Darier sign

Darier’s sign, named after the French dermatologist Ferdinand-Jean Darier, is considered to be a sign of cutaneous mastocytosis ¹. Gentle rubbing or stroking of lesions of cutaneous mastocytosis is followed by local itching, erythema, and weal formation within 2–5 minutes, which may last from 30 minutes to several hours. The pathophysiology of Darier’s sign involves stroking-induced degranulation of the increased number of functionally normal dermal mast cells, followed by exocytosis of effector molecules such as histamine and heparin ². Of all the variants of cutaneous mastocytosis, Darier’s sign is most commonly encountered in urticaria pigmentosa, with up to 94% positivity reported in children with urticaria pigmentosa in a clinical analysis of 71 childhood cases with cutaneous mastocytosis ³. However, its positivity has been reported in only 50% cases of solitary mastocytoma ⁴. Intriguingly, Darier’s sign has also been reported in conditions other than cutaneous mastocytosis, such as leukemia cutis, juvenile xanthogranuloma, histiocytosis X, and rarely in cutaneous large T-cell lymphoma ¹. Darier’s sign needs to be severalized from Pseudo-Darier’s sign, an augury of congenital smooth muscle hamartomas, characterized by transient piloerection and elevation or increased induration of the lesion induced by rubbing ². Uncontrolled stroking of mastocytomas should be avoided in patients who have had a systemic reaction such as miosis and asthmalike symptoms in their past ⁵.

The Darier sign usually is not positive in patients with telangiectasia macularis eruptive perstans because the lesions are paucicellular, and, therefore, mast cells may not be present in sufficient numbers for significant degranulation to occur.

What are mast cells?

Mast cells are healthy cells in the body, usually found in the skin and other tissues. Mast cells have a role in the early steps of the body’s coordination of healing responses to an injury. Granules within the mast cells contain histamine and other chemicals.

• histamine
• leukotriene C4
• prostaglandin D2
• carboxypeptidase
• heparin
• cathepsin G-like protease
• tryptase
• tumour necrosis factor-A
• chymase
• interleukin-8
• others

When a mast cell is activated, these chemicals are released into the surrounding skin. Mast cell chemicals are mediators of inflammation, and cause the blood vessels to leak, resulting in localised itching, swelling, redness and sometimes blistering. This reaction is normal in insect bites and is thought to be a protective mechanism. For example, a mosquito injects saliva when it bites. The saliva triggers mast cell activation to a varying degree, depending on the individual’s hypersensitivity to the saliva. The unpleasant itch soon persuades the person to try to avoid getting bitten again.

Rubbing an area of skin affected by mastocytosis may also activate the mast cells. The rubbed skin becomes reddened, swollen and itchy within a few minutes (Darier sign). In young children, the rubbed area may later blister.

Darier’s sign causes

When a urticaria pigmentosa or mastocytoma lesion is stroked, it typically urticates, becoming pruritic, edematous, and erythematous. This change is referred to as the Darier sign, which is explainable on the basis of mast cell degranulation induced by physical stimulation.

Mastocytosis is the term for a diverse group of clonal hematopoietic disorders characterized by a pathologic accumulation single (or clonal) population of mast cells in tissue, such as the skin, bone marrow, liver, spleen, gastrointestinal tract, and lymph nodes ⁶. Mast cell accumulation can be limited to the skin (cutaneous mastocytosis) or involve extracutaneous tissues, often in combination with skin involvement (systemic mastocytosis) ⁶. Cutaneous mastocytosis can be subclassified into solitary cutaneous mastocytoma, maculopapular cutaneous mastocytosis (urticaria pigmentosa), and diffuse cutaneous mastocytosis ⁷.

The severity of symptoms depends on the number of mast cells in the tissues ⁸. A high load of mast cells leads to more severe symptoms. Cutaneous mastocytosis causes itching, swelling and blistering of the affected skin, particularly when it is rubbed or scratched.

Most forms of mastocytosis are caused by a mutation of the KIT gene on the 4q12 chromosome – a mutation that increases cellular reproduction. The c-KIT gene mutation creates an overgrowth of one cell line of mast cells. This clonal expansion of mast cells leads to areas of abnormal skin that easily reddens, swells and itches. The c-KIT mutation can also lead to the proliferation of mast cells within the bone marrow, resulting in systemic mastocytosis.

In some cases, the genetic disorder is inherited, but in most cases, it is spontaneous, and there is no family history of mastocytosis.

Solitary mastocytoma

Mastocytoma is the name given to a form of cutaneous mastocytosis in which there is a dermal accumulation of mast cells forming one to three solitary lesions ⁹.

What causes a mastocytoma?

KIT gene, which codes for a transmembrane tyrosine receptor on the mast cell responsible for its growth and function ¹⁰.

Activation of mast cells causes them to release histamine and other chemicals, which causes localised redness, swelling, itching, and, sometimes, blistering.

What are the clinical features of mastocytoma?

One to three mastocytomas usually appear in early childhood within the first few months of age. They can occur on any site of the body.

