Information on the following diseases can be found in the Related Disorders section of this report:

• Agammaglobulinemias, Primary
• Cayler syndrome
• CHARGE syndrome
• Conotruncal anomaly face syndrome
• Hypoparathyroidism
• Opitz-GBBB syndrome
• Severe combined immunodeficiency
• Velocardiofacial syndrome (aka Shprintzen syndrome)
• Wiskott-Aldrich syndrome

Abnormally low levels of parathyroid hormone secretion from the parathyroid glands (hypoparathyroidism) may be the first symptom of DiGeorge syndrome that is noted. Low parathyroid hormone levels may lead to seizures (hypocalcemic) during the first few days of life. (For more information, choose "Hypoparathyroidism" as your search term in the Rare Disease Database.)

Children with DGS have a thymus gland that may be underdeveloped or even missing in its entirety. Such children develop frequent infections from viruses, fungi, and certain bacteria (e.g., Pneumocystis carinii). Common symptoms of these infections may include chronic nasal infections, diarrhea, fungal infections of the mouth (thrush or oral candidiasis), and/or pneumonia. However, most children with DiGeorge syndrome have some thymic tissue. When most of the thymus is present, the deficiencies of the immune system and associated symptoms may be minimal or absent.

Children with DGS also have characteristic facial features such as abnormally wide-set eyes (hypertelorism), a downward or upward slant to the eyes, and notched, low-set, or short ears. The external ears (pinna) may have abnormal folds. Some children with DiGeorge syndrome may experience loss of hearing or deafness. The nose may be squared at the tip and be abnormally large and rounded (bulbous). The mouth may be unusually small and, in some cases, a vertical groove (cleft) may be present on the lip. Children with this disorder may have an unusual nasal quality to their speech. Some children with DiGeorge syndrome may be unusually short (short stature).

Structural abnormalities of the heart occurs in about 74 percent of fetuses with DGS, including malformations of a fetal artery that later develops into the aortic and pulmonary arteries (truncus arteriosus), interrupted aortic arch, right aortic arch, ventricular septal defect, and Tetralogy of Fallot. (For more information on these disorders, choose "Ventricular Septal Defect" and "Tetralogy of Fallot" as your search terms in the Rare Disease Database.)

Neurological problems may include mild to moderate learning difficulties; muscle cramps and twitching accompanied by stiffness of the wrist and ankle joints (tetany); convulsive seizures; behavioral abnormalities; and/or moderate to severe depressive episodes. Some children with DiGeorge syndrome may also have abnormalities of the digestive system (gastrointestinal tract). Moderate mental retardation may also be present.

In most cases, DiGeorge syndrome is thought to occur randomly (sporadically) due to spontaneous deletion of chromosomal material from the long arm (q) of chromosome 22 (22q11.2). In fewer cases, DGS may also occur as an isolated finding in individuals within certain families (kindreds). In such cases, DiGeorge syndrome is inherited as an autosomal dominant trait.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 22q11" refers to band 11 on the long arm of chromosome 22. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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 new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

There does not appear to be a single gene that is responsible for the development of DGS. The genetics of this disorder are more complicated. Clinical researchers have concluded that the gene TBX1 is missing in patients with DGS. That gene appears to be responsible for many of the signs of DGS, such as heart defects, cleft palate, low concentrations of calcium in the blood and some of the facial features. The loss of a gene known as COMT is said to be responsible for the increased probability that a patient will have behavioral problems and mental illness.

In some cases, DiGeorge syndrome may occur in infants born to mothers who consumed alcohol or used certain medications (such as vitamin A derivatives) during pregnancy. In addition, the syndrome may also occur in association with chromosomal malformation syndromes, such as chromosome 22, monosomy [deletion] 22q, or other disorders, including CHARGE association. (For more information, choose "CHARGE" as your search term in the Rare Disease Database.)

DiGeorge syndrome is a very rare disorder that affects males and females in equal numbers. Estimates of the prevalence of DGS vary considerably. Some studies suggest the prevalence in the USA of 1 in 4,000 newborns, while others suggest that the figure is closer to 1 in 6,400 newborns. Overseas. the prevalence ranges from 1 in 66,000 newborns in Australia to 1 in 20,00 in Germany.

Agammaglobulinemias, Primary
Primary agammaglobulinemias are a group of inherited antibody deficiency disorders characterized by abnormalities in the function of cells that are associated with the body's immunity (B and T lymphocytes). This causes a susceptibility to recurring bacterial infections. The bacteria, Giardia lamblia, is typically the cause of chronic inflammation of the intestines and diarrhea in patients with all forms of primary agammaglobulinemias. (For more information on this disorder, choose "Primary Agammaglobulinemias" as your search term in the Rare Disease Database.)

