Unusual Presentation of Vascular Ehlers Danlos Syndrome in a Pediatric Patient

Institutional review board approval as an exempt study was obtained before review of medical records or production of this case report (#10854). The patient is an otherwise healthy 15-year-old male who developed sudden, severe abdominal pain after throwing a baseball. He denied any trauma before the onset of pain, which was exacerbated by running. He admitted to some intermittent abdominal pain in the past but never as significant and debilitating as the current episode. He initially presented to a community hospital where a computed tomography of the abdomen/pelvis revealed large hematomas at the left rectus muscle, as well as pelvic and retroperitoneal hematomas (Figs 1 and 2). His symptoms were considered consistent with these imaging findings and not felt to be incidental. He was transferred to our pediatric quaternary referral center for further care.

His past surgical history included a circumcision, as well as bilateral inguinal hernia repair. There was no known excessive bleeding during or after these procedures. Initially, his family denied any previous signs or symptoms of CTDs or concern for bleeding disorders. Later in the hospital course, they did recall some easy bruising and hyperextensibility, which they described as being “knocked kneed” and “double jointed.” There was no history of joint dislocations or prolonged/irregular bleeding.

Upon arrival to Riley Hospital for Children at Indiana University Health, laboratories were obtained including complete blood count, comprehensive metabolic panel, prothrombin time (PT), partial prothrombin time (PTT), and international normalized ratio (INR); PT/PTT within normal limits, INR 1.1, platelet 350 k/cumm. Although the basic screening workup for bleeding disorders often includes bleeding time and thrombin time,¹  these were not pursued at the time given the lack of history of frequent bleeding and the normal laboratory testing. On exam, he demonstrated hyperextensibility of both elbows and knees, with the ability to touch his thumbs to his forearms. He was admitted to the pediatric general surgery service for serial abdominal examinations and hemoglobin (hgb) trending. His initial hgb was 10.8 mg/dL, which decreased to 8.5 mg/dL 24 hours later. He remained hemodynamically stable and never required transfusion. He progressed well with resolution of the pain. His hgb rose without intervention to 9.6 mg/dL on hospital day 4 and he was discharged from the hospital.

The differential included CTD and vascular malformation given the lack of trauma history. We felt we could not evaluate for a malformation until the hematoma resolved. The genetic medicine team was consulted regarding the possibility of CTD. A thorough review of family history did not reveal any previous spontaneous bleeding, organ rupture, or concern for CTD. His genetics workup included an expanded CTD panel (evaluating ACTA2, BGN, CBS, COLA3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, LOX, MAT2A, MED12, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD2, SMAD3, SMAD4, TGFB2, TGFB3, TGFBR1, TGFBR2), as well as MRI of the abdomen, magnetic resonance angiography of the brain, and echocardiogram. He was found to have a heterozygous variant in COL3A1, located at 2q31-q32, leading to haploinsufficiency and detrimental defects.²  This 36-base pair deletion at exon 39 (c.2685_2720del36:p.Ser896_pro907 del) is predicted to disrupt normal protein folding and function in the triple helical domain, consistent with vEDS. To our knowledge, other family members declined genetic testing.

Our patient presented with spontaneous intramuscular/pelvic hematomas. The differential diagnosis for a hematoma may include trauma, vascular malformation, bleeding disorders, and CTD such as EDS. There was no history of significant trauma that would explain the radiographic findings and the patient’s signs and symptoms. Although the workup did not suggest a bleeding disorder given normal PT, PTT, INR, and platelets, in hindsight, the screening for an underlying bleeding disorder may have been inadequate. Increased propensity for bleeding/bruising is common in EDS patients,³  with some studies suggesting increased bleeding severity scores⁴  and platelet dysfunction.⁵  Our patient did not have significant history of bleeding to prompt an increased level of concern for a bleeding or platelet dysfunction-related disorder. His symptoms plus radiographic and physical examination findings seemed to correlate best with a CTD such as vEDS. This was similar to a previously published report of an intramuscular hematoma of the left calf after “trivial trauma” in a 14-year-old male who was then found to have EDS⁶ ; however, the precipitating event and history were more subtle in our case.

