Gardner-Diamond syndrome

What is Gardner-Diamond syndrome?

Gardner-Diamond syndrome (GDS) is an uncommon psychodermatological condition characterised by painful purpura, ranging in size from small petechiae to purpura to larger patches of ecchymosis. While it may appear spontaneous in some instances, a thorough history frequently reveals a preceding episode of severe physiological stress.

Gardner-Diamond syndrome is also known as psychogenic purpura, autoerythrocyte sensitisation, and painful purpura or bruising syndrome. Initial reports linking psychological manifestations with painful skin haemorrhage or purpura date to the late 1920s. Gardner and Diamond are credited eponymously following their case series of four patients with GDS in 1955.

Who gets Gardner-Diamond syndrome?

The prevalence of GDS is thought to be very rare. However, epidemiologic data are limited to case reports and small case series, including one from a hospital in the United States that reported 76 cases over a period of 40 years.

GDS most commonly occurs in young adult women with underlying mental health concerns or following an episode of severe physiological or psychological stress; it has also been reported in men and adolescents. Antecedent stressful life events have been reported as risk factors.

Concurrent psychiatric illnesses are more common among GDS patients than in the general population and include:

• Major depression
• Anxiety disorders
• Dissociative disorder
• Personality disorders
• Post-traumatic stress disorder.

What causes Gardner-Diamond syndrome?

The pathophysiology of GDS is poorly understood. Several hypotheses have been proposed, including the potential for psychological stress to derange hemostatic factors (such as to induce the production of endogenous glucocorticoids or antifibrinolytic proteins or to disrupt platelets), thereby leading to bleeding under the skin.

Gardner and Diamond initially proposed a possible mechanism for GDS (termed "autoerythrocyte sensitisation") in which there is increased sensitivity to extravasated red blood cells, resulting in painful purpura. Indeed, there is some indirect immunofluorescence data to suggest that autosensitisation to phosphatidylserine (a phosphoglyceride of the red blood cell membrane) may be involved in the pathogenesis of GDS. However, this theory remains debatable.

Furthermore, it remains uncertain if GDS is a distinct clinical entity rather than the resulting manifestation of multiple different pathophysiologies.

What are the clinical features of Gardner-Diamond syndrome?

It is typical for GDS to have a relapsing and remitting course with variable intervals between painful occurrences. While the limbs and trunk are the most common sites, GDS lesions can occur anywhere on the body and most commonly appear after trauma or surgery, but can also be atraumatic in origin. Severe emotional disturbance is frequently present.

Fatigue and malaise are common during the prodromal phase. Skin lesions are usually preceded by burning, itching, a stinging sensation or pain, followed by cutaneous induration after a few hours. With time, the lesions can enlarge and become oedematous, erythematous, and frequently very painful. There is no typical bruising pattern that characterises GDS.

The intensity of pain and oedema can be severe, leading to acute limb immobilisation; this can be mistaken for acute compartment syndrome or cellulitis. Eventually, most lesions will regress and disappear completely over one or more weeks.

GDS can be associated with such somatic symptoms as fever, arthralgia, myalgia, headache, dizziness, abdominal pain, nausea, vomiting, or diarrhoea; frank haemorrhage has also been reported.

Some clinical signs that are NOT consistent with GDS include isolated petechiae; dental/gum bleeding; deep tissue, muscle, or joint haemorrhage; or joint deformity.

How do clinical features vary in differing types of skin?

There have been no reported cases regarding GDS in darker Fitzpatrick skin types.

What are the complications of Gardner-Diamond syndrome?

Accurate diagnosis of GDS is important to limit unnecessary medical interventions/ procedures and to treat any symptoms.

How is Gardner-Diamond syndrome diagnosed?

GDS is a diagnosis of exclusion. While a so-called ’autoerythrocyte sensitisation test’ was first proposed in the initial description of the syndrome by Gardner and Diamond, it has neither been clinically validated nor standardised and is not recommended.

As there is no specific clinical finding, such as bleeding configuration or distribution, or laboratory test that is specific for GDS, a high clinical suspicion is necessary to make the diagnosis.