Cayler syndrome
Cayler syndrome, also known as "asymmetric crying facies with cardiac defects," is an extremely rare disorder characterized by congenital heart defects and the underdevelopment or absence of one of the muscles that control the movements of the lower lip. The disorder is present at birth (congenital) and is usually first noticed when the infant cries or smiles. Half of the lower lip cannot be drawn down and outward because of the incomplete development (hypoplasia) or absence (agenesis) of the depressor anguli oris muscle.

Congenital heart defects associated with Cayler syndrome may include ventricular septal defects, atrial septal defects, and/or tetralogy of Fallot. In some rare cases, individuals may have an abnormally small head (microcephaly), unusually small jawbones (micrognathia), small eyes (microphthalmos), and/or mental retardation. Most cases of Cayler syndrome are thought to be inherited as an autosomal dominant trait. (For more information on this disorder, choose "Cayler syndrome" as your search term in the Rare Disease Database.)

CHARGE syndrome
CHARGE syndrome is a rare disorder that arises during early fetal development and affects multiple organ systems. The term CHARGE comes from the first letter of some of the more common features seen in these children:

(C) = coloboma and cranial nerve abnormalities -- defects of the eyeball
(H) = heart defects
(A ) = atresia of the choanae (blocked nasal breathing passages)
(R) = retardation of growth and development
(G) = genital and urinary abnormalities
(E) = ear abnormalities and hearing loss

Diagnosis is based on a different set of features (see below). In addition to the CHARGE features, most children with CHARGE syndrome have other features, including characteristic facial features, cleft lip or palate, esophageal atresia (blind-ending food pipe) or tracheoesophageal fistula (connection between the wind pipe and the food pipe). The symptoms of CHARGE syndrome vary greatly from one child to another. The exact cause of CHARGE is not known. Most cases occur randomly, for no apparent reason (sporadic). There are a few familial cases. (For more information on this disorder, choose "CHARGE syndrome" as your search term in the Rare Disease Database.)

Conotruncal anomaly face syndrome
A syndrome of dysmorphic facies and conotruncal heart defects having common genetic characteristics with DiGeorge and Shprinzen syndromes. It is considered a variant of the CATCH 22 syndrome. Conotruncal heart defects are also known as outflow tract defects. Common types of conotruncal heart defects are truncus arteriosus, transposition of the great arteries, double outlet of the right ventricle, and tetralogy of Fallot. In truncus arteriosus, also known as common truncus, there is a single outflow tract instead of a separate aorta and pulmonary artery. Transposition of the great arteries consists of the great arteries being switched so that the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta originate from the right ventricle. Tetralogy of Fallot involves a ventricular septal defect, right ventricular outflow tract obstruction such as pulmonary atresia or stenosis, aorta overriding the ventricular septum, and right ventricular hypertrophy. Other types of conotruncal defects include pulmonary atresia with ventricular septal defect and aortopulmonary window.

Hypoparathyroidism
Hypoparathyroidism is a disorder that causes lower than normal levels of calcium in the blood due to insufficient levels of parathyroid hormones. This condition can be inherited or it can be associated with other disorders such as DiGeorge syndrome. Symptoms of this disorder may include general weakness, muscle cramps, and tingling or burning of the hands and feet. Other symptoms may include excessive nervousness, loss of memory, headaches, and uncontrollable cramping muscle movements of the wrists and feet. (For more information on this disorder, choose "Hypoparathyroidism" as your search term in the Rare Disease Database.)

Opitz-GBBB syndrome
Opitz G/BBB syndrome or Opitz syndrome is a genetic disorder that may be evident at birth. The syndrome may be characterized by distinctive malformations of the head and facial (craniofacial) area, including widely set eyes (ocular hypertelorism); an abnormal groove in the upper lip (cleft lip); incomplete closure of the roof of the mouth (cleft palate); upwardly or downwardly slanting eyelid folds (palpebral fissures); vertical skin folds that may cover the eyes' inner corners (epicanthal folds); or a wide, flat nasal bridge. In addition, in affected males, abnormalities typically include failure of the testes to descend into the scrotum (cryptorchidism), clefting of the scrotum (bifid scrotum), or abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias). Affected individuals may also have malformations of the windpipe (trachea) and the larynx, which connects the trachea and the throat (pharynx); underdevelopment of the lungs (pulmonary hypoplasia); and associated swallowing and breathing difficulties. Opitz syndrome may also be characterized by additional abnormalities, including partial or complete closure of the anal opening (imperforate anus); underdevelopment or absence of the thick band of nerve fibers that joins the two hemispheres of the brain (hypoplasia or agenesis of the corpus callosum); kidney (renal) abnormalities; heart (cardiac) defects; or mental retardation.

