermont, Burlington, VT 05401Douglas A. Marchuk, Ph.D.
Duke University, Durham, NC 27710Robert I. White, Jr., M.D.
Yale University, New Haven, CT 06520-80421
Berg JN, Guttmacher AE, Marchuk DA, Porteous MBM. Clinical heterogeneity in hereditary haemorrhagic telangiectasia: are pulmonary arteriovenous malformations more common in families linked to endoglin? J Med Genet (in press).
2
Barzilai B ,Waggoner AD ,Spessert C ,Picus D ,Goodenberger D . Two-dimensional echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol 1991;68:1507-1510
CrossRef | Web of Science | Medline3
Whyte MK ,Peters AM ,Hughes JM , et al. Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations. Thorax 1992;47:790-796
CrossRef | Web of Science | Medline4
White RI Jr ,Pollak JS . Pulmonary arteriovenous malformations: diagnosis with three-dimensional helical CT -- a breakthrough without contrast media. Radiology 1994;191:613-614
Web of Science | Medline5
Vase P ,Holm M ,Arendrup H . Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand 1985;218:105-109
CrossRef | Web of Science | Medline
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