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

• Primary Agammaglobulinemias
• Severe Combined Immunodeficiency
• DiGeorge Syndrome
• Ataxia Telangiectasia
• Acquired Immune Deficiency Syndrome (AIDS)
• Wiskott-Aldrich Syndrome
• Immunodeficiencies (General)
• .

Infants with Nezelof syndrome typically have frequent and severe infections, beginning at birth. These infections may include oral thrush (Candidiasis), diarrhea, skin infections, bacterial infections that invade the blood (septicemia), urinary tract infections, measles, and lung infections. Acute inflammation of the lungs (pneumonia) caused by the bacteria Pneumocystis carinii and chronic diarrhea are characteristic symptoms of Nezelof syndrome. Infections of the tissue covering the brain (meningitis) are a threat to infants and children with NS. Other infections that may occur include cow pox (vaccinia), cytomegalovirus, rubella (measles), pseudomonas, and mycobacterial infections. Generally the child's physical growth is delayed and there is a general loss of muscle. (For more information on these disorders, choose "Candidiasis," "Cowpox," "Measles," and "Cytomegalovirus" as your search terms in the Rare Disease Database.)

In some cases, Nezelof syndrome is associated with an immunodeficiency known as purine nucleoside phosphorylase deficiency (PNPD). Among those individuals, symptoms may include a progressive loss of neurological function characterized by paralysis of the arms and legs accompanied by uncontrolled muscle contractions (spastic paralysis). The other conditions that may result from PNPD include the abnormal destruction of red blood cells (autoimmune hemolytic anemia) and abnormally low levels of circulating platelets. Reduced platelet count results in hemorrhaging into the body tissues, particularly the skin (thrombocytopenic purpura). (For more information on these disorders, choose "Graft-Versus- Host," "Anemia," and "Purpura" as your search terms in the Rare Disease Database.)

Low levels of circulating T lymphocytes and abnormally low numbers of other lymph cells (lymphopenia) are common laboratory findings in children with Nezelof syndrome. There may also be a decrease in the number of specialized white blood cells that destroy and remove cellular waste and bacteria (neutrophils). High concentrations of other granular white blood cells (eosinophils) are also present. Lymph glands decrease in size in people with this syndrome.

The cause of Nezelof syndrome is not fully understood. It is thought that it might be inherited as an autosomal recessive or an X-linked recessive genetic trait. It is possible that the syndrome represents some combination of genetic and external factors.

Nezelof sndrome is an extremely rare disorder that affects males slightly more often than females. Approximately 100 cases have been described in the medical literature.

Symptoms of the following disorders can be similar to those of Nezelof syndrome. Comparisons may be useful for a differential diagnosis:

Acquired immune deficiency syndrome (AIDS) is an immunosuppressive disorder caused by infection with the human immunodeficiency virus (HIV). The immune deficiency occurs as a result of the HIV virus destroying specific T cells. An initial period without symptoms may be followed by the development of swollen lymph nodes (lymphadenopathy). Eventually, most people with AIDS experience a progression of infections because of the compromised immune system. However, AIDS is a contagious disease whereas inherited immune deficiencies such as Nezelof syndrome are not transmitted from person to person except when they may be inherited.

Ataxia telangiectasia is a severe, rare, inherited neurological disorder characterized by the progressive loss of motor coordination in the arms, legs, and head (cerebellar ataxia). Some cases of this disorder are associated with immunodeficiencies (IgA or IgE). Mental development may be normal in the early stages of the disease, but progressive dementia may occur. This disease usually begins in infancy but may not be apparent until the child is school age. Classic red spots or telangiectasia appear in the eyes, and later the face and roof of the mouth. (For more information on this disorder, choose "Ataxia Telangiectasia" as your search term in the Rare Disease Database.)

Cartilage-hair hypoplasia (CHH) is an autosomal recessive inherited disorder that is predominantly associated with immunodeficiency and leads to short-limb dwarfism. Cartilage-hair hypoplasia and other models (phenotypes) of short-limb dwarfism are associated with shortening of the long bones of both the arms and the legs. CHH is a variant of short-limb dwarfism in which fine sparse hair is also present. The immunodeficiency in cartilage-hair hypoplasia is an isolated T-cell immunodeficiency, isolated B-cell immunodeficiency, or combined T- and B-cell immunodeficiency.

