Letter to the Editor: Spontaneous Colon Perforation in Ehlers-Danlos Syndrome Type IV Caused by a Novel,Spontaneous,De novo Mutation of COL3A1

To the Editor:

Clinicians recognize common causes of colon perforation, including diverticulitis, obstruction, pseudo-obstruction (ileus), iatrogenesis, ischemia, megacolon, and neoplasia. ¹ On occasion, patients present with an unusual etiology. We describe a perforation associated with colonic elastosis, resulting in a new diagnosis of Ehlers-Danlos syndrome type IV (EDS-IV) that was associated with a previously unreported, de novo genetic mutation.

A 35-year-old male presented with peritonitis. Imaging suggested colon perforation, and a 1-cm splenic artery aneurysm was noted incidentally. The patient underwent midline abdominal exploration. Almost immediately, extreme tissue fragility was apparent, manifested by a 30-cm laceration of small bowel mesentery during routine exposure, which was repaired with minimal blood loss. A 5-mm perforation of the antimesenteric border of the sigmoid colon was noted with minimal induration. Sigmoidectomy was performed with creation of an end-sigmoid colostomy and Hartmann pouch at mid-rectum. Recovery was uneventful, including wound healing. Pathology was remarkable for elastosis; there was no diverticulosis coli.

In retrospect, the patient reported episodic abdominal pain since childhood. At one point, a gastric emptying study had revealed marked dysmotility. There was “easy bruising” but no history of joint pain or dislocations, nor family history of connective tissue disorder. The patient was referred for detailed evaluation. Echocardiography was normal, as was ophthalmic evaluation. Serial cross-sectional imaging revealed the splenic aneurysm to be unchanged, and no other vascular lesions.

Genetic testing (University of Washington, Laboratory for Precision Diagnostics-Collagen Diagnostic Laboratory) revealed EDS-IV (vascular EDS [vEDS]). A single allele located at 2q32.2 harbored genotype COL3A1 (c.1124G>T) denoted p.Gly381Val, which was unknown to the laboratory and not listed in the Database of Collagen Mutations (now the Leiden Open Variations Database). Genetic counseling was obtained for his family. His parents tested negative, so the mutation was de novo. One of his four children, a female, harbors the mutation.

Coloproctostomy with a hand-sewn, two-layer anastomosis four months later was notable for adhesions and extreme fragility of small bowel, but recovery was again uneventful. The patient has had no intestinal or vascular complications during eight-year follow-up.

Ehlers-Danlos syndrome type IV is characterized by thin, translucent skin with visible veins; marked bruising; joint dislocations; and the major complications of arterial (aneurysmal), intestinal, or uterine rupture.^2–4 In addition to tissue fragility, both neoplasia and spontaneous perforation of the gastrointestinal tract, usually colon,^5–7 are recognized.

Among 14 known variations of EDS, the molecular basis is understood for 13.^2,3 Mutation of COL3A1 is specific to EDS-IV. COL3A1 encodes the three pro-alpha1 chains of type III collagen of extensible connective tissues (e.g., skin, lung, uterus, intestine, blood vessels). ⁸ Most of the glycine mutations express collagen with reduced thermal stability, which is more susceptible to proteinases. This report is novel for its description of a unique amino acid substitution not described heretofore.

The diagnosis was unknown at the time of presentation, so sigmoid colectomy with end-colostomy and Hartmann pouch were performed with subsequent re-anastomosis. Re-perforation may occur with this approach, especially in males. There is high risk for anastomotic dehiscence after restoration of bowel continuity^9–11 ; total abdominal colectomy with end-ileostomy or ileo-proctostomy may be advisable when EDS-IV is known.^10,11