Correspondence

Ehlers–Danlos Syndrome Type IV

N Engl J Med 2000; 343:366-368August 3, 2000

Article

To the Editor:

As one of the medical advisers to the Ehlers–Danlos Support Group in Britain, I have examined and advised more than a dozen families with Ehlers–Danlos syndrome type IV. I would like to draw attention to a few clinical features that did not appear to be present in the large series of patients studied by Pepin et al. (March 9 issue).1 In my experience, teenage boys are at high risk for arterial rupture, which is often fatal. This may be because during the prepubertal growth spurt, the defective collagen is further weakened. In addition, patients who undergo surgery are prone to have arterial rupture in the postoperative period. This may be because of the increase in collagenase activity after surgical trauma.

Pepin et al. comment that preexisting aneurysms are only occasionally documented among those who have arterial ruptures. The reason, I believe, is that patients with Ehlers–Danlos syndrome type IV do not have true aneurysms. Aneurysms, if present, follow arterial tears and are walled-in hematomas or pseudoaneurysms.2 Finally, I would like to draw attention to the danger of varicose-vein surgery in unrecognized cases of Ehlers–Danlos syndrome type IV, since the extreme fragility of all blood vessels can lead to a loss of a limb or even loss of life.3 These tragic cases support Pepin and colleagues' suggestion that knowledge of the diagnosis prevents complications.

Andras Pal Barabas, M.D.
West Suffolk Hospital, Bury St. Edmunds IP33 2QZ, United Kingdom

3 References

1. 1

   Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000;342:673-680
   Full Text | Web of Science | Medline

2. 2

   Barabas AP. Ehlers–Danlos syndrome. In: Greenhalgh RM, Mannick JA, eds. The cause and management of aneurysms. London: W.B. Saunders, 1990:57-67.
   

3. 3

   Barabas AP. Vascular complications in the Ehlers-Danlos syndrome, with special reference to the “arterial type“ or Sack's syndrome. J Cardiovasc Surg (Torino) 1972;13:160-167
   Web of Science | Medline

To the Editor:

Pepin et al. describe a group of patients with Ehlers–Danlos syndrome type IV. In the accompanying editorial, Pyeritz states that “detecting the biochemical defect in Ehlers–Danlos syndrome type IV is simpler, more sensitive, and cheaper than finding a specific mutation in COL3A1.”1 We report a case in which the standard biochemical assay failed to detect abnormal type III collagen or procollagen but in which molecular testing revealed a mutation in the COL3A1 gene.

A 40-year-old man with a history of bilateral renal-artery stenosis and spontaneous hematothorax was admitted with possible appendicitis. Laparotomy revealed a pulseless ileocolic artery and an ischemic colon. Despite resection of the ischemic parts, the patient needed a second laparotomy, performed the next day, which revealed new intestinal ischemia, again necessitating resection. On the third day, another laparotomy was needed and revealed a ruptured abdominal aorta. A final laparotomy, which was performed on day 9, showed a ruptured gallbladder. Further surgical intervention was deemed futile, and the patient died on day 28 after admission.

The patient's family history was negative for the Ehlers–Danlos syndrome, and he had no skin or joint abnormalities. Reevaluation of intestinal and renal specimens obtained earlier revealed necrotic degeneration of the vascular wall, aneurysms, and medial degeneration. A fibroblast culture was performed, but the electrophoretic mobility of type III collagen and the ratio of type III to type I collagen were normal (Figure 1AFigure 1Analysis of Collagen and Sequencing of Complementary DNA.). Analysis of complementary DNA (cDNA) revealed that the eighth exon of the COL3A1 gene was missing in 50 percent of the messenger RNA (mRNA) (Figure 1B) as a result of a base substitution in intron 8 (+5G→A). The normal appearance of type III collagen may be due to the fact that skipping exon 8 results in a shorter protein and not a shift in the reading frame. The formation of the triple helix is hampered, but the mutation is close to the N-terminal end and does not result in overmodification.

This case demonstrates that the standard biochemical assay for Ehlers–Danlos syndrome type IV may produce false negative results and that a search for a COL3A1 mutation can be diagnostic. Therefore, we would like to caution against the suggestion that molecular testing is of limited value in the diagnosis of Ehlers–Danlos syndrome type IV, since it can identify additional cases that may be missed by the biochemical assay.

Yigal M. Pinto, M.D., Ph.D.
University Hospital Groningen, 9713 GZ Groningen, the Netherlands

Gerard Pals, Ph.D.
University Hospital Vrije Universiteit, 1081 HV Amsterdam, the Netherlands

Jan G. Zijlstra, M.D., Ph.D.
Jaap E. Tulleken, M.D., Ph.D.
University Hospital Groningen, 9713 GZ Groningen, the Netherlands

1 References

1. 1

   Pyeritz RE. Ehlers-Danlos syndrome. N Engl J Med 2000;342:730-732
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The vascular type of the Ehlers–Danlos syndrome, also known as Ehlers–Danlos syndrome type IV and the Sack–Barabas variety, does affect young people adversely. In our study, male index patients were more likely than female index patients to have vascular rupture as their first complication (as shown in Table 1 of our article). Among those with vascular first complications for whom ages were known, 21 male subjects (35 percent) and 10 female subjects (34 percent) were 20 years of age or younger. Three male subjects and one female subject 20 years of age or younger died as a result of the initial arterial complication. In the entire cohort we studied, vascular events were the most common cause of death in subjects of both sexes (Table 2 of our article). We agree with Barabas that complications often come in rapid succession and that surgery in patients not known to have the disorder can be fraught with difficulty.

