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Velocardiofacial syndrome

22q11.2 deletion syndrome (also called DiGeorge syndrome and velocardiofacial syndrome) is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2. more...

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease

The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms include heart defects that are often present from birth, an opening in the roof of the mouth (a cleft palate or other defect in the palate), learning disabilities, recurrent infections caused by problems with the immune system, and mild differences in facial features. Affected individuals may also have kidney abnormalities, low levels of calcium in the blood (which can result in seizures), significant feeding difficulties, autoimmune disorders such as rheumatoid arthritis, and an increased risk of developing mental illnesses such as schizophrenia and bipolar disorder.

Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. Doctors named these conditions DiGeorge syndrome, velocardiofacial syndrome (also called Shprintzen syndrome), and conotruncal anomaly face syndrome. In addition, some children with the 22q11.2 deletion were diagnosed with Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.


Individuals with a 22q11 deletion have a range of findings, including:

  • Congenital heart disease (74% of individuals), particularly conotruncal malformations (tetralogy of Fallot, interrupted aortic arch, ventricular septal defect, and truncus arteriosus)
  • palatal abnormalities (69%), particularly velopharyngeal incompetence (VPI), submucosal cleft palate, and cleft palate; characteristic facial features (present in the majority of Caucasian individuals)
  • learning difficulties (70-90%)
  • an immune deficiency regardless of their clinical presentation (77%)
  • hypocalcemia (50%)
  • significant feeding problems (30%)
  • renal anomalies (37%)
  • hearing loss (both conductive and sensorineural)
  • laryngotracheoesophageal anomalies
  • growth hormone deficiency
  • autoimmune disorders
  • seizures (without hypocalcemia)
  • skeletal abnormalities

Thymus, parathyroid glands and heart derive from the same primitive embryonic structure and that is why these three organs are dysfunctioned together in this disease. Affected patients (usually children) are prone to yeast infections.


The disease is related with genetic deletions (loss of a small part of the genetic material) found on the long arm of the 22nd chromosome. Some patients with similar clinical features may have deletions on the short arm of chromosome 10.


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Primary care and primary immunodeficiencies - Editorial
From American Family Physician, 11/15/03 by Kathleen E. Sullivan

In this issue of American Family Physician, Cooper and associates (1) provide a timely review of the diagnostic considerations of common primary immunodeficiencies. This is an exciting time in the field of immunology. It is worth reflecting on a few recent advances and highlighting the importance of maintaining a high index of suspicion for immunodeficiencies.

In 1997, the World Health Organization listed 60 primary immunodeficiencies. (2) An update in 1999 listed 71 defects of immunologic function and another 39 disorders in which immunodeficiency was a component. (3) Since that time, the genetic defects for most immunodeficiencies have been identified, and new disorders have been recognized at a rate of one to two per year.

The improved understanding of signaling pathways and mechanisms of host defense also has led to the development of interventions for primary immunodeficiencies. The most dramatic new management strategy is gene therapy for adenosine deaminase-deficient and X-linked forms of severe combined immunodeficiency. (4) The use of gene therapy remains somewhat controversial, but further refinements should improve its safety. Yet, the article by Cooper and colleagues (1) is a reminder that treatment advances are not helpful unless physicians can make the diagnosis early.

There is as yet no national database on primary immunodeficiencies. The most common diagnosis is IgA deficiency, with an estimated frequency of approximately one case per 500 white persons. (5) Excluding developmental delay of immunoglobulin production (transient hypogammaglobulinemia of infancy, which occurs in an estimated one of every 1,000 infants (5)), the next most common primary immunodeficiency is chromosome 22q11.2 deletion syndrome (DiGeorge syndrome). This syndrome occurs with an estimated frequency of one case per 3,000 live births, (6) regardless of ethnic or racial background.

Most family physicians can expect to encounter patients with primary immunodeficiencies. The most common primary immunodeficiencies would be seen in most large clinical practices. However, to ensure timely diagnosis, the family physician also should be familiar with the less common immunodeficiency disorders.

The article by Cooper and associates is important because it reminds the family physician to be alert to clinical presentations. With more than 70 disorders classified as congenital immunodeficiencies and other syndromes in which immunodeficiency is a significant component, it is somewhat overwhelming to attempt a thorough cataloging. Instead, it is helpful to remember that nearly all immunodeficiencies can be categorized according to the effector "arm" of the immune system that is impaired.

