Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

Clinical trial: Biomarker for Hereditary Angioedema Disease Type 1 (BioHAE)

Summary: Development of a new MS-based biomarker for the early and sensitive diagnosis of hereditary angioedema disease type 1 from the blood

Detailed description: Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries).
  In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals. The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions.
  The characteristic symptom of hereditary angioedema is recurrent episodes of swelling of affected areas due to the accumulation of excessive body fluid. The areas of the body most commonly affected include the hands, feet, eyelids, lips, and/or genitals. Edema may also occur in the mucous membranes that line the respiratory and digestive tracts, which is more common in people with hereditary angioedema than in those who have other forms of angioedema (i.e., acquired or traumatic). People with this disorder typically have areas of swelling that are hard and painful, not red and itchy (pruritic). A skin rash (urticaria) rarely is present.
  The symptoms of hereditary angioedema may recur and can become more severe. Injury, severe pain, surgery, dental procedures, viral illness, and/or stress can trigger or worsen the recurring symptoms.
  Symptoms associated with swelling in the digestive system (gastrointestinal tract) include nausea, vomiting, acute abdominal pain, and/or other signs of obstruction. Edema of the throat (pharynx) or voice-box (larynx) can result in pain, difficulty swallowing (dysphagia), difficulty speaking (dysphonia), noisy respiration (stridor), and potentially life-threatening asphyxiation.
  Hereditary angioedema is inherited as an autosomal dominant trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
  Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a spontaneous new mutation (gene change) in the affected individual.
  The symptoms of hereditary angioedema type I develop due to a deficiency of a protein known as complement component C1 esterase inhibitor.
  The gene that causes hereditary angioedema is located on the long arm of chromosome 11 (11q12-q13.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual.
  Hereditary angioedema is a rare disorder that affects males and females in equal numbers. Symptoms typically begin in early childhood. An estimated one in 50,000 to 150,000 individuals is affected by this disorder worldwide.
  Symptoms of the following disorders can be similar to those of hereditary angioedema. Comparisons may be useful for a differential diagnosis:
  Acute nonhereditary angioedema affects the skin and mucous membranes. It commonly clears up on its own after 1 or 2 days. Any number of allergens may be responsible including drugs, insect stings, bites, and certain foods (e.g., eggs, shellfish, nuts, and fruits). Some people can have very severe allergic reactions (anaphylaxis) that may result in respiratory angioedema. Acquired angioedema can also occur because of immune disorders (e.g., B-cell lymphoprolif-erative disease), chronic lymphocytic leukemia, multiple myeloma, lupus (SLE), chronic sinusi-tis, dental infection, or certain blood disorders (essential cryoglobulinemias). Other acquired edemas may occur because of surgery (i.e., mastectomy), malignancy, and/or autoimmune diseases. Acquired angioedema may occur at any age. (For more information on these disor-ders, choose "Anaphylaxis," "Leukemia," "Myeloma," "Lupus," and "Cryoglobulinemia" as your search term in the Rare Disease Database.)
  Cutis laxa is a rare congenital or acquired connective tissue disorder characterized by limp or slack skin. The affected areas of the skin may be thickened and dark. This disorder is usually diagnosed at birth or early in infancy. The initial symptom is usually an episode of swelling on the face and may be confused with hereditary angioedema. Cutis laxa progresses causing skin changes and damage to blood vessels. (For more information on this disorder, choose "Cutis Laxa" as your search term in the Rare Disease Database.) Diagnosis
  The diagnosis of hereditary angioedema is made by a thorough clinical evaluation, a detailed patient history, and blood tests that detect decreased levels of complement proteins. In in-stances of high clinical suspicion and recurrent episodic angioedema of uncertain etiology, genetic testing is indicated.
  The diagnosis is complicated because HAE is extremely rare and most physicians may never see a patient with the disorder. In addition, most cases of angioedema are caused by an allergic reaction. Abdominal attacks may be mistaken for conditions such as appendicitis and often results in unnecessary exploratory surgery. Often, patients are misdiagnosed as having psychosomatic symptoms and are inappropriately referred for psychiatric evaluation.
  New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.
  Therefore it is the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and there-by with an earlier treatment.

Eligibility: INCLUSION CRITERIA
  -  Informed consent will be obtained from the patient or the parents before any study related procedures.
  -  Patients of both genders older than 2 months
  -  The patient has a diagnosis of hereditary angioedema disease type 1 or a high-grade suspicion for hereditary angioedema disease type 1
  -  High-grade suspicion present, if one or more inclusion criteria are valid:
  Positive family anamnesis for hereditary angioedema disease type 1
  Swelling of the skin (most common symptom)
  Swelling of the hands and feet
  Abdominal pain (sometimes severe)
  Laryngeal edema (medical emergency)
  EXCLUSION CRITERIA
  -  No Informed consent from the patient or the parents before any study related procedures.
  -  Patients of both gender younger than 2 months
  -  No diagnosis of hereditary angioedema disease type 1 or no valid criteria for profound suspicion of hereditary angioedema disease type 1

Relevance to patient case: not relevant