We sympathize with the difficulties encountered by Pinto et al. in identifying persons with splice-site mutations that affect introns near the 5' end of the triple-helix coding region. We found that the subtle shift in mobility of α1 (III) chains in gels is more readily apparent when the pro-α1 (III) chains in molecules secreted into the medium of cultured cells are examined under reducing conditions. If the clinical findings are compatible, this shift is sufficient to confirm the diagnosis.

We agree that molecular analysis, either with the use of cDNA synthesized from RNA or by analysis of individual exons amplified from genomic DNA, occasionally is a valuable adjunct to diagnosis. Two of the patients in our series had the same mutation that Pinto et al. describe (IVS8+5G→A). In addition, three had mutations that resulted in the skipping of exon 7 (IVS7+1G→C in two and a complex rearrangement of the same donor site in the third), and three had mutations in which exon 9 was skipped (IVS9+1G→A, IVS9+2T→G, and IVS9+2T→A). All had subtle but detectable shifts in the electrophoretic mobilities of the pro-α1 (III) chains or in the efficiency of secretion of the molecules. More difficult to detect at the protein level are mutations that result in premature-termination codons in the COL3A1 transcript and that destabilize the mRNA. These mutations reduce the amount of type III procollagen produced to about half the normal level, a difference that may be difficult to appreciate. In such cases, the analysis of heterozygosity for expressed polymorphic sequences in genomic DNA and in RNA is a valuable adjunct to diagnosis.

Peter H. Byers, M.D.
Ulrike Schwarze, M.D.
Melanie Pepin, M.S., C.G.C.
University of Washington, Seattle, WA 98195

Author/Editor Response

My experience with patients affected by the vascular form of the Ehlers–Danlos syndrome confirms several of the clinical issues raised by Barabas and by Pinto et al. First, rupture of a large artery or a viscus and major surgery seemingly unleash factors that contribute to further disruption of connective tissue. This process requires investigation so that measures in addition to surgery can be undertaken to reduce morbidity and mortality. Second, arteries usually rupture without antecedent dilatation or dissection, and except for trauma, the precipitants are unknown. Finally, arterial rupture may be stabilized by the formation of a pseudoaneurysm, and in such cases careful observation rather than aggressive treatment may be the better part of valor.1

Pinto and colleagues suggest that not all defects in type III procollagen may be detectable in all biochemical genetics laboratories. This is true in theory, but in practice most failures to detect alterations at the level of the protein in patients with the vascular form of the Ehlers–Danlos syndrome probably occur for a variety of technical reasons. Analysis at the level of the mRNA or of the gene sequence may be of additional value, for example, to detect a mutation, to establish linkage, or to determine whether both alleles are being expressed. Unfortunately, at this time, no laboratory in the United States performs analyses of the genes of interest as a clinical service.

Reed E. Pyeritz, M.D., Ph.D.
MCP Hahnemann School of Medicine, Pittsburgh, PA 15212

1 References

1. 1

   Pyeritz RE, Stolle CA, Parfrey NA, Myers JC. Ehlers-Danlos syndrome IV due to a novel defect in type III procollagen. Am J Med Genet 1984;19:607-622
   CrossRef | Web of Science | Medline

Citing Articles (7)

Citing Articles

1. 1

   S. W. Hetts, J. D. English, C. F. Dowd, R. T. Higashida, J. T. Scanlon, V. V. Halbach. (2011) Pediatric Intracranial Aneurysms: New and Enlarging Aneurysms after Index Aneurysm Treatment or Observation. American Journal of Neuroradiology
   CrossRef

2. 2

   Philippe Charlier, Dominique P. Germain, Xavier Jeunemaître, Stanislas Grassyn Delisle, Jean-Claude Alvarez, Geoffroy Lorin de la Grandmaison. (2011) Sudden death associated to vascular Ehlers–Danlos syndrome. A case report. Legal Medicine 13:3, 145-147
   CrossRef

3. 3

   Eduardo J. Mortani Barbosa, Reed E. Pyeritz, Harold Litt, Benoit Desjardins. (2011) Vascular Ehlers-Danlos syndrome presenting as rapidly progressive multiple arterial aneurysms and dissections. American Journal of Medical Genetics Part An/a-n/a
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4. 4

   Atsushi Watanabe, Tomoki Kosho, Takahiro Wada, Noriyasu Sakai, Mitsuo Fujimoto, Yoshimitsu Fukushima, Takashi Shimada. (2007) Genetic Aspects of the Vascular Type of Ehlers-Danlos Syndrome (vEDS, EDSIV) in Japan. Circulation Journal 71:2, 261-265
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5. 5

   Gustavo S. Oderich, Jean M. Panneton, Thomas C. Bower, Noralane M. Lindor, Kenneth J. Cherry, Audra A. Noel, Manju Kalra, Timothy Sullivan, Peter Gloviczki. (2005) The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: A 30-year experience. Journal of Vascular Surgery 42:1, 98-106
   CrossRef

6. 6

   HY Kroes, G Pals, AJ Van Essen. (2003) Ehlers-Danlos syndrome type IV: unusual congenital anomalies in a mother and son with a COL3A1 mutation and a normal collagen III protein profile. Clinical Genetics 63:3, 224-227
   CrossRef

7. 7

   B.T. Müller, O. Modlich, H.B. Prisack, H. Bojar, J.D. Schipke, T. Goecke, P. Feindt, T. Petzold, E. Gams, W. Müller, W. Hort, W. Sandmann. (2002) Gene Expression Profiles in the Acutely Dissected Human Aorta. European Journal of Vascular and Endovascular Surgery 24:4, 356-364
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