A diagnosis of GDS should only be made after ruling out possible physiological or physical causes, such as an underlying bleeding disorder; skin, collagen or elastin, soft tissue, or vascular aetiology; trauma; or self-inflicted injurу (whether factitious or malingering).

Depending on patient presentation and clinical history, the prudent clinician should consider obtaining the following for individuals presenting with painful purpura:

• A thorough bleeding history and a review of diet (eg, vitamin C and vitamin K intake), medications (eg, aspirin, NSAIDs), and any over-the-counter supplements (eg, garlic, vitamin E) that could promote bleeding
• A complete blood count (CBC), platelet count with morphology, prothrombin time (РΤ), activated partial thromboplastin time (аΡTТ), and testing for renal and hepatic function. If this testing is negative and there is a positive family history and/or when confronted with major skin or mucosal bleeding, testing for von Willebrand disease (VWD) may also be considered.
• A skin biopsy, while not usually necessary, may be useful to exclude vasculitis in the appropriate clinical setting.

While a detailed psychiatric evaluation is paramount if GDS is suspected, the presence of a psychiatric disorder does not eliminate the possibility of a serious underlying bleeding diathesis that may be unrelated to GDS.

What is the differential diagnosis for Gardner-Diamond syndrome?

• Bleeding disorders: such as low platelet count, platelet function defects, or defects in clotting factors or in the fibrinolytic system
• Achenbach syndrome is a similar but more localised disorder of painful purpura. Like GDS, Achenbach syndrome is not associated with underlying bleeding diathesis or other concerning laboratory findings and should be considered in the differential diagnosis of GDS. While not believed to be psychogenic in nature, the painful purpura of Achenbach syndrome may also appear to be spontaneous or to follow minor trauma (in up to 30% of patients)
• Skin, connective tissue and vascular disorders, including both congenital and acquired conditions.
  • Congenital disorders: Ehlers-Danlos syndrome, osteogenesis imperfecta. Patients with these conditions have a higher tendency for easy bruising. Other conditions, such as hereditary haemorrhagic telangiectasia/Osler-Weber-Rendu syndrome, also present with petechiae, purpura, and/or ecchymoses
  • Acquired conditions, such as vitamin C or vitamin K deficiency, small vessel vasculitis, and amyloidosis, can also present with purpura.
• Medications that increase risk of bleeding can cause purpura. These include:
  • Antiplatelet agents, such as aspirin and NSAIDs
  • Anticoagulants, such as warfarin, direct oral anticoagulants (rivaroxaban, dabigatran) and parenteral anticoagulants (unfractionated heparin, low molecular weight heparin, fondaparinux)
  • Steroids (systemic and topical)
  • Mood stabilisers, such as selective serotonin reuptake inhibitors (SSRIs)
  • Illicit drugs, such as cocaine and cannabis
• Physical abuse (domestic, sexual)
• Self-inflicted injury (malingering or factitious purpura)

What is the treatment for Gardner-Diamond syndrome?

General measures

A multidisciplinary, team-based approach that includes dermatology, haematology, primary care, and psychiatry/mental health services and focuses on improving underlying psychological as well as medical concerns is an essential part of effective treatment. Consistent communication and support for the patient and family, including frequent ‘check-in’ visits with primary care as well as ongoing visits with a mental health practitioner as symptoms dictate, are vital.

Surgical intervention, such as for hemarthrosis, should be done if medically necessary. However, other non-indicated interventions, such as steroid injections, joint exploration, or even splenectomy are not recommended.

Specific measures

There is no specific treatment for GDS. Most patients seem to benefit from a combination approach of cognitive behavioural therapy and antidepressant/anxiolytic treatment. Other approaches that have been tried with variable success have included antihistamines, corticosteroids, hormones, and vitamins.

Refractory GDS may require more frequent psychotherapist/psychiatrist input for therapy, or titration or selection of alternate psychoactive medications to achieve long-term success.

What is the outcome for Gardner-Diamond syndrome?

The overall prognosis for this condition is reasonably good. However, relapses and remissions are common and may last for several years. Chronological recurrence around the anniversary mark of major life events is not uncommon.

The severity of lesions may fluctuate with each relapse. Relief of acute stress and psychological factors is crucial in maintaining remissions.