Pain, bruising, lacerations, orthopedic fractures, and soft tissue swelling are all very common complaints in the pediatric emergency department. However, these injuries or findings are usually accompanied by a history of recent trauma or other plausible explanation. Although nonaccidental trauma should always be considered in instances where injury patterns are not concordant with the story of trauma/injury, especially in children aged <4 years, EDS may warrant consideration. There have been several case reports of misdiagnosed child abuse in the setting of EDS.⁷  Initial evaluation of a child with injuries out of proportion to provided history should involve screening for physical abuse, accompanied by an appropriate workup. Previous studies have demonstrated that a standardized and focused approach to evaluate a child in whom nonaccidental trauma may have occurred has shown improvement in detecting such abuse.⁸ 

If an underlaying CTD is considered in the differential diagnosis, providers may consider starting their evaluation using the Beighton Score. This 9-point scoring system is based on a patient’s ability to perform certain maneuvers associated with the generalized joint hypermobility often found in CTDs. The Beighton Score has been validated in children as young as 6 years and was created using findings in 8 joints.⁹  These maneuvers described in Table 1 can easily be completed on initial examination to assess for the possibility of EDS. Previous studies have shown a score >5 is associated with the diagnosis of EDS.³  The Beighton Score provides basic screening and has been shown to have a high specificity but low sensitivity in evaluating generalized joint hypermobility.¹⁰ 

In 1986, the International Congress of Human Genetics met in Berlin, often referred to as the Berlin Nosology, to discuss various heritable CTDs. At that time, 11 subtypes of EDS were recognized.¹¹  This has evolved into the most recent classification with 13 subtypes according to the 2017 International Classification. EDS has been described to have inheritance patterns of autosomal dominant and recessive; several of which have proven genetic links to various collagen genes.¹²  Results of genetic testing in combination with clinical features, beyond that of joint hypermobility, skin hyperextensibility, and tissue fragility, assist in further classifying EDS subtypes (Table 2). Our patient was found to have a deletion-related COL3A1 variant, but there are >600 known genetic variants associated with vEDS. This can range from single amino acid substitutions to exon skipping, as well as changes in splice sites and deletions.¹³  All these variants lead to alterations in the structure of type III collagen, resulting in vEDS.

Patients with vEDS are at increased risk of spontaneous vascular rupture or dissection. Unexplained rupture of bowel, uterus, and other organs, as well as development of spontaneous pneumothorax, have also been recognized as sequalae of the disorder. The majority of individuals will be diagnosed before the age of 18 years given positive family history or after experiencing a major complication (spontaneous ruptures as discussed above).¹⁴  When a child experiences 1 of these adverse events without evidence of trauma or other causative etiology, such as the spontaneous large intramuscular hematoma in our patient, the diagnosis of EDS should be considered. The presence of tissue fragility that contributes to these adverse events is associated with significant morbidity and mortality. Diagnosis of this disorder allows for lifestyle recommendations/modifications and surveillance. Blood pressure control has been shown to minimize or delay development of arterial dissections and/or ruptures. Antihypertensive agents such as β blockers are often initiated,¹⁵  as we did for our patient. He was started on, and has continued, carvedilol, with close follow-up with cardiology. Serial echocardiograms, as well as magnetic resonance angiography, are often used, though no formal imaging surveillance recommendations are in place. The interval at which studies are obtained are often dependent upon pathology, extent of disease, and provider, with studies suggesting 18-month intervals as the current usual practice¹⁵ .

We describe a case of vEDS in a pediatric patient found to have multiple hematomas without history of recent trauma. The diagnosis of EDS, or other CTD, requires a high degree of clinical suspicion, especially when not accompanied with family history of CTDs. Providers should be aware that, although EDS is associated with joint hypermobility, skin hyperextensibility, and tissue fragility, these findings may be subtle and often overlooked by patients and their families. CTD may be broad and nonspecific, allowing them to be mistaken for other conditions including nonaccidental trauma. Patients presenting with tissue injury or organ rupture without a supporting history of trauma or other causative history should prompt consideration of underlying CTD.

EDS

Ehlers Danlos syndrome

CTD

connective tissue disorder

PT

prothrombin time

PTT

partial thromboplastin time

INR

international normalized ratio

Hgb

hemoglobin

vEDS

vascular Ehlers Danlos syndrome