An 83-year-old nursing home resident was admitted following a syncopal episode. She had complained of pruritus and flushing off and on over the last year. On examination she had dermatographia.

What is the most likely diagnosis?

History

Mast cells were originally named Mastzellen by Paul Ehrlich. [Mastzellen means to chew in German and Ehrlich felt this was an appropriate name as he thought the granules in the mast cells were due to overfeeding.]

In 1936 Sezary suggested that the disorder associated with a pruritic, pigmented urticarial rash be named mastocytosis. The first description of this disorder was made almost 50 years earlier by Nettleship and Tay in 1869, when they reported the case of a two-year-old girl with a hyperpigmented urticarial rash.

Definition

Mastocytosis is a relatively rare clinical disorder characterized by increased numbers of mast cells in the skin or other organs. While most forms are characterized by a pruritic skin lesion, there has recently been increased awareness that the condition may be associated with a variety of systemic conditions. Approximately one-third of cases present for the first time in adulthood.

Pathophysiology

The reason for the proliferation of mast cells is not understood. Mast cells develop from bone marrow progenitors expressing the CD₃₄ antigen. Growth of mast cells requires a mast cell growth factor and an interaction between cytokines and the c-kit receptor on mast cells. Mutations in the gene regulatory element for c-kit have been reported in patients with mastocytosis.(1) In general, mastocytosis is a relatively benign disorder but it rarely can be associated with lymphadenopathy and eosinophilia or present as a mast cell leukemia. Both of these conditions are fatal. The condition can be either localized to the skin or present with a variety of systemic manifestations.

Localized Dermatological Lesions(1),(2),(3)

• Dermatographia [This is a classical "wheel and flare" reaction that remains for some period of time after writing on the skin. It occurs in approximately 15% of normals and is invariably present in patients with mastocytosis.
• Pruritus
• Erythematous Acneiform Papules [These come and go and appear to be related to local tissue response to histamine and other mast cell secretions.]
• Solitary Mastocytoma
• Urticaria Pigmentosum [Reddish brown plaques or macules present in 14 to 100% of cases.]
• Darrier's Sign [Urtication of lesions, from mild trauma, such as ribing, which is produced secondary to mast-cell degranulation and histamine and prostaglandin release.]
• Telangiectasia
• Petechiae
• Telangiectasia macularis eruptiva perstans [Occurs only in adults. Red, telangiectatic macules. They are not pruritic.]
• Diffuse cutaneous mastocytosis [Occurs only in children. Includes bullae - blistering.]
• Angioedema

Systemic Disorders

Mast Cell Mediated

• Flushing
• Palpitations/tachycardia
• Hypotension
• Dizziness
• Headache
• Syncope(4),(5),(6) [often associated with attacks consisting of flushing, dizziness, headache, dyspnea and chest pain. Exacerbated by physical exertion, emotional anxiety and heat. Prostaglandin D₂ appears to be an important mediator of the mastocytosis associated syncope].
• Rhinitis
• Dyspnea [not associated with wheezing (bronchospasm)]
• Anaphylaxis
• Gastrointestinal Symptoms(7) abdominal cramping, diarrhea, epigastric pain, nausea, vomiting, malabsorption, gastric acid hypersecretion and peptic ulcer disease].
• Neurological Disorders [Paresthesiae and very rarely focal symptoms].
• Cognitive Deficits(10) [Depression, irritability, attentional deficits, decreased memory]
• Urge Incontinence [Detrusor mastocytosis]
• Osteoporosis(8),(9) [fractures of long bones, pelvis, vertebrae, and ribs]

Infiltrative Signs and Symptoms

• Hepatomegaly [Increased alkaline phosphatase]
• Splenomegaly
• Osteosclerosis(8),(9)
• Lymphadenopathy
• Bone marrow invasion [normochromic, normocytic anemia; leukopenia; thrombocytopenia]

Nonspecific Symptoms

• Fatigue
• Fever
• Weight loss

Factors that Precipitate Acute Attacks

• Morphine
• Alcohol
• Aspirin
• NSAIDs
• Beta adrenergic antagonists
• Alpha adrenergic agonists

Differential Diagnosis of Flushing

1. Pheochromocytoma [feel flushed but look pale]
2. Renal cell carcinoma [associated with ectopic prostaglandin production often have diarrhea and hypercalcemia]
3. Medullary carcinoma of the thyroid
4. Carcinoid syndrome
5. Menopause
6. VIPoma [Vasoactive intestinal peptide producing tumor]
7. Systemic mastocytosis

Diagnostic Tests

1. Plasma tryptase - best available screening test [may need to be measured during an acute episode]
2. Urinary histamine metabolites [N-methylhistamine and 1-methyl-4-imidazole acetic acid]
3. Metabolite PGD₂ in urine
4. Increased skin mast cells on dermal biopsy.
5. Bone marrow aspiration
6. Serum histamine(11) [poor sensitivity and specificity]
7. Nonspecific findings [anemia, leukopenia, thrombocytopenia, eosinophilia, increased IgE, increased alkaline phosphatase]
8. Possible other tests [DEXA; bone scan; gastrointestinal workup; EEG]

Management

1. H₁ antagonists combined with H₂ antagonists
2. High dose aspirin in order to maintain plasma salicylate levels at 20 to 30 mg/dl to inhibit PGD₂. Beware that low dose aspirin can precipitate mast cell activation.
3. Cromolyn sodium (a mast cell stabilizer) for long term symptoms
4. Steroids for malabsorption
5. Interferon(12),(13) (experimental)