Opitz syndrome was originally categorized as two distinct disorders: i.e., Opitz G and Opitz BBB syndromes. Yet many investigators have since determined that the disorders represent the same clinical entity with different modes of genetic transmission. The form of the disorder previously designated as Opitz BBB syndrome is transmitted as an X-linked trait. This X-linked disorder appears to be caused by changes (mutations) of a gene, known as MID1 (for "midline-1"), that is located on the short arm (p) of chromosome X (Xp22). The form originally classified as Opitz G syndrome is inherited as an autosomal dominant trait. It is thought to result from deletions of genetic material from the long arm (q) of chromosome 22 (22q11.2). (For more information on this disorder, choose "Opitz G/BBB" as your search term in the Rare Disease Database.)

Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is a group of rare, congenital disorders characterized by little or no immune response. A person with this disorder is susceptible to recurring infections with bacteria, viruses, fungi, and other infectious agents. If untreated, this disorder may result in frequent, severe infections, growth retardation, and can be life- threatening. Other symptoms of this disorder may include weight loss, weakness, infections of the middle ear, and skin infections. (For more information on this disorder, choose "Severe Combined Immunodeficiency" as your search term in the Rare Disease Database.)

Velocardiofacial syndrome (aka Shprintzen Syndrome)
Velocardiofacial syndrome, (VCFS), a rare genetic disorder, is characterized by abnormalities of the head and facial (craniofacial) area, heart defects that are present at birth (congenital heart defects), diminished muscle tone (hypotonia), mild small stature, slight delays in the acquisition of skills requiring the coordination of mental and muscular activities (psychomotor retardation), and learning disabilities. Some of those affected also develop psychiatric problems.

The syndrome is associated with many different features, and not all will be present in every case. Cleft palate (an opening in the roof of the mouth) and characteristic facial features are among the most common features found with this syndrome.

The heart defect most often associated with velocardiofacial syndrome is an abnormal opening in the fibrous partition (septum) that separates the heart's two lower chambers (ventricular septal defect). Additional symptoms and findings often associated with the disorder may include eye (ocular) defects such as clouding of the lenses of the eyes (cataracts) and/or abnormalities of blood vessels in the nerve-rich membranes lining the eyes (tortuous retinal vessels). Psychiatric problems may vary as well, from moderate behavioral change to severe bipolar mood swings or schizophrenia. The range and severity of symptoms vary greatly from case to case.

Velocardiofacial syndrome is inherited as an autosomal dominant genetic trait and is sometimes known as chromosome 22q11 deletion spectrum because it is associated with multiple identifying features known to occur as a result of a deletion of genetic material on chromosome 22. (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

Wiskott-Aldrich syndrome
Wiskott-Aldrich syndrome is a rare inherited disorder of childhood characterized by immunodeficiency that results in recurrent skin rashes (eczema) and abnormally low levels of circulating platelets in the blood (thrombocytopenia). Symptoms of this disorder may include excessive bleeding from circumcision or minor trauma. Bleeding, which can be severe, may also occur in the intestines or stomach. Red skin rashes (petechiae) are common in children with this disorder. (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of DiGeorge syndrome may be confirmed by a thorough clinical evaluation, extensive patient and family history, and specialized tests. Blood tests may reveal abnormally low levels of calcium (neonatal hypocalcemia) indicating that the parathyroid glands are malfunctioning. Other specialized tests may demonstrate a significantly low level of T-cells in the blood indicating that the thymus glands are deficient or missing. In 90 percent of the cases, chromosomal analysis reveals a deletion on the long arm of chromosome 22 (22q11.2).

Treatment
To control infantile seizures associated with DSG, blood calcium levels must be increased. Orally administered calcium and vitamin D may be sufficient to control seizure activity. In some cases of DiGeorge syndrome, immune system function tends to improve after the first few years of life (unless the thymus gland is missing or very, severely underdeveloped).

When infections occur in children with DSG, they must be treated vigorously with appropriate drugs (such as antifungal medications, antibiotic drugs) and/or supportive measures. Trimethoprim-sulfamethoxazole and the orphan drug pentamidine isethionate may be used to treat infections caused by Pseudomonas carinii. Cytomegalovirus and generalized herpes simplex infections are usually treated with antiviral agents. Severe Candida and related fungi infections may respond to treatment with the drug amphotericin B.

Children with severe immunodeficiencies associated with DGS must be protected as much as possible from recurring infections. They should not be immunized with live viral vaccines. The administration of corticosteroid drugs or any drug that suppresses the immune system (immunosuppressant) must also be avoided. If blood transfusions are necessary due to accidents or surgery, the blood must be exposed to high levels of radiation (irradiated) or "washed" to remove all living white blood cells (lymphocytes) that might cause graft-versus-host disease (GVHD). (For more information on this disorder, choose "Graft Versus Host" as your search term in the Rare Disease Database.)

