J Korean Med Sci.  2007 Aug;22(4):698-705. 10.3346/jkms.2007.22.4.698.

Genetic Analysis of Three Korean Patients with Clinical Features of Ehlers-Danlos Syndrome Type IV

Affiliations
  • 1Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. dkkim@smc.samsung.co.kr
  • 2Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 3Garak High School, Seoul, Korea.
  • 4Department of Cardiology, Konkuk University, College of Medicine, Seoul, Korea.

Abstract

Ehlers-Danlos syndrome (EDS) is a hereditary disorder of the connective tissue. EDS type IV (EDS IV), the vascular type of the disease, is characterized by easy bruising, thin skin with visible veins, and spontaneous rupture of the large arteries, uterus, or bowel. EDS IV is caused by mutations in the gene for type III procollagen (COL3A1). However, recent studies suggest that the causative mutation of EDS IV is not homogeneous. We report our experience with three patients presenting with clinical features of type IV EDS. A 48-yr-old woman presented with acute aortic dissection (patient 1) and 36-yr-old and 21-yr-old women presented with carotidcavernous fistula (patients 2 and 3, respectively). All three patients bruised easily. Two patients (patients 1 and 3) had thin transparent skin with visible veins. Genetic analysis of COL3A1 revealed a Gly732Val (c.2195G>T) mutation in patient 1 and a duplication of 15 base pairs (c.3221_3235dup) which resulted in an interposition of five amino acids (p.Gly1074_Pro1078dup) in patient 2. However, no mutations were observed in COL3A1 or transforming growth factor beta receptors 1 and 2 in patients 3, which might be either due to a deletion of single or multiple exons in the COL3A1 gene or due to a genetic heterogeneity. This is the first report of genetically confirmed cases of EDS IV in Korea.

Keyword

Ehlers-Danlos Syndrome Type IV; COL3A1; Mutation; Dissection; Carotid-cavernous Sinus Fistula

MeSH Terms

Adult
Aged
Amino Acid Sequence
Base Sequence
Collagen Type III/*genetics
DNA Mutational Analysis
Ehlers-Danlos Syndrome/*genetics/*pathology
Female
Genetic Heterogeneity
Humans
Korea
Male
Molecular Sequence Data
*Mutation
Pedigree
Tomography, X-Ray Computed

Figure

  • Fig. 1 (A) The patient's skin was very thin with visible vessels over the upper thorax. A minor trauma caused by the detachment of the electrocardiographic electrode elicited excessive bruising. (B, C). The patient's skin over the hands and feet was thin and finely wrinkled (acrogeria). Equinus deformity was noted in both feet. (D) An radiography of the hands showed osteoporosis and absorption of the midshafts of the finger bones (acroosteolysis).

  • Fig. 2 Computed tomography (CT) of the thoracoabdominal aorta. (A, B) Initial CT demonstrated aortic dissection, which involved the abdominal aorta and spared the thoracic aorta. (C and D) Seven days later, the dissection showed retrograde progression and rupture, which produced hemoperitoneum (*), retroperitoneal hemorrhage (**), and hemothorax (***). Intramural hematoma was noted in the descending thoracic aorta (D).

  • Fig. 3 Pedigrees of the families. Squares indicate male family members, circles indicate female family members, and symbols with slashes indicate deceased family members. Open symbols indicate unaffected family members, filled symbols indicate probands, and shaded symbols indicate family members who are or were probably affected. (A) patient 1, (B) patient 2, (C) patient 3.

  • Fig. 4 Direct sequencing of COL3A1 gene revealed a G-to-T transition at cDNA position 2195 (arrow; c.2195G>T) resulting in a Gly732Val missense mutation. Wild type alleles in her siblings suggested a de novo mutation.

  • Fig. 5 (A) The skin showed a bruise at the trauma site. (B) The patient's foot showed chronic dislocation of the first metatarsal joint. (C) The patient had mild hyperextensibility of the fingers. (D) Left internal carotid angiogram, lateral view, showed a high-flow, direct carotid-cavernous fistula in the early arterial phase (arrow).

  • Fig. 6 Direct sequencing of the COL3A1 gene revealed a duplication of 15 base pairs (c.3221_3235dup), which results in an interposition of five amino acids (p.Gly1074_Pro1078dup). The duplicated segment of nucleotides and amino acids in mutant allele and its original position in normal allele were marked in bold characters. The critical glycine residues were marked in gray square boxes. The solid arrow points to the additional interposed amino acids, and the open arrow indicates a subsequently formed repeat unit composed of only two amino acids (Gly-X).

  • Fig. 7 (A) The patient's skin over the upper thorax was very thin and translucent with visible vessels. (B) The patient's skin showed a bruise and visible veins in the leg. (C) Left internal carotid angiogram, lateral view, showed a high-flow, direct carotid-cavernous fistula in the early arterial phase (arrow) and an aneurysm in the cervical portion of the left internal carotid artery (arrowhead). (D) A computed tomography scan demonstrated a large ovoid aneurysm of the left renal artery (arrow) and a medium-sized aneurysm of the splenic artery (arrowhead).


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