Typical characteristics of mastocytoma are:

• A firm, macule or indurated plaque 1–5 cm in diameter
• The surface may be pitted (peau d’orange appearance)
• Red, pink, yellow or brown in colour
• Intermittent itching, especially when rubbed
• Rubbing causes the lesion to urticate (redden and swell) for 15 minutes or so (a positive Darier sign). A blister may occur.

Occasionally localised or generalised flushing may occur when the mast cells release chemicals such as histamine into the skin.

How is mastocytoma diagnosed?

Mastocytoma can usually be diagnosed clinically, especially when a positive Darier sign is elicited. Dermatoscopy is non-specific ¹¹, and the usual patterns seen in melanocytic naevus are absent. Blood tests are not required.

A skin biopsy reveals a monomorphous mononuclear cell infiltrate that stains positively with a c-KIT and tryptase immunoperoxidase stains ¹⁰.

What is the differential diagnosis with mastocytoma?

At first, it is common for symptomatic mastocytoma to be thought to be a persistent insect bite reaction. If the lesion is not itchy, a congenital or early-onset melanocytic nevus may be considered.

Four or more mast cell lesions are best described as maculopapular cutaneous mastocytosis (urticaria pigmentosa).

If Darier sign is positive in adult-onset mastocytoma, the possibility of more widespread cutaneous mastocytosis or systemic mastocytosis should be considered, especially if there are systemic symptoms such as flushing.

What is the treatment for mastocytoma?

Scratching or trauma to the lesion should be minimised to avoid itch, swelling, and blistering.

If the mastocytoma is causing a lot of itching, this can often be relieved with an oral antihistamine. Topical tacrolimus ointment has also been reported to reduce symptoms due to a mastocytoma.

A mastocytoma in a cosmetically sensitive area may be excised ¹⁰, but localized urtication may persist within the scar ¹².

What is the outcome for mastocytoma?

Mastocytomas arising in infancy usually disappear before puberty ⁹.

Urticaria pigmentosa

Urticaria pigmentosa also called maculopapular cutaneous mastocytosis, is the most common form of mastocytosis in adults and children.

Urticaria pigmentosa or maculopapular mastocytosis in adults is unlikely to resolve with time. It is associated with systemic involvement, where the mastocytosis spreads to more than one tissue (see below).

Exercise or heat can aggravate symptoms of cutaneous mastocytosis. A severe reaction can result in flushing and faintness.

Certain medications can cause mast cell degranulation and should be avoided if there is extensive urticaria pigmentosa. These include:

• Aspirin (salicylates) and other nonsteroidal anti-inflammatory drugs
• Codeine and morphine (narcotics)
• Alcohol
• Anticholinergics

People with urticaria pigmentosa may get a severe allergic reaction from bee or wasp stings, hence they may need to carry an injectable epinephrine/adrenaline kit.

Maculopapular cutaneous mastocytosis in children

Maculopapular cutaneous mastocytosis most often affects infants, with the first patches appearing at a few months of age. They patches are often confused with moles or with insect bites at first, but the lesions persist and gradually increase in number for several months or years. They can appear on any part of the body including the scalp, face, trunk and limbs.

In young children, it is common for the mastocytosis patches to blister when rubbed. If many patches are rubbed or activate spontaneously at the same time, the infant may become irritable, but is uncommon for severe symptoms to arise.

Over time, the mastocytosis becomes less itchy and eventually the patches fade away. By the teenage years, most patches will have gone.

Maculopapular cutaneous mastocytosis in adults

Maculopapular cutaneous mastocytosis can sometimes develop for the first time in an adult. Just a few lesions may appear, or many. The lesions can be unsightly and itchy. Unfortunately, in adults, urticaria pigmentosa tends to persist long-term. Sometimes patients can have systemic symptoms (such as flushing, itching, low blood pressure, anaphylactic shock, diarrhoea and bleeding from the gastrointestinal tract), which suggest the presence of systemic mastocytosis.

Localized cutaneous mastocytosis has rarely been reported to arise in an area of radiation treatment for breast cancer for unknown reasons.

Maculopapular cutaneous mastocytosis diagnosis

The appearance of maculopapular cutaneous mastocytosis is generally so characteristic that no specific tests are necessary. However, occasionally a skin biopsy is needed to confirm the diagnosis (see maculopapular cutaneous mastocytosis pathology). If there are any symptoms suggesting internal involvement (systemic mastocytosis), refer to our page on mastocytosis for further information. Tests may include:

• Blood count
• Serum tryptase
• DEXA bone scan
• Bone marrow examination

Maculopapular cutaneous mastocytosis treatment

Maculopapular cutaneous mastocytosis is not serious, and does not require any treatment in most cases (unless there is also systemic involvement). The following can be helpful.

• Oral antihistamines
• Topical steroids
• Potent steroid creams applied for several months under occlusion can reduce itching and unsightliness, but the patches tend to recur within a few months. Topical steroids are only suitable
• for limited areas.
• Topical calcineurin inhibitors, such as pimecrolimus cream
• Phototherapy
• This form of ultraviolet radiation is the most effective treatment for adults with maculopapular cutaneous mastocytosis. Two or three treatments each week are required for several months.
• Narrowband UVB or (if available) photochemotherapy (PUVA) lessens the itch and improves the appearance. The cutaneous mastocytosis is likely to recur within six to twelve months.

References

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