The Food and Drug Administration (FDA) recommends that individuals with weakened immune systems should exercise caution when consuming certain fruit and vegetable juices. The FDA recommends that such individuals should drink only pasteurized versions of these juices, since unpasteurized juices may contain harmful bacteria that could cause overwhelming infectious illnesses.

Anatomical abnormalities associated with DiGeorge syndrome may be corrected with surgery as necessary. Cardiac surgery is often necessary when heart defects are life threatening. Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

As of this writing (11/2006), four clinical trials having to do with DiGeorge syndrome were listed on the NIH web site devoted to clinical trials.

The National Center for Research Resources (NCRR) and the Children’s Hospital of Pennsylvania are co-sponsoring a clinical trial designed to highlight the Immunologic Evaluation of Patients with DiGeorge Syndrome or Velocardiofacial Syndrome. The principal investigator is Dr. Kathleen E. Sullivan (215-590-1697) and the identifier is NCT00005102.

The National Institute of Mental Health is sponsoring a clinical trial designed to understand how the genes missing in 22q11.2 syndrome are related to the increased occurrence of psychiatric problems. The clinical trial identifier number is NCT00105274.

The Fred Hutchinson Cancer Research Center of the University of Washington Medical School is sponsoring a study the effect of the transplantation of bone marrow (derived from the patient) plus the administration of cyclosporine and mycophenolate mofetil (immuno-suppressive drugs), on the outcomes of patients with primary T-cell immunodeficiency disorders. The principal investigator is Dr. Lauri Burroughs and the clinical trial identifier number is NCT00008450.

The University Medical Center of Utrecht, The Dutch Brain Foundation, and the Children’s Hospital of Philadelphia (CHOP) are collaborating on a clinical trial designed to study, over a period of time, the course of the psychiatric symptoms in children with 22q11.2 deletion syndrome. They also want to identify the genes, if any, that contribute to the occurrence of these symptoms. The principal investigator at CHOP is Dr. Jacob A. S. Vorstman (215-590-2862) and the clinical trial identifier number is NCT00161109

A group at Duke University Medical Center has had substantial success in treating DiGeorge syndrome by thymus transplantation using the immunosuppressant drug Thymoglobulin. For more information contact:

M. Louise Markert, M.D., Ph.D.
Associate Professor
Dept. of Pediatrics
Duke University Medical Center
368 Jones Building, Box 3068
Durham, NC 27710
Tel: (919) 684-6263
E-mail: marke001@nc.duke.edu

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. DiGeorge Syndrome. Entry Number; 188400: Last Edit Date; 9/18/2006.

TEXTBOOKS
Emmanuel BS. Chromosome 22q11 Deletion Spectrum. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:70-71.

DiGeorge AM. DiGeorge Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:178-79.

Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1036-37.

Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:821-22.

Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill Companies. New York, NY; 2005:1942-43.

Janeway CAJr, Travers P, Walport M, Shlomchik MJ. Immunobiology, 6th ed. Garland Science Publishing. New York, NY; 2005:482-83.

JOURNAL ARTICLES
Lavi RF, Kamchaisatian W, Sleasman JW, Martin DP, et al. thymic output markers indicate immune dysfunction in DiGeorge syndrome. J Allergy Clin Immunol. 2006;118:1184-86.

Driscoll DA. Molecular and genetic aspects of DiGeorge/velocardiofacial syndrome. Methods Mol Med. 2006;126:43-55.

Vorstman JA, Jalali GR, Rappaport EF, Hacker AM, Scott C, Emmanuel BS. MLPA: a rapid, reliable and sensitive method for detection and analysis of abnormalities of 22q. Hum Mutat. 2006;27:814-21.

Jolin EM, Weller EB, Weller RA. Velocardiofacial syndrome: is there a neuropsychiatric phenotype? Curr Psychiatry Rep. 2006;8:96-101.

Goldmuntz E. DiGeorge syndrome: new insights. Clin Perinatol. 2005;32:963-78.

Connell F, Hodgson S. Oue evolving understanding of 22q11 deletion syndrome. Dev Med Child Neurol. 2005;47:796.

Shprintzen RJ, Higgins AM, Antshel K, Fremont W, Roizen N, Kates W. Velo-cardio-facial syndrome. Curr Opin Pediatr. 2005;17:725-30.

Market ML, Alexieff MJ, Li J, Sarzotti M, et al. Postnatal thymus transplantation with immunosuppression as a treatment for DiGeorge syndrome. Blood. 2004;104:2574-81.

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