DiGeorge syndrome is a very rare immune deficiency that results from developmental defects in the thymus and parathyroid glands. The defects in the parathyroid gland lead to seizures during the first few days of life. Frequent infections from viruses, fungi, and bacteria are characteristic of this disorder. Children with DiGeorge syndrome frequently have chronic nasal infections, diarrhea, oral Candidiasis, and Pneumocystis pneumonia. (For more information on this disorder, choose "DiGeorge" as your search term in the Rare Disease Database.)

Primary agammaglobulinemias are a group of inherited immune deficiencies characterized by insufficient antibodies. The most frequent symptoms of these disorders are usually repeated bacterial infections. This results in inflammation of the intestines and chronic diarrhea. Repeated infections of the middle ear and respiratory tract may also occur. Areas of patchy, reddish skin may appear around the eyes, fingers, knees, and ankles. Some children with primary agammaglobulinemias experience joint swelling and pain. (For more information on this disorder, choose "Primary Agammaglobulinemias" as your search term in the Rare Disease Database.)

Purine nucleoside phosphorylase (PNP) deficiency is a metabolic disorder that leads to severe combined immunodeficiency (SCID). PNP deficiency causes decreased numbers of T cells and lymphopenia. Serum immunoglobulin (Ig) levels are normal to near-normal, but antibodies are deficient. Purine nucleoside phosphorylase deficiency is an autosomal recessive disorder that results in the accumulation of toxic metabolites, in this case toxic to T-cell development. PNP deficiency is also associated with neurologic symptoms, including mental retardation and muscle spasticity, in 67 percent of patients. In addition, PNP deficiency is associated with increased risk of autoimmune disorders, such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, and lupus.

Severe combined immunodeficiency (SCID) is a group of rare, congenital disorders characterized by little if any immune response. A person with these disorders is susceptible to recurring infections with bacteria, viruses, fungi, as well as other infectious agents. If left untreated, these disorders result in frequent severe infections and growth retardation, and may be life-threatening. Other symptoms of the severe combined immunodeficiencies 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.)

Wiskott-Aldrich syndrome is a rare X-linked 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). The first symptom is often bloody diarrhea. Other symptoms may include excessive bleeding from circumcision or minor trauma. Severe bleeding may also occur in the intestines or stomach. Red skin rashes (petechiae) are also typical. (For more information on this disorder, choose "Wiskott-Aldrich" as your search term in the Rare Disease Database.)

Diagnosis
Nezelof syndrome may be suspected if common infections do not respond to common antibiotic treatment. Diagnosis is usually based upon the results of a variety of blood tests. Low level of T-cell concentration combined with normal concentrations of immunoglobulins may lead to a diagnosis.

Treatment
During the prenatal period, the transplantation of thymus to the fetus has been tried successfully for several decades. More recently, stem cell transplants have been the treatment of choice when possible.

Each infection that occurs in people with Nezelof syndrome must be treated vigorously with antifungal, antibiotic, or other drugs according to the cause of the infection. Acute inflammation of the lungs (pneumonia) caused by the bacteria Pneumocystis carinii can be particularly resistant to treatment.

Individuals with Nezelof Syndrome must be protected from exposure to infectious agents. They must not be immunized with live viral vaccines. Corticosteroid drugs (i.e., prednisone), other pharmaceuticals that suppress the immune system (i.e., cyclosporine), and surgical removal of the spleen (splenectomy) must be avoided. If blood transfusions become necessary, the blood must be irradiated or "washed" to remove all live lymphocytes that might cause graft-versus-host disease.

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

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Immune Defect Due To Absence of Thymus. Entry Number; 242700: Last Edit Date;10/28/2004.

TEXTBOOKS
Insel RA, Scheer BG, Knutsen AP. Nezelof Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:408.

Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:1037.

Frank MM, Austen KF, Claman HN, et al., eds. Samter’s Immunological Diseases. 5th ed. Little Brown and Company, Boston, MA; 1995:1154-55.

FROM THE INTERNET
Nezelof Syndrome. Madisons Foundation. Last Revision on 1/13/2004. 2pp.
www.madisonsfoundation.org/content/3/1/printdisplay.asp?did=321

Immunodeficiency Diseases. Chapter XII – Outline. Medical College of Georgia. nd. 2pp.
www.lin.mcg.edu/edu/esimmuno/ch12/outline.htm

Immunodeficiency Diseases. Chapter XII -- T Cell Deficiencies. Medical College of Georgia. nd. 2pp.
www.lin.mcg.edu/edu/esimmuno/ch12/tcelldef.htm

Cartilage-Hair Hypoplasia. Madisons Foundation. Last revision on 11/24/2004. 3pp.
www.madisonsfoundation.org/content/3/1/printdisplay.asp?did=72