Patients with disorders of antibody production or function nearly always present with common recurrent infections. Each infection is unremarkable, but the frequency of the infections is excessive. Patients with common variable immunodeficiency (which becomes apparent later in life than other primary immunodeficiency disorders) typically present with new-onset recurrent sinusitis or bronchitis. Patients with antibody deficiencies usually do not look chronically ill.

The diagnosis of a disorder of antibody production or function nearly always will be suspected by the family physician, who has insight into a patient's pattern of visits for acute illnesses. Screening laboratory tests are readily obtainable and usually consist of immunoglobulin determinations and measurements of antibody responses to immunizations. Timely diagnosis of antibody defects is important, because untreated patients develop progressive end-organ damage and are at risk for life-threatening enteroviral infections.

Unlike patients with antibody disorders, who generally have typical infections, patients with T-cell defects often have unusual infections or atypical infections with common organisms. In children, T-cell defects are less common than antibody defects. In adults, T-cell defects (other than those resulting from human immunodeficiency virus [HIV] infection) seldom will be new diagnoses.

Recognition of patients with significant T-cell deficiencies is imperative, because delay of therapy adversely affects outcome. In infants, the frequencies of HIV infection and severe combined immunodeficiency are nearly the same. Thus, in most situations where HIV testing would be considered, primary T-cell defects also should be considered.

Although severe combined immunodeficiency may have various presentations, one key characteristic is the persistence of infection. In the absence of T-cell function, a simple upper respiratory tract infection progresses inexorably over one to two months. Hence, the family physician should be suspicious when an infant has an infection with a prolonged or atypical course.

A helpful finding is that most infants with severe combined immunodeficiency have diminished lymphocyte counts (less than 2,800 cells per [mm.sup.3] [2.8 3 [10.sup.9] per L]). An infant with chronic diarrhea, chronic wheezing, or recurrent Candida and a low lymphocyte count should be seen immediately by an immunologist. Urgent intervention is required for patients with severe combined immunodeficiency. Generally, the first step in analyzing these patients is to obtain lymphocyte counts, which often suggest the diagnosis of severe combined immunodeficiency.

Severe combined immunodeficiency nearly always is treated with stem cell transplantation. Polyethylene glycol-modified adenosine deaminase and gene therapy constitute reasonable experimental alternatives in certain patients. The success of all three treatments depends greatly on the status of the child at the time therapy is initiated. While stem cell transplantation or gene therapy is curative, an infant with severe end-organ compromise is less likely to survive the procedure. (7)

The primary immunodeficiencies with the least definable presentations are the phagocytic disorders. Most neutrophil disorders result in increased susceptibility to staphylococcal infections, whereas most macrophage activation disorders result in increased susceptibility to atypical mycobacterial infections. In addition, patients with neutrophil disorders often are predisposed to fungal and unusual bacterial infections. There are no easily obtainable screening tests for phagocytic disorders. Each disorder has its own specific diagnostic test.

The family physician is particularly well placed to recognize an abnormal infection pattern in a patient and initiate a work-up for suspected immunodeficiency disorder. Management of the patient with a primary immunodeficiency disorder requires a meticulous approach. Infections must be treated aggressively, and surveillance for unusual infections, malignancy, or autoimmune disease is critical. With appropriate medical support, the patient with a primary immunodeficiency disorder can be expected to lead a full and productive life.

Resources for patients, physicians, and caregivers are available through two organizations: the Immune Deficiency Foundation (http:// and The Jeffrey Modell Foundation (http://www.jmfworld. com).


(1.) Cooper MA, Pommering TL, Koranyi K. Primary immunodeficiencies. Am Fam Physician 2003;68: 2001-8,2011.

(2.) Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol 1997; 109(suppl 1): 1-28.

(3.) Primary immunodeficiency diseases. Report of an IUIS scientific committee. International Union of Immunological Societies. Clin Exp Immunol 1999; 118(suppl 1):1-28.

(4.) Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Immunity 2001;15:1-4.

(5.) Stiehm ER. Immunologic disorders in infants and children. 4th ed. Philadelphia: Saunders, 1996.

(6.) Devriendt K, Fryns JP, Mortier G, van Thienen MN, Keymolen K. The annual incidence of DiGeorge/ velocardiofacial syndrome. J Med Genet 1998; 35:789-90.

(7.) Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Myers LA, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-16.

Kathleen E. Sullivan, M.D., Ph.D., is director of the immunology clinic at The Children's Hospital of Philadelphia.

Address correspondence to Kathleen E. Sullivan, M.D., Ph.D., Division of Immunology, The Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Reprints are not available from the author.

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group

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